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Martín Pérez C, Ruiz-Rius S, Ramírez-Morros A, Vidal M, Opi DH, Santamaria P, Blanco J, Vidal-Alaball J, Beeson JG, Molinos-Albert LM, Aguilar R, Ruiz-Comellas A, Moncunill G, Dobaño C. Post-vaccination IgG4 and IgG2 class switch associates with increased risk of SARS-CoV-2 infections. J Infect 2025; 90:106473. [PMID: 40113142 DOI: 10.1016/j.jinf.2025.106473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2025] [Revised: 02/28/2025] [Accepted: 03/12/2025] [Indexed: 03/22/2025]
Abstract
OBJECTIVES Repeated COVID-19 mRNA vaccinations increase SARS-CoV-2 IgG4 antibodies, indicating extensive IgG class switching following the first booster dose. This shift in IgG subclasses raises concerns due to the limited ability of IgG4 to mediate Fc-dependent effector functions. METHODS To assess the impact of IgG4 induction on protective immunity, we analyzed longitudinal SARS-CoV-2 IgG subclasses, C1q and FcγR responses, and neutralizing activity in a well-characterized cohort of healthcare workers in Spain. RESULTS Elevated IgG4 levels and higher ratios of non-cytophilic to cytophilic antibodies after booster vaccination were significantly associated with an increased risk of breakthrough infections (IgG4 HR[10-fold increase]=1.8, 95% CI=1.2-2.7; non-cytophilic to cytophilic ratio HR[10-fold increase]=1.5, 95% CI=1.1-1.9). Moreover, an increased non-cytophilic to cytophilic antibody ratio correlated with reduced functionality, including neutralization. CONCLUSIONS These findings suggest a potential association between IgG4 induction by mRNA vaccination and a higher risk of breakthrough infection, warranting further investigation into vaccination strategies to ensure sustained protection.
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Affiliation(s)
- Carla Martín Pérez
- ISGlobal, Barcelona, Catalonia, Spain; Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain
| | - Sílvia Ruiz-Rius
- ISGlobal, Barcelona, Catalonia, Spain; Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain
| | - Anna Ramírez-Morros
- Unitat de Suport a la Recerca de la Catalunya Central, Fundació Institut Universitari per a la Recerca a l'Atenció Primària de Salut Jordi Gol i Gurina, Manresa, Spain
| | - Marta Vidal
- ISGlobal, Barcelona, Catalonia, Spain; Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain
| | - D Herbert Opi
- Burnet Institute, Melbourne, Australia; Department of Infectious Diseases, University of Melbourne, Australia; School of Translational Medicine, Monash University, Australia
| | - Pere Santamaria
- Institut d'Investigacions Biomèdiques August Pi Sunyer, Barcelona, Spain; Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Julià Blanco
- IrsiCaixa, Badalona, Spain; CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Barcelona, Spain; Department of Medicine. Faculty of Medicine. Universitat de Vic-Central de Catalunya, UVic-UCC, Vic, Spain; Institut Germans Trias I Pujol, IGTP, Badalona, Spain
| | - Josep Vidal-Alaball
- Unitat de Suport a la Recerca de la Catalunya Central, Fundació Institut Universitari per a la Recerca a l'Atenció Primària de Salut Jordi Gol i Gurina, Manresa, Spain; Department of Medicine. Faculty of Medicine. Universitat de Vic-Central de Catalunya, UVic-UCC, Vic, Spain; Health Promotion in Rural Areas Research Group, Gerència d'Atenció Primària i a la Comunitat Catalunya Central, Institut Català de la Salut, Manresa, Spain
| | - James G Beeson
- Burnet Institute, Melbourne, Australia; Department of Infectious Diseases, University of Melbourne, Australia; School of Translational Medicine, Monash University, Australia
| | - Luis M Molinos-Albert
- ISGlobal, Barcelona, Catalonia, Spain; Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain
| | - Ruth Aguilar
- ISGlobal, Barcelona, Catalonia, Spain; Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain
| | - Anna Ruiz-Comellas
- Unitat de Suport a la Recerca de la Catalunya Central, Fundació Institut Universitari per a la Recerca a l'Atenció Primària de Salut Jordi Gol i Gurina, Manresa, Spain; Department of Medicine. Faculty of Medicine. Universitat de Vic-Central de Catalunya, UVic-UCC, Vic, Spain; Health Promotion in Rural Areas Research Group, Gerència d'Atenció Primària i a la Comunitat Catalunya Central, Institut Català de la Salut, Manresa, Spain; Centre d'Atenció Primària (CAP) Sant Joan de Vilatorrada, Gerència d'Atenció Primària i a la Comunitat Catalunya Central, Institut Català de la Salut, Spain
| | - Gemma Moncunill
- ISGlobal, Barcelona, Catalonia, Spain; Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain; CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Barcelona, Spain.
| | - Carlota Dobaño
- ISGlobal, Barcelona, Catalonia, Spain; Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain; CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Barcelona, Spain.
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Xu J, Hu H, Sun Y, Zhao Z, Zhang D, Yang L, Lu Q. The fate of immune complexes in membranous nephropathy. Front Immunol 2024; 15:1441017. [PMID: 39185424 PMCID: PMC11342396 DOI: 10.3389/fimmu.2024.1441017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 07/24/2024] [Indexed: 08/27/2024] Open
Abstract
The most characteristic feature of membranous nephropathy (MN) is the presence of subepithelial electron dense deposits and the consequential thickening of the glomerular basement membrane. There have been great advances in the understanding of the destiny of immune complexes in MN by the benefit of experimental models represented by Heymann nephritis. Subepithelial immune complexes are formed in situ by autoantibodies targeting native autoantigens or exogenous planted antigens such as the phospholipase A2 receptor (PLA2R) and cationic BSA respectively. The nascent immune complexes would not be pathogenic until they develop into immune deposits. Podocytes are the major source of autoantigens in idiopathic membranous nephropathy. They also participate in the modulation and removal of the immune complexes to a large extent. The balance between deposition and clearance is regulated by a wide range of factors such as the composition and physicochemical properties of the immune complexes and the complement system. Complement components such as C3 and C1q have been reported to be precipitated with the deposits whereas a complement regulatory protein CR1 expressed by podocytes is involved in the phagocytosis of immune complexes by podocytes. Podocytes regulate the dynamic change of immune complexes which is disturbed in membranous nephropathy. To elucidate the precise fate of the immune complexes is essential for developing more rational and novel therapies for membranous nephropathy.
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Affiliation(s)
- Jie Xu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Haikun Hu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Yuhe Sun
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Zihan Zhao
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Danyuan Zhang
- Qi Huang of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Lei Yang
- Department of Nephropathy, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Qingyi Lu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
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Pas HH, van der Molen M, van Nijen-Vos L, Nijenhuis M, Bremer J. The Autoimmune IgG Subclass Response Defines the IgG Deposition Pattern in Pemphigus Patient Skin. J Invest Dermatol 2024; 144:1649-1650. [PMID: 38272208 DOI: 10.1016/j.jid.2023.12.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 12/21/2023] [Accepted: 12/21/2023] [Indexed: 01/27/2024]
Affiliation(s)
- Hendri H Pas
- Center of Expertise for Blistering Diseases, Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
| | - Marije van der Molen
- Center of Expertise for Blistering Diseases, Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Laura van Nijen-Vos
- Center of Expertise for Blistering Diseases, Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Miranda Nijenhuis
- Center of Expertise for Blistering Diseases, Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Jeroen Bremer
- Center of Expertise for Blistering Diseases, Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Zemelka-Wiacek M, Agache I, Akdis CA, Akdis M, Casale TB, Dramburg S, Jahnz-Różyk K, Kosowska A, Matricardi PM, Pfaar O, Shamji MH, Jutel M. Hot topics in allergen immunotherapy, 2023: Current status and future perspective. Allergy 2024; 79:823-842. [PMID: 37984449 DOI: 10.1111/all.15945] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 10/10/2023] [Accepted: 11/04/2023] [Indexed: 11/22/2023]
Abstract
The importance of allergen immunotherapy (AIT) is multifaceted, encompassing both clinical and quality-of-life improvements and cost-effectiveness in the long term. Key mechanisms of allergen tolerance induced by AIT include changes in memory type allergen-specific T- and B-cell responses towards a regulatory phenotype with decreased Type 2 responses, suppression of allergen-specific IgE and increased IgG1 and IgG4, decreased mast cell and eosinophil numbers in allergic tissues and increased activation thresholds. The potential of novel patient enrolment strategies for AIT is taking into account recent advances in biomarkers discoveries, molecular allergy diagnostics and mobile health applications contributing to a personalized approach enhancement that can increase AIT efficacy and compliance. Artificial intelligence can help manage and interpret complex and heterogeneous data, including big data from omics and non-omics research, potentially predict disease subtypes, identify biomarkers and monitor patient responses to AIT. Novel AIT preparations, such as synthetic compounds, innovative carrier systems and adjuvants, are also of great promise. Advances in clinical trial models, including adaptive, complex and hybrid designs as well as real-world evidence, allow more flexibility and cost reduction. The analyses of AIT cost-effectiveness show a clear long-term advantage compared to pharmacotherapy. Important research questions, such as defining clinical endpoints, biomarkers of patient selection and efficacy, mechanisms and the modulation of the placebo effect and alternatives to conventional field trials, including allergen exposure chamber studies are still to be elucidated. This review demonstrates that AIT is still in its growth phase and shows immense development prospects.
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Affiliation(s)
| | - Ioana Agache
- Faculty of Medicine, Transylvania University, Brasov, Romania
| | - Cezmi A Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University Zurich, Davos, Switzerland
| | - Mübeccel Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University Zurich, Davos, Switzerland
| | - Thomas B Casale
- Departments of Medicine and Pediatrics and Division of Allergy and Immunology, Joy McCann Culverhouse Clinical Research Center, University of South Florida, Tampa, Florida, USA
| | - Stephanie Dramburg
- Department of Pediatric Respiratory Care, Immunology and Critical Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Karina Jahnz-Różyk
- Department of Internal Diseases, Pneumonology, Allergology and Clinical Immunology, Military Institute of Medicine-National Research Institute, Warsaw, Poland
| | - Anna Kosowska
- Department of Clinical Immunology, Wroclaw Medical University, Wroclaw, Poland
- ALL-MED Medical Research Institute, Wroclaw, Poland
| | - Paolo M Matricardi
- Department of Pediatric Respiratory Care, Immunology and Critical Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Oliver Pfaar
- Section of Rhinology and Allergy, Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Marburg, Philipps-Universität Marburg, Marburg, Germany
| | - Mohamed H Shamji
- Allergy and Clinical Immunology, National Heart and Lung Institute, Imperial College London, London, UK
| | - Marek Jutel
- Department of Clinical Immunology, Wroclaw Medical University, Wroclaw, Poland
- ALL-MED Medical Research Institute, Wroclaw, Poland
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Aoki R, Tanaka T. Pathogenesis of Warthin's Tumor: Neoplastic or Non-Neoplastic? Cancers (Basel) 2024; 16:912. [PMID: 38473274 DOI: 10.3390/cancers16050912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 02/14/2024] [Accepted: 02/19/2024] [Indexed: 03/14/2024] Open
Abstract
Warthin's tumor is the second most frequent neoplasm next to pleomorphic adenoma in the salivary gland, mostly in the parotid gland. The epithelial cells constituting a tumor are characterized by the presence of mitochondria that undergo structural and functional changes, resulting in the development of oncocytes. In addition to containing epithelial cells, Warthin's tumors contain abundant lymphocytes with lymph follicles (germinal centers) that are surrounded by epithelial cells. The pathogenesis of Warthin's tumor is not fully understood, and several hypotheses have been proposed. The risk factors for the development of Warthin's tumor, which predominantly occurs in males, include aging, smoking, and radiation exposure. Recently, it has been reported that chronic inflammation and aging cells promote the growth of Warthin's tumor. Several reports regarding the origin of the tumor have suggested that (1) Warthin's tumor is an IgG4-related disease, (2) epithelial cells that compose Warthin's tumor accumulate mitochondria, and (3) Warthin's tumor is a metaplastic lesion in the lymph nodes. It is possible that the pathogenesis of Warthin's tumor includes mitochondrial metabolic abnormalities, accumulation of aged cells, chronic inflammation, and senescence-associated secretory phenotype (SASP). In this short review, we propose that DNA damage, metabolic dysfunction of mitochondria, senescent cells, SASP, human papillomavirus, and IgG4 may be involved in the development of Warthin's tumor.
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Affiliation(s)
- Ryogo Aoki
- Department of Diagnostic Pathology (DDP) & Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, 7-l Kashima-Cho, Gifu City 500-8513, Gifu, Japan
| | - Takuji Tanaka
- Department of Diagnostic Pathology (DDP) & Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, 7-l Kashima-Cho, Gifu City 500-8513, Gifu, Japan
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Espino AM, Armina-Rodriguez A, Alvarez L, Ocasio-Malavé C, Ramos-Nieves R, Rodriguez Martinó EI, López-Marte P, Torres EA, Sariol CA. The Anti-SARS-CoV-2 IgG1 and IgG3 Antibody Isotypes with Limited Neutralizing Capacity against Omicron Elicited in a Latin Population a Switch toward IgG4 after Multiple Doses with the mRNA Pfizer-BioNTech Vaccine. Viruses 2024; 16:187. [PMID: 38399963 PMCID: PMC10893502 DOI: 10.3390/v16020187] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 01/19/2024] [Accepted: 01/21/2024] [Indexed: 02/25/2024] Open
Abstract
The aim of this study was to analyze the profiles of IgG subclasses in COVID-19 convalescent Puerto Rican subjects and compare these profiles with those of non-infected immunocompetent or immunocompromised subjects that received two or more doses of an mRNA vaccine. The most notable findings from this study are as follows: (1) Convalescent subjects that were not hospitalized developed high and long-lasting antibody responses. (2) Both IgG1 and IgG3 subclasses were more prevalent in the SARS-CoV-2-infected population, whereas IgG1 was more prevalent after vaccination. (3) Individuals that were infected and then later received two doses of an mRNA vaccine exhibited a more robust neutralizing capacity against Omicron than those that were never infected and received two doses of an mRNA vaccine. (4) A class switch toward the "anti-inflammatory" antibody isotype IgG4 was induced a few weeks after the third dose, which peaked abruptly and remained at high levels for a long period. Moreover, the high levels of IgG4 were concurrent with high neutralizing percentages against various VOCs including Omicron. (5) Subjects with IBD also produced IgG4 antibodies after the third dose, although these antibody levels had a limited effect on the neutralizing capacity. Knowing that the mRNA vaccines do not prevent infections, the Omicron subvariants have been shown to be less pathogenic, and IgG4 levels have been associated with immunotolerance and numerous negative effects, the recommendations for the successive administration of booster vaccinations to people should be revised.
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Affiliation(s)
- Ana M. Espino
- Department of Microbiology and Medical Zoology, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA; (A.A.-R.); (L.A.); (C.O.-M.); (R.R.-N.)
| | - Albersy Armina-Rodriguez
- Department of Microbiology and Medical Zoology, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA; (A.A.-R.); (L.A.); (C.O.-M.); (R.R.-N.)
| | - Laura Alvarez
- Department of Microbiology and Medical Zoology, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA; (A.A.-R.); (L.A.); (C.O.-M.); (R.R.-N.)
| | - Carlimar Ocasio-Malavé
- Department of Microbiology and Medical Zoology, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA; (A.A.-R.); (L.A.); (C.O.-M.); (R.R.-N.)
| | - Riseilly Ramos-Nieves
- Department of Microbiology and Medical Zoology, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA; (A.A.-R.); (L.A.); (C.O.-M.); (R.R.-N.)
| | - Esteban I. Rodriguez Martinó
- Gastroenterology Research Unit, School of Medicine, University of Puerto Rico, San Juan, PR 00925, USA; (E.I.R.M.); (P.L.-M.); (E.A.T.)
- Department of Medicine, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA
| | - Paola López-Marte
- Gastroenterology Research Unit, School of Medicine, University of Puerto Rico, San Juan, PR 00925, USA; (E.I.R.M.); (P.L.-M.); (E.A.T.)
- Department of Medicine, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA
| | - Esther A. Torres
- Gastroenterology Research Unit, School of Medicine, University of Puerto Rico, San Juan, PR 00925, USA; (E.I.R.M.); (P.L.-M.); (E.A.T.)
- Department of Medicine, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA
| | - Carlos A. Sariol
- Department of Microbiology and Medical Zoology, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA; (A.A.-R.); (L.A.); (C.O.-M.); (R.R.-N.)
- Department of Medicine, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA
- Unit of Comparative Medicine, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA
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Fawcett C, Tickle JR, Coles CH. Facilitating high throughput bispecific antibody production and potential applications within biopharmaceutical discovery workflows. MAbs 2024; 16:2311992. [PMID: 39674918 DOI: 10.1080/19420862.2024.2311992] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 01/08/2024] [Accepted: 01/25/2024] [Indexed: 12/17/2024] Open
Abstract
A major driver for the recent investment surge in bispecific antibody (bsAb) platforms and products is the multitude of distinct mechanisms of action that bsAbs offer compared to a combination of two monoclonal antibodies. Four bsAb products were granted first regulatory approvals in the US or EU during 2023 and the biopharmaceutical industry pipeline is brimming with bsAb candidates across a broad range of therapeutic applications. In previously reported bsAb discovery campaigns, following a hypothesis-based choice of two specific target proteins, selections and screening activities have often been performed in mono-specific formats. The conversion to bispecific modalities has usually been positioned toward the end of the discovery process and has involved small numbers of lead molecules, largely due to challenges in expressing, purifying, and analyzing large numbers of bsAbs. In this review, we discuss emerging strategies to facilitate the production of expanded bsAb panels, focusing particularly upon combinatorial methods to generate bsAb matrices. Such technologies will enable screening in. bispecific formats at earlier stages of discovery campaigns, not only widening the accessible protein space to maximize chances of success, but also advancing empirical bi-target validation activities to assess initial target selection hypotheses.
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Affiliation(s)
- Caitlin Fawcett
- Large Molecule Discovery, GSK, GSK Medicines Research Centre, Stevenage, UK
- Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow, UK
| | - Joseph R Tickle
- Large Molecule Discovery, GSK, GSK Medicines Research Centre, Stevenage, UK
| | - Charlotte H Coles
- Large Molecule Discovery, GSK, GSK Medicines Research Centre, Stevenage, UK
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Masciocchi S, Businaro P, Scaranzin S, Morandi C, Franciotta D, Gastaldi M. General features, pathogenesis, and laboratory diagnostics of autoimmune encephalitis. Crit Rev Clin Lab Sci 2024; 61:45-69. [PMID: 37777038 DOI: 10.1080/10408363.2023.2247482] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 08/09/2023] [Indexed: 10/02/2023]
Abstract
Autoimmune encephalitis (AE) is a group of inflammatory conditions that can associate with the presence of antibodies directed to neuronal intracellular, or cell surface antigens. These disorders are increasingly recognized as an important differential diagnosis of infectious encephalitis and of other common neuropsychiatric conditions. Autoantibody diagnostics plays a pivotal role for accurate diagnosis of AE, which is of utmost importance for the prompt recognition and early treatment. Several AE subgroups can be identified, either according to the prominent clinical phenotype, presence of a concomitant tumor, or type of neuronal autoantibody, and recent diagnostic criteria have provided important insights into AE classification. Antibodies to neuronal intracellular antigens typically associate with paraneoplastic neurological syndromes and poor prognosis, whereas antibodies to synaptic/neuronal cell surface antigens characterize many AE subtypes that associate with tumors less frequently, and that are often immunotherapy-responsive. In addition to the general features of AE, we review current knowledge on the pathogenic mechanisms underlying these disorders, focusing mainly on the potential role of neuronal antibodies in the most frequent conditions, and highlight current theories and controversies. Then, we dissect the crucial aspects of the laboratory diagnostics of neuronal antibodies, which represents an actual challenge for both pathologists and neurologists. Indeed, this diagnostics entails technical difficulties, along with particularly interesting novel features and pitfalls. The novelties especially apply to the wide range of assays used, including specific tissue-based and cell-based assays. These assays can be developed in-house, usually in specialized laboratories, or are commercially available. They are widely used in clinical immunology and in clinical chemistry laboratories, with relevant differences in analytic performance. Indeed, several data indicate that in-house assays could perform better than commercial kits, notwithstanding that the former are based on non-standardized protocols. Moreover, they need expertise and laboratory facilities usually unavailable in clinical chemistry laboratories. Together with the data of the literature, we critically evaluate the analytical performance of the in-house vs commercial kit-based approach. Finally, we propose an algorithm aimed at integrating the present strategies of the laboratory diagnostics in AE for the best clinical management of patients with these disorders.
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Affiliation(s)
- Stefano Masciocchi
- Neuroimmunology Research Section, IRCCS Mondino Foundation, Pavia, Italy
- Department of Brain and Behavioral Sciences, Università degli Studi di Pavia, Pavia, Italy
| | - Pietro Businaro
- Neuroimmunology Research Section, IRCCS Mondino Foundation, Pavia, Italy
- Department of Brain and Behavioral Sciences, Università degli Studi di Pavia, Pavia, Italy
| | - Silvia Scaranzin
- Neuroimmunology Research Section, IRCCS Mondino Foundation, Pavia, Italy
| | - Chiara Morandi
- Neuroimmunology Research Section, IRCCS Mondino Foundation, Pavia, Italy
| | - Diego Franciotta
- Neuroimmunology Research Section, IRCCS Mondino Foundation, Pavia, Italy
| | - Matteo Gastaldi
- Neuroimmunology Research Section, IRCCS Mondino Foundation, Pavia, Italy
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Kappen J, Diamant Z, Agache I, Bonini M, Bousquet J, Canonica GW, Durham SR, Guibas GV, Hamelmann E, Jutel M, Papadopoulos NG, Roberts G, Shamji MH, Zieglmayer P, Gerth van Wijk R, Pfaar O. Standardization of clinical outcomes used in allergen immunotherapy in allergic asthma: An EAACI position paper. Allergy 2023; 78:2835-2850. [PMID: 37449468 DOI: 10.1111/all.15817] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 06/17/2023] [Accepted: 06/20/2023] [Indexed: 07/18/2023]
Abstract
INTRODUCTION In allergic asthma patients, one of the more common phenotypes might benefit from allergen immunotherapy (AIT) as add-on intervention to pharmacological treatment. AIT is a treatment with disease-modifying modalities, the evidence for efficacy is based on controlled clinical trials following standardized endpoint measures. However, so far there is a lack of a consensus for asthma endpoints in AIT trials. The aim of a task force (TF) of the European Academy of Allergy and Clinical Immunology (EAACI) is evaluating several outcome measures for AIT in allergic asthma. METHODS The following domains of outcome measures in asthmatic patients have been evaluated for this position paper (PP): (i) exacerbation rate, (ii) lung function, (iii) ICS withdrawal, (iv) symptoms and rescue medication use, (v) questionnaires (PROMS), (vi) bronchial/nasal provocation, (vii) allergen exposure chambers (AEC) and (viii) biomarkers. RESULTS Exacerbation rate can be used as a reliable objective primary outcome; however, there is limited evidence due to different definitions of exacerbation. The time after ICS withdrawal to first exacerbation is considered a primary outcome measure. Besides, the advantages and disadvantages and clinical implications of further domains of asthma endpoints in AIT trials are elaborated in this PP. CONCLUSION This EAACI-PP aims to highlight important aspects of current asthma measures by critically evaluating their applicability for controlled trials of AIT.
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Affiliation(s)
- Jasper Kappen
- Department of Pulmonology, STZ Centre of Excellence for Asthma, COPD and Respiratory Allergy, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands
- Department of National Heart and Lung Institute, Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Imperial College London, London, UK
| | - Zuzana Diamant
- Departmentt of Microbiology Immunology & Transplantation, KU Leuven, Catholic University of Leuven, Leuven, Belgium
- Department of Respiratory Medicine & Allergology, Institute for Clinical Science, Skane University Hospital, Lund University, Lund, Sweden
- Department of Clinical Pharmacy & Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Respiratory Medicine, First Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czech Republic
| | | | - Matteo Bonini
- Department of National Heart and Lung Institute, Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Imperial College London, London, UK
- Department of Cardiovascular and Thoracic Sciences, Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Clinical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli - IRCCS, Rome, Italy
| | - Jean Bousquet
- Charite Universitatsmedizin Berlin Campus Berlin Buch, MASK-air, Montpellier, France
| | - G Walter Canonica
- Personalized Medicine Asthma & Allergy Clinic Humanitas University & Research Hospital-IRCCS, Milan, Italy
| | - Stephen R Durham
- Department of National Heart and Lung Institute, Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Imperial College London, London, UK
- MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK
| | - George V Guibas
- Department of Allergy and Clinical Immunology, Royal Preston Hospital, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK
- School of Biological Sciences, Medicine and Health, University of Manchester, Manchester, UK
| | - Eckard Hamelmann
- Children's Center Bethel, University Hospital Bielefeld, University Bielefeld, Bielefeld, Germany
| | - Marek Jutel
- Department of Clinical Immunology, Wroclaw Medical University, Wroclaw, Poland
- ALL-MED Medical Research Institute, Wroclaw, Poland
| | | | - Graham Roberts
- The David Hide Asthma and Allergy Research Centre, St Mary's Hospital, Newport, UK
- NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK
- Paediatric Allergy and Respiratory Medicine (MP803), Clinical & Experimental Sciences & Human Development in Health Academic Units University of Southampton Faculty of Medicine & University Hospital Southampton, Southampton, UK
| | - Mohamed H Shamji
- Department of National Heart and Lung Institute, Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Imperial College London, London, UK
- MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK
| | - Petra Zieglmayer
- Karl Landsteiner University, Competence Center for Allergology and Immunology, Krems, Austria
| | - Roy Gerth van Wijk
- Section of Allergology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Oliver Pfaar
- Department of Otorhinolaryngology, Head and Neck Surgery, Section of Rhinology and Allergy, University Hospital Marburg, Philipps-Universität Marburg, Marburg, Germany
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10
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Bolton MJ, Santos JJS, Arevalo CP, Griesman T, Watson M, Li SH, Bates P, Ramage H, Wilson PC, Hensley SE. IgG3 subclass antibodies recognize antigenically drifted influenza viruses and SARS-CoV-2 variants through efficient bivalent binding. Proc Natl Acad Sci U S A 2023; 120:e2216521120. [PMID: 37603748 PMCID: PMC10469028 DOI: 10.1073/pnas.2216521120] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 07/12/2023] [Indexed: 08/23/2023] Open
Abstract
The constant domains of antibodies are important for effector functions, but less is known about how they can affect binding and neutralization of viruses. Here, we evaluated a panel of human influenza virus monoclonal antibodies (mAbs) expressed as IgG1, IgG2, or IgG3. We found that many influenza virus-specific mAbs have altered binding and neutralization capacity depending on the IgG subclass encoded and that these differences result from unique bivalency capacities of the subclasses. Importantly, subclass differences in antibody binding and neutralization were greatest when the affinity for the target antigen was reduced through antigenic mismatch. We found that antibodies expressed as IgG3 bound and neutralized antigenically drifted influenza viruses more effectively. We obtained similar results using a panel of SARS-CoV-2-specific mAbs and the antigenically advanced B.1.351 and BA.1 strains of SARS-CoV-2. We found that a licensed therapeutic mAb retained neutralization breadth against SARS-CoV-2 variants when expressed as IgG3, but not IgG1. These data highlight that IgG subclasses are not only important for fine-tuning effector functionality but also for binding and neutralization of antigenically drifted viruses.
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Affiliation(s)
- Marcus J. Bolton
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA19104
| | - Jefferson J. S. Santos
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA19104
| | - Claudia P. Arevalo
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA19104
| | - Trevor Griesman
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA19104
| | - Megan Watson
- Department of Microbiology and Immunology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA19107
| | - Shuk Hang Li
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA19104
| | - Paul Bates
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA19104
| | - Holly Ramage
- Department of Microbiology and Immunology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA19107
| | - Patrick C. Wilson
- Drukier Institute for Children's Health, Department of Pediatrics, Weill Cornell Medicine, New York, NY10021
| | - Scott E. Hensley
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA19104
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11
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Uversky VN, Redwan EM, Makis W, Rubio-Casillas A. IgG4 Antibodies Induced by Repeated Vaccination May Generate Immune Tolerance to the SARS-CoV-2 Spike Protein. Vaccines (Basel) 2023; 11:vaccines11050991. [PMID: 37243095 DOI: 10.3390/vaccines11050991] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 05/12/2023] [Accepted: 05/15/2023] [Indexed: 05/28/2023] Open
Abstract
Less than a year after the global emergence of the coronavirus SARS-CoV-2, a novel vaccine platform based on mRNA technology was introduced to the market. Globally, around 13.38 billion COVID-19 vaccine doses of diverse platforms have been administered. To date, 72.3% of the total population has been injected at least once with a COVID-19 vaccine. As the immunity provided by these vaccines rapidly wanes, their ability to prevent hospitalization and severe disease in individuals with comorbidities has recently been questioned, and increasing evidence has shown that, as with many other vaccines, they do not produce sterilizing immunity, allowing people to suffer frequent re-infections. Additionally, recent investigations have found abnormally high levels of IgG4 in people who were administered two or more injections of the mRNA vaccines. HIV, Malaria, and Pertussis vaccines have also been reported to induce higher-than-normal IgG4 synthesis. Overall, there are three critical factors determining the class switch to IgG4 antibodies: excessive antigen concentration, repeated vaccination, and the type of vaccine used. It has been suggested that an increase in IgG4 levels could have a protecting role by preventing immune over-activation, similar to that occurring during successful allergen-specific immunotherapy by inhibiting IgE-induced effects. However, emerging evidence suggests that the reported increase in IgG4 levels detected after repeated vaccination with the mRNA vaccines may not be a protective mechanism; rather, it constitutes an immune tolerance mechanism to the spike protein that could promote unopposed SARS-CoV2 infection and replication by suppressing natural antiviral responses. Increased IgG4 synthesis due to repeated mRNA vaccination with high antigen concentrations may also cause autoimmune diseases, and promote cancer growth and autoimmune myocarditis in susceptible individuals.
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Affiliation(s)
- Vladimir N Uversky
- Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Elrashdy M Redwan
- Biological Science Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia
- Therapeutic and Protective Proteins Laboratory, Protein Research Department, Genetic Engineering and Biotechnology Research Institute, City for Scientific Research and Technology Applications, New Borg EL-Arab, Alexandria 21934, Egypt
| | - William Makis
- Cross Cancer Institute, Alberta Health Services, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada
| | - Alberto Rubio-Casillas
- Autlan Regional Hospital, Health Secretariat, Autlan 48900, Jalisco, Mexico
- Biology Laboratory, Autlan Regional Preparatory School, University of Guadalajara, Autlan 48900, Jalisco, Mexico
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12
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Strobl MR, Demir H, Sánchez Acosta G, Drescher A, Kitzmüller C, Möbs C, Pfützner W, Bohle B. The role of IgG 1 and IgG 4 as dominant IgE-blocking antibodies shifts during allergen immunotherapy. J Allergy Clin Immunol 2023; 151:1371-1378.e5. [PMID: 36657603 DOI: 10.1016/j.jaci.2023.01.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 01/02/2023] [Accepted: 01/06/2023] [Indexed: 01/18/2023]
Abstract
BACKGROUND The induction of allergen-specific IgE-blocking antibodies is a hallmark of allergen immunotherapy (AIT). The inhibitory bioactivity has largely been attributed to IgG4; however, our recent studies indicated the dominance of IgG1 early in AIT. OBJECTIVES Here, the IgE-blocking activity and avidity of allergen-specific IgG1 and IgG4 antibodies were monitored throughout 3 years of treatment. METHODS Serum samples from 24 patients were collected before and regularly during AIT with birch pollen. Bet v 1-specific IgG1 and IgG4 levels were determined by ELISA and ImmunoCAP, respectively. Unmodified and IgG1- or IgG4-depleted samples were compared for their inhibition of Bet v 1-induced basophil activation. The stability of Bet v 1-antibody complexes was compared by ELISA and by surface plasmon resonance. RESULTS Bet v 1-specific IgG1 and IgG4 levels peaked at 12 and 24 months of AIT, respectively. Serological IgE-blocking peaked at 6 months and remained high thereafter. In the first year of therapy, depletion of IgG1 clearly diminished the inhibition of basophil activation while the absence of IgG4 hardly reduced IgE-blocking. Then, IgG4 became the main inhibitory isotype in most individuals. Both isotypes displayed high avidity to Bet v 1 ab initio of AIT, which did not increase during treatment. Bet v 1-IgG1 complexes were enduringly more stable than Bet v 1-IgG4 complexes were. CONCLUSIONS In spite of the constant avidity of AIT-induced allergen-specific IgG1 and IgG4 antibodies, their dominance in IgE-blocking shifted in the course of treatment. The blocking activity of allergen-specific IgG1 should not be underestimated, particularly early in AIT.
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Affiliation(s)
- Maria R Strobl
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Hilal Demir
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Gabriela Sánchez Acosta
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Anja Drescher
- Cytiva Europe GmbH, Freiburg, Department of Dermatology and Allergology, Philipps-Universität Marburg, Freiburg and Marburg, Germany
| | - Claudia Kitzmüller
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Christian Möbs
- Clinical and Experimental Allergology, Department of Dermatology and Allergology, Philipps-Universität Marburg, Marburg, Germany
| | - Wolfgang Pfützner
- Clinical and Experimental Allergology, Department of Dermatology and Allergology, Philipps-Universität Marburg, Marburg, Germany
| | - Barbara Bohle
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
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13
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Svilenov HL, Delhommel F, Siebenmorgen T, Rührnößl F, Popowicz GM, Reiter A, Sattler M, Brockmeyer C, Buchner J. Extrinsic stabilization of antiviral ACE2-Fc fusion proteins targeting SARS-CoV-2. Commun Biol 2023; 6:386. [PMID: 37031320 PMCID: PMC10082628 DOI: 10.1038/s42003-023-04762-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 03/24/2023] [Indexed: 04/10/2023] Open
Abstract
The angiotensin-converting enzyme 2 (ACE2) is a viral receptor used by sarbecoviruses to infect cells. Fusion proteins comprising extracellular ACE2 domains and the Fc part of immunoglobulins exhibit high virus neutralization efficiency, but the structure and stability of these molecules are poorly understood. We show that although the hinge between the ACE2 and the IgG4-Fc is highly flexible, the conformational dynamics of the two ACE2 domains is restricted by their association. Interestingly, the conformational stability of the ACE2 moiety is much lower than that of the Fc part. We found that chemical compounds binding to ACE2, such as DX600 and MLN4760, can be used to strongly increase the thermal stability of the ACE2 by different mechanisms. Together, our findings reveal a general concept for stabilizing the labile receptor segments of therapeutic antiviral fusion proteins by chemical compounds.
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Affiliation(s)
- Hristo L Svilenov
- Center for Functional Protein Assemblies (CPA) and School of Natural Sciences, Department of Bioscience, Technical University of Munich, 85748, Garching, Germany.
- Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium.
| | - Florent Delhommel
- Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany
- Bavarian NMR Center, School of Natural Sciences, Department of Bioscience, Technical University of Munich, Garching, 85748, Munich, Germany
| | - Till Siebenmorgen
- Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany
- Bavarian NMR Center, School of Natural Sciences, Department of Bioscience, Technical University of Munich, Garching, 85748, Munich, Germany
| | - Florian Rührnößl
- Center for Functional Protein Assemblies (CPA) and School of Natural Sciences, Department of Bioscience, Technical University of Munich, 85748, Garching, Germany
| | - Grzegorz M Popowicz
- Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany
- Bavarian NMR Center, School of Natural Sciences, Department of Bioscience, Technical University of Munich, Garching, 85748, Munich, Germany
| | | | - Michael Sattler
- Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany
- Bavarian NMR Center, School of Natural Sciences, Department of Bioscience, Technical University of Munich, Garching, 85748, Munich, Germany
| | | | - Johannes Buchner
- Center for Functional Protein Assemblies (CPA) and School of Natural Sciences, Department of Bioscience, Technical University of Munich, 85748, Garching, Germany.
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14
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Wang H, Su C, Li Z, Ma C, Hong L, Li Z, Ma X, Xu Y, Wei X, Geng Y, Zhang W, Li P, Gu J. Evaluation of multiple immune cells and patient outcomes in esophageal squamous cell carcinoma. Front Immunol 2023; 14:1091098. [PMID: 36891293 PMCID: PMC9986480 DOI: 10.3389/fimmu.2023.1091098] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 01/30/2023] [Indexed: 02/22/2023] Open
Abstract
Recent reports indicate that immune cells in solid cancers have significant predictive and therapeutic value. IgG4 is a subclass of IgG and we recently found that it exerted an inhibitory effect in tumor immunity. We aimed to assess the significance of IgG4 and T cell subtypes in tumor prognosis. We investigated the density, distribution and relationship of five immune markers CD4, CD8, Foxp3, IL-10 and IgG4 with multiple immunostaining method in 118 esophageal squamous cell carcinoma (ESCC) together with clinical data. The relationship among different immune cell types and with clinical data were analyzed with Kaplan-Meier survival analysis and Cox proportional hazards model to identify independent risk factors among immune and clinicopathological parameters. Five-year survival rate of these patients treated with surgery reached 61%. Higher number of CD4+ plus CD8+ T cells predicted better prognosis (p=0.01) in tertiary lymphoid structure (TLS) and could add to the value of TNM staging. Density of the newly identified immune inhibitor IgG4+ B lymphocytes was found positively correlated to that of CD4+ cells (p=0.02) and IL-10+ cells (p=0.0005), but number of infiltrating IgG4+ cells by itself was not an independent factor for prognosis. However, increased serum concentration of IgG4 indicated a poor prognosis of ESCC (p=0.03). 5-year survival rate of esophageal cancer after surgery has been significantly improved. Increased T cells in TLS predicted better survival, suggesting that T cells in TLS may actively participate in anti-tumor immunity. Serum IgG4 could be a useful predictor of prognosis.
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Affiliation(s)
- Hui Wang
- Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China
| | - Chanjuan Su
- Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China
| | - Ziteng Li
- Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China
| | - Changchun Ma
- Department of Radiation Oncology, Affiliated Cancer Hospital, Shantou University Medical College, Shantou, Guangdong, China
| | - Liangli Hong
- Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China
| | - Zhe Li
- Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China
| | - Xiaonan Ma
- Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China
| | - Yien Xu
- Department of Radiation Oncology, Affiliated Cancer Hospital, Shantou University Medical College, Shantou, Guangdong, China
| | - Xiaolong Wei
- Department of Pathology, Affiliated Cancer Hospital, Shantou University Medical College, Shantou, Guangdong, China
| | - Yiqun Geng
- Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China
| | - Weifeng Zhang
- Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China
| | - Penghao Li
- Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China.,Jinxin Research Institute for Reproductive Medicine and Genetics, Xinan Hospital for Maternal and Child Health Care, Chengdu, China
| | - Jiang Gu
- Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, China.,Jinxin Research Institute for Reproductive Medicine and Genetics, Xinan Hospital for Maternal and Child Health Care, Chengdu, China
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15
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Origuchi T, Uchida T, Sakaguchi T, Matsuo H, Michitsuji T, Umeda M, Shimizu T, Koga T, Kawashiri SY, Iwamoto N, Ichinose K, Tamai M, Ichinose M, Ando K, Horie I, Nakao N, Irie J, Kawakami A. Immunoglobulin G4-related disease with Marked Eosinophilia: A Case Report and Literature Review. Intern Med 2022. [PMID: 36351576 DOI: 10.2169/internalmedicine.0453-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
We encountered a 78-year-old Japanese man with IgG4-related sialoadenitis complicated with marked eosinophilia. We diagnosed him with IgG4-RD (related disease) with a submandibular gland tumor, serum IgG4 elevation, IgG4-positive plasma cell infiltration, and storiform fibrosis. During follow-up after total incision of the submandibular gland, the peripheral eosinophil count was markedly elevated to 29,480/μL. The differential diagnosis of severe eosinophilia without IgG4-RD was excluded. The patient exhibited a prompt response to corticosteroid therapy. His peripheral blood eosinophil count was the highest ever reported among similar cases. We also review previous cases of IgG4-RD with severe eosinophilia.
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Affiliation(s)
- Tomoki Origuchi
- Department of Immunology and Rheumatology, Unit of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Japan
- Department of Physical Therapy, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Tomohisa Uchida
- Department of Immunology and Rheumatology, Unit of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Tatsuki Sakaguchi
- Department of Immunology and Rheumatology, Unit of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Haruna Matsuo
- Department of Immunology and Rheumatology, Unit of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Toru Michitsuji
- Department of Immunology and Rheumatology, Unit of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Masataka Umeda
- Department of Immunology and Rheumatology, Unit of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Toshimasa Shimizu
- Department of Immunology and Rheumatology, Unit of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Tomohiro Koga
- Department of Immunology and Rheumatology, Unit of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Shin-Ya Kawashiri
- Department of Immunology and Rheumatology, Unit of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Naoki Iwamoto
- Department of Immunology and Rheumatology, Unit of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Kunihiro Ichinose
- Department of Immunology and Rheumatology, Unit of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Mami Tamai
- Department of Immunology and Rheumatology, Unit of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Masahiro Ichinose
- Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Japan
| | - Koji Ando
- Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Japan
| | - Ichiro Horie
- Department of Endocrinology and Metabolism, Unit of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Nobuhiro Nakao
- Department of Otolaryngology, Nagasaki Harbor Medical Center, Japan
| | - Junji Irie
- Department of Pathology, Nagasaki Harbor Medical Center, Japan
| | - Atsushi Kawakami
- Department of Immunology and Rheumatology, Unit of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Japan
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16
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Bolton MJ, Arevalo CP, Griesman T, Li SH, Bates P, Wilson PC, Hensley SE. IgG3 subclass antibodies recognize antigenically drifted influenza viruses and SARS-CoV-2 variants through efficient bivalent binding. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2022:2022.09.27.509738. [PMID: 36203556 PMCID: PMC9536032 DOI: 10.1101/2022.09.27.509738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The constant domains of antibodies are important for effector functions, but less is known about how they can affect binding and neutralization of viruses. Here we evaluated a panel of human influenza virus monoclonal antibodies (mAbs) expressed as IgG1, IgG2 or IgG3. We found that many influenza virus-specific mAbs have altered binding and neutralization capacity depending on the IgG subclass encoded, and that these differences result from unique bivalency capacities of the subclasses. Importantly, subclass differences in antibody binding and neutralization were greatest when the affinity for the target antigen was reduced through antigenic mismatch. We found that antibodies expressed as IgG3 bound and neutralized antigenically drifted influenza viruses more effectively. We obtained similar results using a panel of SARS-CoV-2-specific mAbs and the antigenically advanced B.1.351 strain of SARS-CoV-2. We found that a licensed therapeutic mAb retained neutralization breadth against SARS-CoV-2 variants when expressed as IgG3, but not IgG1. These data highlight that IgG subclasses are not only important for fine-tuning effector functionality, but also for binding and neutralization of antigenically drifted viruses. Significance Influenza viruses and coronaviruses undergo continuous change, successfully evading human antibodies elicited from prior infections or vaccinations. It is important to identify features that allow antibodies to bind with increased breadth. Here we examined the effect that different IgG subclasses have on monoclonal antibody binding and neutralization. We show that IgG subclass is a determinant of antibody breadth, with IgG3 affording increased neutralization of antigenically drifted variants of influenza virus and SARS-CoV-2. Future studies should evaluate IgG3 therapeutic antibodies and vaccination strategies or adjuvants that may skew antibody responses toward broadly reactive isotypes.
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Affiliation(s)
- Marcus J. Bolton
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Claudia P. Arevalo
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Trevor Griesman
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Shuk Hang Li
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Paul Bates
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Patrick C. Wilson
- Department of Medicine, Section of Rheumatology, the Knapp Center for Lupus and Immunology, University of Chicago, Chicago, IL 60637, USA
| | - Scott E. Hensley
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
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17
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McCue AC, Yao Z, Kuhlman B. Advances in modular control of CAR-T therapy with adapter-mediated CARs. Adv Drug Deliv Rev 2022; 187:114358. [PMID: 35618140 PMCID: PMC9939278 DOI: 10.1016/j.addr.2022.114358] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 05/11/2022] [Accepted: 05/18/2022] [Indexed: 11/01/2022]
Abstract
Protein engineering has contributed to successes in the field of T cell-based immunotherapy, including chimeric antigen receptor (CAR) T cell therapy. CAR T cell therapy has become a pillar of cancer immunotherapy, demonstrating clinical effectiveness against B cell malignancies by targeting the B cell antigen CD19. Current gene editing techniques have limited safety controls over CAR T cell activity, which presents a hurdle for control of CAR T cells in patients. Alternatively, CAR T cell activity can be controlled by engineering CARs to bind soluble adapter molecules that direct the interaction between the CAR T cell and target cell. The flexibility in this adapter-mediated approach overcomes the rigid specificity of traditional CAR T cells to allow targeting of multiple cell types. Here we describe adapter CAR T technologies and how these methods emphasize the growing role of protein engineering in the design of programmable tools for T cell therapies.
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Affiliation(s)
- Amelia C McCue
- Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
| | - Zhiyuan Yao
- Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA.
| | - Brian Kuhlman
- Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27514, USA.
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18
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Manral P, Caza TN, Storey AJ, Beck LH, Borza DB. The Alternative Pathway Is Necessary and Sufficient for Complement Activation by Anti-THSD7A Autoantibodies, Which Are Predominantly IgG4 in Membranous Nephropathy. Front Immunol 2022; 13:952235. [PMID: 35874690 PMCID: PMC9301376 DOI: 10.3389/fimmu.2022.952235] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 06/16/2022] [Indexed: 12/12/2022] Open
Abstract
Membranous nephropathy (MN) is an immune kidney disease characterized by glomerular subepithelial immune complexes (ICs) containing antigen, IgG, and products of complement activation. Whereas proteinuria is caused by complement-mediated podocyte injury, the pathways of complement activation remain controversial due to the predominance of IgG4 in ICs, an IgG subclass considered unable to activate complement. THSD7A, a transmembrane protein expressed on podocytes, is the target autoantigen in ~3% of cases of primary MN. In this study, we analyzed sera from 16 patients with THSD7A-associated MN with regard to the anti-THSD7A IgG subclasses and their ability to fix complement in vitro. The serum concentration of anti-THSD7A IgG varied over two orders of magnitude (1.3-243 μg/mL). As a relative proportion of all IgG anti-THSD7A, IgG4 was by far the most abundant subclass (median 79%), followed by IgG1 (median 11%). IgG4 was the dominant subclass of anti-THSD7A antibodies in 14 sera, while IgG1 was dominant in one and co-dominant in another. One quarter of MN sera additionally contained low levels of anti-THSD7A IgA1. ICs formed by predominantly IgG4 anti-THSD7A autoantibodies with immobilized THSD7A were relatively weak activators of complement in vitro, compared to human IgG1 and IgG3 mAbs used as positive control. Complement deposition on THSD7A ICs was dose-dependent and occurred to a significant extent only at relatively high concentration of anti-THSD7A IgG. C3b fixation by THSD7A ICs was completely abolished in factor B-depleted sera, partially inhibited in C4-depleted sera, unchanged in C1q-depleted sera, and also occurred in Mg-EGTA buffer. These results imply that THSD7A ICs predominantly containing IgG4 activate complement at high IgG4 density, which strictly requires a functional alternative pathway, whereas the classical and lectin pathways are dispensable. These findings advance our understanding of how IgG4 antibodies activate complement.
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Affiliation(s)
- Pallavi Manral
- Department of Microbiology, Immunology and Physiology, Meharry Medical College, Nashville, TN, United States
| | | | - Aaron J. Storey
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Laurence H. Beck
- Department of Medicine (Nephrology), Boston University School of Medicine and Boston Medical Center, Boston, MA, United States
| | - Dorin-Bogdan Borza
- Department of Microbiology, Immunology and Physiology, Meharry Medical College, Nashville, TN, United States
- *Correspondence: Dorin-Bogdan Borza,
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19
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Brücksken KA, Loreto Palacio P, Hanschmann EM. Thiol Modifications in the Extracellular Space-Key Proteins in Inflammation and Viral Infection. Front Immunol 2022; 13:932525. [PMID: 35833136 PMCID: PMC9271835 DOI: 10.3389/fimmu.2022.932525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 05/23/2022] [Indexed: 11/13/2022] Open
Abstract
Posttranslational modifications (PTMs) allow to control molecular and cellular functions in response to specific signals and changes in the microenvironment of cells. They regulate structure, localization, stability, and function of proteins in a spatial and temporal manner. Among them, specific thiol modifications of cysteine (Cys) residues facilitate rapid signal transduction. In fact, Cys is unique because it contains the highly reactive thiol group that can undergo different reversible and irreversible modifications. Upon inflammation and changes in the cellular microenvironment, many extracellular soluble and membrane proteins undergo thiol modifications, particularly dithiol-disulfide exchange, S-glutathionylation, and S-nitrosylation. Among others, these thiol switches are essential for inflammatory signaling, regulation of gene expression, cytokine release, immunoglobulin function and isoform variation, and antigen presentation. Interestingly, also the redox state of bacterial and viral proteins depends on host cell-mediated redox reactions that are critical for invasion and infection. Here, we highlight mechanistic thiol switches in inflammatory pathways and infections including cholera, diphtheria, hepatitis, human immunodeficiency virus (HIV), influenza, and coronavirus disease 2019 (COVID-19).
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Affiliation(s)
| | | | - Eva-Maria Hanschmann
- Department of Neurology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany
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20
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Nieto-Gañán I, Iturrieta-Zuazo I, Rita C, Carrasco-Sayalero Á. Revisiting immunological and clinical aspects of membranous nephropathy. Clin Immunol 2022; 237:108976. [PMID: 35276323 DOI: 10.1016/j.clim.2022.108976] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 02/16/2022] [Accepted: 03/05/2022] [Indexed: 11/29/2022]
Abstract
Idiopathic or primary membranous nephropathy (IMN) is one of the most frequent causes of nephrotic syndrome in adults and the elderly. It is characterized by a thickening of the wall of the glomerular capillaries due to the presence of immune complex deposits. 85% of membranous nephropathy cases are classified as primary or idiopathic (IMN). The rest are of secondary origin (SMN), caused by autoimmune conditions or malignant tumors as lung cancer, colon and melanomas. It is an organ-specific autoimmune disease in which the complement system plays an important role with the formation of the membrane attack complex (MAC; C5b-9), which produces an alteration of the podocyte structure. The antigen responsible for 70-80% of IMN is a podocyte protein called M-type phospholipase A2 receptor (PLA2R). More recently, another podocyte antigen has been identified, the "Thrombospondin type-1 domain-containing 7A" (THSD7A), which is responsible for 10% of the cases of negative IMN for anti- PLA2R.
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Affiliation(s)
- Israel Nieto-Gañán
- Immunology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain.
| | - Ignacio Iturrieta-Zuazo
- Immunology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Spain
| | - Claudia Rita
- Immunology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain
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21
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Abstract
IgG4-related conditions affecting the digestive tract are part of a multi-organ fibro-inflammatory disorder termed IgG4-related disease (IgG4-RD), with autoimmune pancreatitis and IgG4-related cholangitis being the most prominent manifestations. Gastrointestinal symptoms include jaundice, weight loss, abdominal pain, biliary strictures, and pancreatic and hepatic masses that mimic malignant diseases. IgG4-RD manifestations occur less frequently elsewhere in the digestive tract, namely in the oesophagus, retroperitoneum or intestine. Evidence-based European guidelines frame the current state-of-the-art in the diagnosis and management of IgG4-related digestive tract disease. Diagnosis is based on histology (if available), imaging, serology, other organ involvement and response to therapy (HISORt criteria). Few biomarkers beyond serum IgG4 concentrations are reliable. The first-line therapy (glucocorticoids) is swiftly effective but disease flares are common at low doses or after tapering. Second-line therapy might consist of other immunosuppressive drugs such as thiopurines or rituximab. Further trials, for example, of anti-CD19 drugs, are ongoing. Although an association between IgG4-RD and the development of malignancies has been postulated, the true nature of this relationship remains uncertain at this time.
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22
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The Blood of the HIV-Infected Patients Contains κ-IgG, λ-IgG, and Bispecific κλ-IgG, Which Possess DNase and Amylolytic Activity. Life (Basel) 2022; 12:life12020304. [PMID: 35207591 PMCID: PMC8880267 DOI: 10.3390/life12020304] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/04/2022] [Accepted: 02/14/2022] [Indexed: 12/26/2022] Open
Abstract
Though hundreds of thousands of papers are currently being published on HIV/AIDS, only tens of hundreds of them are devoted to the antibodies generated during the disease. Most of these papers discuss antibodies in HIV/AIDS as a diagnostic tool, and some articles describe neutralizing antibodies as a promising treatment. In this paper, we used affinity chromatography and ELISA to isolate natural IgG from the blood of 26 HIV-infected patients. IgG preparations were separated into the subfractions containing different types of light chains, and catalytic activities of subfractions were analyzed. Here, we show for the first time that the blood of HIV patients contains ~20% of bispecific κλ-IgG, presented with all IgG subclasses. Analysis of DNA-hydrolyzing and amylolytic activity show that most IgG preparations and subfractions are catalytically active. Our results expand the possible biological functions of natural IgG in HIV infection.
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23
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Fleming A, Castro‐Dopico T, Clatworthy MR. B cell class switching in intestinal immunity in health and disease. Scand J Immunol 2022; 95:e13139. [PMID: 34978077 PMCID: PMC9285483 DOI: 10.1111/sji.13139] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 12/31/2021] [Accepted: 12/31/2021] [Indexed: 12/12/2022]
Abstract
The gastrointestinal tract is colonized by trillions of commensal microorganisms that collectively form the microbiome and make essential contributions to organism homeostasis. The intestinal immune system must tolerate these beneficial commensals, whilst preventing pathogenic organisms from systemic spread. Humoral immunity plays a key role in this process, with large quantities of immunoglobulin (Ig)A secreted into the lumen on a daily basis, regulating the microbiome and preventing bacteria from encroaching on the epithelium. However, there is an increasing appreciation of the role of IgG antibodies in intestinal immunity, including beneficial effects in neonatal immune development, pathogen and tumour resistance, but also of pathological effects in driving chronic inflammation in inflammatory bowel disease (IBD). These antibody isotypes differ in effector function, with IgG exhibiting more proinflammatory capabilities compared with IgA. Therefore, the process that leads to the generation of different antibody isotypes, class-switch recombination (CSR), requires careful regulation and is orchestrated by the immunological cues generated by the prevalent local challenge. In general, an initiating signal such as CD40 ligation on B cells leads to the induction of activation-induced cytidine deaminase (AID), but a second cytokine-mediated signal determines which Ig heavy chain is expressed. Whilst the cytokines driving intestinal IgA responses are well-studied, there is less clarity on how IgG responses are generated in the intestine, and how these cues might become dysfunctional in IBD. Here, we review the key mechanisms regulating class switching to IgA vs IgG in the intestine, processes that could be therapeutically manipulated in infection and IBD.
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Affiliation(s)
- Aaron Fleming
- Molecular Immunity UnitDepartment of MedicineCambridge Institute of Therapeutic Immunology and Infectious DiseasesUniversity of CambridgeCambridgeUK
| | - Tomas Castro‐Dopico
- Molecular Immunity UnitDepartment of MedicineCambridge Institute of Therapeutic Immunology and Infectious DiseasesUniversity of CambridgeCambridgeUK
- The Francis Crick InstituteLondonUK
| | - Menna R. Clatworthy
- Molecular Immunity UnitDepartment of MedicineCambridge Institute of Therapeutic Immunology and Infectious DiseasesUniversity of CambridgeCambridgeUK
- Cellular GeneticsWellcome Trust Sanger InstituteHinxtonUK
- NIHR Cambridge Biomedical Research CentreCambridgeUK
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24
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Song Y, Cai H, Tan Z, Mussa N, Li ZJ. Mechanistic insights into inter-chain disulfide bond reduction of IgG1 and IgG4 antibodies. Appl Microbiol Biotechnol 2022; 106:1057-1066. [DOI: 10.1007/s00253-022-11778-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 12/24/2021] [Accepted: 01/13/2022] [Indexed: 11/29/2022]
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25
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Allen CDC. Features of B Cell Responses Relevant to Allergic Disease. THE JOURNAL OF IMMUNOLOGY 2022; 208:257-266. [PMID: 35017215 PMCID: PMC10054180 DOI: 10.4049/jimmunol.2100988] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 11/04/2021] [Indexed: 01/16/2023]
Abstract
This Brief Review delves into B cell responses in the context of allergy. The primary contribution of B cells to allergy is the production of IgE, the Ab isotype that triggers immediate hypersensitivity reactions through the release of mediators from mast cells and basophils. B cells may also have protective roles in allergy, such as through the production of IgG or as regulatory B cells. In this review, I focus on the basic principles of B cell differentiation and discuss features relevant to allergic immune responses. In particular, I discuss: (1) class-switch recombination; (2) plasma cell differentiation; (3) germinal centers and affinity maturation; and (4) memory B cells and recall responses, with an emphasis on IgE, IgG1, and IgG4. I also consider how B cells may contribute to allergic responses independent of Ab production-for example, by serving as APCs.
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Affiliation(s)
- Christopher D C Allen
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA; Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA; and Department of Anatomy, University of California, San Francisco, San Francisco, CA
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26
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Alfaleh MA, Zawawi A, Al-Amri SS, Hashem AM. David versus goliath: ACE2-Fc receptor traps as potential SARS-CoV-2 inhibitors. MAbs 2022; 14:2057832. [PMID: 35380919 PMCID: PMC8986284 DOI: 10.1080/19420862.2022.2057832] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
Anti-SARS-CoV-2 monoclonal antibodies and vaccines have shown improvement in lowering viral burden and hospitalization. However, emerging SARS-CoV-2 variants contain neutralizing antibody-escape mutations. Therefore, several reports have suggested the administration of recombinant angiotensin-converting enzyme 2 (rACE2) as a soluble receptor trap to block SARS-CoV-2 infection and limit viral escape potential. Several strategies have been implemented to enhance the efficacy of rACE2 as a therapeutic agent. Fc fusions have been used to improve pharmacokinetics and boost the affinity and avidity of ACE2 decoys for the virus spike protein. Furthermore, the intrinsic catalytic activity of ACE2 can be eliminated by introducing point mutations on the catalytic site of ACE2 to obtain an exclusive antiviral activity. This review summarizes different evolution platforms that have been used to enhance ACE2-Fc (i.e., immunoadhesins) as potential therapeutics for the current pandemic or future outbreaks of SARS-associated betacoronaviruses.
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Affiliation(s)
- Mohamed A Alfaleh
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah Saudi Arabia.,Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah Saudi Arabia
| | - Ayat Zawawi
- Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah Saudi Arabia.,Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah Saudi Arabia
| | - Sawsan S Al-Amri
- Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah Saudi Arabia
| | - Anwar M Hashem
- Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah Saudi Arabia.,Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah Saudi Arabia
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27
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Gao Y, Kong L, Liu S, Liu K, Zhu J. Impact of Neurofascin on Chronic Inflammatory Demyelinating Polyneuropathy via Changing the Node of Ranvier Function: A Review. Front Mol Neurosci 2021; 14:779385. [PMID: 34975399 PMCID: PMC8716720 DOI: 10.3389/fnmol.2021.779385] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Accepted: 11/15/2021] [Indexed: 11/18/2022] Open
Abstract
The effective conduction of action potential in the peripheral nervous system depends on the structural and functional integrity of the node of Ranvier and paranode. Neurofascin (NF) plays an important role in the conduction of action potential in a saltatory manner. Two subtypes of NF, NF186, and NF155, are involved in the structure of the node of Ranvier. In patients with chronic inflammatory demyelinating polyneuropathy (CIDP), anti-NF antibodies are produced when immunomodulatory dysfunction occurs, which interferes with the conduction of action potential and is considered the main pathogenic factor of CIDP. In this study, we describe the assembling mechanism and anatomical structure of the node of Ranvier and the necessary cell adhesion molecules for its physiological function. The main points of this study are that we summarized the recent studies on the role of anti-NF antibodies in the changes in the node of Ranvier function and its impact on clinical manifestations and analyzed the possible mechanisms underlying the pathogenesis of CIDP.
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Affiliation(s)
- Ying Gao
- Neuroscience Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Lingxin Kong
- Neuroscience Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Shan Liu
- Neuroscience Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Kangding Liu
- Neuroscience Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Jie Zhu
- Neuroscience Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, China
- Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Karolinska University Hospital Solna, Stockholm, Sweden
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28
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Vakrakou AG, Tzanetakos D, Evangelopoulos ME, Fragoulis GE, Kazakou P, Lekka E, Kafasi N, Tzartos JS, Andreadou E, Koutsis G, Gialafos E, Dimitrakopoulos A, Zampeli E, Rontogianni D, Theocharis S, Zapanti E, Stathopoulos PA, Anagnostouli M, Stefanis L, Kilidireas C. IgG4-related autoimmune manifestations in Alemtuzumab-treated multiple sclerosis patients. J Neuroimmunol 2021; 361:577759. [PMID: 34742035 DOI: 10.1016/j.jneuroim.2021.577759] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 10/09/2021] [Accepted: 10/25/2021] [Indexed: 12/12/2022]
Abstract
We aimed to determine whether Alemtuzumab-induced immune reconstitution affects immunoglobulin and complement levels in the serum of Relapsing-Remitting Multiple Sclerosis (RRMS) patients. IgG4-levels were increased 24-months after treatment initiation compared to baseline levels in twenty-nine patients. Alemtuzumab-treated patients with the highest IgG4-levels were more prone to thyroid-related autoimmune manifestations and specific autoimmune adverse events such as Crohn's disease, Graves' disease, and hemolytic anemia. Compared to baseline, total IgG-levels showed a trend towards reduced levels following two-courses of Alemtuzumab, but no significant change of C3 and/or C4-levels was observed. In conclusion, monitoring of IgG4-levels can serve as a marker for secondary autoimmunity risk in multiple sclerosis patients treated with Alemtuzumab.
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Affiliation(s)
- Aigli G Vakrakou
- Multiple Sclerosis & Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Greece.
| | - Dimitrios Tzanetakos
- Multiple Sclerosis & Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Greece
| | - Maria-Eleptheria Evangelopoulos
- Multiple Sclerosis & Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Greece
| | - George E Fragoulis
- Department of Propaedeutic Internal Medicine, Medical School, Rheumatology Unit, "Laiko" General Hospital, National and Kapodistrian University of Athens, Greece
| | - Paraskevi Kazakou
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Alexandra Hospital, Athens, Greece
| | - Eleni Lekka
- Department of Immunology, Laiko General Hospital, 17 Agiou Thoma str, Athens 11527, Greece
| | - Nikolitsa Kafasi
- Department of Immunology, Laiko General Hospital, 17 Agiou Thoma str, Athens 11527, Greece
| | - John S Tzartos
- Second Department of Neurology, National and Kapodistrian University of Athens, School of Medicine, "Attikon" University Hospital, Rimini 1, Chaidari, 12462, Athens, Greece; Tzartos NeuroDiagnostics, Neuroimmunology, Eslin street 3, 115 23 Athens, Greece
| | - Elissavet Andreadou
- Multiple Sclerosis & Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Greece
| | - Georgios Koutsis
- Multiple Sclerosis & Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Greece
| | - Elias Gialafos
- Multiple Sclerosis & Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Greece
| | - Antonios Dimitrakopoulos
- Multiple Sclerosis & Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Greece
| | - Evanthia Zampeli
- Gastroenterology Department, "Alexandra" Hospital, Athens, Greece
| | | | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Greece
| | | | - Panos-Alexis Stathopoulos
- Multiple Sclerosis & Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Greece
| | - Maria Anagnostouli
- Multiple Sclerosis & Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Greece
| | - Leonidas Stefanis
- Multiple Sclerosis & Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Greece
| | - Constantinos Kilidireas
- Multiple Sclerosis & Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Greece
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29
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Nikolov G, Todordova Y, Emilova R, Hristova D, Nikolova M, Petrunov B. Allergen-Specific IgE and IgG4 as Biomarkers for Immunologic Changes during Subcutaneous Allergen Immunotherapy. Antibodies (Basel) 2021; 10:antib10040049. [PMID: 34940001 PMCID: PMC8698535 DOI: 10.3390/antib10040049] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/24/2021] [Accepted: 12/03/2021] [Indexed: 12/31/2022] Open
Abstract
(1) Background: Biomarkers of efficacy for subcutaneous immunotherapy (SCIT) on allergic rhinitis have not been evaluated in details. The present study aims to assess the relevance of measuring of sIgE, sIgG4 and IgE/IgG4 ratio during SCIT in patients with allergic rhinitis; (2) Methods: 20 patients, 13 men and 7 women aged 19 to 58 years, with clinically manifested seasonal and perennial allergic rhinitis were studied. At the initiation and in the end of the three-year course of SCIT serum allergen-specific IgE and IgG4 were measured with ImmunoCAP system. The sIgE/sIgG4 ratio was calculated as a biomarker for immunologic effectiveness; (3) Results: There was a significant increase of sIgG4 antibodies (p < 0.05), while at the end of SCIT for the sIgE levels no significant changes were seen (p > 0.05). Moreover, 90% of patients showed a decrease of the IgE/IgG4 ratio; (4) Conclusions: In most of treated patients with AR, SCIT with Bulgarian allergen products leads to clear immunological changes. After a 3-year of SCIT there is a significant increase in allergen specific IgG4 levels and both decrease of sIgE and IgE/IgG4 ratio. sIgE, sIgG4 and IgE/IgG4 ratio can be used as a substantial biomarker for predicting immunological effectiveness of SCIT.
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30
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Nawab DH. Vaccinal antibodies: Fc antibody engineering to improve the antiviral antibody response and induce vaccine-like effects. Hum Vaccin Immunother 2021; 17:5532-5545. [PMID: 34844516 PMCID: PMC8903937 DOI: 10.1080/21645515.2021.1985891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 09/21/2021] [Indexed: 10/19/2022] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic highlights the urgent clinical need for efficient virus therapies and vaccines. Although the functional importance of antibodies is indisputable in viral infections, there are still significant unmet needs that require vast improvements in antibody-based therapeutics. The IgG Fc domain can be engineered to produce antibodies with tailored and potent responses that will meet these clinical demands. Engaging Fc receptors (FcRs) to perform effector functions as cytotoxicity, phagocytosis, complement activation, intracellular neutralization and controlling antibody persistence. Furthermore, it produces vaccine-like effects by activating signals to stimulate T-cell responses, have proven to be required for protection, as neutralization alone does not off the full protection capacity of antibodies. This review highlights antiviral Fc functions and FcRs' contributions in linking innate and adaptive immunity against viral threats. Moreover, it provides the latest Fc engineering strategies to improve the safety and efficacy of human antiviral antibodies and vaccines.
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Affiliation(s)
- Dhuha H Nawab
- Pharmacy Department, Ministry of Health, Saudi Arabia
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31
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Communication pathways bridge local and global conformations in an IgG4 antibody. Sci Rep 2021; 11:23197. [PMID: 34853348 PMCID: PMC8636491 DOI: 10.1038/s41598-021-02323-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 11/15/2021] [Indexed: 12/15/2022] Open
Abstract
The affinity of an antibody for its antigen is primarily determined by the specific sequence and structural arrangement of the complementarity-determining regions (CDRs). Recent evidence, however, points toward a nontrivial relation between the CDR and distal sites: variations in the binding strengths have been observed upon mutating residues separated from the paratope by several nanometers, thus suggesting the existence of a communication network within antibodies, whose extension and relevance might be deeper than insofar expected. In this work, we test this hypothesis by means of molecular dynamics (MD) simulations of the IgG4 monoclonal antibody pembrolizumab, an approved drug that targets the programmed cell death protein 1 (PD-1). The molecule is simulated in both the apo and holo states, totalling 4 μs of MD trajectory. The analysis of these simulations shows that the bound antibody explores a restricted range of conformations with respect to the apo one, and that the global conformation of the molecule correlates with that of the CDR. These results support the hypothesis that pembrolizumab featues a multi-scale hierarchy of intertwined global and local conformational changes. The analysis pipeline developed in this work is general, and it can help shed further light on the mechanistic aspects of antibody function.
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32
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Zheng P, Liu X, Lin L, Wu H, Zhao X, Sun B. Efficacy of mite allergen immunotherapy in allergic rhinitis and the immune synergistic effect on cross-allergens. Immunotherapy 2021; 14:217-233. [PMID: 34845913 DOI: 10.2217/imt-2020-0326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: To compare the efficacy of single- and double-species mite allergen immunotherapy. Materials and methods: An open, pseudo-randomized, controlled study was conducted (n = 125 allergic rhinitis patients). The primary end point involved the visual analogue scale. Secondary end points included a basophil activation test and serum specific IgE and IgG4 assays. Results: Visual analogue scale analysis indicated considerable reductions in both groups. Both treatments improved quality of life and induced sIgG4 antibody production. Basophil activation and serum IgE inhibition were not evident in either treatment. Neither treatment displayed an early stage immune synergistic effect on cross-allergens. Conclusions: Both treatments were effective against allergic rhinitis, and statistical differences were not observed. Future studies may require long-term, large-scale research.
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Affiliation(s)
- Peiyan Zheng
- Department of Allergy & Clinical Immunology, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China
| | - Xiaoqing Liu
- Department of Clinical Laboratory, Zhuhai People's Hospital (Zhuhai hospital affiliated with Jinan University), Zhuhai, 519070, China
| | - Lili Lin
- Department of Otolaryngology Head & Neck Surgery, Zhuhai People's Hospital (Zhuhai hospital affiliated with Jinan University), Zhuhai, 519070, China
| | - Huiqin Wu
- Department of Otolaryngology Head & Neck Surgery, Zhuhai People's Hospital (Zhuhai hospital affiliated with Jinan University), Zhuhai, 519070, China
| | - Xiaoming Zhao
- Department of Otolaryngology Head & Neck Surgery, Zhuhai People's Hospital (Zhuhai hospital affiliated with Jinan University), Zhuhai, 519070, China
| | - Baoqing Sun
- Department of Allergy & Clinical Immunology, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China
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33
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Picomolar inhibition of SARS-CoV-2 variants of concern by an engineered ACE2-IgG4-Fc fusion protein. Antiviral Res 2021; 196:105197. [PMID: 34774603 PMCID: PMC8579703 DOI: 10.1016/j.antiviral.2021.105197] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 09/27/2021] [Accepted: 10/26/2021] [Indexed: 01/06/2023]
Abstract
SARS-CoV-2 enters host cells after binding through its spike glycoprotein to the angiotensin-converting enzyme 2 (ACE2) receptor. Soluble ACE2 ectodomains bind and neutralize the virus, yet their short in vivo half-live limits their therapeutic use. This limitation can be overcome by fusing the fragment crystallizable (Fc) part of human immunoglobulin G (IgG) to the ACE2 ectodomain, but this bears the risk of Fc-receptor activation and antibody-dependent cellular cytotoxicity. Here, we describe optimized ACE2-IgG4-Fc fusion constructs that avoid Fc-receptor activation, preserve the desired ACE2 enzymatic activity and show promising pharmaceutical properties. The engineered ACE2-IgG4-Fc fusion proteins neutralize the original SARS-CoV, pandemic SARS-CoV-2 as well as the rapidly spreading SARS-CoV-2 alpha, beta and delta variants of concern. Importantly, these variants of concern are inhibited at picomolar concentrations proving that ACE2-IgG4 maintains - in contrast to therapeutic antibodies - its full antiviral potential. Thus, ACE2-IgG4-Fc fusion proteins are promising candidate anti-antivirals to combat the current and future pandemics.
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Clinical characteristics and outcomes of idiopathic membranous nephropathy with glomerular IgM deposits. Clin Exp Med 2021; 22:455-464. [PMID: 34698950 DOI: 10.1007/s10238-021-00768-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 10/14/2021] [Indexed: 10/20/2022]
Abstract
Glomerular IgM deposition is commonly shown in idiopathic membranous nephropathy, but the clinicopathological features and outcomes of IMN with IgM deposition are unclear. This single-center prospective cohort study enrolled 210 patients with biopsy-proven IMN from January 2016 to December 2018. Clinicopathological features, treatment responses, and kidney outcomes were compared between patients with and without IgM deposition. In total, 76 (36.2%) patients show glomerular IgM deposition. Patients with IgM deposition were younger (45 ± 13.30 vs. 50.59 ± 13.65 years, P = 0.006), had a higher estimated glomerular filtration rate (eGFR) (100.03 [81.31-111.37] vs. 92.67 [74.71-106.63] mL/min/1.73 m2, P = 0.041), and had a lower proportion of nephrotic syndrome (60.5% vs. 75.4%, P = 0.024) at the time of kidney biopsy. Patients with IgM deposition had a significantly higher proportion of focal segmental glomerular sclerosis (FSGS) lesions (27.6% vs. 13.4%, P = 0.011) and C1q deposition (72.4% vs. 57.5%, P = 0.032). Although the treatments and initial treatment responses were comparable, patients with glomerular IgM deposition had a significantly greater proportion of eGFR decline of ≥ 5 mL/min/1.73 m2 per year (log-rank test, P < 0.001) and eGFR decrease of ≥ 10% from baseline (log-rank test, P = 0.003). Cox regression analysis showed that IgM deposition was an independent risk factor of eGFR decline of ≥ 5 mL/min/1.73 m2 per year (HR, 2.442; 95% CI, 1.550-3.848, P < 0.001) and eGFR decline by ≥ 10% from baseline (HR, 2.629; 95% CI, 1.578-4.385, P < 0.001) during follow-up. IgM deposition in the glomeruli is an independent risk factor for decreased renal function in patients with IMN.
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Lorés-Motta L, van Beek AE, Willems E, Zandstra J, van Mierlo G, Einhaus A, Mary JL, Stucki C, Bakker B, Hoyng CB, Fauser S, Clark SJ, de Jonge MI, Nogoceke E, Koertvely E, Jongerius I, Kuijpers TW, den Hollander AI. Common haplotypes at the CFH locus and low-frequency variants in CFHR2 and CFHR5 associate with systemic FHR concentrations and age-related macular degeneration. Am J Hum Genet 2021; 108:1367-1384. [PMID: 34260947 PMCID: PMC8387287 DOI: 10.1016/j.ajhg.2021.06.002] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 05/27/2021] [Indexed: 12/15/2022] Open
Abstract
Age-related macular degeneration (AMD) is the principal cause of blindness in the elderly population. A strong effect on AMD risk has been reported for genetic variants at the CFH locus, encompassing complement factor H (CFH) and the complement-factor-H-related (CFHR) genes, but the underlying mechanisms are not fully understood. We aimed to dissect the role of factor H (FH) and FH-related (FHR) proteins in AMD in a cohort of 202 controls and 216 individuals with AMD. We detected elevated systemic levels of FHR-1 (p = 1.84 × 10-6), FHR-2 (p = 1.47 × 10-4), FHR-3 (p = 1.05 × 10-5) and FHR-4A (p = 1.22 × 10-2) in AMD, whereas FH concentrations remained unchanged. Common AMD genetic variants and haplotypes at the CFH locus strongly associated with FHR protein concentrations (e.g., FH p.Tyr402His and FHR-2 concentrations, p = 3.68 × 10-17), whereas the association with FH concentrations was limited. Furthermore, in an International AMD Genomics Consortium cohort of 17,596 controls and 15,894 individuals with AMD, we found that low-frequency and rare protein-altering CFHR2 and CFHR5 variants associated with AMD independently of all previously reported genome-wide association study (GWAS) signals (p = 5.03 × 10-3 and p = 2.81 × 10-6, respectively). Low-frequency variants in CFHR2 and CFHR5 led to reduced or absent FHR-2 and FHR-5 concentrations (e.g., p.Cys72Tyr in CFHR2 and FHR-2, p = 2.46 × 10-16). Finally, we showed localization of FHR-2 and FHR-5 in the choriocapillaris and in drusen. Our study identifies FHR proteins as key proteins in the AMD disease mechanism. Consequently, therapies that modulate FHR proteins might be effective for treating or preventing progression of AMD. Such therapies could target specific individuals with AMD on the basis of their genotypes at the CFH locus.
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Affiliation(s)
- Laura Lorés-Motta
- Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525EX, the Netherlands; Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, 4070, Switzerland
| | - Anna E van Beek
- Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, 1066CX, the Netherlands; Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam University Medical Centre, Amsterdam, 1105 AZ, the Netherlands; Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, 4051, Switzerland; University of Basel, Basel, 4051, Switzerland
| | - Esther Willems
- Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6525GA, the Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, 6525GA, the Netherlands; Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6525GA, the Netherlands
| | - Judith Zandstra
- Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, 1066CX, the Netherlands; Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam University Medical Centre, Amsterdam, 1105 AZ, the Netherlands
| | - Gerard van Mierlo
- Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, 1066CX, the Netherlands
| | - Alfred Einhaus
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, 4070, Switzerland
| | - Jean-Luc Mary
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, 4070, Switzerland
| | - Corinne Stucki
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, 4070, Switzerland
| | - Bjorn Bakker
- Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525EX, the Netherlands
| | - Carel B Hoyng
- Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525EX, the Netherlands
| | - Sascha Fauser
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, 4070, Switzerland
| | - Simon J Clark
- University Eye Clinic, Department for Ophthalmology, University of Tübingen, 72076, Germany; Institue for Ophthalmic Research, Eberhard Karls University of Tübingen, 72076, Germany; Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, M139PL, United Kingdom
| | - Marien I de Jonge
- Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6525GA, the Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, 6525GA, the Netherlands
| | - Everson Nogoceke
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, 4070, Switzerland
| | - Elod Koertvely
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, 4070, Switzerland
| | - Ilse Jongerius
- Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, 1066CX, the Netherlands; Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam University Medical Centre, Amsterdam, 1105 AZ, the Netherlands
| | - Taco W Kuijpers
- Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam University Medical Centre, Amsterdam, 1105 AZ, the Netherlands; Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, 1066CX, the Netherlands
| | - Anneke I den Hollander
- Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525EX, the Netherlands; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, 6525GA, the Netherlands.
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36
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Zografou C, Vakrakou AG, Stathopoulos P. Short- and Long-Lived Autoantibody-Secreting Cells in Autoimmune Neurological Disorders. Front Immunol 2021; 12:686466. [PMID: 34220839 PMCID: PMC8248361 DOI: 10.3389/fimmu.2021.686466] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 05/28/2021] [Indexed: 12/24/2022] Open
Abstract
As B cells differentiate into antibody-secreting cells (ASCs), short-lived plasmablasts (SLPBs) are produced by a primary extrafollicular response, followed by the generation of memory B cells and long-lived plasma cells (LLPCs) in germinal centers (GCs). Generation of IgG4 antibodies is T helper type 2 (Th2) and IL-4, -13, and -10-driven and can occur parallel to IgE, in response to chronic stimulation by allergens and helminths. Although IgG4 antibodies are non-crosslinking and have limited ability to mobilize complement and cellular cytotoxicity, when self-tolerance is lost, they can disrupt ligand-receptor binding and cause a wide range of autoimmune disorders including neurological autoimmunity. In myasthenia gravis with predominantly IgG4 autoantibodies against muscle-specific kinase (MuSK), it has been observed that one-time CD20+ B cell depletion with rituximab commonly leads to long-term remission and a marked reduction in autoantibody titer, pointing to a short-lived nature of autoantibody-secreting cells. This is also observed in other predominantly IgG4 autoantibody-mediated neurological disorders, such as chronic inflammatory demyelinating polyneuropathy and autoimmune encephalitis with autoantibodies against the Ranvier paranode and juxtaparanode, respectively, and extends beyond neurological autoimmunity as well. Although IgG1 autoantibody-mediated neurological disorders can also respond well to rituximab induction therapy in combination with an autoantibody titer drop, remission tends to be less long-lasting and cases where titers are refractory tend to occur more often than in IgG4 autoimmunity. Moreover, presence of GC-like structures in the thymus of myasthenic patients with predominantly IgG1 autoantibodies against the acetylcholine receptor and in ovarian teratomas of autoimmune encephalitis patients with predominantly IgG1 autoantibodies against the N‐methyl‐d‐aspartate receptor (NMDAR) confers increased the ability to generate LLPCs. Here, we review available information on the short-and long-lived nature of ASCs in IgG1 and IgG4 autoantibody-mediated neurological disorders and highlight common mechanisms as well as differences, all of which can inform therapeutic strategies and personalized medical approaches.
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Affiliation(s)
- C Zografou
- Institute of Neuropathology, University of Zurich, Zurich, Switzerland
| | - A G Vakrakou
- First Department of Neurology, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - P Stathopoulos
- First Department of Neurology, National and Kapodistrian University of Athens Medical School, Athens, Greece
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37
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Wraith DC, Krishna MT. Peptide allergen-specific immunotherapy for allergic airway diseases-State of the art. Clin Exp Allergy 2021; 51:751-769. [PMID: 33529435 DOI: 10.1111/cea.13840] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 01/24/2021] [Accepted: 01/28/2021] [Indexed: 12/13/2022]
Abstract
Allergen-specific immunotherapy (AIT) is the only means of altering the natural immunological course of allergic diseases and achieving long-term remission. Pharmacological measures are able to suppress the immune response and/or ameliorate the symptoms but there is a risk of relapse soon after these measures are withdrawn. Current AIT approaches depend on the administration of intact allergens, often comprising crude extracts of the allergen. We propose that the challenges arising from current approaches, including the risk of serious side-effects, burdensome duration of treatment, poor compliance and high cost, are overcome by application of peptides based on CD4+ T cell epitopes rather than whole allergens. Here we describe evolving approaches, summarize clinical trials involving peptide AIT in allergic rhinitis and asthma, discuss the putative mechanisms involved in their action, address gaps in evidence and propose future directions for research and clinical development.
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Affiliation(s)
- David C Wraith
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Mamidipudi T Krishna
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Department of Allergy and Immunology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
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38
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Muller YD, Nguyen DP, Ferreira LMR, Ho P, Raffin C, Valencia RVB, Congrave-Wilson Z, Roth TL, Eyquem J, Van Gool F, Marson A, Perez L, Wells JA, Bluestone JA, Tang Q. The CD28-Transmembrane Domain Mediates Chimeric Antigen Receptor Heterodimerization With CD28. Front Immunol 2021; 12:639818. [PMID: 33833759 PMCID: PMC8021955 DOI: 10.3389/fimmu.2021.639818] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 02/08/2021] [Indexed: 12/12/2022] Open
Abstract
Anti-CD19 chimeric antigen receptor (CD19-CAR)-engineered T cells are approved therapeutics for malignancies. The impact of the hinge domain (HD) and the transmembrane domain (TMD) between the extracellular antigen-targeting CARs and the intracellular signaling modalities of CARs has not been systemically studied. In this study, a series of 19-CARs differing only by their HD (CD8, CD28, or IgG4) and TMD (CD8 or CD28) was generated. CARs containing a CD28-TMD, but not a CD8-TMD, formed heterodimers with the endogenous CD28 in human T cells, as shown by co-immunoprecipitation and CAR-dependent proliferation of anti-CD28 stimulation. This dimerization was dependent on polar amino acids in the CD28-TMD and was more efficient with CARs containing CD28 or CD8 HD than IgG4-HD. The CD28-CAR heterodimers did not respond to CD80 and CD86 stimulation but had a significantly reduced CD28 cell-surface expression. These data unveiled a fundamental difference between CD28-TMD and CD8-TMD and indicated that CD28-TMD can modulate CAR T-cell activities by engaging endogenous partners.
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Affiliation(s)
- Yannick D Muller
- Department of Surgery, University of California, San Francisco, San Francisco, CA, United States.,Diabetes Center, University of California, San Francisco, San Francisco, CA, United States.,Department of Medicine, Service Immunologie et Allergie, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
| | - Duy P Nguyen
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, United States
| | - Leonardo M R Ferreira
- Department of Surgery, University of California, San Francisco, San Francisco, CA, United States.,Diabetes Center, University of California, San Francisco, San Francisco, CA, United States.,Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA, United States
| | - Patrick Ho
- Department of Surgery, University of California, San Francisco, San Francisco, CA, United States.,Diabetes Center, University of California, San Francisco, San Francisco, CA, United States.,Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA, United States
| | - Caroline Raffin
- Diabetes Center, University of California, San Francisco, San Francisco, CA, United States.,Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA, United States
| | | | - Zion Congrave-Wilson
- Department of Surgery, University of California, San Francisco, San Francisco, CA, United States
| | - Theodore L Roth
- Diabetes Center, University of California, San Francisco, San Francisco, CA, United States.,Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Justin Eyquem
- Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA, United States
| | - Frederic Van Gool
- Diabetes Center, University of California, San Francisco, San Francisco, CA, United States.,Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA, United States
| | - Alexander Marson
- Diabetes Center, University of California, San Francisco, San Francisco, CA, United States.,Department of Medicine, University of California, San Francisco, San Francisco, CA, United States.,Gladstone-UCSF Institute of Genomic Immunology, Gladstone Institutes, San Francisco, CA, United States
| | - Laurent Perez
- Department of Medicine, Service Immunologie et Allergie, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
| | - James A Wells
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, United States.,Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, United States
| | - Jeffrey A Bluestone
- Diabetes Center, University of California, San Francisco, San Francisco, CA, United States.,Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA, United States
| | - Qizhi Tang
- Department of Surgery, University of California, San Francisco, San Francisco, CA, United States.,Diabetes Center, University of California, San Francisco, San Francisco, CA, United States
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39
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Nkurunungi G, Nassuuna J, Mpairwe H, Kabagenyi J, Nampijja M, Sanya RE, Webb EL, Elliott AM. Allergen skin test reactivity and asthma are inversely associated with ratios of IgG4/IgE and total IgE/allergen-specific IgE in Ugandan communities. Clin Exp Allergy 2021; 51:703-715. [PMID: 33512036 PMCID: PMC7610822 DOI: 10.1111/cea.13834] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 11/12/2020] [Accepted: 01/22/2021] [Indexed: 11/28/2022]
Abstract
Background Serum inhibition of allergen‐specific IgE has been associated with competing IgG4 and non‐specific polyclonal IgE. In allergen immunotherapy, beneficial responses have been associated with high IgG4/IgE ratios. Helminths potentiate antibody class switching to IgG4 and stimulate polyclonal IgE synthesis; therefore, we hypothesized a role for helminth‐associated IgG4 and total IgE in protection against atopic sensitization and clinical allergy (asthma) in tropical low‐income countries. Methods Among community residents of Ugandan rural Schistosoma mansoni (Sm)–endemic islands and a mainland urban setting with lower helminth exposure, and among urban asthmatic schoolchildren and non‐asthmatic controls, we measured total, Schistosoma adult worm antigen (SWA)–specific, Schistosoma egg antigen (SEA)–specific and allergen (house dust mite [HDM] and German cockroach)–specific IgE and IgG4 by ImmunoCAP® and/or ELISA. We assessed associations between these antibody profiles and current Sm infection, the rural‐urban environment, HDM and cockroach skin prick test (SPT) reactivity, and asthma. Results Total IgE, total IgG4 and SWA‐, SEA‐ and allergen‐specific IgE and IgG4 levels were significantly higher in the rural, compared to the urban setting. In both community settings, both Sm infection and SPT reactivity were positively associated with allergen‐specific and total IgE responses. SPT reactivity was inversely associated with Schistosoma‐specific IgG4, allergen‐specific IgG4/IgE ratios and total IgE/allergen‐specific IgE ratios. Asthmatic schoolchildren, compared with non‐asthmatic controls, had significantly higher levels of total and allergen‐specific IgE, but lower ratios of allergen‐specific IgG4/IgE and total IgE/allergen‐specific IgE. Conclusions and clinical relevance Our immuno‐epidemiological data support the hypothesis that the IgG4–IgE balance and the total IgE–allergen‐specific IgE balance are more important than absolute total, helminth‐ or allergen‐specific antibody levels in inhibition of allergies in the tropics.
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Affiliation(s)
- Gyaviira Nkurunungi
- Immunomodulation and Vaccines Programme, Medical Research Council / Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine (MRC/UVRI and LSHTM) Uganda Research Unit, Entebbe, Uganda
| | - Jacent Nassuuna
- Immunomodulation and Vaccines Programme, Medical Research Council / Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine (MRC/UVRI and LSHTM) Uganda Research Unit, Entebbe, Uganda
| | - Harriet Mpairwe
- Immunomodulation and Vaccines Programme, Medical Research Council / Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine (MRC/UVRI and LSHTM) Uganda Research Unit, Entebbe, Uganda.,Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - Joyce Kabagenyi
- Immunomodulation and Vaccines Programme, Medical Research Council / Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine (MRC/UVRI and LSHTM) Uganda Research Unit, Entebbe, Uganda
| | - Margaret Nampijja
- Immunomodulation and Vaccines Programme, Medical Research Council / Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine (MRC/UVRI and LSHTM) Uganda Research Unit, Entebbe, Uganda
| | - Richard E Sanya
- Immunomodulation and Vaccines Programme, Medical Research Council / Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine (MRC/UVRI and LSHTM) Uganda Research Unit, Entebbe, Uganda.,College of Health Sciences, Makerere University, Kampala, Uganda
| | - Emily L Webb
- MRC Tropical Epidemiology Group, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - Alison M Elliott
- Immunomodulation and Vaccines Programme, Medical Research Council / Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine (MRC/UVRI and LSHTM) Uganda Research Unit, Entebbe, Uganda.,Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK
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40
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Lee J, Kim DE, Yang JH, Lim M, Yum HY, Kim J. Salivary and lacrimal gland enlargement with serum immunoglobulin G4 elevation. Clin Exp Pediatr 2021; 64:93-95. [PMID: 33332953 PMCID: PMC7873388 DOI: 10.3345/cep.2020.01319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 10/21/2020] [Indexed: 11/27/2022] Open
Affiliation(s)
- Jinseok Lee
- Department of Pediatrics, Seoul Medical Center, Seoul, Korea
| | - Da-Eun Kim
- Department of Pediatrics, Seoul Medical Center, Seoul, Korea
| | - Jeong-Hwan Yang
- Department of Pediatrics, Seoul Medical Center, Seoul, Korea
| | - Misun Lim
- Department of Pediatrics, Seoul Medical Center, Seoul, Korea
| | - Hye Yung Yum
- Department of Pediatrics, Seoul Medical Center, Seoul, Korea
| | - JoongGon Kim
- Department of Pediatrics, Seoul Medical Center, Seoul, Korea
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41
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Willsmore ZN, Harris RJ, Crescioli S, Hussein K, Kakkassery H, Thapa D, Cheung A, Chauhan J, Bax HJ, Chenoweth A, Laddach R, Osborn G, McCraw A, Hoffmann RM, Nakamura M, Geh JL, MacKenzie-Ross A, Healy C, Tsoka S, Spicer JF, Papa S, Barber L, Lacy KE, Karagiannis SN. B Cells in Patients With Melanoma: Implications for Treatment With Checkpoint Inhibitor Antibodies. Front Immunol 2021; 11:622442. [PMID: 33569063 PMCID: PMC7868381 DOI: 10.3389/fimmu.2020.622442] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 12/04/2020] [Indexed: 12/12/2022] Open
Abstract
The contributions of the humoral immune response to melanoma are now widely recognized, with reports of positive prognostic value ascribed to tumor-infiltrating B cells (TIL-B) and increasing evidence of B cells as key predictors of patient response to treatment. There are disparate views as to the pro- and anti-tumor roles of B cells. B cells appear to play an integral role in forming tumor-associated tertiary lymphoid structures (TLSs) which can further modulate T cell activation. Expressed antibodies may distinctly influence tumor regulation in the tumor microenvironment, with some isotypes associated with strong anti-tumor immune response and others with progressive disease. Recently, B cells have been evaluated in the context of cancer immunotherapy. Checkpoint inhibitors (CPIs), targeting T cell effector functions, have revolutionized the management of melanoma for many patients; however, there remains a need to accurately predict treatment responders. Increasing evidence suggests that B cells may not be simple bystanders to CPI immunotherapy. Mature and differentiated B cell phenotypes are key positive correlates of CPI response. Recent evidence also points to an enrichment in activatory B cell phenotypes, and the contribution of B cells to TLS formation may facilitate induction of T cell phenotypes required for response to CPI. Contrastingly, specific B cell subsets often correlate with immune-related adverse events (irAEs) in CPI. With increased appreciation of the multifaceted role of B cell immunity, novel therapeutic strategies and biomarkers can be explored and translated into the clinic to optimize CPI immunotherapy in melanoma.
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Affiliation(s)
- Zena N Willsmore
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, Tower Wing, Guy's Hospital, London, United Kingdom
| | - Robert J Harris
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, Tower Wing, Guy's Hospital, London, United Kingdom
| | - Silvia Crescioli
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, Tower Wing, Guy's Hospital, London, United Kingdom
| | - Khuluud Hussein
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, Tower Wing, Guy's Hospital, London, United Kingdom
| | - Helen Kakkassery
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, Tower Wing, Guy's Hospital, London, United Kingdom
| | - Deepika Thapa
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, Tower Wing, Guy's Hospital, London, United Kingdom
| | - Anthony Cheung
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, Tower Wing, Guy's Hospital, London, United Kingdom.,Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Cancer Centre, London, United Kingdom
| | - Jitesh Chauhan
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, Tower Wing, Guy's Hospital, London, United Kingdom
| | - Heather J Bax
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, Tower Wing, Guy's Hospital, London, United Kingdom.,School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Hospital, London, United Kingdom
| | - Alicia Chenoweth
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, Tower Wing, Guy's Hospital, London, United Kingdom.,Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Cancer Centre, London, United Kingdom
| | - Roman Laddach
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, Tower Wing, Guy's Hospital, London, United Kingdom.,Department of Informatics, Faculty of Natural and Mathematical Sciences, King's College London, London, United Kingdom
| | - Gabriel Osborn
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, Tower Wing, Guy's Hospital, London, United Kingdom
| | - Alexa McCraw
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, Tower Wing, Guy's Hospital, London, United Kingdom
| | - Ricarda M Hoffmann
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, Tower Wing, Guy's Hospital, London, United Kingdom
| | - Mano Nakamura
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, Tower Wing, Guy's Hospital, London, United Kingdom
| | - Jenny L Geh
- Department of Plastic Surgery at Guy's, King's, and St. Thomas' Hospitals, London, United Kingdom
| | - Alastair MacKenzie-Ross
- Department of Plastic Surgery at Guy's, King's, and St. Thomas' Hospitals, London, United Kingdom
| | - Ciaran Healy
- Department of Plastic Surgery at Guy's, King's, and St. Thomas' Hospitals, London, United Kingdom
| | - Sophia Tsoka
- Department of Informatics, Faculty of Natural and Mathematical Sciences, King's College London, London, United Kingdom
| | - James F Spicer
- School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Hospital, London, United Kingdom
| | - Sophie Papa
- Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.,ImmunoEngineering, School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Linda Barber
- School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Hospital, London, United Kingdom
| | - Katie E Lacy
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, Tower Wing, Guy's Hospital, London, United Kingdom
| | - Sophia N Karagiannis
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, Tower Wing, Guy's Hospital, London, United Kingdom.,Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Cancer Centre, London, United Kingdom
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Ghosh D, Bernstein JA. Health Effects of Trimellitic Anhydride Occupational Exposure: Insights from Animal Models and Immunosurveillance Programs. Clin Rev Allergy Immunol 2021; 59:61-77. [PMID: 32594360 DOI: 10.1007/s12016-020-08801-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Acid anhydrides are used by chemical industries as plasticizers. Trimellitic acid (TMA) is an acid anhydride widely utilized in factories to produce paints, varnishes, and plastics. In addition to causing direct irritant effects, TMA can augment antibody responses in exposed factory workers leading to occupational asthma. Therefore, industries producing TMA have implemented occupational immunosurveillance programs (OISPs) to ensure early diagnosis and medical management, involving exposure reduction/ complete removal of sensitized workers from exposure areas. Multiple animal models (mice strains, rat stains, guinea pig, swine) with different exposure patterns (dermal, nasal, vapor inhalation exposures for different time frames) have been described to elucidate the pathophysiology of TMA exposure. In TMA factories, in spite of implementing advanced environmental controls and personal protective measures to limit exposure, workers become TMA-sensitized. Animal models revealed sIgG, sIgE, sIgA, and sIgM along with pulmonary lesions, cellular infiltrates, alveolar hemorrhage, and pneumonitis associated with TMA exposure. Molecular studies showed involvement of specific functional gene clusters related to cytokine and chemokine responses, lung remodeling, and arginase function. However, thus far, there is no evidence supporting fetotoxic or carcinogenic effects of TMA. OISP data showed IgG and IgE responses in exposed factory workers. Interestingly, timelines for detectable sIgG response, in conjunction with its magnitude, have been shown to be a predictor for future sIgE response. OISPs have been very successful so far at creating a healthy and safe working environment for TMA-exposed factory workers. Graphical Abstract Trimellitic Acid (TMA), used to produce paints, varnishes and plastics, can cause irritant-mediated and immune-mediated occupational health problems. NCBI pubmed search indicated that multiple animal models (different animal types, with chronic vs. acute exposure type, using TMA dust/suspension applied via dermal or other routes) have been used by investigators to elucidate the pathobiology of TMA-exposure. Several outcomes have been measured including humoral, lung/ airway, lymph nodes and dermal/ ear thickening responses. Studies on human subjects have been conducted mostly as parts of Occupational immunosurveillance programs (OISPs) implemented to identify TMA-sensitized workers (using ImmunoCAP and Skin prick testing), monitoring them longitudinally and their medical management including exposure reduction/ complete removal of sensitized workers from exposure areas. Clinical management also includes identification of irritant-induced and/ or immune-mediated outcomes of TMA occupational exposure. Collectively, these studies have led to important insights into the pathomechanism of TMA-exposure and have been very successful at creating a safe working environment for TMA-exposed factory workers.
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Affiliation(s)
- Debajyoti Ghosh
- Division of Immunology, Allergy Section, Department of Internal Medicine, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, 45267, USA
| | - Jonathan A Bernstein
- Division of Immunology, Allergy Section, Department of Internal Medicine, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, 45267, USA.
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Landa J, Guasp M, Petit-Pedrol M, Martínez-Hernández E, Planagumà J, Saiz A, Ruiz-García R, García-Fernández L, Verschuuren J, Saunders-Pullman R, Ramirez-Gómez L, Geschwind MD, Dalmau J, Sabater L, Graus F. Seizure-related 6 homolog like 2 autoimmunity: Neurologic syndrome and antibody effects. NEUROLOGY(R) NEUROIMMUNOLOGY & NEUROINFLAMMATION 2021; 8:e916. [PMID: 33144342 PMCID: PMC7641326 DOI: 10.1212/nxi.0000000000000916] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 09/21/2020] [Indexed: 12/03/2022]
Abstract
OBJECTIVE To describe the clinical syndrome of 4 new patients with seizure-related 6 homolog like 2 antibodies (SEZ6L2-abs), study the antibody characteristics, and evaluate their effects on neuronal cultures. METHODS SEZ6L2-abs were initially identified in serum and CSF of a patient with cerebellar ataxia by immunohistochemistry on rat brain sections and immunoprecipitation from rat cerebellar neurons. We used a cell-based assay (CBA) of HEK293 cells transfected with SEZ6L2 to test the serum of 95 patients with unclassified neuropil antibodies, 331 with different neurologic disorders, and 10 healthy subjects. Additional studies included characterization of immunoglobulin G (IgG) subclasses and the effects of SEZ6L2-abs on cultures of rat hippocampal neurons. RESULTS In addition to the index patient, SEZ6L2-abs were identified by CBA in 3/95 patients with unclassified neuropil antibodies but in none of the 341 controls. The median age of the 4 patients was 62 years (range: 54-69 years), and 2 were female. Patients presented with subacute gait ataxia, dysarthria, and mild extrapyramidal symptoms. Initial brain MRI was normal, and CSF pleocytosis was found in only 1 patient. None improved with immunotherapy. SEZ6L2-abs recognized conformational epitopes. IgG4 SEZ6L2-abs were found in all 4 patients, and it was the predominant subclass in 2. SEZ6L2-abs did not alter the number of total or synaptic SEZ6L2 or the AMPA glutamate receptor 1 (GluA1) clusters on the surface of hippocampal neurons. CONCLUSIONS SEZ6L2-abs associate with a subacute cerebellar syndrome with frequent extrapyramidal symptoms. The potential pathogenic effect of the antibodies is not mediated by internalization of the antigen.
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Affiliation(s)
- Jon Landa
- From the Neuroimmunology Program (J.L., M.G., M.P.-P., E.M.-H., J.P., A.S., J.D., L.S., F.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Service of Neurology (M.G., E.M.-H., A.S., J.D.), Hospital Clinic, Barcelona; Centro de Investigación Biomédica en Red (M.G., J.D., L.S.), Enfermedades Raras (CIBERER); Immunology Department (R.R.-G.), Centre Diagnòstic Biomèdic, Hospital Clinic, Barcelona; Neurology Department (L.G.-F.), Hospital General San Jorge, Huesca, Spain; Leiden University Medical Center (J.V.), Leiden, The Netherlands; Icahn School of Medicine (R.S.-P.), Mount Sinai Beth Israel, New York; Massachussetts General Hospital (L.R.-G.), Department of Neurology, Boston; UCSF Department of Neurology Memory and Aging Center (M.D.G.), San Francisco, CA; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; and Dr. Petit-Pedrol is now with Interdisciplinary Institute for Neuroscience, UMR 5297, Université de Bordeaux, Bordeaux, France
| | - Mar Guasp
- From the Neuroimmunology Program (J.L., M.G., M.P.-P., E.M.-H., J.P., A.S., J.D., L.S., F.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Service of Neurology (M.G., E.M.-H., A.S., J.D.), Hospital Clinic, Barcelona; Centro de Investigación Biomédica en Red (M.G., J.D., L.S.), Enfermedades Raras (CIBERER); Immunology Department (R.R.-G.), Centre Diagnòstic Biomèdic, Hospital Clinic, Barcelona; Neurology Department (L.G.-F.), Hospital General San Jorge, Huesca, Spain; Leiden University Medical Center (J.V.), Leiden, The Netherlands; Icahn School of Medicine (R.S.-P.), Mount Sinai Beth Israel, New York; Massachussetts General Hospital (L.R.-G.), Department of Neurology, Boston; UCSF Department of Neurology Memory and Aging Center (M.D.G.), San Francisco, CA; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; and Dr. Petit-Pedrol is now with Interdisciplinary Institute for Neuroscience, UMR 5297, Université de Bordeaux, Bordeaux, France
| | - Mar Petit-Pedrol
- From the Neuroimmunology Program (J.L., M.G., M.P.-P., E.M.-H., J.P., A.S., J.D., L.S., F.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Service of Neurology (M.G., E.M.-H., A.S., J.D.), Hospital Clinic, Barcelona; Centro de Investigación Biomédica en Red (M.G., J.D., L.S.), Enfermedades Raras (CIBERER); Immunology Department (R.R.-G.), Centre Diagnòstic Biomèdic, Hospital Clinic, Barcelona; Neurology Department (L.G.-F.), Hospital General San Jorge, Huesca, Spain; Leiden University Medical Center (J.V.), Leiden, The Netherlands; Icahn School of Medicine (R.S.-P.), Mount Sinai Beth Israel, New York; Massachussetts General Hospital (L.R.-G.), Department of Neurology, Boston; UCSF Department of Neurology Memory and Aging Center (M.D.G.), San Francisco, CA; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; and Dr. Petit-Pedrol is now with Interdisciplinary Institute for Neuroscience, UMR 5297, Université de Bordeaux, Bordeaux, France
| | - Eugenia Martínez-Hernández
- From the Neuroimmunology Program (J.L., M.G., M.P.-P., E.M.-H., J.P., A.S., J.D., L.S., F.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Service of Neurology (M.G., E.M.-H., A.S., J.D.), Hospital Clinic, Barcelona; Centro de Investigación Biomédica en Red (M.G., J.D., L.S.), Enfermedades Raras (CIBERER); Immunology Department (R.R.-G.), Centre Diagnòstic Biomèdic, Hospital Clinic, Barcelona; Neurology Department (L.G.-F.), Hospital General San Jorge, Huesca, Spain; Leiden University Medical Center (J.V.), Leiden, The Netherlands; Icahn School of Medicine (R.S.-P.), Mount Sinai Beth Israel, New York; Massachussetts General Hospital (L.R.-G.), Department of Neurology, Boston; UCSF Department of Neurology Memory and Aging Center (M.D.G.), San Francisco, CA; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; and Dr. Petit-Pedrol is now with Interdisciplinary Institute for Neuroscience, UMR 5297, Université de Bordeaux, Bordeaux, France
| | - Jesús Planagumà
- From the Neuroimmunology Program (J.L., M.G., M.P.-P., E.M.-H., J.P., A.S., J.D., L.S., F.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Service of Neurology (M.G., E.M.-H., A.S., J.D.), Hospital Clinic, Barcelona; Centro de Investigación Biomédica en Red (M.G., J.D., L.S.), Enfermedades Raras (CIBERER); Immunology Department (R.R.-G.), Centre Diagnòstic Biomèdic, Hospital Clinic, Barcelona; Neurology Department (L.G.-F.), Hospital General San Jorge, Huesca, Spain; Leiden University Medical Center (J.V.), Leiden, The Netherlands; Icahn School of Medicine (R.S.-P.), Mount Sinai Beth Israel, New York; Massachussetts General Hospital (L.R.-G.), Department of Neurology, Boston; UCSF Department of Neurology Memory and Aging Center (M.D.G.), San Francisco, CA; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; and Dr. Petit-Pedrol is now with Interdisciplinary Institute for Neuroscience, UMR 5297, Université de Bordeaux, Bordeaux, France
| | - Albert Saiz
- From the Neuroimmunology Program (J.L., M.G., M.P.-P., E.M.-H., J.P., A.S., J.D., L.S., F.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Service of Neurology (M.G., E.M.-H., A.S., J.D.), Hospital Clinic, Barcelona; Centro de Investigación Biomédica en Red (M.G., J.D., L.S.), Enfermedades Raras (CIBERER); Immunology Department (R.R.-G.), Centre Diagnòstic Biomèdic, Hospital Clinic, Barcelona; Neurology Department (L.G.-F.), Hospital General San Jorge, Huesca, Spain; Leiden University Medical Center (J.V.), Leiden, The Netherlands; Icahn School of Medicine (R.S.-P.), Mount Sinai Beth Israel, New York; Massachussetts General Hospital (L.R.-G.), Department of Neurology, Boston; UCSF Department of Neurology Memory and Aging Center (M.D.G.), San Francisco, CA; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; and Dr. Petit-Pedrol is now with Interdisciplinary Institute for Neuroscience, UMR 5297, Université de Bordeaux, Bordeaux, France
| | - Raquel Ruiz-García
- From the Neuroimmunology Program (J.L., M.G., M.P.-P., E.M.-H., J.P., A.S., J.D., L.S., F.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Service of Neurology (M.G., E.M.-H., A.S., J.D.), Hospital Clinic, Barcelona; Centro de Investigación Biomédica en Red (M.G., J.D., L.S.), Enfermedades Raras (CIBERER); Immunology Department (R.R.-G.), Centre Diagnòstic Biomèdic, Hospital Clinic, Barcelona; Neurology Department (L.G.-F.), Hospital General San Jorge, Huesca, Spain; Leiden University Medical Center (J.V.), Leiden, The Netherlands; Icahn School of Medicine (R.S.-P.), Mount Sinai Beth Israel, New York; Massachussetts General Hospital (L.R.-G.), Department of Neurology, Boston; UCSF Department of Neurology Memory and Aging Center (M.D.G.), San Francisco, CA; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; and Dr. Petit-Pedrol is now with Interdisciplinary Institute for Neuroscience, UMR 5297, Université de Bordeaux, Bordeaux, France
| | - Lorena García-Fernández
- From the Neuroimmunology Program (J.L., M.G., M.P.-P., E.M.-H., J.P., A.S., J.D., L.S., F.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Service of Neurology (M.G., E.M.-H., A.S., J.D.), Hospital Clinic, Barcelona; Centro de Investigación Biomédica en Red (M.G., J.D., L.S.), Enfermedades Raras (CIBERER); Immunology Department (R.R.-G.), Centre Diagnòstic Biomèdic, Hospital Clinic, Barcelona; Neurology Department (L.G.-F.), Hospital General San Jorge, Huesca, Spain; Leiden University Medical Center (J.V.), Leiden, The Netherlands; Icahn School of Medicine (R.S.-P.), Mount Sinai Beth Israel, New York; Massachussetts General Hospital (L.R.-G.), Department of Neurology, Boston; UCSF Department of Neurology Memory and Aging Center (M.D.G.), San Francisco, CA; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; and Dr. Petit-Pedrol is now with Interdisciplinary Institute for Neuroscience, UMR 5297, Université de Bordeaux, Bordeaux, France
| | - Jan Verschuuren
- From the Neuroimmunology Program (J.L., M.G., M.P.-P., E.M.-H., J.P., A.S., J.D., L.S., F.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Service of Neurology (M.G., E.M.-H., A.S., J.D.), Hospital Clinic, Barcelona; Centro de Investigación Biomédica en Red (M.G., J.D., L.S.), Enfermedades Raras (CIBERER); Immunology Department (R.R.-G.), Centre Diagnòstic Biomèdic, Hospital Clinic, Barcelona; Neurology Department (L.G.-F.), Hospital General San Jorge, Huesca, Spain; Leiden University Medical Center (J.V.), Leiden, The Netherlands; Icahn School of Medicine (R.S.-P.), Mount Sinai Beth Israel, New York; Massachussetts General Hospital (L.R.-G.), Department of Neurology, Boston; UCSF Department of Neurology Memory and Aging Center (M.D.G.), San Francisco, CA; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; and Dr. Petit-Pedrol is now with Interdisciplinary Institute for Neuroscience, UMR 5297, Université de Bordeaux, Bordeaux, France
| | - Rachel Saunders-Pullman
- From the Neuroimmunology Program (J.L., M.G., M.P.-P., E.M.-H., J.P., A.S., J.D., L.S., F.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Service of Neurology (M.G., E.M.-H., A.S., J.D.), Hospital Clinic, Barcelona; Centro de Investigación Biomédica en Red (M.G., J.D., L.S.), Enfermedades Raras (CIBERER); Immunology Department (R.R.-G.), Centre Diagnòstic Biomèdic, Hospital Clinic, Barcelona; Neurology Department (L.G.-F.), Hospital General San Jorge, Huesca, Spain; Leiden University Medical Center (J.V.), Leiden, The Netherlands; Icahn School of Medicine (R.S.-P.), Mount Sinai Beth Israel, New York; Massachussetts General Hospital (L.R.-G.), Department of Neurology, Boston; UCSF Department of Neurology Memory and Aging Center (M.D.G.), San Francisco, CA; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; and Dr. Petit-Pedrol is now with Interdisciplinary Institute for Neuroscience, UMR 5297, Université de Bordeaux, Bordeaux, France
| | - Liliana Ramirez-Gómez
- From the Neuroimmunology Program (J.L., M.G., M.P.-P., E.M.-H., J.P., A.S., J.D., L.S., F.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Service of Neurology (M.G., E.M.-H., A.S., J.D.), Hospital Clinic, Barcelona; Centro de Investigación Biomédica en Red (M.G., J.D., L.S.), Enfermedades Raras (CIBERER); Immunology Department (R.R.-G.), Centre Diagnòstic Biomèdic, Hospital Clinic, Barcelona; Neurology Department (L.G.-F.), Hospital General San Jorge, Huesca, Spain; Leiden University Medical Center (J.V.), Leiden, The Netherlands; Icahn School of Medicine (R.S.-P.), Mount Sinai Beth Israel, New York; Massachussetts General Hospital (L.R.-G.), Department of Neurology, Boston; UCSF Department of Neurology Memory and Aging Center (M.D.G.), San Francisco, CA; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; and Dr. Petit-Pedrol is now with Interdisciplinary Institute for Neuroscience, UMR 5297, Université de Bordeaux, Bordeaux, France
| | - Michael D Geschwind
- From the Neuroimmunology Program (J.L., M.G., M.P.-P., E.M.-H., J.P., A.S., J.D., L.S., F.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Service of Neurology (M.G., E.M.-H., A.S., J.D.), Hospital Clinic, Barcelona; Centro de Investigación Biomédica en Red (M.G., J.D., L.S.), Enfermedades Raras (CIBERER); Immunology Department (R.R.-G.), Centre Diagnòstic Biomèdic, Hospital Clinic, Barcelona; Neurology Department (L.G.-F.), Hospital General San Jorge, Huesca, Spain; Leiden University Medical Center (J.V.), Leiden, The Netherlands; Icahn School of Medicine (R.S.-P.), Mount Sinai Beth Israel, New York; Massachussetts General Hospital (L.R.-G.), Department of Neurology, Boston; UCSF Department of Neurology Memory and Aging Center (M.D.G.), San Francisco, CA; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; and Dr. Petit-Pedrol is now with Interdisciplinary Institute for Neuroscience, UMR 5297, Université de Bordeaux, Bordeaux, France
| | - Josep Dalmau
- From the Neuroimmunology Program (J.L., M.G., M.P.-P., E.M.-H., J.P., A.S., J.D., L.S., F.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Service of Neurology (M.G., E.M.-H., A.S., J.D.), Hospital Clinic, Barcelona; Centro de Investigación Biomédica en Red (M.G., J.D., L.S.), Enfermedades Raras (CIBERER); Immunology Department (R.R.-G.), Centre Diagnòstic Biomèdic, Hospital Clinic, Barcelona; Neurology Department (L.G.-F.), Hospital General San Jorge, Huesca, Spain; Leiden University Medical Center (J.V.), Leiden, The Netherlands; Icahn School of Medicine (R.S.-P.), Mount Sinai Beth Israel, New York; Massachussetts General Hospital (L.R.-G.), Department of Neurology, Boston; UCSF Department of Neurology Memory and Aging Center (M.D.G.), San Francisco, CA; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; and Dr. Petit-Pedrol is now with Interdisciplinary Institute for Neuroscience, UMR 5297, Université de Bordeaux, Bordeaux, France
| | - Lidia Sabater
- From the Neuroimmunology Program (J.L., M.G., M.P.-P., E.M.-H., J.P., A.S., J.D., L.S., F.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Service of Neurology (M.G., E.M.-H., A.S., J.D.), Hospital Clinic, Barcelona; Centro de Investigación Biomédica en Red (M.G., J.D., L.S.), Enfermedades Raras (CIBERER); Immunology Department (R.R.-G.), Centre Diagnòstic Biomèdic, Hospital Clinic, Barcelona; Neurology Department (L.G.-F.), Hospital General San Jorge, Huesca, Spain; Leiden University Medical Center (J.V.), Leiden, The Netherlands; Icahn School of Medicine (R.S.-P.), Mount Sinai Beth Israel, New York; Massachussetts General Hospital (L.R.-G.), Department of Neurology, Boston; UCSF Department of Neurology Memory and Aging Center (M.D.G.), San Francisco, CA; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; and Dr. Petit-Pedrol is now with Interdisciplinary Institute for Neuroscience, UMR 5297, Université de Bordeaux, Bordeaux, France
| | - Francesc Graus
- From the Neuroimmunology Program (J.L., M.G., M.P.-P., E.M.-H., J.P., A.S., J.D., L.S., F.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Service of Neurology (M.G., E.M.-H., A.S., J.D.), Hospital Clinic, Barcelona; Centro de Investigación Biomédica en Red (M.G., J.D., L.S.), Enfermedades Raras (CIBERER); Immunology Department (R.R.-G.), Centre Diagnòstic Biomèdic, Hospital Clinic, Barcelona; Neurology Department (L.G.-F.), Hospital General San Jorge, Huesca, Spain; Leiden University Medical Center (J.V.), Leiden, The Netherlands; Icahn School of Medicine (R.S.-P.), Mount Sinai Beth Israel, New York; Massachussetts General Hospital (L.R.-G.), Department of Neurology, Boston; UCSF Department of Neurology Memory and Aging Center (M.D.G.), San Francisco, CA; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; and Dr. Petit-Pedrol is now with Interdisciplinary Institute for Neuroscience, UMR 5297, Université de Bordeaux, Bordeaux, France.
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Krajewski D, Polukort SH, Gelzinis J, Rovatti J, Kaczenski E, Galinski C, Pantos M, Shah NN, Schneider SS, Kennedy DR, Mathias CB. Protein Disulfide Isomerases Regulate IgE-Mediated Mast Cell Responses and Their Inhibition Confers Protective Effects During Food Allergy. Front Immunol 2020; 11:606837. [PMID: 33414789 PMCID: PMC7783394 DOI: 10.3389/fimmu.2020.606837] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 11/17/2020] [Indexed: 12/15/2022] Open
Abstract
The thiol isomerase, protein disulfide isomerase (PDI), plays important intracellular roles during protein folding, maintaining cellular function and viability. Recent studies suggest novel roles for extracellular cell surface PDI in enhancing cellular activation and promoting their function. Moreover, a number of food-derived substances have been shown to regulate cellular PDI activity and alter disease progression. We hypothesized that PDI may have similar roles during mast cell-mediated allergic responses and examined its effects on IgE-induced mast cell activity during cell culture and food allergy. Mast cells were activated via IgE and antigen and the effects of PDI inhibition on mast cell activation were assessed. The effects of PDI blockade in vivo were examined by treating mice with the irreversible PDI inhibitor, PACMA-31, in an ovalbumin-induced model of food allergy. The role of dietary PDI modulators was investigated using various dietary compounds including curcumin and quercetin-3-rutinoside (rutin). PDI expression was observed on resting mast cell surfaces, intracellularly, and in the intestines of allergic mice. Furthermore, enhanced secretion of extracellular PDI was observed on mast cell membranes during IgE and antigen activation. Insulin turbidimetric assays demonstrated that curcumin is a potent PDI inhibitor and pre-treatment of mast cells with curcumin or established PDI inhibitors such as bacitracin, rutin or PACMA-31, resulted in the suppression of IgE-mediated activation and the secretion of various cytokines. This was accompanied by decreased mast cell proliferation, FcεRI expression, and mast cell degranulation. Similarly, treatment of allergic BALB/c mice with PACMA-31 attenuated the development of food allergy resulting in decreased allergic diarrhea, mast cell activation, and fewer intestinal mast cells. The production of TH2-specific cytokines was also suppressed. Our observations suggest that PDI catalytic activity is essential in the regulation of mast cell activation, and that its blockade may benefit patients with allergic inflammation.
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Affiliation(s)
- Dylan Krajewski
- Department of Pharmaceutical and Administrative Sciences, College of Pharmacy and Health Sciences, Western New England University, Springfield, MA, United States
| | - Stephanie H. Polukort
- Department of Pharmaceutical and Administrative Sciences, College of Pharmacy and Health Sciences, Western New England University, Springfield, MA, United States
| | - Justine Gelzinis
- Department of Pharmaceutical and Administrative Sciences, College of Pharmacy and Health Sciences, Western New England University, Springfield, MA, United States
| | - Jeffrey Rovatti
- Department of Pharmaceutical and Administrative Sciences, College of Pharmacy and Health Sciences, Western New England University, Springfield, MA, United States
| | - Edwin Kaczenski
- Department of Pharmaceutical and Administrative Sciences, College of Pharmacy and Health Sciences, Western New England University, Springfield, MA, United States
| | - Christine Galinski
- Department of Pharmaceutical and Administrative Sciences, College of Pharmacy and Health Sciences, Western New England University, Springfield, MA, United States
| | - Megan Pantos
- Department of Pharmaceutical and Administrative Sciences, College of Pharmacy and Health Sciences, Western New England University, Springfield, MA, United States
| | - Nickul N. Shah
- Pioneer Valley Life Sciences Institute, Baystate Medical Center, Springfield, MA, United States
- Department of Veterinary and Animal Sciences, University of Massachusetts at Amherst, Amherst, MA, United States
| | - Sallie S. Schneider
- Pioneer Valley Life Sciences Institute, Baystate Medical Center, Springfield, MA, United States
- Department of Veterinary and Animal Sciences, University of Massachusetts at Amherst, Amherst, MA, United States
| | - Daniel R. Kennedy
- Department of Pharmaceutical and Administrative Sciences, College of Pharmacy and Health Sciences, Western New England University, Springfield, MA, United States
| | - Clinton B. Mathias
- Department of Pharmaceutical and Administrative Sciences, College of Pharmacy and Health Sciences, Western New England University, Springfield, MA, United States
- Department of Veterinary and Animal Sciences, University of Massachusetts at Amherst, Amherst, MA, United States
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Floreani A, Okazaki K, Uchida K, Gershwin ME. IgG4-related disease: Changing epidemiology and new thoughts on a multisystem disease. J Transl Autoimmun 2020; 4:100074. [PMID: 33490938 PMCID: PMC7806798 DOI: 10.1016/j.jtauto.2020.100074] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 11/19/2020] [Accepted: 12/10/2020] [Indexed: 02/07/2023] Open
Abstract
IgG4-related disease (IgG4-RD) represents an immune-mediated fibroinflammatory condition with peculiar histopathologic changes that can affect various organs. In 2012 its unified nomenclature was published, which allows to abandon other synonymous names. Up to now, only little is known about its epidemiology around the world. However, although it is generally considered a rare condition, the number of patients with IgG4-RD is increasing enormously. Likewise, the annual number of publications on this subject has increased progressively. The spectrum of clinical manifestations in IgG4-RD is highly variable, depending on the severity of the disease as well as the presence of organ(s) involvement. This review gives an overview on changing epidemiology of IgG4-RD focusing the attention on the large cohorts of patients published in the literature.
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Affiliation(s)
- Annarosa Floreani
- Scientific Consultant IRCCS Negrar, Verona, Italy
- Senior Scholar, University of Padova, Italy
| | - Kazuichi Okazaki
- Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan
| | - Kazushige Uchida
- Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan
| | - M. Eric Gershwin
- Division of Rheumatology Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, USA
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Kanagaratham C, El Ansari YS, Lewis OL, Oettgen HC. IgE and IgG Antibodies as Regulators of Mast Cell and Basophil Functions in Food Allergy. Front Immunol 2020; 11:603050. [PMID: 33362785 PMCID: PMC7759531 DOI: 10.3389/fimmu.2020.603050] [Citation(s) in RCA: 114] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 10/22/2020] [Indexed: 12/15/2022] Open
Abstract
Food allergy is a major health issue, affecting the lives of 8% of U.S. children and their families. There is an urgent need to identify the environmental and endogenous signals that induce and sustain allergic responses to ingested allergens. Acute reactions to foods are triggered by the activation of mast cells and basophils, both of which release inflammatory mediators that lead to a range of clinical manifestations, including gastrointestinal, cutaneous, and respiratory reactions as well as systemic anaphylaxis. Both of these innate effector cell types express the high affinity IgE receptor, FcϵRI, on their surface and are armed for adaptive antigen recognition by very-tightly bound IgE antibodies which, when cross-linked by polyvalent allergen, trigger degranulation. These cells also express inhibitory receptors, including the IgG Fc receptor, FcγRIIb, that suppress their IgE-mediated activation. Recent studies have shown that natural resolution of food allergies is associated with increasing food-specific IgG levels. Furthermore, oral immunotherapy, the sequential administration of incrementally increasing doses of food allergen, is accompanied by the strong induction of allergen-specific IgG antibodies in both human subjects and murine models. These can deliver inhibitory signals via FcγRIIb that block IgE-induced immediate food reactions. In addition to their role in mediating immediate hypersensitivity reactions, mast cells and basophils serve separate but critical functions as adjuvants for type 2 immunity in food allergy. Mast cells and basophils, activated by IgE, are key sources of IL-4 that tilts the immune balance away from tolerance and towards type 2 immunity by promoting the induction of Th2 cells along with the innate effectors of type 2 immunity, ILC2s, while suppressing the development of regulatory T cells and driving their subversion to a pathogenic pro-Th2 phenotype. This adjuvant effect of mast cells and basophils is suppressed when inhibitory signals are delivered by IgG antibodies signaling via FcγRIIb. This review summarizes current understanding of the immunoregulatory effects of mast cells and basophils and how these functions are modulated by IgE and IgG antibodies. Understanding these pathways could provide important insights into innovative strategies for preventing and/or reversing food allergy in patients.
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Affiliation(s)
- Cynthia Kanagaratham
- Division of Immunology, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, United States
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States
| | - Yasmeen S. El Ansari
- Division of Immunology, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, United States
- Institute of Laboratory Medicine, Philipps University Marburg, Marburg, Germany
| | - Owen L. Lewis
- Division of Immunology, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, United States
| | - Hans C. Oettgen
- Division of Immunology, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, United States
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States
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Yamaguchi Y, Barb AW. A synopsis of recent developments defining how N-glycosylation impacts immunoglobulin G structure and function. Glycobiology 2020; 30:214-225. [PMID: 31822882 DOI: 10.1093/glycob/cwz068] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 07/26/2019] [Accepted: 08/21/2019] [Indexed: 12/21/2022] Open
Abstract
Therapeutic monoclonal antibodies (mAbs) are the fastest growing group of drugs with 11 new antibodies or antibody-drug conjugates approved by the Food and Drug Administration in 2018. Many mAbs require effector function for efficacy, including antibody-dependent cell-mediated cytotoxicity triggered following contact of an immunoglobulin G (IgG)-coated particle with activating crystallizable fragment (Fc) γ receptors (FcγRs) expressed by leukocytes. Interactions between IgG1 and the FcγRs require post-translational modification of the Fc with an asparagine-linked carbohydrate (N-glycan). Though the structure of IgG1 Fc and the role of Fc N-glycan composition on disease were known for decades, the underlying mechanism of how the N-glycan affected FcγR binding was not defined until recently. This review will describe the current understanding of how N-glycosylation impacts the structure and function of the IgG1 Fc and describe new techniques that are poised to provide the next critical breakthroughs.
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Affiliation(s)
| | - Adam W Barb
- Department of Biochemistry and Molecular Biology and Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, 30602
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El Ansari YS, Kanagaratham C, Lewis OL, Oettgen HC. IgE and mast cells: The endogenous adjuvant. Adv Immunol 2020; 148:93-153. [PMID: 33190734 DOI: 10.1016/bs.ai.2020.10.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Mast cells and IgE are most familiar as the effectors of type I hypersensitivity reactions including anaphylaxis. It is becoming clear however that this pair has important immunomodulatory effects on innate and adaptive cells of the immune system. In this purview, they act as endogenous adjuvants to ignite evolving immune responses, promote the transition of allergic disease into chronic illness and disrupt the development of active mechanisms of tolerance to ingested foods. Suppression of IgE-mediated mast cell activation can be exerted by molecules targeting IgE, FcɛRI or signaling kinases including Syk, or by IgG antibodies acting via inhibitory Fcγ receptors. In 2015 we reviewed the evidence for the adjuvant functions of mast cells. This update includes the original text, incorporates some important developments in the field over the past five years and discusses how interventions targeting these pathways might have promise in the development of strategies to treat allergic disease.
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Affiliation(s)
- Yasmeen S El Ansari
- Division of Immunology, Boston Children's Hospital, Boston, MA, United States; Institute of Laboratory Medicine, Philipps University Marburg, Marburg, Germany
| | - Cynthia Kanagaratham
- Division of Immunology, Boston Children's Hospital, Boston, MA, United States; Department of Pediatrics, Harvard Medical School, Boston, MA, United States
| | - Owen L Lewis
- Division of Immunology, Boston Children's Hospital, Boston, MA, United States
| | - Hans C Oettgen
- Division of Immunology, Boston Children's Hospital, Boston, MA, United States; Department of Pediatrics, Harvard Medical School, Boston, MA, United States.
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Miyashita K, Lutz J, Hudgins LC, Toib D, Ashraf AP, Song W, Murakami M, Nakajima K, Ploug M, Fong LG, Young SG, Beigneux AP. Chylomicronemia from GPIHBP1 autoantibodies. J Lipid Res 2020; 61:1365-1376. [PMID: 32948662 PMCID: PMC7604722 DOI: 10.1194/jlr.r120001116] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Some cases of chylomicronemia are caused by autoantibodies against glycosylphosphatidylinositol-anchored HDL binding protein 1 (GPIHBP1), an endothelial cell protein that shuttles LPL to the capillary lumen. GPIHBP1 autoantibodies prevent binding and transport of LPL by GPIHBP1, thereby disrupting the lipolytic processing of triglyceride-rich lipoproteins. Here, we review the "GPIHBP1 autoantibody syndrome" and summarize clinical and laboratory findings in 22 patients. All patients had GPIHBP1 autoantibodies and chylomicronemia, but we did not find a correlation between triglyceride levels and autoantibody levels. Many of the patients had a history of pancreatitis, and most had clinical and/or serological evidence of autoimmune disease. IgA autoantibodies were present in all patients, and IgG4 autoantibodies were present in 19 of 22 patients. Patients with GPIHBP1 autoantibodies had low plasma LPL levels, consistent with impaired delivery of LPL into capillaries. Plasma levels of GPIHBP1, measured with a monoclonal antibody-based ELISA, were very low in 17 patients, reflecting the inability of the ELISA to detect GPIHBP1 in the presence of autoantibodies (immunoassay interference). However, GPIHBP1 levels were very high in five patients, indicating little capacity of their autoantibodies to interfere with the ELISA. Recently, several GPIHBP1 autoantibody syndrome patients were treated successfully with rituximab, resulting in the disappearance of GPIHBP1 autoantibodies and normalization of both plasma triglyceride and LPL levels. The GPIHBP1 autoantibody syndrome should be considered in any patient with newly acquired and unexplained chylomicronemia.
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Affiliation(s)
- Kazuya Miyashita
- Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Japan
- Immuno-Biological Laboratories (IBL), Fujioka, Gunma, Japan
| | - Jens Lutz
- Medical Clinic, Nephrology-Infectious Diseases, Central Rhine Hospital Group, Koblenz, Germany
| | - Lisa C Hudgins
- Rogosin Institute, Weill Cornell Medical College, New York, NY, USA
| | - Dana Toib
- Department of Pediatrics, Drexel University, Philadelphia, PA, USA
- Section of Pediatric Rheumatology, St. Christopher's Hospital for Children, Philadelphia, PA, USA
| | - Ambika P Ashraf
- Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Wenxin Song
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Masami Murakami
- Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Katsuyuki Nakajima
- Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Michael Ploug
- Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark
- Biotechnology Research Innovation Center, Copenhagen University, Copenhagen, Denmark
| | - Loren G Fong
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Stephen G Young
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Anne P Beigneux
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
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50
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Wang H, Xu Q, Zhao C, Zhu Z, Zhu X, Zhou J, Zhang S, Yang T, Zhang B, Li J, Yan M, Liu R, Ma C, Quan Y, Zhang Y, Zhang W, Geng Y, Chen C, Chen S, Liu D, Chen Y, Tian D, Su M, Chen X, Gu J. An immune evasion mechanism with IgG4 playing an essential role in cancer and implication for immunotherapy. J Immunother Cancer 2020; 8:jitc-2020-000661. [PMID: 32819973 PMCID: PMC7443307 DOI: 10.1136/jitc-2020-000661] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/02/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Recent impressive advances in cancer immunotherapy have been largely derived from cellular immunity. The role of humoral immunity in carcinogenesis has been less understood. Based on our previous observations we hypothesize that an immunoglobulin subtype IgG4 plays an essential role in cancer immune evasion. METHODS The distribution, abundance, actions, properties and possible mechanisms of IgG4 were investigated with human cancer samples and animal tumor models with an extensive array of techniques both in vitro and in vivo. RESULTS In a cohort of patients with esophageal cancer we found that IgG4-containing B lymphocytes and IgG4 concentration were significantly increased in cancer tissue and IgG4 concentrations increased in serum of patients with cancer. Both were positively related to increased cancer malignancy and poor prognoses, that is, more IgG4 appeared to associate with more aggressive cancer growth. We further found that IgG4, regardless of its antigen specificity, inhibited the classic immune reactions of antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis and complement-dependent cytotoxicity against cancer cells in vitro, and these effects were obtained through its Fc fragment reacting to the Fc fragments of cancer-specific IgG1 that has been bound to cancer antigens. We also found that IgG4 competed with IgG1 in reacting to Fc receptors of immune effector cells. Therefore, locally increased IgG4 in cancer microenvironment should inhibit antibody-mediated anticancer responses and help cancer to evade local immune attack and indirectly promote cancer growth. This hypothesis was verified in three different immune potent mouse models. We found that local application of IgG4 significantly accelerated growth of inoculated breast and colorectal cancers and carcinogen-induced skin papilloma. We also tested the antibody drug for cancer immunotherapy nivolumab, which was IgG4 in nature with a stabilizing S228P mutation, and found that it significantly promoted cancer growth in mice. This may provide an explanation to the newly appeared hyperprogressive disease sometimes associated with cancer immunotherapy. CONCLUSION There appears to be a previously unrecognized immune evasion mechanism with IgG4 playing an essential role in cancer microenvironment with implications in cancer diagnosis and immunotherapy.
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Affiliation(s)
- Hui Wang
- Department of Pathology and Pathophysiology, Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Shantou University Medical College, Shantou, China
| | - Qian Xu
- Department of Pathology and Pathophysiology, Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Shantou University Medical College, Shantou, China
| | - Chanyuan Zhao
- Department of Pathology and Pathophysiology, Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Shantou University Medical College, Shantou, China
| | - Ziqi Zhu
- Department of Pathology and Pathophysiology, Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Shantou University Medical College, Shantou, China
| | - Xiaoqing Zhu
- Department of Pathology and Pathophysiology, Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Shantou University Medical College, Shantou, China
| | - Junjie Zhou
- Department of Pathology and Pathophysiology, Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Shantou University Medical College, Shantou, China
| | - Shuming Zhang
- Department of Pathology and Pathophysiology, Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Shantou University Medical College, Shantou, China
| | - Tiqun Yang
- Department of Pathology and Pathophysiology, Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Shantou University Medical College, Shantou, China
| | - Biying Zhang
- Department of Pathology and Pathophysiology, Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Shantou University Medical College, Shantou, China
| | - Jun Li
- Department of Pathology and Pathophysiology, Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Shantou University Medical College, Shantou, China
| | - Meiling Yan
- Department of Pathology and Pathophysiology, Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Shantou University Medical College, Shantou, China
| | - Renming Liu
- Department of Pathology and Pathophysiology, Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Shantou University Medical College, Shantou, China
| | - Changchun Ma
- Department of Radiation Oncology, Affiliated Cancer Hospital, Shantou University Medical College, Shantou, Guangdong, China
| | - Yan Quan
- Department of Pathology and Pathophysiology, Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Shantou University Medical College, Shantou, China
| | - Yongqu Zhang
- Department of Breast Center, Affiliated Cancer Hospital, Shantou University Medical College, Shantou, Guangdong, China
| | - Weifeng Zhang
- Department of Pathology and Pathophysiology, Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Shantou University Medical College, Shantou, China
| | - Yiqun Geng
- Department of Pathology and Pathophysiology, Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Shantou University Medical College, Shantou, China
| | - Chuangzhen Chen
- Department of Radiation Oncology, Affiliated Cancer Hospital, Shantou University Medical College, Shantou, Guangdong, China
| | - Shaobin Chen
- Department of Thoracic Surgery, Affiliated Cancer Hospital, Shantou University Medical College, Shantou, Guangdong, China
| | - Ditian Liu
- Department of Thoracic Surgery, Affiliated Cancer Hospital, Shantou University Medical College, Shantou, Guangdong, China
| | - Yuping Chen
- Department of Thoracic Surgery, Affiliated Cancer Hospital, Shantou University Medical College, Shantou, Guangdong, China
| | - Dongping Tian
- Department of Pathology and Pathophysiology, Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Shantou University Medical College, Shantou, China
| | - Min Su
- Department of Pathology and Pathophysiology, Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Shantou University Medical College, Shantou, China
| | - Xueling Chen
- Department of Pathology and Pathophysiology, Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Shantou University Medical College, Shantou, China
| | - Jiang Gu
- Department of Pathology and Pathophysiology, Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Shantou University Medical College, Shantou, China
- Jinxin Research Institute for Reproductive Medicine and Genetics, Jinjiang Hospital for Maternal and Child Health Care, Chengdu, China
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