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Posa A. Spike protein-related proteinopathies: a focus on the neurological side of spikeopathies. Ann Anat 2025:152662. [PMID: 40254264 DOI: 10.1016/j.aanat.2025.152662] [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: 02/24/2025] [Revised: 04/07/2025] [Accepted: 04/09/2025] [Indexed: 04/22/2025]
Abstract
BACKGROUND The spike protein (SP) is an outward-projecting transmembrane glycoprotein on viral surfaces. SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), responsible for COVID-19 (Coronavirus Disease 2019), uses SP to infect cells that express angiotensin converting enzyme 2 (ACE2) on their membrane. Remarkably, SP has the ability to cross the blood-brain barrier (BBB) into the brain and cause cerebral damage through various pathomechanisms. To combat the COVID-19 pandemic, novel gene-based products have been used worldwide to induce human body cells to produce SP to stimulate the immune system. This artificial SP also has a harmful effect on the human nervous system. STUDY DESIGN Narrative review. OBJECTIVE This narrative review presents the crucial role of SP in neurological complaints after SARS-CoV-2 infection, but also of SP derived from novel gene-based anti-SARS-CoV-2 products (ASP). METHODS Literature searches using broad terms such as "SARS-CoV-2", "spike protein", "COVID-19", "COVID-19 pandemic", "vaccines", "COVID-19 vaccines", "post-vaccination syndrome", "post-COVID-19 vaccination syndrome" and "proteinopathy" were performed using PubMed. Google Scholar was used to search for topic-specific full-text keywords. CONCLUSIONS The toxic properties of SP presented in this review provide a good explanation for many of the neurological symptoms following SARS-CoV-2 infection and after injection of SP-producing ASP. Both SP entities (from infection and injection) interfere, among others, with ACE2 and act on different cells, tissues and organs. Both SPs are able to cross the BBB and can trigger acute and chronic neurological complaints. Such SP-associated pathologies (spikeopathies) are further neurological proteinopathies with thrombogenic, neurotoxic, neuroinflammatory and neurodegenerative potential for the human nervous system, particularly the central nervous system. The potential neurotoxicity of SP from ASP needs to be critically examined, as ASPs have been administered to millions of people worldwide.
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Affiliation(s)
- Andreas Posa
- University Clinics and Outpatient Clinics for Radiology, Neuroradiology and Neurology, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, 06120 Halle (Saale), Germany.
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2
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Peyronel F, Della-Torre E, Maritati F, Urban ML, Bajema I, Schleinitz N, Vaglio A. IgG4-related disease and other fibro-inflammatory conditions. Nat Rev Rheumatol 2025:10.1038/s41584-025-01240-x. [PMID: 40195520 DOI: 10.1038/s41584-025-01240-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/07/2025] [Indexed: 04/09/2025]
Abstract
IgG4-related disease (IgG4-RD) is a fibro-inflammatory disorder usually characterized by multi-organ involvement. Its pathogenesis is complex and involves genetic and environmental factors, while immune responses usually mediate organ damage and promote fibrosis, which is a key feature of the disease. IgG4 responses, however, are not exclusive to IgG4-RD and can be encountered in other diseases with phenotypes that partially overlap that of IgG4-RD. Although IgG4-RD has clinical and histological hallmarks, the lack of validated diagnostic criteria often makes the diagnosis challenging, requiring a multi-dimensional approach that integrates clinical, radiological and serological data. The present Review covers recent advances in the understanding of disease drivers and its clinical phenotypes, mainly focusing on the differential diagnosis with potential IgG4-RD mimickers, namely histiocytoses, lymphoproliferative disorders, systemic vasculitides and other immune-mediated conditions. The Review also provides a schematic approach to IgG4-RD treatment, including a brief overview of glucocorticoid-sparing agents and emerging therapies, from B cell-depleting monoclonal antibodies to cytokine-targeting drugs, the majority of which are currently under investigation in randomized clinical trials.
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Affiliation(s)
- Francesco Peyronel
- Nephrology and Dialysis Unit, Meyer Children's Hospital IRCCS, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Emanuel Della-Torre
- University Vita-Salute San Raffaele, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Federica Maritati
- Nephrology, Dialysis and Kidney Transplant Unit, IRCCS-Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Maria L Urban
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Ingeborg Bajema
- Department of Pathology and Medical Biology, University Medical Centre Groningen, Groningen, The Netherlands
| | - Nicolas Schleinitz
- Assistance Publique-Hôpitaux de Marseille, Aix-Marseille Université, Department of Internal Medicine Hôpital Timone, Marseille, France
| | - Augusto Vaglio
- Nephrology and Dialysis Unit, Meyer Children's Hospital IRCCS, Florence, Italy.
- Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", University of Florence, Florence, Italy.
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Wang H, Ciccocioppo R, Terai S, Shoeibi S, Carnevale G, De Marchi G, Tsuchiya A, Ishii S, Tonouchi T, Furuyama K, Yang Y, Mito M, Abe H, Di Tinco R, Cardinale V. Targeted animal models for preclinical assessment of cellular and gene therapies in pancreatic and liver diseases: regulatory and practical insights. Cytotherapy 2025; 27:259-278. [PMID: 39755978 DOI: 10.1016/j.jcyt.2024.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 11/08/2024] [Accepted: 11/10/2024] [Indexed: 01/07/2025]
Abstract
Cellular and gene therapy (CGT) products have emerged as a popular approach in regenerative medicine, showing promise in treating various pancreatic and liver diseases in numerous clinical trials. Before these therapies can be tested in human clinical trials, it is essential to evaluate their safety and efficacy in relevant animal models. Such preclinical testing is often required to obtain regulatory approval for investigational new drugs. However, there is a lack of detailed guidance on selecting appropriate animal models for CGT therapies targeting specific pancreatic and liver conditions, such as pancreatitis and chronic liver diseases. In this review, the gastrointestinal committee for the International Society for Cell and Gene Therapy provides a summary of current recommendations for animal species and disease model selection, as outlined by the US Food and Drug Administration, with references to EU EMA and Japan PMDA. We discuss a range of small and large animal models, as well as humanized models, that are suitable for preclinical testing of CGT products aimed at treating pancreatic and liver diseases. For each model, we cover the associated pathophysiology, commonly used metrics for assessing disease status, the pros and limitations of the models, and the relevance of these models to human conditions. We also summarize the use and application of humanized mouse and other animal models in evaluating the safety and efficacy of CGT products. This review aims to provide comprehensive guidance for selecting appropriate animal species and models to help bridge the gap between the preclinical research and clinical trials using CGT therapies for specific pancreatic and liver diseases.
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Affiliation(s)
- Hongjun Wang
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA; Ralph H Johnson Veteran Medical Center, Charleston, South Carolina, USA.
| | - Rachele Ciccocioppo
- Department of Medicine, Gastroenterology Unit, Pancreas Institute, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Sara Shoeibi
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Gianluca Carnevale
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with Interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia De Marchi
- Department of Medicine, Gastroenterology Unit, Pancreas Institute, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Soichi Ishii
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Takafumi Tonouchi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Kaito Furuyama
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Yuan Yang
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Masaki Mito
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Hiroyuki Abe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Rosanna Di Tinco
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with Interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Vincenzo Cardinale
- Department of Translational and Precision Medicine, University of Rome, Rome, Italy.
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He L, Zhan L, Yang Y, He W. Similarities and differences of a proliferation-inducing ligand expression in lacrimal gland lesions of patients with IgG4-associated ophthalmic diseases and mucosa-associated lymphoid tissue lymphoma. Front Immunol 2025; 16:1514003. [PMID: 40040702 PMCID: PMC11876129 DOI: 10.3389/fimmu.2025.1514003] [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: 10/19/2024] [Accepted: 01/31/2025] [Indexed: 03/06/2025] Open
Abstract
Objective This study aimed to investigate the expression condition of a proliferation-inducing ligand (APRIL) in lacrimal gland lesions of patients with IgG4-associated ophthalmic diseases (IgG4-ROD) and mucosa-associated lymphoid tissue (MALT) lymphoma. Patients and methods Fifteen patients with IgG4-ROD, 3 with MALT lymphoma, and 1 with elevated IgG4 with lacrimal gland lesions, treated in West China Hospital of Sichuan University from April 2022 to November 2023, were included. Immunofluorescence staining was used to detect the expression of APRIL in the specimen of lacrimal gland. Results The average expression level of APRIL in patients with lacrimal gland lesions of IgG4-ROD and MALT lymphoma were 8471.12 pixels/HPF and 2950.78 pixels/HPF respectively. The positive rates of APRIL were 10.49% and 7.23% respectively. CD138 and APRIL were colocalized, and the positive rate of their colocalization was 8.83%, and the positive areas of colocalization coincidence was 946.84 pixels/HPF in patients with IgG4-ROD. CD20 and APRIL were colocalized, and the positive rate of their colocalization was 7.04%, and the positive areas of colocalization coincidence was 949.78 pixels/HPF in patients with MALT lymphoma. We also found that the expression level and the positive rate of APRIL were positively correlated with the level of serum IgG4 in IgG4-ROD patients (r=0.5820, P=0.029; r= 0.6261, P=0.017; respectively). In addition, the positive rate and the positive areas of CD138 and APRIL colocalization were also positively correlated with serum IgG4 level (r=0.6420, P=0.013; r= 0.5673, P=0.034; respectively). Conclusion APRIL is highly expressed in lacrimal gland lesions of patients with IgG4-ROD and MALT lymphoma. This overexpression may facilitate the enrichment of CD138+ plasma cells and is associated with elevated serum IgG4 levels in patients with IgG4-ROD. Additionally, it may promote the proliferation of CD20+ B lymphocytes in patients with MALT lymphoma.APRIL may play a certain role in the possible transformation of IgG4-ROD into MALT lymphoma.
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Affiliation(s)
- Lvfu He
- Department of Ophthalmology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, China
| | - Lisha Zhan
- The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, China
| | - Yu Yang
- Department of Ophthalmology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Weimin He
- Department of Ophthalmology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
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Mendoza-Vargas LÁ, Sevilla-Fuentes S, Bautista-Becerril B, Berthaúd-González B, Falfán-Valencia R, Félix-Martínez LP, Avila-Páez M, Manilla-González J. IgG4-RD-Associated Mikulicz Syndrome Without Classic Systemic Involvement-A Case Report. J Clin Med 2025; 14:958. [PMID: 39941629 PMCID: PMC11818687 DOI: 10.3390/jcm14030958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 01/27/2025] [Accepted: 01/30/2025] [Indexed: 02/16/2025] Open
Abstract
Background: IgG4-related disease is a rare, chronic inflammatory disorder characterized by lymphoplasmacytic infiltration, 'storiform' fibrosis, and elevated IgG4 levels in affected tissues. This disease has a broad and heterogeneous clinical spectrum that includes four main phenotypes: pancreatic-hepatobiliary disease, retroperitoneal/aortic fibrosis, head and neck disease, and Mikulicz syndrome. Case Description: An 85-year-old male patient with a clinical presentation, which is unusual outside Asia, of IgG4-related disease phenotype Mikulicz syndrome, characterized by bilateral dacryoadenitis, orbital pseudotumor, and no evidence of significant systemic participation. Despite extensive involvement in the orbital and glandular region, the patient did not develop serious organ complications, a behavior rarely documented in the literature. Despite the serum IgG4 levels being normal (<135 mg/dL), the clinical and radiological picture suggested IgG4-RD, emphasizing the need for a biopsy for a definitive diagnosis. Histopathological examination revealed a dense lymphoplasmacytic infiltrate, storiform fibrosis, and more than 40% IgG4-positive cells, confirming the diagnosis. Results: Treatment with prednisone was initiated alongside azathioprine for long-term control. Calcium and vitamin D3 supplementation were added to prevent glucocorticoid-induced osteoporosis. Remarkable clinical improvement was observed within 24 h, with progressive orbital and glandular symptoms resolution. Over a year, the patient exhibited complete resolution of the orbital tumors, total recovery of vision, and no relapses. The only sequelae observed were dry eye. Conclusions: This case highlights the need to consider IgG4-RD with normal serum IgG4 levels, the importance of histopathology for diagnosis, and the efficacy of steroids as first-line treatment. A multidisciplinary approach is essential for timely treatment.
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Affiliation(s)
| | | | - Brandon Bautista-Becerril
- Laboratorio HLA, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico;
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico
| | | | - Ramcés Falfán-Valencia
- Laboratorio HLA, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico;
| | | | - Mauricio Avila-Páez
- Facultad de Medicina, Universidad Nacional Autónoma de México, Campus Ciudad Universitaria, Mexico City 04510, Mexico
| | - Jennifer Manilla-González
- Facultad de Medicina, Universidad Popular Autónoma del Estado de Puebla, Campus Puebla, Puebla 72410, Mexico
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Bencardino S, Matichecchia CS, Fanizza J, Peyrin-Biroulet L, Della-Torre E, Danese S, D'Amico F. IgG4 in the gut: Gastrointestinal IgG4-related disease or a new subtype of inflammatory bowel disease. Autoimmun Rev 2025; 24:103720. [PMID: 39653260 DOI: 10.1016/j.autrev.2024.103720] [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: 08/31/2024] [Revised: 11/27/2024] [Accepted: 12/06/2024] [Indexed: 12/13/2024]
Abstract
IgG4-related disease (IgG4-RD) is a chronic inflammatory condition characterized by tissue infiltration with IgG4-positive plasma cells, leading to fibrosis and organ dysfunction. While primarily affecting the pancreas, bile ducts, and salivary glands, IgG4-RD can also involve the gastrointestinal tract, raising questions about its relationship with inflammatory bowel disease (IBD). Recent studies suggest that patients with IBD may exhibit histological and serological features consistent with IgG4-RD, such as a dense lymphoplasmacytic infiltration, a storiform-type of fibrosis and a prominent IgG4 immune response. This overlap represents a diagnostic challenge, as differentiating between primary IBD and IgG4-RD involving the gut is crucial for appropriate treatment. Further research is essential to delineate the prevalence of tissue and serum IgG4 expression in patients with IBD. This approach could classify subtypes of IBD, enabling advancements in non-invasive diagnosis and monitoring as well as personalized therapies. The purpose of this review is to summarize the available evidence regarding intestinal involvement in IgG4-RD and the role of both serum and tissue IgG4 in inflammatory bowel diseases IBD.
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Affiliation(s)
- Sarah Bencardino
- Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy
| | - Cosimo Simone Matichecchia
- Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy
| | - Jacopo Fanizza
- Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, INFINY Institute, INSERM NGERE, CHRU Nancy, F-54500 Vandœuvre-lès-Nancy, France
| | - Emanuel Della-Torre
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy
| | - Ferdinando D'Amico
- Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy.
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Oguz AK, Oygur CS, Gur Dedeoglu B, Dogan Turacli I, Serin Kilicoglu S, Ergun I. The Platelet-Specific Gene Signature in the Immunoglobulin G4-Related Disease Transcriptome. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:162. [PMID: 39859144 PMCID: PMC11767091 DOI: 10.3390/medicina61010162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 01/04/2025] [Accepted: 01/15/2025] [Indexed: 01/27/2025]
Abstract
Background and Objectives: Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated, fibroinflammatory, multiorgan disease with an obscure pathogenesis. Findings indicating excessive platelet activation have been reported in systemic sclerosis, which is another autoimmune, multisystemic fibrotic disorder. The immune-mediated, inflammatory, and fibrosing intersections of IgG4-RD and systemic sclerosis raised a question about platelets' role in IgG4-RD. Materials and Methods: By borrowing transcriptomic data from Nakajima et al. (GEO repository, GSE66465) we sought a platelet contribution to the pathogenesis of IgG4-RD. GEO2R and BRB-ArrayTools were used for class comparisons, and WebGestalt for functional enrichment analysis. During the selection of differentially expressed genes (DEGs), the translationally active but significantly low amount of platelet mRNA was specifically considered. The platelet-specific gene signature derived was used for cluster analysis of patient and control groups. Results: When IgG4-RD patients were compared with controls, 268 DEGs (204 with increased and 64 with decreased expression) were detected. Among these, a molecular signature of 22 platelet-specific genes harbored genes important for leukocyte-platelet aggregate formation (i.e., CLEC1B, GP1BA, ITGA2B, ITGB3, SELP, and TREML1) and extracellular matrix synthesis (i.e., CLU, PF4, PPBP, SPARC, and THBS1). Functional enrichment analysis documented significantly enriched terms related to platelets, including but not limited to "platelet reactivity", "platelet degranulation", "platelet aggregation", and "platelet activation". During clustering, the 22 gene signatures successfully discriminated IgG4-RD and the control and the IgG4-RD before and after treatment groups. Conclusions: Patients with IgG4-RD apparently display an activated platelet phenotype with a potential contribution to disease immunopathogenesis. If the platelets' role is validated through further carefully designed research, the therapeutic potentials of selected conventional and/or novel antiplatelet agents remain to be evaluated in patients with IgG4-RD. Transcriptomics and/or proteomics research with platelets should take into account the relatively low amounts of platelet mRNA, miRNA, and protein. Secondary analysis of omics data sets has great potential to reveal new and valuable information.
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Affiliation(s)
- Ali Kemal Oguz
- Department of Internal Medicine, Faculty of Medicine, Ufuk University, 06510 Ankara, Turkey
| | - Cagdas Sahap Oygur
- Department of Internal Medicine (Rheumatology), Faculty of Medicine, Baskent University, 06490 Ankara, Turkey;
| | - Bala Gur Dedeoglu
- Department of Biotechnology, Biotechnology Institute, Ankara University, 06135 Ankara, Turkey;
| | - Irem Dogan Turacli
- Department of Medical Biology, Faculty of Medicine, Ufuk University, 06510 Ankara, Turkey;
| | - Sibel Serin Kilicoglu
- Department of Histology & Embryology, Faculty of Medicine, Baskent University, 06790 Ankara, Turkey;
| | - Ihsan Ergun
- Department of Internal Medicine (Nephrology), Faculty of Medicine, Ufuk University, 06510 Ankara, Turkey;
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Sun Y, Huang S, Zhang B, Peng Y, Lu H, Jia Y, Sun R, Zhang F, Zhou J, Peng L, Li M, Zhang W, Fei Y. Efficacy and safety of anti-CD19 CAR-T in a mouse model of IgG4-related disease. Int Immunopharmacol 2025; 145:113779. [PMID: 39672025 DOI: 10.1016/j.intimp.2024.113779] [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: 09/30/2024] [Revised: 11/30/2024] [Accepted: 12/01/2024] [Indexed: 12/15/2024]
Abstract
Dysregulated B-cell activation plays pivotal roles in IgG4-related disease (IgG4-RD), which makes B-cell depletion a potential strategy for IgG4-RD treatment. In this study, we aimed to investigate the feasibility of applying anti-CD19 chimeric antigen receptor T(CAR-T) cell therapy to IgG4-RD treatment in a mouse disease model based on LatY136F knock-in (Lat) mice. We constructed murine anti-CD19 CARs with either CD28 or 4-1BB as the intracellular costimulatory motif and evaluated the therapeutic function of the corresponding CAR-T cells by infusing them into Lat mice. Next, we assessed the safety of CAR-T infusion by evaluating the risk of cytokine release syndrome (CRS) and the antiviral capabilities in a mouse influenza infection model. Finally, we performed human anti-CD19 CAR-T manufacturing from IgG4-RD patients and evaluated its activation level and functional effects in vitro. Compared with 1D3 antibody treatment, the adoptive transfer of anti-CD19 CAR-T cells with CD28 costimulatory motif showed comparable B-cell-depletion effect in Lat mice. Furthermore, the transfer of syngeneic anti-CD19 CAR-T cells also decreased the percentage of plasma cells as well as IL-4 secreting Th cells, therefore attenuating the inflammation and fibrosis condition. CAR-T cells with CD28 costimulatory motif showed better therapeutic efficiency without the incidence of serious CRS events or increasing the risk of infection. In addition, we validated the feasibility of human CAR-T preparation in vitro from IgG4-RD patients. Taken together, these results show that anti-CD19 CAR-T therapy was effective in the treatment of a murine model of IgG4-RD, indicating its potential for clinical use in patients.
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Affiliation(s)
- Yeting Sun
- Department of Rheumatology and Clinical Immunology, Department of Health Management, Peking Union Medical College and Chinese Academy of Medical Sciences, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, China; The Ministry of Education Key Laboratory, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Beijing, China
| | - Sicheng Huang
- Department of Rheumatology and Clinical Immunology, Department of Health Management, Peking Union Medical College and Chinese Academy of Medical Sciences, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, China; The Ministry of Education Key Laboratory, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Beijing, China
| | - Bo Zhang
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Yu Peng
- Department of Rheumatology, the Second Affiliated Hospital of Zhejiang University, School of Medicine, Zhejiang, China
| | - Hui Lu
- Affiliated Beijing Chaoyang Hospital of Capital Medical University, Beijing, China
| | - Yimeng Jia
- Department of Rheumatology and Clinical Immunology, Department of Health Management, Peking Union Medical College and Chinese Academy of Medical Sciences, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, China; The Ministry of Education Key Laboratory, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Beijing, China
| | - Ruijie Sun
- Department of Rheumatology and Clinical Immunology, Department of Health Management, Peking Union Medical College and Chinese Academy of Medical Sciences, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, China; The Ministry of Education Key Laboratory, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Beijing, China
| | | | - Jiaxin Zhou
- Department of Rheumatology and Clinical Immunology, Department of Health Management, Peking Union Medical College and Chinese Academy of Medical Sciences, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, China; The Ministry of Education Key Laboratory, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Beijing, China
| | - Linyi Peng
- Department of Rheumatology and Clinical Immunology, Department of Health Management, Peking Union Medical College and Chinese Academy of Medical Sciences, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, China; The Ministry of Education Key Laboratory, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Beijing, China
| | - Mengtao Li
- Department of Rheumatology and Clinical Immunology, Department of Health Management, Peking Union Medical College and Chinese Academy of Medical Sciences, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, China; The Ministry of Education Key Laboratory, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Beijing, China
| | - Wen Zhang
- Department of Rheumatology and Clinical Immunology, Department of Health Management, Peking Union Medical College and Chinese Academy of Medical Sciences, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, China; The Ministry of Education Key Laboratory, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Beijing, China.
| | - Yunyun Fei
- Department of Rheumatology and Clinical Immunology, Department of Health Management, Peking Union Medical College and Chinese Academy of Medical Sciences, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, China; Department of Health Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
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Badshah MB, Khan QA, Kazi N, Ansari RA, Verma R. IgG4-related retroperitoneal fibrosis presenting as a peripancreatic mass: a case series. Ann Med Surg (Lond) 2025; 87:36-42. [PMID: 40109592 PMCID: PMC11918540 DOI: 10.1097/ms9.0000000000002749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Accepted: 11/05/2024] [Indexed: 03/22/2025] Open
Abstract
Introduction IgG4-related disease (IgG4-RD) is a chronic, immune-mediated disorder characterized by widespread inflammation and fibrosis, leading to potential organ dysfunction if untreated. Often underdiagnosed due to subtle and varied symptoms, the disease can affect multiple organ systems. This case series highlights two patients who were diagnosed as cases of IgG4-related retroperitoneal fibrosis. Methods A total of two patients were included in this prospective case series who presented to the gastroenterology department of a tertiary care hospital with the same signs and symptoms and were diagnosed with IgG4-related retroperitoneal fibrosis (IgG4-RPF). Case summary Two patients were included in our case series, aged 25 and 26 years. The chief complaints included dull, radiating epigastric pain, other symptoms include diffuse abdominal pain, intensified, accompanied by nausea, vomiting, and episodic diarrhea, and a history of B-cell lymphoproliferative disorder. Endoscopic ultrasound (EUS)-)-guided biopsies were performed, showing findings consistent with (IgG4-RPF). Both patients were started on a regimen of prednisolone, pantoprazole, and vitamin D, which they tolerated well without adverse effects. They were advised to follow up with a CT scan after one month. Conclusion IgG4-related disease (IgG4-RD) is a rare, chronic condition often presenting as retroperitoneal fibrosis (RPF) and affecting multiple organs. Serum IgG4 levels can be normal in certain cases, histopathological and radiological investigations are necessary for the correct diagnosis. Early initiation of immunosuppressive drugs are necessary for the disease control.
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Affiliation(s)
| | | | - Naima Kazi
- Khyber Girls Medical College, Peshawar, Pakistan
| | | | - Ravina Verma
- St. George's University School of Medicine, True Blue, Grenada
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10
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Zhang Z, Zhang Y, Chen Z, Xia L. Emerging roles of SLAMF7 in immune cells and related diseases. Innate Immun 2025; 31:17534259251326700. [PMID: 40091370 PMCID: PMC11912174 DOI: 10.1177/17534259251326700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 12/21/2024] [Accepted: 02/21/2025] [Indexed: 03/19/2025] Open
Abstract
Immune cells are heterogeneous and perform different functions in different microenvironment, thus playing different roles in different stages of diseases. Studies have shown that immune cells are involved in the pathogenesis of many diseases, and there is a causal association of immune cells with disease states. Signaling Lymphocyte Activation Molecule family (SLAMF) members are a newly appreciated group of specific receptors that are mainly expressed in immune cells and whose role is to regulate the function of immune cells. SLAMF7, also known as CD319, has been widely reported in multiple myeloma, and in recent years, more and more studies have shown that SLAMF7 is widely involved in the function of immune cells and the progression of breast cancer, acquired immune deficiency syndrome, systemic lupus erythematosus and other immune cells-related diseases. However, the mechanisms underlying the regulatory role of SLAMF7 on immune cells, and the impact on the progression of immune cells-related diseases remain poorly elucidated. In this review, we summarize current knowledge about the role of SLAMF7 in immune cells and related diseases such as cancer, infectious disease, autoimmune disease and atherosclerosis, and the therapeutic strategy targeting SLAMF7 is also described. By better understanding the role and regulation of SLAMF7, we hope to provide new insights and directions for improving the diagnosis and treatment of inflammation.
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Affiliation(s)
- Zheng Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Ying Zhang
- Department of Biochemistry and Molecular Biology, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Zeyu Chen
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Lin Xia
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China
- Institute of Hematological Disease, Jiangsu University, Zhenjiang, China
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11
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Aung T, Celestin M, Bau S, Saab S. An Unusual Case of Chylous Ascites. Cureus 2024; 16:e76018. [PMID: 39835005 PMCID: PMC11743697 DOI: 10.7759/cureus.76018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 12/18/2024] [Indexed: 01/22/2025] Open
Abstract
Chylous ascites occur when the lymphatic flow is blocked or disrupted, causing a leakage of fluid into the peritoneal space. It can be caused by a number of etiologies and identifying the exact cause can be challenging. We present the case of a 77-year-old man who presented with chylous ascites. An abdominal computed tomography scan revealed an abnormal spiculated mass and lymph nodes in the central mesentery encasing the pancreas, raising suspicion of pancreatic malignancy. A subsequent mesenteric biopsy indicated sclerosing mesenteritis characterized by dense fibrous tissue and positive Immunoglobulin G4 (IgG4) staining, leading to a final diagnosis of IgG4-related disease (IgG4-RD). The patient responded positively to a treatment regimen that included systemic steroids and rituximab. This case, with its atypical presentation of IgG4-RD, contributes to our understanding of this rare disease, providing valuable insights for future diagnosis and treatment.
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Affiliation(s)
- Thanda Aung
- Rheumatology, University of California Los Angeles David Geffen School of Medicine, Los Angeles, USA
| | - Mia Celestin
- Rheumatology, University of California Los Angeles David Geffen School of Medicine, Los Angeles, USA
| | - Sherona Bau
- Hepatology, University of California Los Angeles David Geffen School of Medicine, Los Angeles, USA
| | - Sammy Saab
- Hepatology, University of California Los Angeles David Geffen School of Medicine, Los Angeles, USA
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12
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Lin X, Lin P, Fan J, Zhang B, Liang F, Han P, Liu X, Huang X. IgG4-related disease with nasopharyngeal malignancy-like manifestations. Front Immunol 2024; 15:1322159. [PMID: 38966645 PMCID: PMC11222309 DOI: 10.3389/fimmu.2024.1322159] [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: 10/15/2023] [Accepted: 03/22/2024] [Indexed: 07/06/2024] Open
Abstract
Background IgG4-related disease (IgG4-RD) was characterized by single or multiple masses in organs, which may mimic various inflammatory and malignant diseases. Here, we summarize 4 patients with aggressive manifestations of IgG4-RD that mimic nasopharynx cancer to provide some new sights for the diagnosis of IgG4-RD. Case summary Four patients were included in our series. The age ranged from 53 to 64 years old, and the duration of the disease ranged from 4 to 6 months. The chief complaints included headache, rhinorrhea, or diplopia. All patients had more than 10 IgG4+ plasma cells/HPF in immunohistochemistry with plasma lgG4 levels ranging from 218 mg/dL to 765 mg/dL. All of them met the diagnostic criteria of lgG4-RD. Conclusion The described case is highly similar to the clinical manifestations of nasopharyngeal carcinoma. Although pathology is the gold standard, there are still limitations. Serological IgG4 can help confirm the diagnosis. Timely diagnosis of IgG4-RD is of great significance in preventing secondary organ damage in patients with active diseases.
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Affiliation(s)
- Xijun Lin
- Department of Otolaryngology-Head and Neck Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Peiliang Lin
- Department of Otolaryngology-Head and Neck Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jianming Fan
- Department of Otolaryngology-Head and Neck Surgery, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Biying Zhang
- Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Faya Liang
- Department of Otolaryngology-Head and Neck Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ping Han
- Department of Otolaryngology-Head and Neck Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiang Liu
- Department of Otolaryngology-Head and Neck Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoming Huang
- Department of Otolaryngology-Head and Neck Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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13
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Jain AK, Sundaram S, Tyagi U, Kale A, Patkar S, Patil P, Deodhar K, Ramadwar M, Yadav S, Chaudhari V, Shrikhande S, Mehta S. IgG4-related disorders of the gastrointestinal tract: Experience from a tertiary care centre with systematic review of Indian literature. Indian J Gastroenterol 2024; 43:548-556. [PMID: 37823986 DOI: 10.1007/s12664-023-01437-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 07/24/2023] [Indexed: 10/13/2023]
Abstract
INTRODUCTION IgG4-related disease (IgG4-RD) is a rare disease entity in India. We aimed at studying the clinical profile of IgG4-RD of gastrointestinal tract (GIT) from our centre, while systematically reviewing data from India. METHODS Retrospective review of IgG4-RD of GIT was done using electronic medical records between January 2013 and July 2022. Literature search was done for studies of IgG4-RD of the GIT reported from India from 2000 till January 2023. Case series, case reports of IgG4-RD of GIT and case reports describing GIT with multi-organ involvement were included in the review. Primary outcome measure was response to treatment. Secondary outcome measure was relapse after remission. RESULTS Thirty-one patients were included with 71% (22/31) having autoimmune pancreatitis. The diagnosis was achieved on surgical specimen in 35% (11/31) patients. Steroid was given to 64% (20/31) patients with remission achieved in 70% (14/20) patients. Four patients exhibitted response to prolonged course of steroids with maintenance azathioprine. Relapse was seen in four (20%) patients who achieved remission. Of 731 articles screened, 48 studies (four case series and 44 case reports) were included in the literature review. Of 95 patients described, steroids were given to 65.2% (62/95), while surgery was done in 33.6% (32/95). Remission was seen in 96.6% (85/88) with relapse occurring in 11.4% (10/88) patients on follow-up. CONCLUSION One-third patients of IgG4-RD of GIT are diagnosed after surgery. Response to steroids is good with relapse occurring in up to 12% patients.
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Affiliation(s)
- Aadish Kumar Jain
- Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Homi Bhabha National Institute, Dr. E Borges Road, Parel, Mumbai, 400 012, India
| | - Sridhar Sundaram
- Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Homi Bhabha National Institute, Dr. E Borges Road, Parel, Mumbai, 400 012, India.
| | - Unique Tyagi
- Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Homi Bhabha National Institute, Dr. E Borges Road, Parel, Mumbai, 400 012, India
| | - Aditya Kale
- Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Homi Bhabha National Institute, Dr. E Borges Road, Parel, Mumbai, 400 012, India
| | - Shraddha Patkar
- Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, 400 012, India
| | - Prachi Patil
- Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Homi Bhabha National Institute, Dr. E Borges Road, Parel, Mumbai, 400 012, India
| | - Kedar Deodhar
- Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, 400 012, India
| | - Mukta Ramadwar
- Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, 400 012, India
| | - Subhash Yadav
- Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, 400 012, India
| | - Vikram Chaudhari
- Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, 400 012, India
| | - Shailesh Shrikhande
- Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, 400 012, India
| | - Shaesta Mehta
- Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Homi Bhabha National Institute, Dr. E Borges Road, Parel, Mumbai, 400 012, India
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14
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Pinheiro FAG, Pereira IA, de Souza AWS, Giardini HAM, Cordeiro RA. IgG4-related disease-rare but you should not forget it. Adv Rheumatol 2024; 64:35. [PMID: 38702764 DOI: 10.1186/s42358-024-00374-y] [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: 01/15/2024] [Accepted: 04/19/2024] [Indexed: 05/06/2024] Open
Abstract
Immunoglobulin G4-related disease is a systemic immune-mediated disease with insidious evolution characterized by fibroinflammatory lesions over virtually any organ system. Despite the remarkable progression of knowledge, its etiology remains undefined. Due to its relapse-remitting pattern, it could accumulate irreversible damage, increasing comorbidities and mortality. This paper emphasizes key concepts for diagnosing and treating patients with this condition.
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Affiliation(s)
- Frederico Augusto Gurgel Pinheiro
- Rheumatology Division, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.
- Universidade Federal de São Paulo - Disciplina de Reumatologia, Rua Botucatu, 740, 3o andar, São Paulo, SP, 04023-062, Brazil.
| | | | | | | | - Rafael Alves Cordeiro
- Rheumatology Division, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
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15
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Muñoz Forti K, Weisman GA, Jasmer KJ. Cell type-specific transforming growth factor-β (TGF-β) signaling in the regulation of salivary gland fibrosis and regeneration. J Oral Biol Craniofac Res 2024; 14:257-272. [PMID: 38559587 PMCID: PMC10979288 DOI: 10.1016/j.jobcr.2024.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 01/13/2024] [Accepted: 03/09/2024] [Indexed: 04/04/2024] Open
Abstract
Salivary gland damage and hypofunction result from various disorders, including autoimmune Sjögren's disease (SjD) and IgG4-related disease (IgG4-RD), as well as a side effect of radiotherapy for treating head and neck cancers. There are no therapeutic strategies to prevent the loss of salivary gland function in these disorders nor facilitate functional salivary gland regeneration. However, ongoing aquaporin-1 gene therapy trials to restore saliva flow show promise. To identify and develop novel therapeutic targets, we must better understand the cell-specific signaling processes involved in salivary gland regeneration. Transforming growth factor-β (TGF-β) signaling is essential to tissue fibrosis, a major endpoint in salivary gland degeneration, which develops in the salivary glands of patients with SjD, IgG4-RD, and radiation-induced damage. Though the deposition and remodeling of extracellular matrix proteins are essential to repair salivary gland damage, pathological fibrosis results in tissue hardening and chronic salivary gland dysfunction orchestrated by multiple cell types, including fibroblasts, myofibroblasts, endothelial cells, stromal cells, and lymphocytes, macrophages, and other immune cell populations. This review is focused on the role of TGF-β signaling in the development of salivary gland fibrosis and the potential for targeting TGF-β as a novel therapeutic approach to regenerate functional salivary glands. The studies presented highlight the divergent roles of TGF-β signaling in salivary gland development and dysfunction and illuminate specific cell populations in damaged or diseased salivary glands that mediate the effects of TGF-β. Overall, these studies strongly support the premise that blocking TGF-β signaling holds promise for the regeneration of functional salivary glands.
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Affiliation(s)
- Kevin Muñoz Forti
- Christopher S. Bond Life Sciences Center and Department of Biochemistry, University of Missouri, United States
| | - Gary A. Weisman
- Christopher S. Bond Life Sciences Center and Department of Biochemistry, University of Missouri, United States
| | - Kimberly J. Jasmer
- Christopher S. Bond Life Sciences Center and Department of Biochemistry, University of Missouri, United States
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16
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Tanaka S, Yamamoto T, Iwata A, Kiuchi M, Kokubo K, Iinuma T, Sugiyama T, Hanazawa T, Hirahara K, Ikeda K, Nakajima H. Single-cell RNA sequencing of submandibular gland reveals collagen type XV-positive fibroblasts as a disease-characterizing cell population of IgG4-related disease. Arthritis Res Ther 2024; 26:55. [PMID: 38378635 PMCID: PMC10877852 DOI: 10.1186/s13075-024-03289-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 02/16/2024] [Indexed: 02/22/2024] Open
Abstract
OBJECTIVES IgG4-related disease (IgG4-RD) is a systemic autoimmune disease with an unknown etiology, affecting single/multiple organ(s). Pathological findings include the infiltration of IgG4-producing plasma cells, obliterative phlebitis, and storiform fibrosis. Although immunological studies have shed light on the dysregulation of lymphocytes in IgG4-RD pathogenesis, the role of non-immune cells remains unclear. This study aimed to investigate the demographics and characteristics of non-immune cells in IgG4-RD and explore potential biomarkers derived from non-immune cells in the sera. METHODS We conducted single-cell RNA sequence (scRNA-seq) on non-immune cells isolated from submandibular glands of IgG4-RD patients. We focused on fibroblasts expressing collagen type XV and confirmed the presence of those fibroblasts using immunohistochemistry. Additionally, we measured the levels of collagen type XV in the sera of IgG4-RD patients. RESULTS The scRNA-seq analysis revealed several distinct clusters consisting of fibroblasts, endothelial cells, ductal cells, and muscle cells. Differential gene expression analysis showed upregulation of COL15A1 in IgG4-RD fibroblasts compared to control subjects. Notably, COL15A1-positive fibroblasts exhibited a distinct transcriptome compared to COL15A1-negative counterparts. Immunohistochemical analysis confirmed a significant presence of collagen type XV-positive fibroblasts in IgG4-RD patients. Furthermore, immune-suppressive therapy in active IgG4-RD patients resulted in decreased serum levels of collagen type XV. CONCLUSIONS Our findings suggest that collagen type XV-producing fibroblasts may represent a disease-characterizing non-immune cell population in IgG4-RD and hold potential as a disease-monitoring marker.
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Affiliation(s)
- Shigeru Tanaka
- Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba, 260-8670, Japan.
| | - Takuya Yamamoto
- Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba, 260-8670, Japan
| | - Arifumi Iwata
- Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba, 260-8670, Japan
| | - Masahiro Kiuchi
- Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kota Kokubo
- Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tomohisa Iinuma
- Department of Otorhinolaryngology/Head & Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takahiro Sugiyama
- Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba, 260-8670, Japan
| | - Toyoyuki Hanazawa
- Department of Otorhinolaryngology/Head & Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kiyoshi Hirahara
- Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kei Ikeda
- Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba, 260-8670, Japan.
- Department of Rheumatology, Dokkyo Medical University, 880 Kitakobayashi, Shimotsuga, Tochigi, Mibu, 321 - 0293, Japan.
| | - Hiroshi Nakajima
- Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba, 260-8670, Japan
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17
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Bennouna I, Bali MA, Gomez Galdon M, Veron Sanchez A. An Uncommon Expression of Immunoglobulin G4 (IgG4)-Related Disease: Sclerosing Mesenteritis Concomitant With IgG4-Related Autoimmune Pancreatitis. Cureus 2023; 15:e50529. [PMID: 38222156 PMCID: PMC10787606 DOI: 10.7759/cureus.50529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/14/2023] [Indexed: 01/16/2024] Open
Abstract
A 63-year-old male presented to our oncological hospital with a one-year evolving abdominal pain, with an abdominal mass feeling. Contrast-enhanced computed tomography displayed two soft tissue masses, one at the mesentery root and the second around the pancreatic tail; at the same time the patient presented with hyperlipasemia. Endoscopic biopsy for the pancreatic mass and surgical biopsy of the mesenteric one were performed in order to narrow diagnosis. No neoplastic cells but only dense fibro-inflammatory changes with immunoglobulin G4 (IgG4)-positive plasma cell inclusions were observed for both biopsies. A diagnostic and therapeutic strategy based on high suspicion of IgG4-related disease was adopted, with good clinical and imaging response to corticotherapy.
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Affiliation(s)
- Ilias Bennouna
- Radiology, Centre Hospitalier Interrégional Edith Cavell (CHIREC) Braine l'Alleud, Bruxelles, BEL
- Radiology, Institut Jules Bordet, Bruxelles, BEL
| | | | - Maria Gomez Galdon
- Pathology, Hôpital Universitaire de Bruxelles, Institut Jules Bordet, Brussels, BEL
| | - Ana Veron Sanchez
- Radiology, Hôpital Universitaire de Bruxelles, Institut Jules Bordet, Brussels, BEL
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18
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Perugino C, Culver EL, Khosroshahi A, Zhang W, Della-Torre E, Okazaki K, Tanaka Y, Löhr M, Schleinitz N, Falloon J, She D, Cimbora D, Stone JH. Efficacy and Safety of Inebilizumab in IgG4-Related Disease: Protocol for a Randomized Controlled Trial. Rheumatol Ther 2023; 10:1795-1808. [PMID: 37792260 PMCID: PMC10654302 DOI: 10.1007/s40744-023-00593-7] [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] [Received: 07/11/2023] [Accepted: 08/08/2023] [Indexed: 10/05/2023] Open
Abstract
INTRODUCTION Immunoglobulin G4-related disease (IgG4-RD) is a debilitating multiorgan disease characterized by recurring flares leading to organ dysfunction, decreased quality of life, and mortality. Glucocorticoids, the standard of care for IgG4-RD, are associated with substantial treatment-related toxicity. Inebilizumab, an antibody directed against CD19, mediates the rapid and durable depletion of CD19+ B cells thought to be involved in IgG4-RD pathogenesis. We describe the first international, prospective, double-blind, placebo-controlled trial to evaluate the safety and efficacy of B-cell depletion for flare prevention in IgG4-RD (MITIGATE). METHODS The study was designed by an international panel of physicians with expertise in IgG4-RD. Critical trial design decisions included the selection of participants, definition of clinically meaningful primary and secondary endpoints, accommodation of standard of care, and development of flare diagnostic criteria. The study is approved for conduct in 22 countries. PLANNED OUTCOMES The primary efficacy endpoint is time from randomization to the occurrence of the first centrally adjudicated and investigator-treated disease flare during the 1-year randomized controlled period. A set of novel, organ-specific flare diagnostic criteria were developed specifically for this trial, incorporating symptoms and signs, laboratory findings, imaging study results, and pathology data. MITIGATE aims to accrue 39 flares for the primary endpoint, which provides sufficient power to detect a relative risk reduction of 65% in the inebilizumab group. It is anticipated that enrollment of 160 participants will achieve this goal. Additional endpoints include safety, annualized flare rate, flare-free complete remission, quality-of-life measures, and cumulative glucocorticoid use. MITIGATE represents the first randomized, double-blind, placebo-controlled trial of any treatment strategy conducted in IgG4-RD. Data from this study will provide insights into the natural history and pathophysiology of IgG4-RD and the efficacy and safety of B-cell depletion as a therapeutic avenue. TRIAL REGISTRATION NCT04540497.
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Affiliation(s)
- Cory Perugino
- Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA
| | - Emma L Culver
- Translational Gastroenterology Unit, John Radcliffe Hospital, and Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Arezou Khosroshahi
- Division of Rheumatology, Emory University School of Medicine, Atlanta, GA, USA
| | - Wen Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China
| | - Emanuel Della-Torre
- Unit of Immunology, Rheumatology, Allergy, and Rare Diseases (UnIRAR), San Raffaele Hospital, Milan, Italy
| | - Kazuichi Okazaki
- Department of Internal Medicine, Kansai Medical University Kori Hospital, Osaka, Japan
| | - Yoshiya Tanaka
- The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Matthias Löhr
- Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Nicolas Schleinitz
- Département de Medecine Interne, CHU Timone, AP-HM, Aix-Marseille Université, Marseille, France
| | | | - Dewei She
- Horizon Therapeutics, Rockville, MD, USA
| | | | - John H Stone
- Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
- Rheumatology Unit, Massachusetts General Hospital, 55 Fruit Street, Suite Yawkey 4, Boston, MA, 02114, USA.
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19
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Kersten R, Trampert DC, Herta T, Hubers LM, Maillette de Buy Wenniger LJ, Verheij J, van de Graaf SFJ, Beuers U. IgG4-related cholangitis - a mimicker of fibrosing and malignant cholangiopathies. J Hepatol 2023; 79:1502-1523. [PMID: 37598939 DOI: 10.1016/j.jhep.2023.08.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 07/24/2023] [Accepted: 08/14/2023] [Indexed: 08/22/2023]
Abstract
IgG4-related cholangitis (IRC) is the major hepatobiliary manifestation of IgG4-related disease (IgG4-RD), a systemic fibroinflammatory disorder. The pathogenesis of IgG4-RD and IRC is currently viewed as multifactorial, as there is evidence of a genetic predisposition while environmental factors, such as blue-collar work, are major risk factors. Various autoantigens have been described in IgG4-RD, including annexin A11 and laminin 511-E8, proteins which may exert a partially protective function in cholangiocytes by enhancing secretion and barrier function, respectively. For the other recently described autoantigens, galectin-3 and prohibitin 1, a distinct role in cholangiocytes appears less apparent. In relation to these autoantigens, oligoclonal expansions of IgG4+ plasmablasts are present in patients with IRC and disappear upon successful treatment. More recently, specific T-cell subtypes including regulatory T cells, follicular T helper 2 cells, peripheral T helper cells and cytotoxic CD8+ and CD4+ SLAMF7+ T cells have been implicated in the pathogenesis of IgG4-RD. The clinical presentation of IRC often mimics other biliary diseases such as primary sclerosing cholangitis or cholangiocarcinoma, which may lead to inappropriate medical and potentially invalidating surgical interventions. As specific biomarkers are lacking, diagnosis is made according to the HISORt criteria comprising histopathology, imaging, serology, other organ manifestations and response to therapy. Treatment of IRC aims to prevent or alleviate organ damage and to improve symptoms and consists of (i) remission induction, (ii) remission maintenance and (iii) long-term management. Glucocorticosteroids are highly effective for remission induction, after which immunomodulators can be introduced for maintenance of remission as glucocorticosteroid-sparing alternatives. Increased insight into the pathogenesis of IRC will lead to improved diagnosis and novel therapeutic strategies in the future.
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Affiliation(s)
- Remco Kersten
- Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - David C Trampert
- Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Toni Herta
- Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam University Medical Centers, Amsterdam, the Netherlands; Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Lowiek M Hubers
- Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | | | - Joanne Verheij
- Department of Pathology, Amsterdam University Medical Centers, the Netherlands
| | - Stan F J van de Graaf
- Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Ulrich Beuers
- Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam University Medical Centers, Amsterdam, the Netherlands.
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20
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Mohrag M, Abdulrasak M, Binsalman M, Darraj M. A Case Report of a Challenging Disease: Immunoglobulin G4-Related Disease With Acute Kideny Injury. J Med Cases 2023; 14:339-343. [PMID: 37868324 PMCID: PMC10586334 DOI: 10.14740/jmc4159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 10/09/2023] [Indexed: 10/24/2023] Open
Abstract
Immunoglobulin G4-related disease (IgG4-RD), which was initially identified as a type of autoimmune pancreatitis around the year 2000, is now widely acknowledged to be a systemic sickness. Based on both general and organ-specific criteria, alongside laboratory measurements of IgG4-subtype, the diagnosis is made. The diagnosis requires, however, a heightened index of suspicion, especially given the nonspecific clinical presentation. In addition to this, the symptoms may be "disseminated" in time and the multitude of organ-system involvement may seem initially unrelated. Furthermore, IgG4 levels may be falsely normal especially during the first presentation of IgG4-RD. We report a case of a 33-year-old male who was referred by his general practitioner (GP) to the fast access nephrology clinic due to elevated creatinine and fatigue, which was found after the patient had undergone some investigations at the GP office. He had history of atopic dermatitis and a prior admission for acute pancreatitis of unknown cause and recent bilateral anterior uveitis treated with steroid eyedrops. His urinalysis showed one to two granular casts per high-power field (HPF), and his creatinine was 262 µmol/L (previously normal). Three main differential diagnoses were considered given the patient's history: sarcoidosis, tubulointerstitial nephritis with uveitis (TINU) and IgG4-related disorder. Investigations were undertaken in that regard showing elevated serum IgG4 levels (2.7 times upper-limit of normal). Renal biopsy demonstrated tubulointerstitial nephritis (TIN) with 30 IgG4-positive plasma cells per HPF. Given the patient's presentation over time, a diagnosis of IgG4-TIN was considered. The patient was treated with high-dose steroids and has shown signs of improvement of both his renal and ocular problems. The uniqueness of the case is reflected through the fact that IgG4-renal disease is usually diagnosed in patients with an already established manifestation of another organ, whilst in our patient the renal involvement led to establishing IgG4-RD. It is also important to note that, in spite of initially negative serum IgG4 levels, the diagnosis still needs to be considered especially if multisystem involvement is present (as in this case).
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Affiliation(s)
- Mostafa Mohrag
- Department of Medicine, Faculty of Medicine, Jazan University, Jazan, Saudi Arabia
| | - Mohammed Abdulrasak
- Department of Clinical Sciences, Malmo, Lund University, Malmo, Sweden
- Department of Gastroenterology and Nutrition, Skane University Hospital, Malmo, Sweden
| | - Mohammed Binsalman
- Department of Clinical Sciences, Malmo, Lund University, Malmo, Sweden
- Department of Gastroenterology and Nutrition, Skane University Hospital, Malmo, Sweden
| | - Majid Darraj
- Department of Medicine, Faculty of Medicine, Jazan University, Jazan, Saudi Arabia
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21
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Parry PI, Lefringhausen A, Turni C, Neil CJ, Cosford R, Hudson NJ, Gillespie J. 'Spikeopathy': COVID-19 Spike Protein Is Pathogenic, from Both Virus and Vaccine mRNA. Biomedicines 2023; 11:2287. [PMID: 37626783 PMCID: PMC10452662 DOI: 10.3390/biomedicines11082287] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 07/17/2023] [Accepted: 07/24/2023] [Indexed: 08/27/2023] Open
Abstract
The COVID-19 pandemic caused much illness, many deaths, and profound disruption to society. The production of 'safe and effective' vaccines was a key public health target. Sadly, unprecedented high rates of adverse events have overshadowed the benefits. This two-part narrative review presents evidence for the widespread harms of novel product COVID-19 mRNA and adenovectorDNA vaccines and is novel in attempting to provide a thorough overview of harms arising from the new technology in vaccines that relied on human cells producing a foreign antigen that has evidence of pathogenicity. This first paper explores peer-reviewed data counter to the 'safe and effective' narrative attached to these new technologies. Spike protein pathogenicity, termed 'spikeopathy', whether from the SARS-CoV-2 virus or produced by vaccine gene codes, akin to a 'synthetic virus', is increasingly understood in terms of molecular biology and pathophysiology. Pharmacokinetic transfection through body tissues distant from the injection site by lipid-nanoparticles or viral-vector carriers means that 'spikeopathy' can affect many organs. The inflammatory properties of the nanoparticles used to ferry mRNA; N1-methylpseudouridine employed to prolong synthetic mRNA function; the widespread biodistribution of the mRNA and DNA codes and translated spike proteins, and autoimmunity via human production of foreign proteins, contribute to harmful effects. This paper reviews autoimmune, cardiovascular, neurological, potential oncological effects, and autopsy evidence for spikeopathy. With many gene-based therapeutic technologies planned, a re-evaluation is necessary and timely.
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Affiliation(s)
- Peter I. Parry
- Children’s Health Research Clinical Unit, Faculty of Medicine, The University of Queensland, South Brisbane, QLD 4101, Australia
- Department of Psychiatry, College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia
| | - Astrid Lefringhausen
- Children’s Health Defence (Australia Chapter), Huskisson, NSW 2540, Australia; (A.L.); (R.C.); (J.G.)
| | - Conny Turni
- Microbiology Research, QAAFI (Queensland Alliance for Agriculture and Food Innovation), The University of Queensland, St. Lucia, QLD 4072, Australia;
| | - Christopher J. Neil
- Department of Medicine, University of Melbourne, Melbourne, VIC 3010, Australia;
| | - Robyn Cosford
- Children’s Health Defence (Australia Chapter), Huskisson, NSW 2540, Australia; (A.L.); (R.C.); (J.G.)
| | - Nicholas J. Hudson
- School of Agriculture and Food Science, The University of Queensland, Brisbane, QLD 4072, Australia;
| | - Julian Gillespie
- Children’s Health Defence (Australia Chapter), Huskisson, NSW 2540, Australia; (A.L.); (R.C.); (J.G.)
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22
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Wang W, Kang X, Ding Y, Mao L, Dilinuer A, Li W. IgG4-Related Disease Manifested as Cutaneous Plasmacytosis: A Case Report. Clin Cosmet Investig Dermatol 2023; 16:1997-2004. [PMID: 37554302 PMCID: PMC10404591 DOI: 10.2147/ccid.s406199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 07/08/2023] [Indexed: 08/10/2023]
Abstract
BACKGROUND IgG4-related disease (IgG4-RD) is a rare fibroinflammatory disease that has a high tendency to misdiagnosis in clinics. CASE PRESENTATION A 48-year-old man developed a rash with progressive itching 3 years ago after hormone therapy for an ocular "inflammatory pseudotumor". The disease condition of this patient involved multiple organs which involved the skin. The patient was misdiagnosed with other diseases during the period of hospitalization, leading to poor therapeutic effects and repeated skin lesions. The dermatopathological report indicated plasma cell proliferative disorder, with IgG4/IgG exceeding 40% and abnormally elevated serum IgG4 levels. After the patient was diagnosed with IgG4-RD, a series of treatments improved skin lesions, relieved other symptoms, and decreased serum IgG4 levels. CONCLUSION IgG4-RD is a highly misdiagnosed disease that deserves the attention of physicians. The patient we reported could be considered a representative case of IgG4-RD that presents with skin lesions. For patients with suspected IgG4-RD, serum IgG4 testing should be performed, and further imaging, serological tests, and pathology examinations are needed to exclude malignancy, infection, and autoimmune diseases.
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Affiliation(s)
- Weijia Wang
- Department of Dermatology and Venereology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, People’s Republic of China
- Xinjiang Clinical Research Center for Dermatologic Diseases, Urumqi, People’s Republic of China
- Xinjiang Key Laboratory of Dermatology Research (XJYS1707), Urumqi, People’s Republic of China
| | - Xiaojing Kang
- Department of Dermatology and Venereology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, People’s Republic of China
- Xinjiang Clinical Research Center for Dermatologic Diseases, Urumqi, People’s Republic of China
- Xinjiang Key Laboratory of Dermatology Research (XJYS1707), Urumqi, People’s Republic of China
| | - Yuan Ding
- Department of Dermatology and Venereology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, People’s Republic of China
- Xinjiang Clinical Research Center for Dermatologic Diseases, Urumqi, People’s Republic of China
- Xinjiang Key Laboratory of Dermatology Research (XJYS1707), Urumqi, People’s Republic of China
| | - Lidan Mao
- Department of Dermatology and Venereology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, People’s Republic of China
- Xinjiang Clinical Research Center for Dermatologic Diseases, Urumqi, People’s Republic of China
- Xinjiang Key Laboratory of Dermatology Research (XJYS1707), Urumqi, People’s Republic of China
| | - Abudureyimu Dilinuer
- Department of Dermatology and Venereology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, People’s Republic of China
- Xinjiang Clinical Research Center for Dermatologic Diseases, Urumqi, People’s Republic of China
- Xinjiang Key Laboratory of Dermatology Research (XJYS1707), Urumqi, People’s Republic of China
| | - Wenzheng Li
- Department of Dermatology and Venereology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, People’s Republic of China
- Xinjiang Clinical Research Center for Dermatologic Diseases, Urumqi, People’s Republic of China
- Xinjiang Key Laboratory of Dermatology Research (XJYS1707), Urumqi, People’s Republic of China
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23
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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: 38] [Impact Index Per Article: 19.0] [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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24
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Poto R, Loffredo S, Marone G, Di Salvatore A, de Paulis A, Schroeder JT, Varricchi G. Basophils beyond allergic and parasitic diseases. Front Immunol 2023; 14:1190034. [PMID: 37205111 PMCID: PMC10185837 DOI: 10.3389/fimmu.2023.1190034] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 04/14/2023] [Indexed: 05/21/2023] Open
Abstract
Basophils bind IgE via FcεRI-αβγ2, which they uniquely share only with mast cells. In doing so, they can rapidly release mediators that are hallmark of allergic disease. This fundamental similarity, along with some morphological features shared by the two cell types, has long brought into question the biological significance that basophils mediate beyond that of mast cells. Unlike mast cells, which mature and reside in tissues, basophils are released into circulation from the bone marrow (constituting 1% of leukocytes), only to infiltrate tissues under specific inflammatory conditions. Evidence is emerging that basophils mediate non-redundant roles in allergic disease and, unsuspectingly, are implicated in a variety of other pathologies [e.g., myocardial infarction, autoimmunity, chronic obstructive pulmonary disease, fibrosis, cancer, etc.]. Recent findings strengthen the notion that these cells mediate protection from parasitic infections, whereas related studies implicate basophils promoting wound healing. Central to these functions is the substantial evidence that human and mouse basophils are increasingly implicated as important sources of IL-4 and IL-13. Nonetheless, much remains unclear regarding the role of basophils in pathology vs. homeostasis. In this review, we discuss the dichotomous (protective and/or harmful) roles of basophils in a wide spectrum of non-allergic disorders.
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Affiliation(s)
- Remo Poto
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
- World Allergy Organization (WAO), Center of Excellence (CoE), Naples, Italy
| | - Stefania Loffredo
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
- World Allergy Organization (WAO), Center of Excellence (CoE), Naples, Italy
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
- Institute of Experimental Endocrinology and Oncology “G. Salvatore”, National Research Council (CNR), Naples, Italy
| | - Gianni Marone
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
- World Allergy Organization (WAO), Center of Excellence (CoE), Naples, Italy
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
- Institute of Experimental Endocrinology and Oncology “G. Salvatore”, National Research Council (CNR), Naples, Italy
| | - Antonio Di Salvatore
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Amato de Paulis
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
- World Allergy Organization (WAO), Center of Excellence (CoE), Naples, Italy
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
| | - John T. Schroeder
- Division of Allergy and Clinical Immunology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Gilda Varricchi
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
- World Allergy Organization (WAO), Center of Excellence (CoE), Naples, Italy
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
- Institute of Experimental Endocrinology and Oncology “G. Salvatore”, National Research Council (CNR), Naples, Italy
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25
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Li P, Zhou Y, Liu H, Yin W, Li J, Luo M. IgG4-related disease with kidney and lymph nodes involvement: a case-based review. Rheumatol Int 2023; 43:1183-1193. [PMID: 36912940 DOI: 10.1007/s00296-023-05295-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 02/23/2023] [Indexed: 03/14/2023]
Abstract
IgG4-related disease (IgG4-RD), a rare immune-mediated chronic fibro-inflammatory condition, has various initial symptoms, thus posing diagnostic and therapeutic challenges. Here, we report a case of IgG4-RD in a 35-year-old man with initial clinical symptoms of facial edema and recent onset of proteinuria. It took more than 1 year from the onset of clinical symptoms to diagnosis. Pathological examination of renal biopsy revealed significant renal interstitial lymphoid tissue hyperplasia simulating growth pattern of lymphoma. Immunohistochemical (IHC) staining results showed that CD4 + T lymphocyte hyperplasia was dominant. There was no significant deletion of CD2/CD3/CD5/CD7. No monoclone was detected in TCR gene rearrangement. IHC staining showed that the number of IgG4-positive cells was greater than 100/HPF. The ratio of IgG4/IgG was greater than 40%. Combined with clinically examinations, IgG4-related tubulointerstitial nephritis was considered. Further cervical lymph node biopsy results suggested IgG4-related lymphadenopathy. He received methylprednisolone 40 mg/day intravenously for 10 days, leading to normal results of laboratory tests and clinical manifestations. The patient had a good prognosis without recurrence during 14 months of follow-up. This case report can be used as a reference for early diagnosis and treatment of such patients in the future.
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Affiliation(s)
- Ping Li
- Department of Pathology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, 518036, Guangdong Province, China.
| | - Yuejia Zhou
- Department of Radiation Oncology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, 518036, Guangdong Province, China
| | - Huanyu Liu
- Department of Pathology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, 518036, Guangdong Province, China
| | - Weihua Yin
- Department of Pathology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, 518036, Guangdong Province, China
| | - Jian Li
- Department of Pathology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, 518036, Guangdong Province, China
| | - Minghua Luo
- Department of Pathology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, 518036, Guangdong Province, China
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26
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IgG4-Related Oesophageal Disease with Cytomegalovirus Infection: A Case Report. J Pers Med 2023; 13:jpm13030493. [PMID: 36983676 PMCID: PMC10059879 DOI: 10.3390/jpm13030493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 03/06/2023] [Accepted: 03/08/2023] [Indexed: 03/12/2023] Open
Abstract
Immunoglobulin G4-related disease (IgG4-RD) is a fibrous inflammatory process related to immunomodulation. The involvement of the pancreato-biliary tract, retroperitoneum/aorta, head and neck, and salivary glands are the most frequently observed disease phenotypes, differing in their epidemiological features, serological findings, and prognostic outcomes. IgG4-RD was combined with oesophageal ulcers, and the patients were infected with cytomegalovirus at the time of the examination. This constituted a huge challenge in the diagnosis and treatment of oesophageal ulcers. We report the case of a 53-year-old male who experienced nausea, vomiting, and anaemia recurrently for many years. According to his medical records, an upper gastrointestinal endoscopy revealed an oesophageal ulcer, and he had had numerous hospital visits for anaemia but with no definitive diagnosis, and he had responded poorly to therapy. However, with persistent symptoms, he came to our hospital and, according to the results of the upper gastrointestinal endoscopy, a serum IgG4 test, and histopathological and immunohistochemical staining, he was finally diagnosed with IgG4-related oesophageal disease combined with a cytomegalovirus infection. We hope that through this case, we can learn more about IgG4-RD and, at the same time, give clinicians a better understanding of IgG4-RD combined with oesophageal ulceration, a new understanding of cytomegalovirus infections, and improved clinical knowledge.
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27
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Lanzillotta M, Stone JH, Della-Torre E. B-Cell depletion therapy in IgG4-related disease: State of the art and future perspectives. Mod Rheumatol 2023; 33:258-265. [PMID: 35983918 DOI: 10.1093/mr/roac098] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/13/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022]
Abstract
IgG4-related disease (IgG4-RD) is an increasingly recognized immune-mediated fibroinflammatory disorder that promptly responds to glucocorticoids but commonly relapses during steroid tapering or after discontinuation. In the last few years, B-cell depletion therapy with rituximab (RTX) proved to be effective in the induction of remission and maintenance treatment of IgG4-RD, providing a new powerful tool in the management of this emerging condition. In this review, we outline the pathogenetic rationale for using B-cell depleting agents in IgG4-RD, we summarize available clinical experience with RTX in this disease, and we describe future possible therapies targeting B-lymphocytes that are now in the pipeline.
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Affiliation(s)
- Marco Lanzillotta
- IRCCS San Raffaele Scientific Institute, Università Vita-Salute San Raffaele, Milan, Italy.,Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - John H Stone
- Rheumatology Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Emanuel Della-Torre
- IRCCS San Raffaele Scientific Institute, Università Vita-Salute San Raffaele, Milan, Italy.,Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
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28
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Wu H, Lei D, Zhang X, Wang M, Wang Y, Xia J, Chen F, Chen B, Tian Y. Effects of Fibulin-5 Gene Silencing on Proliferation and Apoptosis of IgG4-ROD Lacrimal Gland Fibroblasts. Stem Cells Int 2023; 2023:2742839. [PMID: 36818161 PMCID: PMC9937754 DOI: 10.1155/2023/2742839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/13/2022] [Accepted: 10/12/2022] [Indexed: 02/12/2023] Open
Abstract
Objective This study is aimed at discussing the value of RNA interference technology on inhibiting lacrimal gland fibrosis in IgG4-related ocular disease (IgG4-ROD). Methods Six patients with IgG4-ROD who came to the hospital for surgical treatment from October 2018 to August 2019 were selected, and their diseased lacrimal glands were taken for primary cell culture and fibroblast identification. High efficiency and specificity small interference RNA (siRNA) plasmid vector was constructed, its inhibitory effect on fibroblast proliferation was determined by CCK-8 assay, and the appropriate concentration was selected as the siRNA concentration for subsequent experiments. RT-PCR and Western blot detected the relative expression levels of Fibulin-5 mRNA and protein in the cells 48 hours after transfection. The apoptosis rate of each group of cells at 24 hours, 48 hours, and 72 hours after transfection was detected by flow cytometry, and the proliferation and apoptosis of cells after silencing Fibulin-5 were analyzed and compared. Results 24 hours after transfection, there was no significant difference in the proliferation rate among the four groups (P > 0.05); 48 hours and 72 hours after Fibulin-5 siRNA transfection, the proliferation activity of the transfected cells was significantly decreased compared with the 0 nM group, and the inhibitory effect of 75 nM siRNA was the strongest. The expression of Fibulin-5 mRNA and protein in the siRNA-transfected cells was significantly decreased compared with the blank and empty vector negative siRNA groups, and the difference was statistically significant (P < 0.05). The apoptosis rate of cells in the Fibulin-5 siRNA transfection group was significantly higher than that of cells in the blank and empty vector negative siRNA groups, and the difference was statistically significant (P < 0.05). Conclusion Fibulin-5 siRNA recombinant plasmid can significantly downregulate the mRNA and protein expressions of target gene Fibulin-5 and promote apoptosis after transfection into IgG4-ROD lacrimal gland fibroblasts. It is speculated that Fibulin-5 can be used as a target to effectively inhibit the fibrosis of lacrimal gland tissues by RNAi technique.
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Affiliation(s)
- Huarong Wu
- Department of Ophthalmology, Anqing Municipal Hospital, Anqing, China
| | - Daikun Lei
- Department of Ophthalmology, Beijing Road Medical District, General Hospital of Xinjiang Military Region, Urumqi, Xinjiang, China
| | - Xiaoling Zhang
- Department of Ophthalmology, Beijing Road Medical District, General Hospital of Xinjiang Military Region, Urumqi, Xinjiang, China
| | - Mengfei Wang
- AIER Eye Hospital Group, Sichuan Eye Hospital, Sichuan, China
| | - Yuanyuan Wang
- Department of Ophthalmology, The First People's Hospital of Pinghu (Pinghu Hospital Affiliated to Hangzhou Medical University), Pinghu, China
| | - Jie Xia
- Department of Ophthalmology, Lujiang County People's Hospital, Hefei, China
| | - Fan Chen
- Department of Ophthalmology, Anqing Municipal Hospital, Anqing, China
| | - Bei Chen
- Department of Ophthalmology, Anqing Municipal Hospital, Anqing, China
| | - Yanming Tian
- Department of Ophthalmology, Beijing Road Medical District, General Hospital of Xinjiang Military Region, Urumqi, Xinjiang, China
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29
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Yang F, Liu Z, Zhang Y, Li P, Zhu Y, Zhu Q, Zhang B. Case report: Clinical highlights and radiological classification of IgG4-related spinal pachymeningitis: A rare case series and updated review of the literature. Front Oncol 2023; 12:1035056. [PMID: 36703781 PMCID: PMC9873374 DOI: 10.3389/fonc.2022.1035056] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 12/22/2022] [Indexed: 01/12/2023] Open
Abstract
Purpose Hypertrophic pachymeningitis associated with immunoglobulin G4-related disease (IgG4-RD) has been rarely reported, and there is little information and no clear consensus on the management of IgG4-related spinal pachymeningitis (IgG4-RSP). The present study described its possible clinical features, including the symptoms, imaging, treatment and prognosis of patients with IgG4-RSP. Methods We report three patients who presented with progressive neurological dysfunction due to spinal cord compression. Relevant articles were searched from the PubMed, Web of Science, and Embase databases, and the resulting literature was reviewed. Results The literature review provided a summary of 45 available cases, which included three cases from our center. Progressive worsening of neurological impairment was observed in 22 patients (48.9%). The lesions involved the thoracic spine (n=28, 62.2%), cervical spine (n=26, 57.8%), lumbar spine (n=9, 20.0%), and sacral spine (n=1, 2.2%). Furthermore, the lesions were located in the dura mater (n=18, 40.0%), epidural space (n=17, 37.8%), intradural-extramedullary space (n=9, 20.0%), and intramedullary space (n=1, 2.2%). On magnetic resonance imaging (MRI), the lesions generally appeared as striated, fusiform, or less often lobulated oval changes, with homogeneous (n=17,44.7%) and dorsal (n=15,39.5%) patterns being the most common. Thirty-five patients had homogeneous T1 gadolinium enhancement. Early surgical decompression, corticosteroid treatment, and steroid-sparing agents offered significant therapeutic advantages. A good therapeutic response to disease recurrence was observed with the medication. Conclusion The number of reported cases of IgG4-RSP remains limited, and patients often have progressive worsening of their neurological symptoms. The features of masses identified on the MRI should be considered. The prognosis was better with decompression surgery combined with immunosuppressive therapy. Long-term corticosteroid treatment and steroid-sparing agent maintenance therapy should be ensured. A systemic examination is recommended to identify the presence of other pathologies.
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Nista EC, De Lucia SS, Manilla V, Schepis T, Pellegrino A, Ojetti V, Pignataro G, Zileri dal Verme L, Franceschi F, Gasbarrini A, Candelli M. Autoimmune Pancreatitis: From Pathogenesis to Treatment. Int J Mol Sci 2022; 23:ijms232012667. [PMID: 36293522 PMCID: PMC9604056 DOI: 10.3390/ijms232012667] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/14/2022] [Accepted: 10/18/2022] [Indexed: 11/05/2022] Open
Abstract
Autoimmune pancreatitis (AIP) is a rare disease. The diagnosis of AIP is difficult and should be made by a comprehensive evaluation of clinical, radiological, serological, and pathological findings. Two different types of AIP have been identified: autoimmune pancreatitis type 1 (AIP-1), which is considered a pancreatic manifestation of multiorgan disease related to IgG4, and autoimmune pancreatitis type 2 (AIP-2), which is considered a pancreas-specific disease not related to IgG4. Although the pathophysiological conditions seem to differ between type 1 and type 2 pancreatitis, both respond well to steroid medications. In this review, we focused on the pathogenesis of the disease to develop a tool that could facilitate diagnosis and lead to the discovery of new therapeutic strategies to combat autoimmune pancreatitis and its relapses. The standard therapy for AIP is oral administration of corticosteroids. Rituximab (RTX) has also been proposed for induction of remission and maintenance therapy in relapsing AIP-1. In selected patients, immunomodulators such as azathioprine are used to maintain remission. The strength of this review, compared with previous studies, is that it focuses on the clear difference between the two types of autoimmune pancreatitis with a clearly delineated and separate pathogenesis. In addition, the review also considers various therapeutic options, including biologic drugs, such as anti-tumor necrosis factor (TNF) therapy, a well-tolerated and effective second-line therapy for AIP type 2 relapses or steroid dependence. Other biologic therapies are also being explored that could provide a useful therapeutic alternative to corticosteroids and immunosuppressants, which are poorly tolerated due to significant side effects.
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Affiliation(s)
- Enrico Celestino Nista
- Department of Medical and Surgical Sciences, Università Cattolica Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Sara Sofia De Lucia
- Department of Medical and Surgical Sciences, Università Cattolica Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Vittoria Manilla
- Department of Medical and Surgical Sciences, Università Cattolica Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Tommaso Schepis
- Department of Medical and Surgical Sciences, Università Cattolica Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Antonio Pellegrino
- Department of Medical and Surgical Sciences, Università Cattolica Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Veronica Ojetti
- Department of Emergency, Anesthesiological, and Reanimation Sciences, Università Cattolica Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Giulia Pignataro
- Department of Emergency, Anesthesiological, and Reanimation Sciences, Università Cattolica Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Lorenzo Zileri dal Verme
- Department of Medical and Surgical Sciences, Università Cattolica Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Francesco Franceschi
- Department of Emergency, Anesthesiological, and Reanimation Sciences, Università Cattolica Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Department of Medical and Surgical Sciences, Università Cattolica Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Marcello Candelli
- Department of Emergency, Anesthesiological, and Reanimation Sciences, Università Cattolica Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
- Correspondence:
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Zhang Z, Liu Y, Zhang L, Cheng C, Zuo C. Renal Pelvis Immunoglobulin G4-Related Disease Mimicking Malignant Tumor: A Case of 18 F-FDG and 68 Ga-FAPI PET/CT Imaging. Clin Nucl Med 2022; 47:815-816. [PMID: 35619197 DOI: 10.1097/rlu.0000000000004292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
ABSTRACT A space-occupying lesion in the left renal pelvis was found in a 56-year-old man. The patient voluntarily participated in a clinical trial of 68 Ga-FAPI in solid tumors. PET/CT images revealed an intense 18 F-FDG and 68 Ga-FAPI uptake in this lesion. Malignant tumor was suspected. The patient subsequently underwent laparoscopic partial nephrectomy. The postoperative pathological examination established the diagnosis of immunoglobulin G4-related disease.
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Affiliation(s)
- Zeyu Zhang
- From the Departments of Nuclear Medicine
| | - Yanfang Liu
- Pathology, Changhai Hospital, Navy Medical University, Shanghai, China
| | - Lu Zhang
- From the Departments of Nuclear Medicine
| | - Chao Cheng
- From the Departments of Nuclear Medicine
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Miyao M, Kawai C, Kotani H, Minami H, Abiru H, Hamayasu H, Yamamoto A, Tamaki K. Fatal Dieulafoy lesion with IgG4-related disease: An autopsy case report. Leg Med (Tokyo) 2022; 57:102059. [DOI: 10.1016/j.legalmed.2022.102059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/24/2022] [Accepted: 04/04/2022] [Indexed: 02/07/2023]
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T Cell Roles and Activity in Chronic Sclerosing Sialadenitis as IgG4-Related Disease: Current Concepts in Immunopathogenesis. Autoimmune Dis 2022; 2022:5689883. [PMID: 35769404 PMCID: PMC9236833 DOI: 10.1155/2022/5689883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 06/07/2022] [Indexed: 11/18/2022] Open
Abstract
IgG4-related disease is a multiorgan immunological fibroinflammatory disorder characterized by lymphoplasmacytic infiltration and fibrosis in multiple organs accompanied by high serum IgG4 levels. The salivary glands are the most common organs involved in this disease. Recently, chronic sclerosing sialadenitis affecting salivary glands, formerly known as Küttner's tumor, and Mikulicz's disease have been classified as a class of IgG4-related diseases. The etiopathobiology of IgG4-related disease is not fully understood. It has recently been hypothesized that the inflammatory and fibrotic process and the increased serum IgG4+ levels in IgG4-related disease are the result of an interaction between B cells and T helper cells, suggesting that T cells may play a key role in the pathogenesis of this disease. The aim of this review is to discuss the proposed roles of different T cell subsets in the pathogenesis of IgG4-related disease focusing on their roles in immunopathogenesis of IgG4-related sialadenitis.
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Qi Z, Liu J, Li G, Zhang Y. Immunoglobulin G4-Related Spinal Intramedullary Inflammatory Pseudotumor: A Case Report and Literature Review. Front Neurol 2022; 13:878414. [PMID: 35837229 PMCID: PMC9275449 DOI: 10.3389/fneur.2022.878414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 05/09/2022] [Indexed: 11/13/2022] Open
Abstract
Immunoglobulin G4-related disease (IgG4-RD) is an autoimmune disease that affects several organs. An inflammatory pseudotumor is a histologically proven benign tumor-like lesion that most commonly involves the lung and orbit. It is rare in the central nervous system, but rarest in the spinal canal. In this report, we present a case of IgG4-related intramedullary spinal inflammatory pseudotumor, along with a literature review. A 29-year-old male was transferred to the Department of Neurosurgery of Lanzhou University Second Hospital with progressive quadriparesis after numbness and weakness in both lower limbs for 50 days. Enhanced magnetic resonance imaging (MRI) of the spine revealed an isointense signal on T1-weighted images and a hyperintense signal on T2-weighted images from an enhanced mass located at the thoracic vertebrae region, for which a schwannoma was highly suspected. Then, a posterior median approach was adopted. The lesion was resected. The patient received further glucocorticoid after the diagnosis of an IgG4-related inflammatory pseudotumor was established, and the patient's symptoms improved, such as quadriparesis and lower limb weakness. This case highlights the importance of considering IgG4-related inflammatory pseudotumor as a differential diagnosis in patients with lesions involving the spinal intramedullary compartment and lower limb weakness when other more threatening causes have been excluded. IgG4-related inflammatory pseudotumor is etiologically unclear and prognostically unpredictable, and imaging may not help establish the diagnosis of IgG4-related inflammatory pseudotumor due to its resemblance to malignant tumors, and total resection might not be warranted. Glucocorticoid and surgery are usually the first-line treatments used.
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Affiliation(s)
- Zhou Qi
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Jianli Liu
- Department of Medical Imaging, Lanzhou University Second Hospital, Lanzhou, China
| | - Guoqiang Li
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Yinian Zhang
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China
- Neurosurgery Center of Zhujiang Hospital of Southern Medical University, Guangzhou, China
- *Correspondence: Yinian Zhang
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Jiang X, Lan L, Zhou Q, Wang H, Wang H, Chen J, Han F. Characteristics and renal survival of patients with lupus nephritis with glomerular immunoglobulin G 4 deposition: a single-centre retrospective analysis. Lupus Sci Med 2022; 9:9/1/e000690. [PMID: 35710146 PMCID: PMC9204402 DOI: 10.1136/lupus-2022-000690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 06/09/2022] [Indexed: 11/03/2022]
Abstract
OBJECTIVE Renal injury is common in SLE. Immune complex deposition plays an important role in the development of lupus nephritis (LN), while little is known about glomerular IgG4 deposition in patients with LN. This study aimed to investigate the characteristics and renal outcome of patients with LN with glomerular IgG4 deposition. METHODS This is a single-centre retrospective study enrolling 89 patients with biopsy-proven LN. Clinicopathological features, treatment responses and renal outcomes were collected and compared between patients with and without glomerular IgG4 deposition. Renal outcome events include progression of renal dysfunction and end-stage renal disease. RESULTS Thirty (33.7%) patients had glomerular IgG4 deposition. Patients with glomerular IgG4 deposition had lower serum albumin level (25.06±8.61 g/L vs 28.29±6.31 g/L, p=0.05), more class V LN (60.0% vs 35.6%, p=0.03), more positive phospholipase A2 receptor (PLA2R) staining (43.3% vs 18.6%, p=0.01), more IgG1 deposits (96.7% vs 64.4%, p=0.01) and less C3 deposits (46.7% vs 72.9%, p=0.02) than those without glomerular IgG4 deposition. They also had better renal survival than those without glomerular IgG4 deposition (96.7% vs 79.7%, p=0.03). Multivariate Cox regression showed that high serum creatinine level (relative risk (RR)=1.005, 95% CI 1.002 to 1.008, p=0.01) and high Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores (RR=1.078, 95% CI 1.004 to 1.157, p=0.04) independently correlated with poor renal outcome, while glomerular IgG4 deposition tended to correlate with good renal outcome (RR=5.95, 95% CI 0.759 to 45.97, p=0.09). Further, patients with both glomerular IgG4 and PLA2R positivity (n=13) had higher levels of serum C3 and C4 and less glomerular C3 deposits compared with those with positive IgG4 but negative PLA2R in the glomerulus (n=17), and had a tendency of low SLEDAI score (p=0.07). CONCLUSIONS Patients with LN with glomerular IgG4 deposits may have better renal survival, and patients with LN with simultaneous glomerular IgG4 and PLA2R deposits may have low disease activity.
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Affiliation(s)
- Xue Jiang
- Kidney Disease Center, the First Affiliated Hospital, Zhejiang University School of Medicine; Institute of Nephrology, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province; Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, Zhejiang, China.,Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Lan Lan
- Kidney Disease Center, the First Affiliated Hospital, Zhejiang University School of Medicine; Institute of Nephrology, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province; Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, Zhejiang, China
| | - Qin Zhou
- Kidney Disease Center, the First Affiliated Hospital, Zhejiang University School of Medicine; Institute of Nephrology, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province; Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, Zhejiang, China
| | - Huijing Wang
- Kidney Disease Center, the First Affiliated Hospital, Zhejiang University School of Medicine; Institute of Nephrology, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province; Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, Zhejiang, China
| | - Huiping Wang
- Kidney Disease Center, the First Affiliated Hospital, Zhejiang University School of Medicine; Institute of Nephrology, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province; Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, Zhejiang, China
| | - Jianghua Chen
- Kidney Disease Center, the First Affiliated Hospital, Zhejiang University School of Medicine; Institute of Nephrology, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province; Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, Zhejiang, China
| | - Fei Han
- Kidney Disease Center, the First Affiliated Hospital, Zhejiang University School of Medicine; Institute of Nephrology, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province; Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, Zhejiang, China
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Katayama Y, Katsuyama T, Shidahara K, Nawachi S, Asano Y, Ohashi K, Miyawaki Y, Katsuyama E, Narazaki M, Matsumoto Y, Sada KE, Wada J. A case of recurrent IgG4-related disease successfully treated with belimumab after remission of systemic lupus erythematosus. Rheumatology (Oxford) 2022; 61:e308-e310. [PMID: 35595251 DOI: 10.1093/rheumatology/keac284] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 04/21/2022] [Accepted: 04/29/2022] [Indexed: 11/12/2022] Open
Affiliation(s)
- Yu Katayama
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Takayuki Katsuyama
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Kenta Shidahara
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Shoichi Nawachi
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Yosuke Asano
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Keiji Ohashi
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Yoshia Miyawaki
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Eri Katsuyama
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Mariko Narazaki
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Yoshinori Matsumoto
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Ken-Ei Sada
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.,Department of Clinical Epidemiology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, 783-8505, Japan
| | - Jun Wada
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
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Bertoni M, Giani A, Tozzini S, Di Natale ME. Sclerosing Mesenteritis as an Uncommon Site of Involvement of IgG4-Related Disease: A Case Report With an Updated Review of the Literature. Cureus 2022; 14:e25041. [PMID: 35719809 PMCID: PMC9199380 DOI: 10.7759/cureus.25041] [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] [Accepted: 05/13/2022] [Indexed: 11/05/2022] Open
Abstract
Immunoglobulin G4-related disease (IgG4-RD) is an uncommon immune-mediated disorder most commonly involving the pancreas, lacrimal, and salivary glands. Immunoglobulin G4-related sclerosing mesenteritis (IgG4-RSM) is a rare site of involvement that usually mimics the imaging characteristics of mesenteric malignancies. Herein, we report a case of IgG4-RSM followed by an updated and comprehensive review of the literature. A 73-year-old woman presented with colicky abdominal pain in the right hypochondrium. The findings on contrast medium computed tomography (CMCT) showed a swelling of the mesenteric root with vascular structures surrounded by slightly contrast-impregnated tissue and irregular margins. The 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET) showed an area of inhomogeneous and intense hypermetabolism of the mesenteric root. Hence, laparoscopic resection of the mesenteric root was performed to distinguish such masses from malignant tumors, obtaining specimens for histopathologic examination. The latter exhibited tissue infiltration with lymphocytes, IgG4-positive plasma cells, and fibrosis, indicating a diagnosis of IgG4-RSM in the presence of both elevated serum IgG4 levels and the aforementioned imaging findings. With steroid therapy, no clinical signs of re-exacerbation within a one-year follow-up were observed and serum IgG4 levels returned to normality. Aiming to evaluate the real frequency of IgG4-RSM in view of the 2017 Comprehensive Diagnostic Criteria (CDC) of IgG4-RD, we undertook a complete MEDLINE, EMBASE, Web of Science, and Scopus database search of all case reports of IgG4-RSM published so far. Such criteria were met in only six cases with a definite diagnosis. This case highlights the mesentery as a rare site of involvement of IgG-RD and allows us to advance knowledge of IgG4-RSM.
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林 惜, 林 沛, 刘 翔. [IgG4-related disease with nasopharyngeal malignancy-like manifestations]. LIN CHUANG ER BI YAN HOU TOU JING WAI KE ZA ZHI = JOURNAL OF CLINICAL OTORHINOLARYNGOLOGY, HEAD, AND NECK SURGERY 2022; 36:293-296. [PMID: 35511623 PMCID: PMC10128187 DOI: 10.13201/j.issn.2096-7993.2022.04.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Indexed: 06/14/2023]
Abstract
Objective:The purpose of this article was to discuss the clinical features and imaging characteristics of IgG4-related disease（IgG4-RD） in order to identify nasopharyngeal IgG4-RD at an early stage. Methods:The basic information of the patients, including age, sex, symptoms, disease duration and treatment process, was collected through the electronic case system. Laboratory tests including nasal endoscopy, EBV levels, IgG4 levels and C-reactive protein levels were recorded during hospitalization and outpatient follow-up. All radiological imaging and postoperative pathology data are collected, analyzed and summarized. Results:All patients underwent partial excisional biopsy of the lesion. The pathological findings showed inflammatory granulomatous and fibrous tissue hyperplasia with a high infiltration of lymphocytes, plasma cells and neutrophils, and immunohistochemistry examination showed IgG4+ plasma cells were more than 10 per high magnification field. Combining medical history, imaging, serological findings and relevant treatment, all four patients were diagnosed with IgG4-associated disease. And their symptoms improved significantly after hormonal and immunosuppressive treatment. Conclusion: IgG4-RD has a highly similar clinical presentation with nasopharyngeal carcinoma. Differentiation from IgG4-RD should be considered for those pathology cannot be clarified by multiple biopsies. Timely diagnosis of IgG4-RD is important to prevent secondary organ damage in patients with active disease.
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Affiliation(s)
- 惜君 林
- 中山大学孙逸仙纪念医院耳鼻咽喉头颈外科(广州, 510000)Department of Otolaryngology Head and Neck Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510000, China
| | - 沛亮 林
- 中山大学孙逸仙纪念医院耳鼻咽喉头颈外科(广州, 510000)Department of Otolaryngology Head and Neck Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510000, China
| | - 翔 刘
- 中山大学孙逸仙纪念医院耳鼻咽喉头颈外科(广州, 510000)Department of Otolaryngology Head and Neck Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510000, China
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Yang Y, Wang C, Shi L, Yang S, Liu Y, Luo J, Wang C. Clinical Characteristics and CD4+ T Cell Subsets in IgG4-Related Disease. Front Immunol 2022; 13:825386. [PMID: 35432312 PMCID: PMC9010737 DOI: 10.3389/fimmu.2022.825386] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 03/09/2022] [Indexed: 12/04/2022] Open
Abstract
Objectives To characterize the clinical features of IgG4-related disease (IgG4-RD) and analyze the peripheral T lymphocyte subsets and cytokine levels. Methods A total of 52 patients with newly diagnosed IgG4-RD were enrolled in the retrospective study. Baseline clinical characteristics and examinational findings were systematically reviewed. Results IgG4-RD patients had a male predominance, with an average age of 57.4 ± 10.3 years (range 27-81). The mean number of involved organs was 2.7 (range 1-8). Submandibular gland (57.7%) and lacrimal gland/orbit (40.4%) were the most commonly involved organs. Serum IgG4 increased in 97.9% of the patients, the median level was 1300 (585.25, 1975) mg/dl. Decreased C3 and C4 accounted for 77.8% and 55.6% of this patient cohort, respectively. Receiver operating characteristic (ROC) test indicated the possibility of lung/pleura involvement when C3 was less than 0.570 g/l (AUC = 0.788, P = 0.014), and kidney involvement when C3 was less than 0.545 g/l (AUC = 0.796, P = 0.014). Compared with healthy controls (HC), the absolute Th1 counts were higher in IgG4-RD patients (157.58 cells/μl vs. 130.54 cells/μl, P = 0.038), while the absolute counts of Th2, Th17 and T regulatory (Treg) cells, as well as Th17/Treg ratio were not statistically different. The levels of serum IL-4, IL-6, IL-10, IL-17, TNF-α, and IFN-γ were higher in patients with IgG4-RD as compared with HC (P < 0.001). Serum IL-10 was positively correlated with IL-4, TNF-α and IFN-γ, but uncorrelated with Treg cells. Serum IgG4 level was positively associated with the number of affected organs, eosinophil counts, and ESR, whereas inversely associated with C3, C4, IgM, and IgA. Conclusion Submandibular and lacrimal glands are the most commonly involved organs in IgG4-RD. Serum C3 level could be a predictor of lung/pleura and kidney involvement in the disease process. Elevated Th1 cells are probably related to chronic inflammation and fibrosis. Treg cells are unlikely to play an important role in the pathogenesis of IgG4-RD.
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Affiliation(s)
- Yan Yang
- Department of Rheumatology and Immunology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Chen Wang
- Department of Pathology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Lei Shi
- Department of Rheumatology and Immunology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Shuoran Yang
- Department of Oral and Maxillofacial Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Yan Liu
- Department of Rheumatology and Immunology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Jing Luo
- Department of Rheumatology Laboratory, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Caihong Wang
- Department of Rheumatology and Immunology, The Second Hospital of Shanxi Medical University, Taiyuan, China
- *Correspondence: Caihong Wang,
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40
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Huang J, Qi Y, Zeng X, Huang W, Chen D. Simultaneous quantification of plasma immunoglobulin subclasses for assessment of maternal and fetal immune response during pregnancy. J Chromatogr A 2022; 1673:463096. [DOI: 10.1016/j.chroma.2022.463096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 04/19/2022] [Accepted: 04/28/2022] [Indexed: 11/29/2022]
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Minici C, Testoni S, Della-Torre E. B-Lymphocytes in the Pathophysiology of Pancreatic Adenocarcinoma. Front Immunol 2022; 13:867902. [PMID: 35359944 PMCID: PMC8963963 DOI: 10.3389/fimmu.2022.867902] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 02/23/2022] [Indexed: 12/12/2022] Open
Abstract
Pancreatic adenocarcinoma is highly infiltrated by B lymphocytes but the relevance of these immune cells in tumor development has been surprisingly overlooked until recently. Based on available evidence from other solid tumors, interaction between B lymphocytes and neoplastic cells is probably not uniformly stimulatory or inhibitory. Although presentation of tumor antigens to T cells and production of antitumor immunoglobulins might intuitively suggest a prominent tumor suppressive activity, specific subsets of B lymphocytes can secrete growth factors for neoplastic cells and immunosuppressive cytokines thus promoting escape from immunosurveillance and cancer progression. Because many of these mechanisms might also be implicated in the development of PDAC, and immune-modulation of B-cell activity is nowadays possible at different levels, determining the role of B-lymphocytes in this lethal cancer becomes of utmost importance to design novel therapeutic strategies. This review aims to discuss the emerging role of B cells in PDAC tumorigenesis, progression, and associated stromal reaction.
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Affiliation(s)
- Claudia Minici
- Università Vita-Salute San Raffaele, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Sabrina Testoni
- Pancreato-Biliary Endoscopy and Endosonography Division, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Division of Pancreatic Surgery, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Emanuel Della-Torre
- Università Vita-Salute San Raffaele, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Division of Pancreatic Surgery, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Scientific Institute, Milan, Italy
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Zhang X, Jin X, Guan L, Lin X, Li X, Li Y. IgG4-Related Disease With Gastrointestinal Involvement: Case Reports and Literature Review. Front Immunol 2022; 13:816830. [PMID: 35359937 PMCID: PMC8960130 DOI: 10.3389/fimmu.2022.816830] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 02/18/2022] [Indexed: 12/02/2022] Open
Abstract
IgG4-related disease is an immune-mediated chronic, systemic, and autoinflammatory disease that can affect various organs throughout the body. The most commonly affected areas are the pancreas and biliary system. Due to the diverse clinical manifestations of the disease, it affects widely distributed organs. Thus, it is often easy to misdiagnose or miss. The digestive tract is a rarely affected system, and most IgG4-related gastric diseases manifest as tumors detected by endoscopy. This article reports two special cases with IgG4-related disease involving atrophic gastritis and intestinal polyps to provide a more empirical and theoretical basis for clinical diagnosis and treatment.
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Affiliation(s)
- Xinhe Zhang
- Gastroenterology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xing Jin
- Gastroenterology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Lin Guan
- Gastroenterology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xuyong Lin
- Department of Pathology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xuedan Li
- Radiology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yiling Li
- Gastroenterology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
- *Correspondence: Yiling Li,
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Ireifej B, Dhamrah U, Song D, Bitar J, Jaiswal V, Nepal G, Pathak N, Freijat M. Cerebellar infarction as the initial presentation of IgG4-related disease. Clin Case Rep 2022; 10:e05614. [PMID: 35340659 PMCID: PMC8931459 DOI: 10.1002/ccr3.5614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 11/21/2022] Open
Abstract
Although IgG4-RD has CNS manifestations, cerebellar involvement has only been reported in three cases. Our patient presented with cerebellar symptoms, several cerebellar infarcts were evident on the brain MRI, and CT abdomen revealed retroperitoneal tumor. Endoscopic biopsy confirmed IgG4-RD. Steroids are the first-line therapy for IgG4-RD, but our patient was lost to follow-up before treatment.
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Affiliation(s)
- Branden Ireifej
- Department of Internal MedicineIcahn School of Medicine at Mount Sinai Elmhurst Hospital CenterNew York CityNew YorkUSA
| | - Umaima Dhamrah
- Department of Internal MedicineIcahn School of Medicine at Mount Sinai Elmhurst Hospital CenterNew York CityNew YorkUSA
| | - David Song
- Department of Internal MedicineIcahn School of Medicine at Mount Sinai Elmhurst Hospital CenterNew York CityNew YorkUSA
| | - Joyce Bitar
- Metropolitan Hospital CenterNew York CityNew YorkUSA
| | | | - Gaurav Nepal
- Department of Internal MedicineTribhuvan University Institute of MedicineKathmanduNepal
| | - Nibesh Pathak
- Department of Internal MedicineTribhuvan University Institute of MedicineKathmanduNepal
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IgG4-related pseudotumours: a series of 12 cases and a review of the literature. Pathology 2022; 54:563-572. [DOI: 10.1016/j.pathol.2021.11.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 11/11/2021] [Accepted: 11/18/2021] [Indexed: 11/22/2022]
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Duggal L, Singh BG, Patel J, Gupta M, Grover AK, Jain N. IgG4-Related Disease: A Clinical Case Series From a Tertiary Care Center in India. J Clin Rheumatol 2022; 28:e56-e62. [PMID: 33105313 DOI: 10.1097/rhu.0000000000001591] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
AIM Immunoglobulin G4-related disease (IgG4-RD) is often an unrecognized, rare fibroinflammatory condition that can involve various organ systems. This study aimed to identify the different clinical patterns of this disease in a single center in North India. METHODS Patients were diagnosed on the basis of published diagnostic criteria for IgG4-RD. Patients' presenting complaints; epidemiologic profiles; and laboratory, radiologic, and histologic findings along with the treatment and outcomes were collected and analyzed. RESULTS In total, 70 patients were diagnosed with the disease. The female-to-male ratio was 0.94:1, and it increased with multiorgan involvement. The mean age of patients was 41.4 years, and the majority of the patients (65.7%) were younger than 50 years. Patients were diagnosed as possible (38.57%), probable (32.85%), and definite (28.57%) IgG4-RD. The incidence of the involvement of orbital and periorbital tissues was the highest (52.9%); however, 13% of the patients had multiple organ involvement. Patients with involvement of the retroperitoneal tissues and the lymph nodes were 8.5% and 5.7%, respectively. Increased serum IgG4 levels were found in 74.3% of the patients with single-organ involvement, whereas all patients with multiorgan involvement had increased IgG4 levels. The majority of patients (94.3%) required immunosuppressive medications along with corticosteroids. Azathioprine was the most commonly used (72.8%) immunosuppressive medication. Rituximab was used in 17.1% of the patients, of whom only one had multisystem involvement. CONCLUSIONS This study depicts the most common patterns of organ involvement, along with the epidemiologic, laboratory, histologic, and radiologic data and response to treatment, in IgG4-RD, with a definite ophthalmology referral bias.
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Tacelli M, Zaccari P, Petrone M, Torre E, Lanzillotta M, Falconi M, Doglioni C, Capurso G, Arcidiacono P. Differential EUS findings in focal type 1 autoimmune pancreatitis and pancreatic cancer: A proof-of-concept study. Endosc Ultrasound 2022; 11:216-222. [PMID: 35142701 PMCID: PMC9258021 DOI: 10.4103/eus-d-21-00111] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Background and Objectives: Autoimmune pancreatitis (AIP) often mimics pancreatic cancer (PC), particularly if presenting as a focal lesion. EUS may orient the differential diagnosis between them. This study aims to identify EUS findings that might be useful to differentiate type 1 focal autoimmune pancreatitis (f-AIP1) and PC. Materials and Methods: F-AIP1 and PC patients were retrospectively collected, matched, and compared. EUS findings considered were: focal mass echogenicity, loss of lobularity, distal atrophy, peripancreatic hypoechoic margins (PHM), pancreatic duct dilation, duct-penetrating sign (DPS), pancreatic/common bile duct thickened walls (PD/CBD-TW), and vessel infiltration (VI). Elastography findings were also recorded. Variables with a P < 0.05 at univariate analysis were included in logistic multiple regression. Results: Fifteen patients with f-AIP and 60 with PC were studied. FE was hypoechoic in all patients from both groups. PHM was observed in 40% of f-AIP1 cases but not in PC ones (P < 0.001). DPS was found in 10/15 (66.7%) f-AIP1 and in 7/60 (11.7%) PC patients (P < 0.001). PD-TW and CBD-TW were observed in 66.7%/60% f-AIP1 cases and in 6.7%/13.6% PC patients, respectively (P < 0.001 for both comparisons). Pancreatic masses were significantly different at EUS elastography (elastic respectively in 71.4% f-AIP1 and 3.8% PC, P < 0.001). VI was suspected in 20% of f-AIPs and 85% of PCs (P < 0.001). At multiple regression, PD-TW, CBD-TW, elastic pattern, and the absence of VI independently supported a diagnosis of f-AIP1. Conclusions: Our results suggest that EUS findings deserve consideration in the diagnostic workup of AIP to improve the differential diagnosis with PC.
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Della-Torre E, Zen Y, Stone JH. IgG4-Related Disease Overview: Pathology, Clinical Picture, and Treatment. PARAPROTEINEMIA AND RELATED DISORDERS 2022:229-250. [DOI: 10.1007/978-3-031-10131-1_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Cai M, Voutnis D, Nair B. Immunoglobulin G4-Related ophthalmic disease and aortitis. ARCHIVES OF MEDICINE AND HEALTH SCIENCES 2022. [DOI: 10.4103/amhs.amhs_71_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Łoń I, Wieliczko M, Lewandowski J, Małyszko J. Retroperitoneal fibrosis is still underdiagnosed entity with poor prognosis. Kidney Blood Press Res 2021; 47:151-162. [PMID: 34915518 DOI: 10.1159/000521423] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 12/08/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Retroperitoneal fibrosis (RPF) is a rare disease characterized by the presence of inflammatory and fibrous retroperitoneal tissue that often encircles abdominal organs including aorta and ureters. Data on the incidence of this disease are limited. SUMMARY The disease may be idiopathic or secondary to infections, malignancies, drugs or radiotherapy. Idiopathic form is an immune-mediated entity and a part of the broader spectrum of idiopathic diseases termed chronic periaortitis, characterized by a morphologically similar fibroinflammatory changes in aorta and surrounding tissues. Taking into account the dominant symptoms and clinical charac-teristics of patients with periaortitis, two subtypes of disease could be distinguished. Vascular subtype include patients with non-dilated aorta or with inflammatory abdominal aortic aneu-rysm, both with and without involvement of adjacent structures and with numerous risk factors for atherosclerosis. In renoureteral subtype obstructive uropathy manifesting with hydronephro-sis and acute kidney injury is predominant finding. Due to the variety of symptoms, diagnosis of RPF remains challenging, difficult and often delayed. A series of diagnostic tests should be performed, in order to confirm the diagnosis idiopathic RPF. Laboratory work-up include eval-uation of inflammatory indices and immunological studies. A biopsy and histopathological evaluation may be necessary to confirm diagnosis and differentiate the disease. Computed to-mography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) are the modalities of choice for the diagnosis and follow-up of this disease. Management of ureteral obstruction, hydronephrosis, and aortic aneurysms often requires surgical evaluation and treatment. The pharmacological treatment of RPF has been evaluated in a few randomized trials and is mainly based on observational studies. Steroid therapy remains the gold standard of treatment. Key messages: Nowadays multidisciplinary team approach with clinical and diagnos-tic experience in both primary and secondary RPF as well as two major subtypes should be offered. Centers specialized in rare diseases with collaboration with other units and referral sys-tem yield the best possible outcomes.
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Affiliation(s)
- Izabela Łoń
- Department of Hypertension, Angiology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Monika Wieliczko
- Department of Nephrology, Dialysis and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Jacek Lewandowski
- Department of Hypertension, Angiology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Jolanta Małyszko
- Department of Nephrology, Dialysis and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
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Capecchi R, Croia C, Puxeddu I, Pratesi F, Cacciato A, Campani D, Boggi U, Morelli L, Tavoni A, Migliorini P. CXCL12/SDF-1 in IgG4-Related Disease. Front Pharmacol 2021; 12:750216. [PMID: 34764871 PMCID: PMC8576100 DOI: 10.3389/fphar.2021.750216] [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: 07/30/2021] [Accepted: 09/17/2021] [Indexed: 02/05/2023] Open
Abstract
Background: SDF-1/CXCL12 is a chemokine with pleiotropic functions in hematopoietic stem cell niche homeostasis, germinal center architecture, B cell maturation, neoangiogenesis, and fibrosis. Recently, the CXCL12/CXCR4/CXCR7 axis was associated with cancer metastasis and autoimmune diseases. The IgG4-related disease (IgG4-RD) is a pathological condition characterized by IgG4+ plasma cells infiltrating fibrotic lesions. The aim of this research is to investigate the relevance of SDF-1/CXCL12 in IgG4-RD. Materials and Methods: Peripheral blood samples were collected before therapy from a single-center cohort of 28 IgG4-RD patients, fulfilling the ACR-EULAR classification criteria. Clinical and serological data were obtained for each patient. In total, 14 healthy donors (NHS), 9 patients with pancreatic ductal adenocarcinoma (PDAC), and 9 with Sjogren syndrome (SSj) were recruited as controls and screened for circulating SDF-1/CXCL12 by ELISA. Moreover, paraffin-embedded pancreatic biopsies obtained from patients with IgG4-RD (n = 7), non-autoimmune pancreatitis (n = 3), PDAC (n = 5), and control tissues (n = 4) were analyzed to study the tissue expression and localization of SDF-1/CXCL12 and one of its receptors, CXCR4, and their potential relation with neutrophil extracellular traps (NETs). Results: IgG4-RD patients had higher serum levels of SDF-1/CXCL12 than normal controls (p = 0.0137). Cytokine levels did not differ between the IgG4-RD autoimmune pancreatitis (AIP) and retroperitoneal fibrosis nor between the single- and multiple-organ involvement. No correlation was seen with the IgG4-RD Responder Index, IgG4 levels, white blood cells, or inflammatory markers in the serum. When compared to SSj, the IgG4-RD AIP subgroup presents higher amounts of serum SDF-1/CXCL12 (p = 0.0275), while no differences are seen in comparison with PDAC. The expression of SDF-1/CXCL12 in the tissue was significantly higher in the IgG4-RD tissue than the normal pancreas, and the tissue with the high SDF-1/CXCL12 expression is characterized by the overall inflammatory cell infiltration, fibrosis, and high level of NETs. Conclusion: Modulating B cell development, neoangiogenesis and fibrosis, and SDF-1/CXCL12 may play a role in IgG4-RD. The higher levels observed in IgG4-RD, as compared to SSj, which closely mimics the disease, can be related to a different pattern of lesions, with prevalent fibrosis seen in IgG4-RD. Taken together, these findings suggest that drugs acting on the CXCL12/CXCR4/CXCR7 axis may affect IgG4-RD.
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Affiliation(s)
- Riccardo Capecchi
- Immuno-Allergology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Cristina Croia
- Immuno-Allergology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Ilaria Puxeddu
- Immuno-Allergology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Federico Pratesi
- Immuno-Allergology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Andrea Cacciato
- Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy
| | - Daniela Campani
- Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy
| | - Ugo Boggi
- Division of General and Transplant Surgery, Azienda Ospedaliero-Universitaria Pisana, University of Pisa, Pisa, Italy
| | - Luca Morelli
- General Surgery Unit, Department of Surgery, Translational and New Technologies in Medicine, University of Pisa, Pisa, Italy
| | - Antonio Tavoni
- Immuno-Allergology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Paola Migliorini
- Immuno-Allergology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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