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Chiang SCC, Yang L, Owsley E, Husami A, Akeno N, Cobb C, Hartog NL, Elizalde A, Seroogy CM, Blanchard-Rohner G, Peng XP, Brager R, Buchbinder D, Cook E, Phillips L, Maricic S, Kalashnikova T, Derfalvi B, Dimitriades VR, Murguía-Favela LE, Gutierrez MJ, Shrikhande A, Steele M, Wilson JL, Wright NAM, Marsh R, Bleesing J, Jordan MB, Marwaha AK. Lipopolysaccharide-responsive and beige-like anchor protein (LRBA) functional deficiency caused by biallelic LRBA missense variants characterized by Evans syndrome or colitis. J Allergy Clin Immunol 2025:S0091-6749(25)00384-7. [PMID: 40220912 DOI: 10.1016/j.jaci.2025.04.003] [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: 10/04/2024] [Revised: 04/01/2025] [Accepted: 04/03/2025] [Indexed: 04/14/2025]
Abstract
BACKGROUND Biallelic loss-of-function mutations in the lipopolysaccharide-responsive and beige-like anchor (LRBA) gene lead to a severe syndrome of early-onset immune dysregulation called LRBA deficiency. Monoallelic CTLA4 mutations lead to a similar phenotype. In both conditions, cytotoxic T lymphocyte-associated protein 4 (CTLA-4) levels are significantly decreased. In previously reported cases of symptomatic disease associated with LRBA pathogenic variants, patients usually have severely decreased or absent LRBA protein levels. OBJECTIVE We describe 5 patients with biallelic missense variants in the LRBA gene presenting predominantly with Evans syndrome or colitis. METHODS LRBA and CTLA-4 levels were investigated in LRBA missense, "classic" LRBA and in CTLA-4 insufficiency samples. RESULTS Surprisingly, all 5 LRBA missense patients had normal expression of LRBA protein. However, CTLA-4 intracellular expression was reduced to similar levels as those seen in patients with CTLA-4 insufficiency at resting state. Lower levels of surface CTLA-4 are seen on cell activation, indicating that these LRBA variants lead to reduced CTLA-4 cell surface expression. Several of the missense variants are shared between unrelated patients in the cohort, suggesting a mutational hot spot or founder effect for those with shared ancestry. CONCLUSION Novel LRBA deficiency variants result in quantitative or qualitative LRBA defects, leading to reduced intracellular resting levels and induced surface levels of CTLA-4.
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Affiliation(s)
- Samuel C C Chiang
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
| | - Li Yang
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Erika Owsley
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Ammar Husami
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Nagako Akeno
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Cristina Cobb
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Nicholas L Hartog
- Allergy and Immunology, Corwell Health, Helen Devos Children's Hospital, College of Human Medicine, Michigan State University, Grand Rapids, Mich
| | | | - Christine M Seroogy
- Division of Allergy, Immunology & Rheumatology, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wis
| | - Geraldine Blanchard-Rohner
- Unit of Immunology, Vaccinology and Rheumatology, Division of General Pediatrics, Department of Pediatrics, Gynecology and Obstetrics, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Xiao P Peng
- Division of Genetic Medicine, Department of Pediatrics, Montefiore Medical Center, Bronx, NY
| | - Rae Brager
- Division of Rheumatology, Immunology and Allergy, Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
| | - David Buchbinder
- Division of Hematology, Children's Hospital of Orange County, Orange, Calif
| | - Eleanor Cook
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Lindsay Phillips
- Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Ontario, Canada
| | - Snezana Maricic
- Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Ontario, Canada
| | - Tatiana Kalashnikova
- Section of Hematology/Immunology, Alberta Children's Hospital, Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
| | - Beata Derfalvi
- Division of Immunology, Department of Pediatrics, Dalhousie University, IWK Health Centre, Halifax, Nova Scotia, Canada
| | - Victoria R Dimitriades
- Division of Pediatric Allergy, Immunology & Rheumatology, UC Davis Health, Sacramento, Calif
| | - Luis E Murguía-Favela
- Section of Hematology/Immunology, Alberta Children's Hospital, Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
| | - Maria J Gutierrez
- Division of Pediatric Allergy, Immunology and Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Anitha Shrikhande
- Department of Medicine and Pediatrics, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY
| | - MacGregor Steele
- Section of Hematology/Immunology, Alberta Children's Hospital, Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
| | - Jo L Wilson
- Division of Allergy, Immunology & Rheumatology, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wis
| | - Nicola A M Wright
- Section of Hematology/Immunology, Alberta Children's Hospital, Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
| | - Rebecca Marsh
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Jack Bleesing
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Michael B Jordan
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Ashish K Marwaha
- Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Ontario, Canada.
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Tey PY, Dufner A, Knobeloch KP, Pruneda JN, Clague MJ, Urbé S. Rapid turnover of CTLA4 is associated with a complex architecture of reversible ubiquitylation. J Cell Biol 2025; 224:e202312141. [PMID: 39404738 PMCID: PMC11486831 DOI: 10.1083/jcb.202312141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 08/14/2024] [Accepted: 09/27/2024] [Indexed: 10/20/2024] Open
Abstract
The immune checkpoint regulator CTLA4 is an unusually short-lived membrane protein. Here, we show that its lysosomal degradation is dependent on ubiquitylation at lysine residues 203 and 213. Inhibition of the v-ATPase partially restores CTLA4 levels following cycloheximide treatment, but also reveals a fraction that is secreted in exosomes. The endosomal deubiquitylase, USP8, interacts with CTLA4, and its loss enhances CTLA4 ubiquitylation in cancer cells, mouse CD4+ T cells, and cancer cell-derived exosomes. Depletion of the USP8 adapter protein, HD-PTP, but not ESCRT-0 recapitulates this cellular phenotype but shows distinct properties vis-à-vis exosome incorporation. Re-expression of wild-type USP8, but neither a catalytically inactive nor a localization-compromised ΔMIT domain mutant can rescue delayed degradation of CTLA4 or counteract its accumulation in clustered endosomes. UbiCRest analysis of CTLA4-associated ubiquitin chain linkages identifies a complex mixture of conventional Lys63- and more unusual Lys27- and Lys29-linked polyubiquitin chains that may underly the rapidity of protein turnover.
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Affiliation(s)
- Pei Yee Tey
- Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Almut Dufner
- Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
| | - Klaus-Peter Knobeloch
- Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
| | - Jonathan N. Pruneda
- Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, USA
| | - Michael J. Clague
- Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Sylvie Urbé
- Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
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Shadur B, NasserEddin A, Zaidman I, Schejter YD, Even-Or E, Berkun Y, Meyts I, Hmedat H, Sulaiman A, Tangye SG, Stepensky P. Successful Haematopoietic Stem Cell Transplantation for LRBA Deficiency with Fludarabine, Treosulfan, and Thiotepa-Based Conditioning. J Clin Immunol 2024; 45:3. [PMID: 39264459 PMCID: PMC11393013 DOI: 10.1007/s10875-024-01770-1] [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: 01/04/2024] [Accepted: 07/19/2024] [Indexed: 09/13/2024]
Abstract
LRBA deficiency is an inborn error of immunity defined by autoimmunity, lymphoproliferation, recurrent infections, cytopenia, and inflammatory bowel disease. Despite recent advances in managing this disease with targeted biologic therapy, haematopoietic stem cell transplant (HSCT) remains the only cure. However, great variability exists between protocols used to transplant patients with LRBA deficiency. We describe a cohort of seven patients with LRBA deficiency who underwent HSCT using a myeloablative, reduced toxicity regime of fludarabine, treosulfan, and thiotepa at two transplantation centres from 2016 to 2019. Data were collected both retrospectively and prospectively, measuring time to engraftment, infectious complications, incidence of graft versus host disease, and post-transplantation chimerism. Six of seven patients survived transplantation, and four of six surviving patients achieving treatment-free survival. We thus recommend that HSCT with fludarabine, treosulfan, and thiotepa-based conditioning be considered in patients with LRBA deficiency.
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Affiliation(s)
- Bella Shadur
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah University Medical Centre, Jerusalem, Israel.
- Garvan Institute of Medical Research, Sydney, Australia.
- School of Clinical Medicine, Faculty of Medicine and Health, UNSW, Sydney, NSW, Australia.
| | - Adeeb NasserEddin
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah University Medical Centre, Jerusalem, Israel
| | - Irina Zaidman
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah University Medical Centre, Jerusalem, Israel
| | - Yael Dinur Schejter
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah University Medical Centre, Jerusalem, Israel
| | - Ehud Even-Or
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah University Medical Centre, Jerusalem, Israel
| | - Yackov Berkun
- Department of General Paediatrics, Hadassah University Medical Centre, Jerusalem, Israel
| | - Isabelle Meyts
- Inborn Errors of Immunity, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Pediatric Immunodeficiency, Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
| | - Hatem Hmedat
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah University Medical Centre, Jerusalem, Israel
| | - Ashraf Sulaiman
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah University Medical Centre, Jerusalem, Israel
| | - Stuart G Tangye
- Garvan Institute of Medical Research, Sydney, Australia
- School of Clinical Medicine, Faculty of Medicine and Health, UNSW, Sydney, NSW, Australia
| | - Polina Stepensky
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah University Medical Centre, Jerusalem, Israel
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Dua J, Jadhav R, Pande V, Bahal M, Mane SV. Novel Lipopolysaccharide-Responsive Vesicle Trafficking, Beach- and Anchor-Containing (LRBA) Gene Mutation Identified in a Pediatric Patient: A Case Report. Cureus 2024; 16:e65434. [PMID: 39184709 PMCID: PMC11344606 DOI: 10.7759/cureus.65434] [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: 06/02/2024] [Accepted: 07/26/2024] [Indexed: 08/27/2024] Open
Abstract
Homozygous mutations in the lipopolysaccharide-responsive vesicle trafficking, beach- and anchor-containing (LRBA) gene lead to a syndrome characterized by early-onset hypogammaglobulinemia, autoimmunity, lymphoproliferation, and inflammatory bowel disease. This report describes a 10-year-old female who experienced three seizure episodes, including two generalized tonic-clonic seizures (GTCS) and one focal seizure, alongside septic shock. The patient had a history of recurrent respiratory tract infections, inflammatory bowel disease, multiple blood transfusions, lymphadenopathy, significant organomegaly, and hematological abnormalities, all consistent with an LRBA deficiency. This case highlights the critical need for prompt recognition and identification of LRBA gene mutations to enable timely management and improve patient outcomes.
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Affiliation(s)
- Jasleen Dua
- Pediatrics, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Dr. D. Y. Patil Vidyapeeth, Pune, IND
| | - Renuka Jadhav
- Pediatrics, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Dr. D. Y. Patil Vidyapeeth, Pune, IND
| | - Vineeta Pande
- Pediatrics, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Dr. D. Y. Patil Vidyapeeth, Pune, IND
| | - Mridu Bahal
- Pediatrics, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Dr. D. Y. Patil Vidyapeeth, Pune, IND
| | - Shailaja V Mane
- Pediatrics, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Dr. D. Y. Patil Vidyapeeth, Pune, IND
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Perez-Perez D, Santos-Argumedo L, Rodriguez-Alba JC, Lopez-Herrera G. Analysis of LRBA pathogenic variants and the association with functional protein domains and clinical presentation. Pediatr Allergy Immunol 2024; 35:e14179. [PMID: 38923448 DOI: 10.1111/pai.14179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 05/29/2024] [Accepted: 06/07/2024] [Indexed: 06/28/2024]
Abstract
LRBA is a cytoplasmic protein that is ubiquitously distributed. Almost all LRBA domains have a scaffolding function. In 2012, it was reported that homozygous variants in LRBA are associated with early-onset hypogammaglobulinemia. Since its discovery, more than 100 pathogenic variants have been reported. This review focuses on the variants reported in LRBA and their possible associations with clinical phenotypes. In this work LRBA deficiency cases reported more than 11 years ago have been revised. A database was constructed to analyze the type of variants, age at onset, clinical diagnosis, infections, autoimmune diseases, and cellular and immunoglobulin levels. The review of cases from 2012 to 2023 showed that LRBA deficiency was commonly diagnosed in patients with a clinical diagnosis of Common Variable Immunodeficiency, followed by enteropathy, neonatal diabetes mellitus, ALPS, and X-linked-like syndrome. Most cases show early onset of presentation at <6 years of age. Most cases lack protein expression, whereas hypogammaglobulinemia is observed in half of the cases, and IgG and IgA levels are isotypes reported at low levels. Patients with elevated IgG levels exhibited more than one autoimmune manifestation. Patients carrying pathogenic variants leading to a premature stop codon show a severe phenotype as they have an earlier onset of disease presentation, severe autoimmune manifestations, premature death, and low B cells and regulatory T cell levels. Missense variants were more common in patients with low IgG levels and cytopenia. This work lead to the conclusion that the type of variant in LRBA has association with disease severity, which leads to a premature stop codon being the ones that correlates with severe disease.
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Affiliation(s)
- D Perez-Perez
- Doctorate Program in Biological Sciences, Autonomous National University of Mexico, Mexico City, Mexico
- Immunodeficiencies Laboratory, National Institute of Pediatrics (INP), Mexico City, Mexico
| | - L Santos-Argumedo
- Biomedicine Department, Center for Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV), Mexico City, Mexico
| | - J C Rodriguez-Alba
- Neuroimmunology and Neurooncology Unit, The National Institute of Neurology and Neurosurgery (NINN), Mexico City, Mexico
- Medicine and Surgery Faculty, Autonomous University Benito Juarez from Oaxaca, Oaxaca, Mexico
| | - G Lopez-Herrera
- Immunodeficiencies Laboratory, National Institute of Pediatrics (INP), Mexico City, Mexico
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Hardtke-Wolenski M, Landwehr-Kenzel S. Tipping the balance in autoimmunity: are regulatory t cells the cause, the cure, or both? Mol Cell Pediatr 2024; 11:3. [PMID: 38507159 PMCID: PMC10954601 DOI: 10.1186/s40348-024-00176-8] [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: 10/22/2023] [Accepted: 03/07/2024] [Indexed: 03/22/2024] Open
Abstract
Regulatory T cells (Tregs) are a specialized subgroup of T-cell lymphocytes that is crucial for maintaining immune homeostasis and preventing excessive immune responses. Depending on their differentiation route, Tregs can be subdivided into thymically derived Tregs (tTregs) and peripherally induced Tregs (pTregs), which originate from conventional T cells after extrathymic differentiation at peripheral sites. Although the regulatory attributes of tTregs and pTregs partially overlap, their modes of action, protein expression profiles, and functional stability exhibit specific characteristics unique to each subset. Over the last few years, our knowledge of Treg differentiation, maturation, plasticity, and correlations between their phenotypes and functions has increased. Genetic and functional studies in patients with numeric and functional Treg deficiencies have contributed to our mechanistic understanding of immune dysregulation and autoimmune pathologies. This review provides an overview of our current knowledge of Treg biology, discusses monogenetic Treg pathologies and explores the role of Tregs in various other autoimmune disorders. Additionally, we discuss novel approaches that explore Tregs as targets or agents of innovative treatment options.
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Affiliation(s)
- Matthias Hardtke-Wolenski
- Hannover Medical School, Department of Gastroenterology Hepatology, Infectious Diseases and Endocrinology, Carl-Neuberg-Str. 1, Hannover, 30625, Germany
- University Hospital Essen, Institute of Medical Microbiology, University Duisburg-Essen, Hufelandstraße 55, Essen, 45122, Germany
| | - Sybille Landwehr-Kenzel
- Hannover Medical School, Department of Pediatric Pneumology, Allergology and Neonatology, Carl-Neuberg-Str. 1, Hannover, 30625, Germany.
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Carl-Neuberg-Str. 1, Hannover, 30625, Germany.
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Kennedy-Batalla R, Acevedo D, Luo Y, Esteve-Solé A, Vlagea A, Correa-Rocha R, Seoane-Reula ME, Alsina L. Treg in inborn errors of immunity: gaps, knowns and future perspectives. Front Immunol 2024; 14:1278759. [PMID: 38259469 PMCID: PMC10800401 DOI: 10.3389/fimmu.2023.1278759] [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: 08/16/2023] [Accepted: 12/13/2023] [Indexed: 01/24/2024] Open
Abstract
Regulatory T cells (Treg) are essential for immune balance, preventing overreactive responses and autoimmunity. Although traditionally characterized as CD4+CD25+CD127lowFoxP3hi, recent research has revealed diverse Treg subsets such as Tr1, Tr1-like, and CD8 Treg. Treg dysfunction leads to severe autoimmune diseases and immune-mediated inflammatory disorders. Inborn errors of immunity (IEI) are a group of disorders that affect correct functioning of the immune system. IEI include Tregopathies caused by genetic mutations affecting Treg development or function. In addition, Treg dysfunction is also observed in other IEIs, whose underlying mechanisms are largely unknown, thus requiring further research. This review provides a comprehensive overview and discussion of Treg in IEI focused on: A) advances and controversies in the evaluation of Treg extended subphenotypes and function; B) current knowledge and gaps in Treg disturbances in Tregopathies and other IEI including Treg subpopulation changes, genotype-phenotype correlation, Treg changes with disease activity, and available therapies, and C) the potential of Treg cell-based therapies for IEI with immune dysregulation. The aim is to improve both the diagnostic and the therapeutic approaches to IEI when there is involvement of Treg. We performed a non-systematic targeted literature review with a knowledgeable selection of current, high-quality original and review articles on Treg and IEI available since 2003 (with 58% of the articles within the last 6 years) in the PubMed database.
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Affiliation(s)
- Rebeca Kennedy-Batalla
- Laboratory of Immune-Regulation, Gregorio Marañón Health Research Institute (IISGM), Madrid, Spain
| | - Daniel Acevedo
- Clinical Immunology and Primary Immunodeficiencies Unit, Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu, Barcelona, Spain
- Clinical Immunology Unit, Hospital Sant Joan de Déu-Hospital Clínic, Barcelona, Spain
- Study Group for Immune Dysfunction Diseases in Children (GEMDIP), Institut de Recerca Sant Joan de Déu, Barcelona, Spain
| | - Yiyi Luo
- Clinical Immunology and Primary Immunodeficiencies Unit, Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu, Barcelona, Spain
- Clinical Immunology Unit, Hospital Sant Joan de Déu-Hospital Clínic, Barcelona, Spain
- Study Group for Immune Dysfunction Diseases in Children (GEMDIP), Institut de Recerca Sant Joan de Déu, Barcelona, Spain
| | - Ana Esteve-Solé
- Clinical Immunology and Primary Immunodeficiencies Unit, Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu, Barcelona, Spain
- Clinical Immunology Unit, Hospital Sant Joan de Déu-Hospital Clínic, Barcelona, Spain
- Study Group for Immune Dysfunction Diseases in Children (GEMDIP), Institut de Recerca Sant Joan de Déu, Barcelona, Spain
| | - Alexandru Vlagea
- Clinical Immunology Unit, Hospital Sant Joan de Déu-Hospital Clínic, Barcelona, Spain
- Immunology Department, Biomedic Diagnostic Center (CDB), Hospital Clínic of Barcelona, Clinical Immunology Unit Hospital Sant Joan de Déu-Hospital Clínic de Barcelona, Barcelona, Spain
| | - Rafael Correa-Rocha
- Laboratory of Immune-Regulation, Gregorio Marañón Health Research Institute (IISGM), Madrid, Spain
| | - Ma Elena Seoane-Reula
- Laboratory of Immune-Regulation, Gregorio Marañón Health Research Institute (IISGM), Madrid, Spain
- Pediatric Immuno-Allergy Unit, Allergy Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Primary Immunodeficiencies Unit, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Laia Alsina
- Clinical Immunology and Primary Immunodeficiencies Unit, Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu, Barcelona, Spain
- Clinical Immunology Unit, Hospital Sant Joan de Déu-Hospital Clínic, Barcelona, Spain
- Study Group for Immune Dysfunction Diseases in Children (GEMDIP), Institut de Recerca Sant Joan de Déu, Barcelona, Spain
- Department of Surgery and Surgical Specializations, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, Spain
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The SMML, Schreurs RRCE, Drewniak A, Bakx R, de Meij TGJ, Budding AE, Poort L, Cense HA, Heij HA, van Heurn LWE, Gorter RR, Bunders MJ. Enhanced Th17 responses in the appendix of children with complex compared to simple appendicitis are associated with microbial dysbiosis. Front Immunol 2024; 14:1258363. [PMID: 38239362 PMCID: PMC10794624 DOI: 10.3389/fimmu.2023.1258363] [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: 07/13/2023] [Accepted: 11/17/2023] [Indexed: 01/22/2024] Open
Abstract
Introduction Appendicitis is one of the most common causes of acute abdominal surgery in children. The clinical course of appendicitis ranges from simple to complex appendicitis. The mechanisms underlying the heterogeneity of appendicitis in children remain largely unclear. Dysregulated T cell responses play an important role in several inflammatory diseases of the intestine, but the extend of T cell dysregulation in appendicitis in children is less well known. Methods To characterize appendiceal T cells in simple and complex appendicitis we performed in-depth immunophenotyping of appendiceal-derived T cells by flow cytometry and correlated this to appendiceal-derived microbiota analyses of the same patient. Results Appendix samples of twenty children with appendicitis (n = 8 simple, n = 12 complex) were collected. T cells in complex appendicitis displayed an increased differentiated phenotype compared to simple appendicitis, including a loss of both CD27 and CD28 by CD4+ T cells and to a lesser extent by CD8+ T cells. Frequencies of phenotypic tissue-resident memory CD69+CD4+ T cells and CD69+CD8+ T cells were decreased in children with complex compared to simple appendicitis, indicating disruption of local tissue-resident immune responses. In line with the increased differentiated phenotype, cytokine production of in particular IL-17A by CD4+ T cells was increased in children with complex compared to simple appendicitis. Furthermore, frequencies of IL-17A+ CD4+ T cells correlated with a dysregulation of the appendiceal microbiota in children with complex appendicitis. Conclusion In conclusion, disruption of local T cell responses, and enhanced pro-inflammatory Th17 responses correlating to changes in the appendiceal microbiota were observed in children with complex compared to simple appendicitis. Further studies are needed to decipher the role of a dysregulated network of microbiota and Th17 cells in the development of complex appendicitis in children.
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Affiliation(s)
- Sarah-May M. L. The
- Department of Paediatric Surgery, Emma Children’s Hospital, Amsterdam University Medical Center (UMC), University of Amsterdam & Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam, Netherlands
- Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Renée R. C. E. Schreurs
- Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Department of Paediatrics, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam & Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Agata Drewniak
- Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Roel Bakx
- Department of Paediatric Surgery, Emma Children’s Hospital, Amsterdam University Medical Center (UMC), University of Amsterdam & Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam, Netherlands
- Amsterdam Gastroenterology and Metabolism Research Institute, Amsterdam, Netherlands
| | - Tim G. J. de Meij
- Amsterdam Reproduction and Development Research Institute, Amsterdam, Netherlands
- Amsterdam Gastroenterology and Metabolism Research Institute, Amsterdam, Netherlands
- Department of Paediatric Gastroenterology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | | | | | - Huib A. Cense
- Department of Surgery, Red Cross Hospital, Beverwijk, Netherlands
| | - Hugo A. Heij
- Department of Paediatric Surgery, Emma Children’s Hospital, Amsterdam University Medical Center (UMC), University of Amsterdam & Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - L. W. Ernest van Heurn
- Department of Paediatric Surgery, Emma Children’s Hospital, Amsterdam University Medical Center (UMC), University of Amsterdam & Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam, Netherlands
- Amsterdam Gastroenterology and Metabolism Research Institute, Amsterdam, Netherlands
| | - Ramon R. Gorter
- Department of Paediatric Surgery, Emma Children’s Hospital, Amsterdam University Medical Center (UMC), University of Amsterdam & Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam, Netherlands
- Amsterdam Gastroenterology and Metabolism Research Institute, Amsterdam, Netherlands
| | - Madeleine J. Bunders
- Leibniz Institute of Virology, Hamburg, Germany
- Third Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Tey PY, Dufner A, Knobeloch KP, Pruneda JN, Clague MJ, Urbé S. Rapid turnover of CTLA4 is associated with a complex architecture of reversible ubiquitylation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.12.31.573735. [PMID: 38260548 PMCID: PMC10802369 DOI: 10.1101/2023.12.31.573735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
The immune checkpoint regulator CTLA4 is an unusually short-lived membrane protein. Here we show that its lysosomal degradation is dependent on ubiquitylation at Lysine residues 203 and 213. Inhibition of the v-ATPase partially restores CTLA4 levels following cycloheximide treatment, but also reveals a fraction that is secreted in exosomes. The endosomal deubiquitylase, USP8, interacts with CTLA4 and its loss enhances CTLA4 ubiquitylation in cancer cells, mouse CD4+ T cells and in cancer cell-derived exosomes. Depletion of the USP8 adapter protein, HD-PTP, but not ESCRT-0 recapitulates this cellular phenotype, but shows distinct properties vis-à-vis exosome incorporation. Re-expression of wild-type USP8, but neither a catalytically inactive, nor a localization-compromised ΔMIT domain mutant can rescue delayed degradation of CTLA4, or counteract its accumulation in clustered endosomes. UbiCRest analysis of CTLA4-associated ubiquitin chain linkages identifies a complex mixture of conventional Lys63- and more unusual Lys27- and Lys29-linked polyubiquitin chains that may underly the rapidity of protein turnover.
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Affiliation(s)
- Pei Yee Tey
- Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown St., Liverpool, L69 3BX, UK
| | - Almut Dufner
- Institute of Neuropathology, Medical Faculty, University of Freiburg, 79106 Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79104 Freiburg, Germany
| | - Klaus-Peter Knobeloch
- Institute of Neuropathology, Medical Faculty, University of Freiburg, 79106 Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79104 Freiburg, Germany
| | - Jonathan N. Pruneda
- Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Michael J. Clague
- Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown St., Liverpool, L69 3BX, UK
| | - Sylvie Urbé
- Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown St., Liverpool, L69 3BX, UK
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10
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Ebrahimi S, Habibzadeh A, Khojasteh-Kaffash S, Valizadeh P, Samieefar N, Rezaei N. Immune checkpoint inhibitors therapy as the game-changing approach for pediatric lymphoma: A brief landscape. Crit Rev Oncol Hematol 2024; 193:104225. [PMID: 38049077 DOI: 10.1016/j.critrevonc.2023.104225] [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: 05/30/2023] [Revised: 11/29/2023] [Accepted: 11/30/2023] [Indexed: 12/06/2023] Open
Abstract
Lymphoma is known as the third most common malignancy in children, and its prevalence and mortality are increasing. Common treatments, including chemotherapy, radiotherapy, and also surgery, despite their efficacy, have many side effects and, have a high chance of disease relapse. Immune Checkpoint Inhibitors (ICIs) offer a promising alternative with potentially fewer risks of relapse and toxicity. This review article aims to investigate the efficacy and safety of ICIs, either as monotherapy or in combination, for pediatric lymphoma patients. ICIs have revolutionized cancer treatment in recent years and have shown remarkable results in several adult cancers. However, their efficacy in treating pediatrics requires further investigation. Nevertheless, some ICIs, including nivolumab, pembrolizumab, and ipilimumab, have demonstrated encouraging outcomes. ICIs therapy is not without risks and can cause side effects, including rash, itching, vitiligo, abdominal pain, diarrhea, dysphagia, epigastric pain, nausea, vomiting, thyroid, and pituitary dysfunction. Overall, this review article highlights the potential benefits and risks of ICIs in treating pediatric lymphoma.
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Affiliation(s)
- Sara Ebrahimi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Adrina Habibzadeh
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Student Research Committee, Fasa University of Medical Sciences, Fasa, Iran
| | - Soroush Khojasteh-Kaffash
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Student Research Committee, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Parya Valizadeh
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Noosha Samieefar
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; USERN Office, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center Hospital, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Science, Tehran, Iran.
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11
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Chen H, Wang X, Wang Y, Chang X. What happens to regulatory T cells in multiple myeloma. Cell Death Discov 2023; 9:468. [PMID: 38129374 PMCID: PMC10739837 DOI: 10.1038/s41420-023-01765-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 12/03/2023] [Accepted: 12/06/2023] [Indexed: 12/23/2023] Open
Abstract
Abnormal tumor microenvironment and immune escape in multiple myeloma (MM) are associated with regulatory T cells (Tregs), which play an important role in maintaining self-tolerance and regulating the overall immune response to infection or tumor cells. In patients with MM, there are abnormalities in the number, function and distribution of Tregs, and these abnormalities may be related to the disease stage, risk grade and prognosis of patients. During the treatment, Tregs have different responses to various treatment regiments, thus affecting the therapeutic effect of MM. It is also possible to predict the therapeutic response by observing the changes of Tregs. In addition to the above, we reviewed the application of Tregs in the treatment of MM. In conclusion, there is still much room for research on the mechanism and application of Tregs in MM.
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Affiliation(s)
- Huixian Chen
- Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Xueling Wang
- Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Yan Wang
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Xiaotian Chang
- Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China.
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12
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Taghizade N, Babayeva R, Kara A, Karakus IS, Catak MC, Bulutoglu A, Haskologlu ZS, Akay Haci I, Tunakan Dalgic C, Karabiber E, Bilgic Eltan S, Yorgun Altunbas M, Sefer AP, Sezer A, Kokcu Karadag SI, Arik E, Karali Z, Ozhan Kont A, Tuzer C, Karaman S, Mersin SS, Kasap N, Celik E, Kocacik Uygun DF, Aydemir S, Kiykim A, Aydogmus C, Ozek Yucel E, Celmeli F, Karatay E, Bozkurtlar E, Demir S, Metin A, Karaca NE, Kutukculer N, Aksu G, Guner SN, Keles S, Reisli I, Kendir Demirkol Y, Arikoglu T, Gulez N, Genel F, Kilic SS, Aytekin C, Keskin O, Yildiran A, Ozcan D, Altintas DU, Ardeniz FO, Dogu EF, Ikinciogullari KA, Karakoc-Aydiner E, Ozen A, Baris S. Therapeutic modalities and clinical outcomes in a large cohort with LRBA deficiency and CTLA4 insufficiency. J Allergy Clin Immunol 2023; 152:1634-1645. [PMID: 37595759 DOI: 10.1016/j.jaci.2023.08.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 08/01/2023] [Accepted: 08/08/2023] [Indexed: 08/20/2023]
Abstract
BACKGROUND LPS-responsive beige-like anchor (LRBA) deficiency (LRBA-/-) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) insufficiency (CTLA4+/-) are mechanistically overlapped diseases presenting with recurrent infections and autoimmunity. The effectiveness of different treatment regimens remains unknown. OBJECTIVE Our aim was to determine the comparative efficacy and long-term outcome of therapy with immunosuppressants, CTLA4-immunoglobulin (abatacept), and hematopoietic stem cell transplantation (HSCT) in a single-country multicenter cohort of 98 patients with a 5-year median follow-up. METHODS The 98 patients (63 LRBA-/- and 35 CTLA4+/-) were followed and evaluated at baseline and every 6 months for clinical manifestations and response to the respective therapies. RESULTS The LRBA-/- patients exhibited a more severe disease course than did the CTLA4+/- patients, requiring more immunosuppressants, abatacept, and HSCT to control their symptoms. Among the 58 patients who received abatacept as either a primary or rescue therapy, sustained complete control was achieved in 46 (79.3%) without severe side effects. In contrast, most patients who received immunosuppressants as primary therapy (n = 61) showed either partial or no disease control (72.1%), necessitating additional immunosuppressants, abatacept, or transplantation. Patients with partial or no response to abatacept (n = 12) had longer disease activity before abatacept therapy, with higher organ involvement and poorer disease outcomes than those with a complete response. HSCT was performed in 14 LRBA-/- patients; 9 patients (64.2%) showed complete remission, and 3 (21.3%) continued to receive immunosuppressants after transplantation. HSCT and abatacept therapy gave rise to similar probabilities of survival. CONCLUSIONS Abatacept is superior to immunosuppressants in controlling disease manifestations over the long term, especially when started early, and it may provide a safe and effective therapeutic alternative to transplantation.
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Affiliation(s)
- Nigar Taghizade
- Department of Pediatrics, School of Medicine, Marmara University, Istanbul, Turkey
| | - Royala Babayeva
- Division of Pediatric Allergy and Immunology, School of Medicine, Marmara University, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey; The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Altan Kara
- TUBITAK Marmara Research Center, Gene Engineering and Biotechnology Institute, Gebze, Turkey
| | | | - Mehmet Cihangir Catak
- Division of Pediatric Allergy and Immunology, School of Medicine, Marmara University, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey; The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Alper Bulutoglu
- Division of Pediatric Allergy and Immunology, School of Medicine, Marmara University, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey; The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Zehra Sule Haskologlu
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Idil Akay Haci
- Division of Pediatric Allergy and Immunology, Dr Behcet Uz Children's Education and Research Hospital, University of Health Sciences, Izmir, Turkey
| | - Ceyda Tunakan Dalgic
- Department of Allergy and Immunology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Esra Karabiber
- Department of Allergy and Immunology, Marmara University Training and Research Hospital, Ministry of Health, Istanbul, Turkey
| | - Sevgi Bilgic Eltan
- Division of Pediatric Allergy and Immunology, School of Medicine, Marmara University, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey; The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Melek Yorgun Altunbas
- Division of Pediatric Allergy and Immunology, School of Medicine, Marmara University, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey; The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Asena Pinar Sefer
- Division of Pediatric Allergy and Immunology, School of Medicine, Marmara University, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey; The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Ahmet Sezer
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Çukurova University, Adana, Turkey
| | | | - Elif Arik
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Gaziantep University, Gaziantep, Turkey
| | - Zuhal Karali
- Division of Pediatric Immunology and Rheumatology, Faculty of Medicine, Uludag University, Bursa, Turkey
| | - Aylin Ozhan Kont
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Can Tuzer
- Department of Allergy and Immunology, Batman Training and Research Hospital, Ministry of Health, Batman, Turkey
| | - Sait Karaman
- Pediatric Allergy and Immunology, Manisa City Hospital, University of Health Sciences, Manisa, Turkey
| | - Selver Seda Mersin
- Department of Allergy and Immunology, Dr Ersin Arslan Training and Research Hospital, Ministry of Health, Gaziantep, Turkey
| | - Nurhan Kasap
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Istanbul Medeniyet University, Istanbul, Turkey
| | - Enes Celik
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Akdeniz University, Antalya, Turkey
| | | | - Sezin Aydemir
- Division of Pediatric Allergy and Immunology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Ayca Kiykim
- Division of Pediatric Allergy and Immunology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Cigdem Aydogmus
- Division of Pediatric Allergy and Immunology, Basaksehir Cam and Sakura City Hospital, University of Health Sciences, Istanbul, Turkey
| | - Esra Ozek Yucel
- Division of Pediatric Allergy and Immunology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Fatih Celmeli
- Division of Pediatric Allergy and Immunology, Antalya Training and Research Hospital, University of Health Sciences, Antalya, Turkey
| | - Emrah Karatay
- Department of Radiology, Marmara University Education and Research Hospital, Istanbul, Turkey
| | - Emine Bozkurtlar
- Department of Pathology, Faculty of Medicine, Marmara University, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Semra Demir
- Department of Allergy and Immunology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Ayse Metin
- Division of Pediatric Immunology, Ankara City Hospital, University of Health Sciences, Ankara, Turkey
| | - Neslihan Edeer Karaca
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Necil Kutukculer
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Guzide Aksu
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Sukru Nail Guner
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Sevgi Keles
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Ismail Reisli
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Yasemin Kendir Demirkol
- Division of Pediatric Genetics, Umraniye Education and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Tugba Arikoglu
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Nesrin Gulez
- Division of Pediatric Allergy and Immunology, Dr Behcet Uz Children's Education and Research Hospital, University of Health Sciences, Izmir, Turkey
| | - Ferah Genel
- Division of Pediatric Allergy and Immunology, Dr Behcet Uz Children's Education and Research Hospital, University of Health Sciences, Izmir, Turkey
| | - Sara Sebnem Kilic
- Division of Pediatric Immunology and Rheumatology, Faculty of Medicine, Uludag University, Bursa, Turkey
| | - Caner Aytekin
- Department of Pediatric Immunology, Dr Sami Ulus Children Health and Diseases Training and Research Hospital, Ankara, Turkey
| | - Ozlem Keskin
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Gaziantep University, Gaziantep, Turkey
| | - Alisan Yildiran
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey
| | - Dilek Ozcan
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Çukurova University, Adana, Turkey
| | - Derya Ufuk Altintas
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Çukurova University, Adana, Turkey
| | - Fatma Omur Ardeniz
- Department of Allergy and Immunology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Esin Figen Dogu
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Ankara University, Ankara, Turkey
| | | | - Elif Karakoc-Aydiner
- Division of Pediatric Allergy and Immunology, School of Medicine, Marmara University, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey; The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Ahmet Ozen
- Division of Pediatric Allergy and Immunology, School of Medicine, Marmara University, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey; The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Safa Baris
- Division of Pediatric Allergy and Immunology, School of Medicine, Marmara University, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey; The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey.
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13
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LaBere B, Nguyen AA, Habiballah SB, Elkins M, Imperial J, Li B, Devana S, Timilsina S, Stubbs SB, Joerger J, Chou J, Platt CD. Clinical utility of measuring CD4 + T follicular cells in patients with immune dysregulation. J Autoimmun 2023; 140:103088. [PMID: 37549449 PMCID: PMC10839119 DOI: 10.1016/j.jaut.2023.103088] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 06/23/2023] [Accepted: 07/11/2023] [Indexed: 08/09/2023]
Abstract
Mechanistic studies of autoimmune disorders have identified circulating T follicular helper (cTfh) cells as drivers of autoimmunity. However, the quantification of cTfh cells is not yet used in clinical practice due to the lack of age-stratified normal ranges and the unknown sensitivity and specificity of this test for autoimmunity. We enrolled 238 healthy participants and 130 patients with common and rare disorders of autoimmunity or autoinflammation. Patients with infections, active malignancy, or any history of transplantation were excluded. In 238 healthy controls, median cTfh percentages (range 4.8%-6.2%) were comparable among age groups, sexes, races, and ethnicities, apart from a significantly lower percentages in children less than 1 year of age (median 2.1%, CI: 0.4%-6.8, p < 0.0001). Among 130 patients with over 40 immune regulatory disorders, a cTfh percentage exceeding 12% had 88% sensitivity and 94% specificity for differentiating disorders with adaptive immune cell dysregulation from those with predominantly innate cell defects. This threshold had a sensitivity of 86% and specificity of 100% for active autoimmunity and normalized with effective treatment. cTfh percentages exceeding 12% distinguish autoimmunity from autoinflammation, thereby differentiating two endotypes of immune dysregulation with overlapping symptoms and different therapies.
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Affiliation(s)
- Brenna LaBere
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Alan A Nguyen
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Saddiq B Habiballah
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Megan Elkins
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Juliet Imperial
- Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Betty Li
- Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Suraj Timilsina
- Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Spencer B Stubbs
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jill Joerger
- Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Janet Chou
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Craig D Platt
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
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Toskov V, Ehl S. Autoimmune lymphoproliferative immunodeficiencies (ALPID) in childhood: breakdown of immune homeostasis and immune dysregulation. Mol Cell Pediatr 2023; 10:11. [PMID: 37702894 PMCID: PMC10499775 DOI: 10.1186/s40348-023-00167-1] [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: 07/19/2023] [Accepted: 09/05/2023] [Indexed: 09/14/2023] Open
Abstract
Many inborn errors of immunity (IEI) manifest with hallmarks of both immunodeficiency and immune dysregulation due to uncontrolled immune responses and impaired immune homeostasis. A subgroup of these disorders frequently presents with autoimmunity and lymphoproliferation (ALPID phenotype). After the initial description of the genetic basis of autoimmune lymphoproliferative syndrome (ALPS) more than 20 years ago, progress in genetics has helped to identify many more genetic conditions underlying this ALPID phenotype. Among these, the majority is caused by a group of autosomal-dominant conditions including CTLA-4 haploinsufficiency, STAT3 gain-of-function disease, activated PI3 kinase syndrome, and NF-κB1 haploinsufficiency. Even within a defined genetic condition, ALPID patients may present with staggering clinical heterogeneity, which makes diagnosis and management a challenge. In this review, we discuss the pathophysiology, clinical presentation, approaches to diagnosis, and conventional as well as targeted therapy of the most common ALPID conditions.
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Affiliation(s)
- Vasil Toskov
- Centre for Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Stephan Ehl
- Centre for Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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15
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Sestan M, Kifer N, Arsov T, Cook M, Ellyard J, Vinuesa CG, Jelusic M. The Role of Genetic Risk Factors in Pathogenesis of Childhood-Onset Systemic Lupus Erythematosus. Curr Issues Mol Biol 2023; 45:5981-6002. [PMID: 37504294 PMCID: PMC10378459 DOI: 10.3390/cimb45070378] [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: 06/22/2023] [Revised: 07/09/2023] [Accepted: 07/12/2023] [Indexed: 07/29/2023] Open
Abstract
The pathogenesis of childhood-onset systemic lupus erythematosus (cSLE) is complex and not fully understood. It involves three key factors: genetic risk factors, epigenetic mechanisms, and environmental triggers. Genetic factors play a significant role in the development of the disease, particularly in younger individuals. While cSLE has traditionally been considered a polygenic disease, it is now recognized that in rare cases, a single gene mutation can lead to the disease. Although these cases are uncommon, they provide valuable insights into the disease mechanism, enhance our understanding of pathogenesis and immune tolerance, and facilitate the development of targeted treatment strategies. This review aims to provide a comprehensive overview of both monogenic and polygenic SLE, emphasizing the implications of specific genes in disease pathogenesis. By conducting a thorough analysis of the genetic factors involved in SLE, we can improve our understanding of the underlying mechanisms of the disease. Furthermore, this knowledge may contribute to the identification of effective biomarkers and the selection of appropriate therapies for individuals with SLE.
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Affiliation(s)
- Mario Sestan
- Department of Paediatrics, University of Zagreb School of Medicine, University Hospital Centre Zagreb, 10000 Zagreb, Croatia
| | - Nastasia Kifer
- Department of Paediatrics, University of Zagreb School of Medicine, University Hospital Centre Zagreb, 10000 Zagreb, Croatia
| | - Todor Arsov
- Faculty of Medical Sciences, University Goce Delchev, 2000 Shtip, North Macedonia
- The Francis Crick Institute, London NW1 1AT, UK
| | - Matthew Cook
- Department of Immunology and Infectious Diseases, The John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia
- Department of Medicine, University of Cambridge, Cambridge CB2 1TN, UK
| | - Julia Ellyard
- Department of Immunology and Infectious Diseases, The John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia
| | | | - Marija Jelusic
- Department of Paediatrics, University of Zagreb School of Medicine, University Hospital Centre Zagreb, 10000 Zagreb, Croatia
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16
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LaBere B, Nguyen AA, Habiballah SB, Elkins M, Imperial J, Li B, Devana S, Timilsina S, Stubbs SB, Joerger J, Chou J, Platt CD. Clinical utility of measuring CD4 + T follicular cells in patients with immune dysregulation. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.06.06.23291032. [PMID: 37333344 PMCID: PMC10274986 DOI: 10.1101/2023.06.06.23291032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/20/2023]
Abstract
Mechanistic studies of autoimmune disorders have identified circulating T follicular helper (cTfh) cells as drivers of autoimmunity. However, the quantification of cTfh cells is not yet used in clinical practice due to the lack of age-stratified normal ranges and the unknown sensitivity and specificity of this test for autoimmunity. We enrolled 238 healthy participants and 130 patients with common and rare disorders of autoimmunity or autoinflammation. Patients with infections, active malignancy, or any history of transplantation were excluded. In 238 healthy controls, median cTfh percentages (range 4.8% - 6.2%) were comparable among age groups, sexes, races, and ethnicities, apart from a significantly lower percentages in children less than 1 year of age (median 2.1%, CI: 0.4% - 6.8, p< 0.0001). Among 130 patients with over 40 immune regulatory disorders, a cTfh percentage exceeding 12% had 88% sensitivity and 94% specificity for differentiating disorders with adaptive immune cell dysregulation from those with predominantly innate cell defects. This threshold had a sensitivity of 86% and specificity of 100% for active autoimmunity and normalized with effective treatment. cTfh percentages exceeding 12% distinguish autoimmunity from autoinflammation, thereby differentiating two endotypes of immune dysregulation with overlapping symptoms and different therapies.
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17
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Mancuso G, Bechi Genzano C, Fierabracci A, Fousteri G. Type 1 diabetes and inborn errors of immunity: Complete strangers or 2 sides of the same coin? J Allergy Clin Immunol 2023; 151:1429-1447. [PMID: 37097271 DOI: 10.1016/j.jaci.2023.03.026] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/31/2023] [Accepted: 03/31/2023] [Indexed: 04/26/2023]
Abstract
Type 1 diabetes (T1D) is a polygenic disease and does not follow a mendelian pattern. Inborn errors of immunity (IEIs), on the other hand, are caused by damaging germline variants, suggesting that T1D and IEIs have nothing in common. Some IEIs, resulting from mutations in genes regulating regulatory T-cell homeostasis, are associated with elevated incidence of T1D. The genetic spectrum of IEIs is gradually being unraveled; consequently, molecular pathways underlying human monogenic autoimmunity are being identified. There is an appreciable overlap between some of these pathways and the genetic variants that determine T1D susceptibility, suggesting that after all, IEI and T1D are 2 sides of the same coin. The study of monogenic IEIs with a variable incidence of T1D has the potential to provide crucial insights into the mechanisms leading to T1D. These insights contribute to the definition of T1D endotypes and explain disease heterogeneity. In this review, we discuss the interconnected pathogenic pathways of autoimmunity, β-cell function, and primary immunodeficiency. We also examine the role of environmental factors in disease penetrance as well as the circumstantial evidence of IEI drugs in preventing and curing T1D in individuals with IEIs, suggesting the repositioning of these drugs also for T1D therapy.
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Affiliation(s)
- Gaia Mancuso
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Camillo Bechi Genzano
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, NY
| | | | - Georgia Fousteri
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
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18
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Gray PE, David C. Inborn Errors of Immunity and Autoimmune Disease. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2023; 11:1602-1622. [PMID: 37119983 DOI: 10.1016/j.jaip.2023.04.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 04/01/2023] [Accepted: 04/21/2023] [Indexed: 05/01/2023]
Abstract
Autoimmunity may be a manifestation of inborn errors of immunity, specifically as part of the subgroup of primary immunodeficiency known as primary immune regulatory disorders. However, although making a single gene diagnosis can have important implications for prognosis and management, picking patients to screen can be difficult, against a background of a high prevalence of autoimmune disease in the population. This review compares the genetics of common polygenic and rare monogenic autoimmunity, and explores the molecular mechanisms, phenotypes, and inheritance of autoimmunity associated with primary immune regulatory disorders, highlighting the emerging importance of gain-of-function and non-germline somatic mutations. A novel framework for identifying rare monogenic cases of common diseases in children is presented, highlighting important clinical and immunologic features that favor single gene disease and guides clinicians in selecting appropriate patients for genomic screening. In addition, there will be a review of autoimmunity in non-genetically defined primary immunodeficiency such as common variable immunodeficiency, and of instances where primary autoimmunity can result in clinical phenocopies of inborn errors of immunity.
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Affiliation(s)
- Paul Edgar Gray
- Sydney Children's Hospital, Randwick, NSW, Australia; Western Sydney University, Penrith, NSW, Australia.
| | - Clementine David
- Sydney Children's Hospital, Randwick, NSW, Australia; The School of Women's & Children's Health, University of New South Wales, Randwick, NSW, Australia
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19
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Waheed N, Naseer M, Haider N, Suleman S, Ullah A. Whole exome sequencing identified a novel splice donor site variant in interleukin 2 receptor alpha chain. Immunogenetics 2023; 75:71-79. [PMID: 36195682 DOI: 10.1007/s00251-022-01278-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 09/25/2022] [Indexed: 11/05/2022]
Abstract
Interleukin 2 receptor alpha chain (IL-2Rα or CD25) deficiency (OMIM #606367) is an immune dysregulation disorder segregating in autosomal recessive form. The disease is caused by biallelic variants in the IL-2Rα gene encoding IL-2Rα also known as CD25 protein. IL-2Rα combines with γ and β chains of interleukin 2 receptor to form a functional interleukin 2 receptor (IL-2R). In the present study, we identified a Pakistani family presenting a unique presentation of IL-2Rα deficiency. Clinical whole exome sequencing revealed a novel splice donor site variant (NM_001378789.1 (NP_001365718); c.64 + 1G > A) in the IL-2Rα gene. American College of Medical Genetics (ACMG) guidelines interpreted the identified variant as likely pathogenic. The IL-2Rα gene mutation usually presents with autoimmunity and immunodeficiency but in our patient, it presents with congenital diarrhea, metabolic crisis, and strong family history of death in infancy due to the similar complications. Her congenital diarrhea is attributed to autoimmunity in the form of autoimmune enteropathy and eczema. The laboratory findings revealed severe metabolic acidosis hypokalemia and elevated lactate and ammonia levels. This is a new presentation of IL-2Rα gene mutation. The present study highlights the importance of clinical whole exome sequencing in the correct diagnosis of congenital disorders. The study will also help clinical geneticists for genetic counseling and prevention of the disease in the affected family.
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Affiliation(s)
- Nadia Waheed
- Department of Pediatrics, Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad, Pakistan
| | - Maryam Naseer
- Department of Pediatrics, Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad, Pakistan
| | - Nighat Haider
- Department of Pediatrics, Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad, Pakistan
| | - Sufyan Suleman
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Asmat Ullah
- Department of Pediatrics, Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad, Pakistan.
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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20
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Peng Y, Tao Y, Zhang Y, Wang J, Yang J, Wang Y. CD25: A potential tumor therapeutic target. Int J Cancer 2023; 152:1290-1303. [PMID: 36082452 DOI: 10.1002/ijc.34281] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 07/17/2022] [Accepted: 08/08/2022] [Indexed: 02/03/2023]
Abstract
CD25 is the alpha-chain of the heterotrimer IL-2 receptor. CD25 is expressed on the surface of both immune and non-immune cells with different frequencies. For cancers, CD25 is expressed at high levels in many types of hematological malignancies, but at low levels in most solid tumors. CD25 is also highly expressed in activated circulating immune cells and regulatory T cells (Tregs). Infiltration of Tregs in the tumor microenvironment can lead to an imbalanced ratio of effector T cells (Teffs) and Tregs, which is associated with the progression of cancers. A rescued Teff/Treg cell ratio indicates an efficient anti-tumor response to immunotherapy. CD25 as a potential target for the depletion of Tregs is critical in developing new immunotherapeutic strategies. Few articles have summarized the relationships between CD25 and tumors, or the recent progress of drugs targeting CD25. In this paper, we will discuss the structures of IL-2 and IL-2R, the biological function of CD25 and its important role in tumor therapy. In addition, the latest research on drugs targeting CD25 has been summarized, providing guidance for future drug development.
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Affiliation(s)
- Yujia Peng
- State Key Laboratory of Biotherapy, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease- related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,West China-California Research Center for Predictive Intervention Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yiran Tao
- State Key Laboratory of Biotherapy, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease- related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,West China-California Research Center for Predictive Intervention Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ya Zhang
- State Key Laboratory of Biotherapy, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease- related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,College of Life Sciences, Sichuan University, Chengdu, Sichuan, China
| | - Jiaxing Wang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Jinliang Yang
- State Key Laboratory of Biotherapy, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease- related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yuxi Wang
- State Key Laboratory of Biotherapy, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease- related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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21
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Stallard L, Siddiqui I, Muise A. Beyond IBD: the genetics of other early-onset diarrhoeal disorders. Hum Genet 2023; 142:655-667. [PMID: 36788146 PMCID: PMC10182111 DOI: 10.1007/s00439-023-02524-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 01/19/2023] [Indexed: 02/16/2023]
Abstract
Diarrhoeal disorders in childhood extend beyond the inflammatory bowel diseases. Persistent and severe forms of diarrhoea can occur from birth and are associated with significant morbidity and mortality. These disorders can affect not only the gastrointestinal tract but frequently have extraintestinal manifestations, immunodeficiencies and endocrinopathies. Genomic analysis has advanced our understanding of these conditions and has revealed precision-based treatment options such as potentially curative haematopoietic stem cell transplant. Although many new mutations have been discovered, there is frequently no clear genotype-phenotype correlation. The functional effects of gene mutations can be studied in model systems such as patient-derived organoids. This allows us to further characterise these disorders and advance our understanding of the pathophysiology of the intestinal mucosa. In this review, we will provide an up to date overview of genes involved in diarrhoeal disorders of early onset, particularly focussing on the more recently described gene defects associated with protein loosing enteropathy.
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Affiliation(s)
- Lorraine Stallard
- SickKids Inflammatory Bowel Disease Centre, The Hospital for Sick Children, Toronto, ON, Canada
| | - Iram Siddiqui
- Division of Pathology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Aleixo Muise
- SickKids Inflammatory Bowel Disease Centre, The Hospital for Sick Children, Toronto, ON, Canada. .,Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada. .,Department of Pediatrics, Institute of Medical Science and Biochemistry, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada.
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22
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Carss KJ, Deaton AM, Del Rio-Espinola A, Diogo D, Fielden M, Kulkarni DA, Moggs J, Newham P, Nelson MR, Sistare FD, Ward LD, Yuan J. Using human genetics to improve safety assessment of therapeutics. Nat Rev Drug Discov 2023; 22:145-162. [PMID: 36261593 DOI: 10.1038/s41573-022-00561-w] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2022] [Indexed: 02/07/2023]
Abstract
Human genetics research has discovered thousands of proteins associated with complex and rare diseases. Genome-wide association studies (GWAS) and studies of Mendelian disease have resulted in an increased understanding of the role of gene function and regulation in human conditions. Although the application of human genetics has been explored primarily as a method to identify potential drug targets and support their relevance to disease in humans, there is increasing interest in using genetic data to identify potential safety liabilities of modulating a given target. Human genetic variants can be used as a model to anticipate the effect of lifelong modulation of therapeutic targets and identify the potential risk for on-target adverse events. This approach is particularly useful for non-clinical safety evaluation of novel therapeutics that lack pharmacologically relevant animal models and can contribute to the intrinsic safety profile of a drug target. This Review illustrates applications of human genetics to safety studies during drug discovery and development, including assessing the potential for on- and off-target associated adverse events, carcinogenicity risk assessment, and guiding translational safety study designs and monitoring strategies. A summary of available human genetic resources and recommended best practices is provided. The challenges and future perspectives of translating human genetic information to identify risks for potential drug effects in preclinical and clinical development are discussed.
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Affiliation(s)
| | - Aimee M Deaton
- Amgen, Cambridge, MA, USA.,Alnylam Pharmaceuticals, Cambridge, MA, USA
| | - Alberto Del Rio-Espinola
- Novartis Institutes for BioMedical Research, Basel, Switzerland.,GentiBio Inc., Cambridge, MA, USA
| | | | - Mark Fielden
- Amgen, Thousand Oaks, MA, USA.,Kate Therapeutics, San Diego, CA, USA
| | | | - Jonathan Moggs
- Novartis Institutes for BioMedical Research, Basel, Switzerland
| | | | | | - Frank D Sistare
- Merck & Co., West Point, PA, USA.,315 Meadowmont Ln, Chapel Hill, NC, USA
| | - Lucas D Ward
- Amgen, Cambridge, MA, USA. .,Alnylam Pharmaceuticals, Cambridge, MA, USA.
| | - Jing Yuan
- Amgen, Cambridge, MA, USA.,Pfizer, Cambridge, MA, USA
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23
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Freund T, Baxter SK, Walsh T, Golan H, Kapelushnik J, Abramsohn-Goldenberg M, Benor S, Sarid N, Ram R, Alcalay Y, Segel R, Renbaum P, Stepensky P, King MC, Torgerson TR, Hagin D. Clinically Complex LRBA Deficiency Due to a Founder Allele in the Georgian Jewish Population. J Clin Immunol 2023; 43:151-164. [PMID: 36063261 DOI: 10.1007/s10875-022-01358-7] [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: 05/13/2022] [Accepted: 08/15/2022] [Indexed: 01/18/2023]
Abstract
Pathogenic variants in LRBA, encoding the LPS Responsive Beige-Like Anchor (LRBA) protein, are responsible for recessive, early-onset hypogammaglobulinemia, severe multi-organ autoimmunity, and lymphoproliferation, with increased risk for malignancy. LRBA deficiency has a wide clinical spectrum with variable age of onset and disease severity. Three apparently unrelated patients with LRBA deficiency, of Georgian Jewish descent, were homozygous for LRBA c.6640C > T, p.R2214*, leading to a stop upstream of the LRBA BEACH domain. Despite carrying the same LRBA genotype, the three patients differed in clinical course: the first patient was asymptomatic until age 25 years; the second presented with failure to thrive at age 3 months; and the third presented at age 7 years with immune cytopenias and severe infections. Two of the patients developed malignancies: the first patient was diagnosed with recurrent Hodgkin's disease at age 36 years, and the second patient developed aggressive gastric cancer at age 15 years. Among Georgian Jews, the carrier frequency of the LRBA p.R2214* allele was 1.6% (4 of 236 Georgian Jewish controls). The allele was absent from other populations. Haplotype analysis showed a shared origin of the mutation. These three patients revealed a pathogenic LRBA founder allele in the Georgian Jewish population, support the diverse and complex clinical spectrum of LRBA deficiency, and support the possibility that LRBA deficiency predisposes to malignancy.
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Affiliation(s)
- Tal Freund
- Allergy and Clinical Immunology Unit, Department of Medicine, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Sarah K Baxter
- Department of Pediatrics, University of Washington and Seattle Children's Research Institute, Seattle, WA, USA.,Department of Medicine and Department of Genome Sciences, University of Washington, Seattle, WA, USA
| | - Tom Walsh
- Department of Medicine and Department of Genome Sciences, University of Washington, Seattle, WA, USA
| | - Hana Golan
- Pediatric Hematology Oncology Department, Safra Children's Hospital, Sheba Medical Center, Ramat-Gan, Israel.,Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Joseph Kapelushnik
- Department of Pediatric Oncology and Department of Hematology, Faculty of Health Sciences, Soroka Medical Center and The Center of Advanced Research and Education in Reproduction (CARER), Ben-Gurion University of the Negev, Beer Sheva, Israel
| | | | - Shira Benor
- Allergy and Clinical Immunology Unit, Department of Medicine, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Nadav Sarid
- Department of Hematology and Stem Cell Transplantation Service, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ron Ram
- Department of Hematology and Stem Cell Transplantation Service, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yifat Alcalay
- Allergy and Clinical Immunology Unit, Department of Medicine, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Reeval Segel
- Shaare Zedek Medical Center and Faculty of Medicine, Medical Genetics Institute, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Paul Renbaum
- Shaare Zedek Medical Center and Faculty of Medicine, Medical Genetics Institute, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Polina Stepensky
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Mary-Claire King
- Department of Medicine and Department of Genome Sciences, University of Washington, Seattle, WA, USA
| | - Troy R Torgerson
- Department of Pediatrics, University of Washington and Seattle Children's Research Institute, Seattle, WA, USA.,Allen Institute for Immunology, Seattle, WA, USA
| | - David Hagin
- Allergy and Clinical Immunology Unit, Department of Medicine, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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24
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Fabozzi F, De Vito R, Gaspari S, Leone F, Delvecchio M, Agolini E, Galaverna F, Mastronuzzi A, Pagliara D, De Ioris MA. Case report: A new pathogenic variant of LRBA deficiency with a complex phenotype and Rosai-Dorfman disease. Front Immunol 2022; 13:944810. [PMID: 36569874 PMCID: PMC9780374 DOI: 10.3389/fimmu.2022.944810] [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: 05/15/2022] [Accepted: 11/23/2022] [Indexed: 12/13/2022] Open
Abstract
We reported a new pathogenic variant of LRBA deficiency with a complex phenotype-neonatal diabetes, very early-onset inflammatory bowel disease, and polyarthritis-who presented with lymph node enlargement. A case of Rosai-Dorfman's disease (RDD) was confirmed. The occurrence of an RDD lesion in LRBA-deficiency has never been reported so far.
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Affiliation(s)
- Francesco Fabozzi
- Department of Hematology/Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy,Department of Pediatrics, University of Tor Vergata, Rome, Italy
| | - Rita De Vito
- Department of Pathology, Bambino Gesù Children’s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Stefania Gaspari
- Department of Hematology/Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Fabrizio Leone
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy
| | | | - Emanuele Agolini
- Laboratory of Medical Genetics, Bambino Gesù Children’s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Federica Galaverna
- Department of Hematology/Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Angela Mastronuzzi
- Department of Hematology/Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Daria Pagliara
- Department of Hematology/Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Maria Antonietta De Ioris
- Department of Hematology/Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy,*Correspondence: Maria Antonietta De Ioris,
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25
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Yadav A, Kumar R, Rawat A, Venkatesan R. Neonatal diabetes with a rare LRBA mutation. BMJ Case Rep 2022; 15:e250243. [PMID: 36423945 PMCID: PMC9693640 DOI: 10.1136/bcr-2022-250243] [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] [Accepted: 11/02/2022] [Indexed: 11/25/2022] Open
Abstract
Neonatal diabetes mellitus (NDM) is characterised by onset of persistent hyperglycaemia within the first 6 months of life. NDM is frequently caused by a mutation in a single gene affecting pancreatic beta cell function. We report an infant, born to a non-consanguineous couple, who presented with osmotic symptoms and diabetic ketoacidosis. The genetic analysis showed a mutation in LRBA (lipopolysaccharide-responsive and beige-like anchor protein) gene. We highlight the importance of considering genetic analysis in every infant with NDM, to understand the nature of genetic mutation, associated comorbidities, response to glibenclamide and future prognosis.
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Affiliation(s)
- Arti Yadav
- Endocrinology and Diabetes Unit, Dpeartment of Paediatrics, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Rakesh Kumar
- Endocrinology and Diabetes Unit, Dpeartment of Paediatrics, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Amit Rawat
- Pediatric Allergy and Immunology Unit, PGIMER, Chandigarh, India
| | - Radha Venkatesan
- Molecular Genetics, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India
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26
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Catak MC, Akcam B, Bilgic Eltan S, Babayeva R, Karakus IS, Akgun G, Baser D, Bulutoglu A, Bayram F, Kasap N, Kiykim A, Hancioglu G, Kokcu Karadag SI, Kendir Demirkol Y, Ozen S, Cekic S, Ozcan D, Edeer Karaca N, Sasihuseyinoglu AS, Cansever M, Ozek Yucel E, Tamay Z, Altintas DU, Aydogmus C, Celmeli F, Cokugras H, Gulez N, Genel F, Metin A, Guner SN, Kutukculer N, Keles S, Reisli I, Kilic SS, Yildiran A, Karakoc-Aydiner E, Lo B, Ozen A, Baris S. Comparing the levels of CTLA-4-dependent biological defects in patients with LRBA deficiency and CTLA-4 insufficiency. Allergy 2022; 77:3108-3123. [PMID: 35491430 DOI: 10.1111/all.15331] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 03/07/2022] [Accepted: 04/04/2022] [Indexed: 01/28/2023]
Abstract
BACKGROUND Lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency and cytotoxic T-lymphocyte protein-4 (CTLA-4) insufficiency are recently described disorders that present with susceptibility to infections, autoimmunity, and lymphoproliferation. Clinical and immunological comparisons of the diseases with long-term follow-up have not been previously reported. We sought to compare the clinical and laboratory manifestations of both diseases and investigate the role of flow cytometry in predicting the genetic defect in patients with LRBA deficiency and CTLA-4 insufficiency. METHODS Patients were evaluated clinically with laboratory assessments for lymphocyte subsets, T follicular helper cells (TFH ), LRBA expression, and expression of CD25, FOXP3, and CTLA4 in regulatory T cells (Tregs) at baseline and 16 h post-stimulation. RESULTS LRBA-deficient patients (n = 29) showed significantly early age of symptom onset, higher rates of pneumonia, autoimmunity, chronic diarrhea, and failure to thrive compared to CTLA-4 insufficiency (n = 12). In total, 29 patients received abatacept with favorable responses and the overall survival probability was not different between transplanted versus non-transplanted patients in LRBA deficiency. Meanwhile, higher probability of survival was observed in CTLA-4-insufficient patients (p = 0.04). The T-cell subsets showed more deviation to memory cells in CTLA-4-insufficiency, accompanied by low percentages of Treg and dysregulated cTFH cells response in both diseases. Cumulative numbers of autoimmunities positively correlated with cTFH frequencies. Baseline CTLA-4 expression was significantly diminished in LRBA deficiency and CTLA-4 insufficiency, but significant induction in CTLA-4 was observed after short-term T-cell stimulation in LRBA deficiency and controls, while this elevation was less in CTLA-4 insufficiency, allowing to differentiate this disease from LRBA deficiency with high sensitivity (87.5%) and specificity (90%). CONCLUSION This cohort provided detailed clinical and laboratory comparisons for LRBA deficiency and CTLA-4 insufficiency. The flow cytometric approach is useful in predicting the defective gene; thus, targeted sequencing can be conducted to provide rapid diagnosis and treatment for these diseases impacting the CTLA-4 pathway.
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Affiliation(s)
- Mehmet C Catak
- Division of Pediatric Allergy and Immunology, Marmara University, School of Medicine, Istanbul, Turkey.,Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey.,The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Bengu Akcam
- Division of Pediatric Allergy and Immunology, Marmara University, School of Medicine, Istanbul, Turkey.,Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey.,The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Sevgi Bilgic Eltan
- Division of Pediatric Allergy and Immunology, Marmara University, School of Medicine, Istanbul, Turkey.,Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey.,The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Royala Babayeva
- Division of Pediatric Allergy and Immunology, Marmara University, School of Medicine, Istanbul, Turkey.,Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey.,The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | | | - Gamze Akgun
- Division of Pediatric Allergy and Immunology, Marmara University, School of Medicine, Istanbul, Turkey.,Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey.,The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Dilek Baser
- Division of Pediatric Allergy and Immunology, Marmara University, School of Medicine, Istanbul, Turkey.,Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey.,The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Alper Bulutoglu
- Division of Pediatric Allergy and Immunology, Marmara University, School of Medicine, Istanbul, Turkey.,Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey.,The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Feyza Bayram
- Division of Pediatric Allergy and Immunology, Marmara University, School of Medicine, Istanbul, Turkey.,Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey.,The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Nurhan Kasap
- Division of Pediatric Allergy and Immunology, Marmara University, School of Medicine, Istanbul, Turkey.,Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey.,The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Ayca Kiykim
- Cerrahpasa Faculty of Medicine, Pediatric Allergy and Immunology, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Gonca Hancioglu
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey
| | - Sefika I Kokcu Karadag
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey
| | - Yasemin Kendir Demirkol
- Division of Pediatric Genetics, University of Health Sciences, Umraniye Education and Research Hospital, Istanbul, Turkey
| | - Selime Ozen
- Division of Pediatric Allergy and Immunology, University of Health Sciences, Dr. Behcet Uz Children's Education and Research Hospital, Izmir, Turkey
| | - Sukru Cekic
- Faculty of Medicine, Pediatric Allergy and Immunology, Uludag University, Bursa, Turkey
| | - Dilek Ozcan
- Division of Pediatric Allergy-Immunology, Faculty of Medicine, Çukurova University, Adana, Turkey
| | - Neslihan Edeer Karaca
- Faculty of Medicine, Pediatric Allergy and Immunology, Ege University, Izmir, Turkey
| | | | - Murat Cansever
- Faculty of Medicine, Pediatric Immunology, Erciyes University, Kayseri, Turkey
| | - Esra Ozek Yucel
- Istanbul Faculty of Medicine, Pediatric Allergy and Immunology, Istanbul University, Istanbul, Turkey
| | - Zeynep Tamay
- Istanbul Faculty of Medicine, Pediatric Allergy and Immunology, Istanbul University, Istanbul, Turkey
| | - Derya U Altintas
- Division of Pediatric Allergy-Immunology, Faculty of Medicine, Çukurova University, Adana, Turkey
| | - Cigdem Aydogmus
- Pediatric Allergy and Immunology, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey
| | - Fatih Celmeli
- Ministry of Health, Antalya Training and Research Hospital, Antalya, Turkey
| | - Haluk Cokugras
- Cerrahpasa Faculty of Medicine, Pediatric Allergy and Immunology, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Nesrin Gulez
- Division of Pediatric Allergy and Immunology, University of Health Sciences, Dr. Behcet Uz Children's Education and Research Hospital, Izmir, Turkey
| | - Ferah Genel
- Division of Pediatric Allergy and Immunology, University of Health Sciences, Dr. Behcet Uz Children's Education and Research Hospital, Izmir, Turkey
| | - Ayse Metin
- Pediatric Immunology and Allergy, University of Health Sciences, Ankara City Hospital, Ankara, Turkey
| | - Sukru N Guner
- Faculty of Medicine, Pediatric Allergy and Immunology, Necmettin Erbakan University, Konya, Turkey
| | - Necil Kutukculer
- Faculty of Medicine, Pediatric Allergy and Immunology, Ege University, Izmir, Turkey
| | - Sevgi Keles
- Faculty of Medicine, Pediatric Allergy and Immunology, Necmettin Erbakan University, Konya, Turkey
| | - Ismail Reisli
- Faculty of Medicine, Pediatric Allergy and Immunology, Necmettin Erbakan University, Konya, Turkey
| | - Sara S Kilic
- Faculty of Medicine, Pediatric Allergy and Immunology, Uludag University, Bursa, Turkey
| | - Alisan Yildiran
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey
| | - Elif Karakoc-Aydiner
- Division of Pediatric Allergy and Immunology, Marmara University, School of Medicine, Istanbul, Turkey.,Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey.,The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Bernice Lo
- Division of Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar.,College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
| | - Ahmet Ozen
- Division of Pediatric Allergy and Immunology, Marmara University, School of Medicine, Istanbul, Turkey.,Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey.,The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Safa Baris
- Division of Pediatric Allergy and Immunology, Marmara University, School of Medicine, Istanbul, Turkey.,Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey.,The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
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Sivasankaran M, Ramesh V, Sankaranarayanan S, Munirathnam D. Gastrointestinal manifestations in children with primary immune deficiencies: A case series. Indian J Gastroenterol 2022; 41:513-518. [PMID: 36334230 DOI: 10.1007/s12664-022-01273-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 06/13/2022] [Indexed: 11/06/2022]
Abstract
Gastrointestinal (GI) manifestations are the second most common complications of primary immune deficiencies (PIDs) after pulmonary disease, affecting up to one-half of children with PIDs. Non-infectious GI manifestations such as allergic, autoimmune, and inflammatory disorders can be the predominant manifestations of PIDs. We present a series of five children who presented predominantly with these GI manifestations of PID, not attributable to infections. Very early age of onset (infancy), parental consanguinity, and failure to respond to hypoallergenic formula led to strong suspicion for underlying PIDs. Next-generation sequencing led to the underlying genetic diagnosis. Early diagnosis and hematopoietic stem cell transplantation could be life-saving in these children.
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Affiliation(s)
- Meena Sivasankaran
- Department of Pediatric Hemato-Oncology, Blood and Marrow Transplantation, Kanchi Kamakoti CHILDs Trust Hospital, 12A Nageswara Road, Numgambakkam, Chennai, 600 034, India.
| | - Venkateswari Ramesh
- Department of Pediatrics, Kanchi Kamakoti CHILDs Trust Hospital, Numgambakkam, Chennai, 600 034, India
| | - Srinivas Sankaranarayanan
- Department of Pediatric Gastroenterology, Kanchi Kamakoti CHILDS Trust Hospital, Numgambakkam, Chennai, 600 034, India
| | - Deenadayalan Munirathnam
- Department of Pediatric Hemato-Oncology, Blood and Marrow Transplantation, Kanchi Kamakoti CHILDs Trust Hospital, 12A Nageswara Road, Numgambakkam, Chennai, 600 034, India
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28
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Regulatory B cells in patients suffering from inborn errors of immunity with severe immune dysregulation. J Autoimmun 2022; 132:102891. [PMID: 36113303 DOI: 10.1016/j.jaut.2022.102891] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 08/02/2022] [Accepted: 08/04/2022] [Indexed: 11/21/2022]
Abstract
BACKGROUND Immune dysregulation as a result of an inborn error of immunity (IEI) leads to the complicated symptoms of refractory multi-organ immune dysregulation. B lymphocytes with immune regulatory capacity (Breg) are activated by environmental triggers and act as regulators of the immune response as observed in several autoimmune diseases. OBJECTIVE We sought to investigate the Breg profile and the CD21low expressing B cells of patients with LRBA deficiency (N = 6) and non-LRBA deficiency IEI (N = 13) with overlapping clinical symptoms of immune dysregulation. Normal values for Breg subpopulations were obtained from patients age-matched healthy cohorts (N = 48). Furthermore, we investigated the impact of abatacept treatment in LRBA deficient patients receiving biweekly abatacept (N = 5). METHODS Using a flow cytometric approach with a pre-formulated antibody panel in peripheral blood samples, Breg subsets including plasmablasts (CD27+CD38hi), transitional B cells (CD24hiCD38hi), and B10 cells (CD24hiCD27+), and additionally the CD21low B cells (CD21lowCD38low) were analyzed. Breg function was assessed by the interleukin-10 expression within the CD19+ population. Additionally, B cell cytokines were measured in cell culture supernatants. RESULTS We observe significant alterations of B cell/Breg subpopulations in the LRBA deficient cohort including a severe lack of memory B cells (P = 0.031) and B10 cells (P = 0.031) as well as a tendency towards higher CD21low B cells (P = 0.063). Within the non-LRBA deficient cohort, we observe a significant expansion of the plasmablasts (P = 0.012), and a tendency towards elevated levels of CD21low expressing B cells (P = 0.063). The treatment with abatacept ameliorated disease symptoms in the LRBA deficient cohort and led to an effective decrease in CD21low B cells over time (P = 0.021). Furthermore, there was a significantly increased level of B cell-activating factor (BAFF; P = 0.02) and lower IL-12p70 secretion upon stimulation (P = 0.020) in the LRBA cohort. CONCLUSION Aberrant maturation of Breg subsets and the pathological expansion of CD21low B cells in patients with IEI may have therapeutic implications. Patients suffering from LRBA deficiency show a lack of memory B cells, insufficient expansion of B10 cells, increased BAFF levels as well as an increase in circulating CD21low B cells. Abatacept treatment results in a steady decrease in CD21low B cells.
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29
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Wang C, Walter JE. Autoantibodies in immunodeficiency syndromes: The Janus faces of immune dysregulation. Blood Rev 2022; 55:100948. [PMID: 35428517 PMCID: PMC11166480 DOI: 10.1016/j.blre.2022.100948] [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: 12/20/2021] [Revised: 02/23/2022] [Accepted: 03/13/2022] [Indexed: 11/02/2022]
Abstract
Immunodeficiency syndromes represent a diverse group of inherited and acquired disorders, characterized by a spectrum of clinical manifestations, including recurrent infections, autoimmunity, lymphoproliferation and malignancy. Autoantibodies against various self-antigens reflect the immune dysregulation underlying these disorders, and could contribute to certain clinical findings, such as susceptibility to opportunistic infections, cytopenia of different hematopoietic lineages, and organ-specific autoimmune diseases. The mechanism of autoantibody production in the context of immunodeficiency remains largely unknown but is likely shaped by both intrinsic genetic aberrations and extrinsic exposures to possible infectious agents. These autoantibodies if harbor neutralizing activities and reach certain levels in the circulation, could disrupt the biological functions of their targets, resulting in specific clinical manifestations. Herein, we reviewed the prevalence of autoantibodies against cytokines, hematopoietic cells and organ-specific antigens in immunodeficiency syndromes and examined their associations with certain clinical findings. Moreover, the potential mechanism of autoantibody production was also discussed. These may shed light on the development of mechanism-based therapies to reset the dysregulated immune system in immunodeficient patients.
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Affiliation(s)
- Chen Wang
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Jolan E Walter
- Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St Petersburg, FL, USA; Division of Pediatric Allergy and Immunology, Massachusetts General Hospital for Children, Boston, MA, USA.
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30
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Kubo S, Miyakawa M, Tada A, Oda H, Motobayashi H, Iwabuchi S, Tamura S, Tanaka M, Hashimoto S. Lactoferrin and its digestive peptides induce interferon-α production and activate plasmacytoid dendritic cells ex vivo. Biometals 2022; 36:563-573. [PMID: 36018422 PMCID: PMC10181974 DOI: 10.1007/s10534-022-00436-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 08/15/2022] [Indexed: 11/25/2022]
Abstract
Plasmacytoid dendritic cells (pDCs) recognise viral single-stranded RNA (ssRNA) or CpG DNA via Toll-like receptor (TLR)-7 and TLR9, and produce interferon (IFN)-α. Activated pDCs upregulate human leukocyte antigen (HLA)-DR and CD86 expression levels. Ingestion of bovine lactoferrin (LF) activates pDCs, but little is known about its effects. In this study, the effects of LF and its pepsin hydrolysate (LFH) on the production of IFN-α from peripheral blood mononuclear cells (PBMCs) and pDCs were examined. PBMCs were prepared from peripheral blood of healthy adults and incubated with LF, LFH, or lactoferricin (LFcin) in the absence or presence of ssRNA derived from human immunodeficiency virus. The concentration of IFN-α in the supernatant and the expression levels of IFN-α, HLA-DR, and CD86 in pDCs were quantified by enzyme-linked immunosorbent assay and flow cytometry. In the absence of ssRNA, the concentration of IFN-α was negligible and LF had no effect on it. In the presence of ssRNA, IFN-α was detected at a certain level, and LF and LFH significantly increased its concentration. The increase caused by LFH and LFcin were comparable. In addition, LF significantly upregulated the expression levels of IFN-α, HLA-DR, and CD86 in pDCs. LF and its digestive peptides induced IFN-α production and activated pDCs in the presence of ssRNA, suggesting that LF modulates the immune system by promoting pDC activation upon viral recognition.
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Affiliation(s)
- Shutaro Kubo
- Food Ingredients and Technology Institute, R&D Division, Morinaga Milk Industry Co., Ltd., 1-83, 5, Higashihara, Zama, Kanagawa, Japan.
| | - Momoko Miyakawa
- Food Ingredients and Technology Institute, R&D Division, Morinaga Milk Industry Co., Ltd., 1-83, 5, Higashihara, Zama, Kanagawa, Japan
| | - Asuka Tada
- Food Ingredients and Technology Institute, R&D Division, Morinaga Milk Industry Co., Ltd., 1-83, 5, Higashihara, Zama, Kanagawa, Japan
| | - Hirotsugu Oda
- Food Ingredients and Technology Institute, R&D Division, Morinaga Milk Industry Co., Ltd., 1-83, 5, Higashihara, Zama, Kanagawa, Japan
| | - Hideki Motobayashi
- Second Department of Surgery, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Wakayama, Japan
| | - Sadahiro Iwabuchi
- Department of Molecular Pathophysiology, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Wakayama, Japan
| | - Shinobu Tamura
- Department of Hematology/Oncology, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Wakayama, Japan
| | - Miyuki Tanaka
- Food Ingredients and Technology Institute, R&D Division, Morinaga Milk Industry Co., Ltd., 1-83, 5, Higashihara, Zama, Kanagawa, Japan
| | - Shinichi Hashimoto
- Department of Molecular Pathophysiology, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Wakayama, Japan
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31
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Padron GT, Hernandez-Trujillo VP. Autoimmunity in Primary Immunodeficiencies (PID). Clin Rev Allergy Immunol 2022:10.1007/s12016-022-08942-0. [PMID: 35648371 DOI: 10.1007/s12016-022-08942-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/04/2022] [Indexed: 11/25/2022]
Abstract
Primary immunodeficiency (PID) may impact any component of the immune system. The number of PID and immune dysregulation disorders is growing steadily with advancing genetic detection methods. These expansive recognition methods have changed the way we characterize PID. While PID were once characterized by their susceptibility to infection, the increase in genetic analysis has elucidated the intertwined relationship between PID and non-infectious manifestations including autoimmunity. The defects permitting opportunistic infections to take hold may also lead the way to the development of autoimmune disease. In some cases, it is the non-infectious complications that may be the presenting sign of PID autoimmune diseases, such as autoimmune cytopenia, enteropathy, endocrinopathies, and arthritis among others, have been reported in PID. While autoimmunity may occur with any PID, this review will look at certain immunodeficiencies most often associated with autoimmunity, as well as their diagnosis and management strategies.
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Affiliation(s)
- Grace T Padron
- Nicklaus Children's Hospital, Miami, FL, USA.
- Allergy and Immunology Care Center of South Florida, Miami Lakes, FL, USA.
| | - Vivian P Hernandez-Trujillo
- Nicklaus Children's Hospital, Miami, FL, USA
- Allergy and Immunology Care Center of South Florida, Miami Lakes, FL, USA
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Kedar P, Dongerdiye R, Chandrakala S, Bargir UA, Madkaikar M. Targeted next-generation sequencing revealed a novel homozygous mutation in the LRBA gene causes severe haemolysis associated with Inborn Errors of Immunity in an Indian family. Hematology 2022; 27:441-448. [PMID: 35413226 DOI: 10.1080/16078454.2022.2058736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
OBJECTIVES LPS-responsive beige-like anchor protein (LRBA) deficiency abolishes LRBA protein expression due to biallelic mutations in the LRBA gene that lead to autoimmune manifestations, inflammatory bowel disease, hypogammaglobulinemia in early stages, and variable clinical manifestations. MATERIALS AND METHODS Mutational analysis of the LRBA gene was performed in Indian patients using targeted Next Generation Sequencing (t-NGS) and confirmed by Sanger sequencing using specific primers of exons 53. Then, bioinformatics analysis and protein modeling for the novel founded mutations were also performed. The genotype, phenotype correlation was done according to the molecular findings and clinical features. RESULTS We report an unusual case of a female patient born of a consanguineous marriage, presented with severe anaemia and jaundice with a history of multiple blood transfusions of unknown cause up to the age of 5 yrs. She had hepatosplenomegaly with recurrent viral and bacterial infections. Tests for hemoglobinopathies, enzymopathies, and hereditary spherocytosis were within the normal limits. The t-NGS revealed a novel homozygous missense variation in exon 53 of the LRBA gene (chr4:151231464C > T; c.7799G > A) (p.C2600Y), and the parents were heterozygous. The further immunological analysis is suggestive of hypogammaglobulinaemia and autoimmune haemolytic anaemia. The bioinformatics tools are suggestive of deleterious and disease-causing variants. CONCLUSION This study concludes the importance of a timely decision of targeted exome sequencing for the molecular diagnostic tool of unexplained haemolytic anaemia with heterogeneous clinical phenotypes.
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Affiliation(s)
- Prabhakar Kedar
- Department of Haematogenetics, ICMR- National Institute of Immunohaematology, Parel, Mumbai, India
| | - Rashmi Dongerdiye
- Department of Haematogenetics, ICMR- National Institute of Immunohaematology, Parel, Mumbai, India
| | | | - Umair Ahmed Bargir
- Department of Pediatric Immunology and Leukocyte Biology, ICMR- National Institute of Immunohaematology, Parel, Mumbai, India
| | - Manisha Madkaikar
- Department of Pediatric Immunology and Leukocyte Biology, ICMR- National Institute of Immunohaematology, Parel, Mumbai, India
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Hawari I, Haris B, Mohammed I, Ericsson J, Khalifa A, Hussain K. Infancy onset diabetes mellitus in a patient with a novel homozygous LRBA mutation. JOURNAL OF CLINICAL AND TRANSLATIONAL ENDOCRINOLOGY CASE REPORTS 2022. [DOI: 10.1016/j.jecr.2022.100108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
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Liu Y, Freeborn J, Armbrister SA, Tran DQ, Rhoads JM. Treg-associated monogenic autoimmune disorders and gut microbial dysbiosis. Pediatr Res 2022; 91:35-43. [PMID: 33731809 PMCID: PMC8446091 DOI: 10.1038/s41390-021-01445-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 11/24/2020] [Accepted: 12/05/2020] [Indexed: 01/31/2023]
Abstract
Primary immunodeficiency diseases (PIDs) caused by a single-gene defect generally are referred to as monogenic autoimmune disorders. For example, mutations in the transcription factor autoimmune regulator (AIRE) result in a condition called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; while mutations in forkhead box P3 lead to regulatory T cell (Treg)-deficiency-induced multiorgan inflammation, which in humans is called "immune dysregulation, polyendocrinopathy, enteropathy with X-linked inheritance" (or IPEX syndrome). Previous studies concluded that monogenic diseases are insensitive to commensal microbial regulation because they develop even in germ-free (GF) animals, a conclusion that has limited the number of studies determining the role of microbiota in monogenic PIDs. However, emerging evidence shows that although the onset of the disease is independent of the microbiota, several monogenic PIDs vary in severity in association with the microbiome. In this review, we focus on monogenic PIDs associated with Treg deficiency/dysfunction, summarizing the gut microbial dysbiosis that has been shown to be linked to these diseases. From limited studies, we have gleaned several mechanistic insights that may prove to be of therapeutic importance in the early stages of life. IMPACT: This review paper serves to refute the concept that monogenic PIDs are not linked to the microbiome. The onset of monogenic PIDs is independent of microbiota; single-gene mutations such as AIRE or Foxp3 that affect central or peripheral immune tolerance produce monogenic diseases even in a GF environment. However, the severity and outcome of PIDs are markedly impacted by the microbial composition. We suggest that future research for these conditions may focus on targeting the microbiome.
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Affiliation(s)
- Yuying Liu
- Department of Pediatrics, Division of Gastroenterology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
| | - Jasmin Freeborn
- Department of Pediatrics, Division of Gastroenterology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Shabba A Armbrister
- Department of Pediatrics, Division of Gastroenterology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Dat Q Tran
- Department of Pediatrics, Division of Gastroenterology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Jon Marc Rhoads
- Department of Pediatrics, Division of Gastroenterology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
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Yao J, Gu H, Mou W, Chen Z, Ma J, Ma H, Li N, Zhang R, Wang T, Jiang J, Wu R. Various phenotypes of LRBA gene with compound heterozygous variation: A case series report of pediatric cytopenia patients. Int J Immunopathol Pharmacol 2022; 36:3946320221125591. [PMID: 36074705 PMCID: PMC9465590 DOI: 10.1177/03946320221125591] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Objective: LPS-responsive beige-like anchor (LRBA) deficiency is one of the most common
monogenic disorders causing common variable immunodeficiency (CVID) and
CVID-like disorders. However, the clinical spectrum of compound heterozygous
(CHZ) LRBA variation should be extended. In this study, we presented five
cases of compound heterozygous LRBA with various refractory cytopenias. Materials and Methods: Retrospective analysis of the clinical manifestations, management, and
outcomes of five cases (from five pedigrees) with LRBA gene
CHZ variants which initially manifested as single/multilineage immune
cytopenias was performed. Results: 1. Gene variations: All five patients inherited the compound heterozygous
LRBA variations from their parents which were thought to be pathogenic.
BEACH, DUF4704, and LamG were the main affected domains of LRBA gene in this
case series. 2. Immune dysregulation of clinic: (1) Hypogammaglobulinemia
were recorded in four patients, and the proportion of Treg was decreased in
two patients. Only one patient had been with increased TCRαβ+CD4/CD8
double-negative T cells (DNT). (2) Lymphoproliferative manifestations were
seen in three patients. (3) All five patients were complained with
cytopenia, although they showed different clinical manifestations. None of
the parents was asymptomatic. (4) Other immune disorders: P5 also had
relapsed infections and autoimmune endocrinopathy. 3. Management and
outcomes: P1 and P5 responded well to immunomodulatory therapy and P3 was
effectively treated with hemophagocytic lymphohistiocytosis (HLH) first-line
regimen chemotherapy. P4 showed no responses to steroids and IVIG. However,
TPO-R agonist was effective. Conclusion: Unlike homozygous mutations, compound heterozygous LRBA variation should
always be kept in mind for the various phenotypes and different treatment
responses.
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Affiliation(s)
- Jiafeng Yao
- Hematology Center, National Center for Children`s Health, 117984Beijing Children`s Hospital, Capital Medical University, Beijing, China
| | - Hao Gu
- Hematologic Disease Laboratory, National Center for Children's Health, 117984Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Wenjun Mou
- Laboratory of Tumor Immunology, National Center for Children's Health, 117984Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Zhenping Chen
- Laboratory of Tumor Immunology, National Center for Children's Health, 117984Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Jie Ma
- Hematology Center, National Center for Children`s Health, 117984Beijing Children`s Hospital, Capital Medical University, Beijing, China
| | - Honghao Ma
- Hematology Center, National Center for Children`s Health, 117984Beijing Children`s Hospital, Capital Medical University, Beijing, China
| | - Nan Li
- Hematology Center, National Center for Children`s Health, 117984Beijing Children`s Hospital, Capital Medical University, Beijing, China
| | - Rui Zhang
- Hematology Center, National Center for Children`s Health, 117984Beijing Children`s Hospital, Capital Medical University, Beijing, China
| | - Tianyou Wang
- Hematologic Disease Laboratory, National Center for Children's Health, 117984Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Jin Jiang
- Hematologic Disease Laboratory, National Center for Children's Health, 117984Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Runhui Wu
- Hematology Center, National Center for Children`s Health, 117984Beijing Children`s Hospital, Capital Medical University, Beijing, China
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Pinzon Grimaldos A, Bini S, Pacella I, Rossi A, Di Costanzo A, Minicocci I, D’Erasmo L, Arca M, Piconese S. The role of lipid metabolism in shaping the expansion and the function of regulatory T cells. Clin Exp Immunol 2021; 208:181-192. [PMID: 35020862 PMCID: PMC9188345 DOI: 10.1093/cei/uxab033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 12/05/2021] [Accepted: 12/10/2021] [Indexed: 12/16/2022] Open
Abstract
Metabolic inflammation, defined as a chronic low-grade inflammation, is implicated in numerous metabolic diseases. In recent years, the role of regulatory T cells (Tregs) as key controllers of metabolic inflammation has emerged, but our comprehension on how different metabolic pathways influence Treg functions needs a deeper understanding. Here we focus on how circulating and intracellular lipid metabolism, in particular cholesterol metabolism, regulates Treg homeostasis, expansion, and functions. Cholesterol is carried through the bloodstream by circulating lipoproteins (chylomicrons, very low-density lipoproteins, low-density lipoproteins). Tregs are equipped with a wide array of metabolic sensors able to perceive and respond to changes in the lipid environment through the activation of different intracellular pathways thus conferring to these cells a crucial metabolic and functional plasticity. Nevertheless, altered cholesterol transport, as observed in genetic dyslipidemias and atherosclerosis, impairs Treg proliferation and function through defective cellular metabolism. The intracellular pathway devoted to the cholesterol synthesis is the mevalonate pathway and several studies have shown that this pathway is essential for Treg stability and suppressive activity. High cholesterol concentrations in the extracellular environment may induce massive accumulation of cholesterol inside the cell thus impairing nutrients sensors and inhibiting the mevalonate pathway. This review summarizes the current knowledge regarding the role of circulating and cellular cholesterol metabolism in the regulation of Treg metabolism and functions. In particular, we will discuss how different pathological conditions affecting cholesterol transport may affect cellular metabolism in Tregs.
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Affiliation(s)
| | | | - Ilenia Pacella
- Department of Internal Clinical, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Alessandra Rossi
- Department of Internal Clinical, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Alessia Di Costanzo
- Department of Translational and Precision Medicine, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy
| | - Ilenia Minicocci
- Department of Translational and Precision Medicine, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy
| | - Laura D’Erasmo
- Department of Translational and Precision Medicine, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy
| | - Marcello Arca
- Department of Translational and Precision Medicine, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy
| | - Silvia Piconese
- Correspondence: Silvia Piconese, Department of Internal Clinical, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.
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Takasawa K, Kanegane H, Kashimada K, Morio T. Endocrinopathies in Inborn Errors of Immunity. Front Immunol 2021; 12:786241. [PMID: 34887872 PMCID: PMC8650088 DOI: 10.3389/fimmu.2021.786241] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 11/01/2021] [Indexed: 11/13/2022] Open
Abstract
Inborn errors of immunity (IEI), caused by hereditary or genetic defects, are a group of more than 400 disorders, in which the immune system, including lymphocytes, neutrophils, macrophages, and complements, does not function properly. The endocrine system is frequently affected by IEI as an associated clinical feature and a complex network of glands which regulate many important body functions, including growth, reproduction, homeostasis, and energy regulation. Most endocrine disorders associated with IEI are hypofunction which would be treated with supplementation therapy, and early diagnosis and appropriate management are essential for favorable long-term outcomes in patients with IEI. In this review, we aimed to comprehensively summarize and discuss the current understanding on the clinical features and the pathophysiology of endocrine disorders in IEI. This review is composed with three parts. First, we discuss the two major pathophysiology of endocrinopathy in IEI, autoimmune response and direct effects of the responsible genes. Next, the details of each endocrinopathy, such as growth failure, hypothyroidism, hypoparathyroidism, adrenal insufficiency, diabetes mellitus (DM) are specified. We also illustrated potential endocrinopathy due to hematopoietic stem cell transplantation, including hypogonadism and adrenal insufficiency due to glucocorticoid therapy.
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Affiliation(s)
- Kei Takasawa
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Hirokazu Kanegane
- Deparment of Child Health Development, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Kenichi Kashimada
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Tomohiro Morio
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
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Salami F, Shariati S, Rasouli SE, Delavari S, Tavakol M, Sadri H, Asghari B, Yazdani R, Rezaei N, Abolhassani H, Azizi G. The Effects of Stimulation with PMA/Ionomycin on CD4+ T cell Proliferation and Surface CD4 Molecule Modulation of Patients with LRBA Deficiency and CVID with the Unsolved Genetic Defect. Endocr Metab Immune Disord Drug Targets 2021; 22:539-544. [PMID: 34886783 DOI: 10.2174/1871530321666211209162834] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 10/08/2021] [Accepted: 11/10/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiencies. LPS-responsive beige-like anchor protein (LRBA) deficiency is a combined immunodeficiency characterized by a CVID-like phenotype. Affected patients by LRBA and CVID present a wide range of clinical manifestations, including hypogammaglobulinemia, recurrent infections, autoimmunity, as well as T cell abnormality. METHODS The study population comprised of patients with CVID (n=10), LRBA deficiency (n=11), and healthy controls (n=12). CD4+ T cell frequency and CD4 MFI (mean fluorescence intensity) were evaluated using flow cytometry before and after stimulation with PMA/ION. RESULTS The frequencies of CD4+ T cells were significantly lower in patients with LRBA deficiency than in HCs before and after treatment. In the unstimulated state, the CD4+ T cells frequency in CVID patients was significantly lower than in HCs. There were no statistically significant differences between patients and healthy individuals in CD4+ T cell proliferation. Compared to HCs, LRBA and CVID patients showed a lower CD4 MFI in unstimulated conditions. Furthermore, CD4 MFI decreased in both patients and the control group following activation. CONCLUSION Despite the reported decrease in CD4+ T cell frequency in patients with CVID and LRBA deficiency, our findings demonstrated that their CD4+ T cells have a normal proliferative response to stimuli similar to healthy individuals.
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Affiliation(s)
- Fereshte Salami
- Research Center for Primary Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran. Iran
| | - Sahar Shariati
- Research Center for Primary Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran. Iran
| | - Seyed Erfan Rasouli
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj. Iran
| | - Samaneh Delavari
- Research Center for Primary Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran. Iran
| | - Marziyeh Tavakol
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj. Iran
| | - Homa Sadri
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj. Iran
| | - Babak Asghari
- Department of Microbiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan. Iran
| | - Reza Yazdani
- Research Center for Primary Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran. Iran
| | - Nima Rezaei
- Research Center for Primary Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran. Iran
| | - Hassan Abolhassani
- Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm. Sweden
| | - Gholamreza Azizi
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj. Iran
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Tang WJ, Hu WH, Huang Y, Wu BB, Peng XM, Zhai XW, Qian XW, Ye ZQ, Xia HJ, Wu J, Shi JR. Potential protein–phenotype correlation in three lipopolysaccharide-responsive beige-like anchor protein-deficient patients. World J Clin Cases 2021; 9:5873-5888. [PMID: 34368306 PMCID: PMC8316938 DOI: 10.12998/wjcc.v9.i21.5873] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 03/22/2021] [Accepted: 05/26/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Patients with lipopolysaccharide (LPS)-responsive beige-like anchor protein (LRBA) deficiency have a variety of clinical symptoms, but there is no apparent genotype–phenotype correlation, and patients carrying the same mutations may have different phenotypes. Therefore, it is not easy for doctors to make a decision regarding hematopoietic stem cell transplantation (HSCT) for LRBA-deficient patients. We hypothesized that there may be a protein–phenotype correlation to indicate HSCT for LRBA-deficient patients.
AIM To report on three Chinese LRBA-deficient patients and determine the correlation between residual protein expression and disease phenotypes.
METHODS Clinical data of three Chinese LRBA-deficient patients were collected, and protein levels were detected by Western blot analysis. In addition, LRBA mutation information of another 83 previously reported patients was summarized.
RESULTS All the major clinical findings indicated enteropathy, but patients 1 and 3 presented with more severe symptoms than patient 2. Endoscopy and histology indicated nonspecific colitis for patients 1 and 3 but Crohn's disease-like colitis for patient 2. Compound heterozygous mutations in LRBA were found in patient 1, and homozygous mutations in LRBA were found in patient 2 and patient 3. Only patient 2 responded well to traditional immunosuppressive treatment. Residual expression of the LRBA protein in patients 1 and 3 was very low, but in patient 2, a more than 0.5-fold in expression of the LRBA protein was found compared to that in the control. After HSCT, patient 1 had increased LRBA protein expression. We summarized the genetic information of 86 patients, and the mutations in patients 1 and 3 were novel mutations.
CONCLUSION We described three Chinese LRBA-deficient patients, two of whom carried novel mutations. These patients had no genotype-phenotype correlations, but their residual LRBA protein expression might be associated with disease outcome and could be an indicator for HSCT.
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Affiliation(s)
- Wen-Juan Tang
- Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children’s Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China
| | - Wen-Hui Hu
- Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children’s Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China
| | - Ying Huang
- Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children’s Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China
| | - Bing-Bing Wu
- The Molecular Genetic Diagnosis Center, Children's Hospital of Fudan University, Shanghai 201102, China
| | - Xiao-Min Peng
- The Molecular Genetic Diagnosis Center, Children's Hospital of Fudan University, Shanghai 201102, China
| | - Xiao-Wen Zhai
- Department of Hematology Oncology, Children's Hospital of Fudan university, National Children's Medical Center, Shanghai 201102, China
| | - Xiao-Wen Qian
- Department of Hematology Oncology, Children's Hospital of Fudan university, National Children's Medical Center, Shanghai 201102, China
| | - Zi-Qing Ye
- Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children’s Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China
| | - Hai-Jiao Xia
- Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children’s Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China
| | - Jie Wu
- Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children’s Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China
| | - Jie-Ru Shi
- Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children’s Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China
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Arnold DE, Chellapandian D, Leiding JW. The Use of Biologic Modifiers as a Bridge to Hematopoietic Cell Transplantation in Primary Immune Regulatory Disorders. Front Immunol 2021; 12:692219. [PMID: 34248986 PMCID: PMC8264452 DOI: 10.3389/fimmu.2021.692219] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 05/12/2021] [Indexed: 11/13/2022] Open
Abstract
Recently, primary immune regulatory disorders have been described as a subset of inborn errors of immunity that are dominated by immune mediated pathology. As the pathophysiology of disease is elucidated, use of biologic modifiers have been increasingly used successfully to treat disease mediated clinical manifestations. Hematopoietic cell transplant (HCT) has also provided definitive therapy in several PIRDs. Although biologic modifiers have been largely successful at treating disease related manifestations, data are lacking regarding long term efficacy, safety, and their use as a bridge to HCT. This review highlights biologic modifiers in the treatment of several PIRDs and there use as a therapeutic bridge to HCT.
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Affiliation(s)
- Danielle E Arnold
- National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Deepak Chellapandian
- Center for Cell and Gene Therapy for Non-Malignant Conditions, Cancer and Blood Disorders Institute, Johns Hopkins All Children's Hospital, St. Petersburg, FL, United States
| | - Jennifer W Leiding
- Center for Cell and Gene Therapy for Non-Malignant Conditions, Cancer and Blood Disorders Institute, Johns Hopkins All Children's Hospital, St. Petersburg, FL, United States.,Division of Allergy and Immunology, Department of Pediatrics, University of South Florida, St. Petersburg, FL, United States
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41
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Kardelen AD, Kara M, Güller D, Ozturan EK, Abalı ZY, Ceylaner S, Kıykım A, Cantez S, Torun SH, Poyrazoglu S, Bas F, Darendelıler F. LRBA deficiency: a rare cause of type 1 diabetes, colitis, and severe immunodeficiency. Hormones (Athens) 2021; 20:389-394. [PMID: 33155142 DOI: 10.1007/s42000-020-00257-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Accepted: 10/28/2020] [Indexed: 12/17/2022]
Abstract
The biological role of the lipopolysaccharide-responsive beige-like anchor (LRBA) protein associated with the immune system is not to date well known. However, it is thought to regulate the CTLA4 protein, an inhibitory immunoreceptor. Chronic diarrhea, autoimmune disorders, organomegaly, frequent recurrent infections, hypogammaglobulinemia, chronic lung manifestations, and growth retardation are some features of LRBA deficiency. This rare disease is observed as a result of homozygous mutations in the LRBA gene. An 11.3-year-old male patient presented because of short stature and high blood glucose level. He had a previous history of lymphoproliferative disease, chronic diarrhea, and recurrent infections. His parents were first-degree consanguineous relatives. A diagnosis of type 1 diabetes mellitus (T1DM) was added to the preexisting diagnoses of immunodeficiency, recurrent infection, enteropathy, chronic diarrhea, lymphadenopathy, hepatomegaly, and short stature. Genetic analysis revealed a homozygous mutation in the LRBA gene, c.5047C>T (p.R1683*) (p.Arg1683*). Abatacept treatment was started: the patient's hospital admission frequency decreased, and glucose regulation improved. At follow-up, growth hormone (GH) deficiency was diagnosed, although it was not treated because the underlying disease was not under control. Nevertheless, the patient's height improved with abatacept treatment. LRBA deficiency should be considered in the presence of consanguineous marriage, diabetes, immunodeficiency, and additional autoimmune symptoms. LRBA phenotypes are variable even when the same variants in the LRBA gene are present. Genetic diagnosis is important to determine optimal treatment options. In addition to chronic malnutrition and immunosuppressive therapy, GH deficiency may be one of the causes of short stature in these patients.
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Affiliation(s)
- Aslı Derya Kardelen
- Department of Pediatric Endocrinology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
| | - Manolya Kara
- Department of Pediatric Infectious Diseases, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Dilek Güller
- Department of Pediatric Gastroenterology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Esin Karakılıc Ozturan
- Department of Pediatric Endocrinology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Zehra Yavas Abalı
- Department of Pediatric Endocrinology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | | | - Ayça Kıykım
- Department of Pediatric Allergy and Immunology, Marmara University School of Medicine, Istanbul, Turkey
| | - Serdar Cantez
- Department of Pediatric Gastroenterology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Selda Hancerlı Torun
- Department of Pediatric Infectious Diseases, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Sukran Poyrazoglu
- Department of Pediatric Endocrinology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Firdevs Bas
- Department of Pediatric Endocrinology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Feyza Darendelıler
- Department of Pediatric Endocrinology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
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Yukina MY, Larina AA, Vasilyev EV, Troshina EA, Dimitrova DA. Search for Genetic Predictors of Adult Autoimmune Polyendocrine Syndrome in Monozygotic Twins. CLINICAL MEDICINE INSIGHTS-ENDOCRINOLOGY AND DIABETES 2021; 14:11795514211009796. [PMID: 33953634 PMCID: PMC8058797 DOI: 10.1177/11795514211009796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 03/18/2021] [Indexed: 11/20/2022]
Abstract
Autoimmune polyendocrine syndromes (APS) are a heterogeneous group of diseases characterized by the presence of autoimmune dysfunction of 2 or more endocrine glands and other non-endocrine organs. The components of the syndrome can manifest throughout life: in childhood—APS type 1 (the juvenile type) and in adulthood—APS type 2, 3, and 4 (the adult types). Adult types of APS are more common in clinical practice. It is a polygenic disease associated with abnormalities in genes encoding key regulatory proteins of the major histocompatibility complex (MHC). The search of for candidate genes responsible for mutations in adult APS is continuing. Genetic predisposition is insufficient for the manifestation of the APS of adults, since the penetrance of the disease, even among monozygotic twins, does not approach 100% (30–70%). The article presents the case of isolated Addison’s disease and APS type 2 in monozygotic twins with a revealed compound heterozygosity in the candidate gene VTCN1.
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43
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Sogkas G, Atschekzei F, Adriawan IR, Dubrowinskaja N, Witte T, Schmidt RE. Cellular and molecular mechanisms breaking immune tolerance in inborn errors of immunity. Cell Mol Immunol 2021; 18:1122-1140. [PMID: 33795850 PMCID: PMC8015752 DOI: 10.1038/s41423-020-00626-z] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 12/11/2020] [Indexed: 02/01/2023] Open
Abstract
In addition to susceptibility to infections, conventional primary immunodeficiency disorders (PIDs) and inborn errors of immunity (IEI) can cause immune dysregulation, manifesting as lymphoproliferative and/or autoimmune disease. Autoimmunity can be the prominent phenotype of PIDs and commonly includes cytopenias and rheumatological diseases, such as arthritis, systemic lupus erythematosus (SLE), and Sjogren's syndrome (SjS). Recent advances in understanding the genetic basis of systemic autoimmune diseases and PIDs suggest an at least partially shared genetic background and therefore common pathogenic mechanisms. Here, we explore the interconnected pathogenic pathways of autoimmunity and primary immunodeficiency, highlighting the mechanisms breaking the different layers of immune tolerance to self-antigens in selected IEI.
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Affiliation(s)
- Georgios Sogkas
- Department of Rheumatology and Immunology, Hannover Medical School, Hanover, Germany.
- Hannover Medical School, Cluster of Excellence RESIST (EXC 2155), Hanover, Germany.
| | - Faranaz Atschekzei
- Department of Rheumatology and Immunology, Hannover Medical School, Hanover, Germany
- Hannover Medical School, Cluster of Excellence RESIST (EXC 2155), Hanover, Germany
| | - Ignatius Ryan Adriawan
- Department of Rheumatology and Immunology, Hannover Medical School, Hanover, Germany
- Hannover Medical School, Cluster of Excellence RESIST (EXC 2155), Hanover, Germany
| | - Natalia Dubrowinskaja
- Department of Rheumatology and Immunology, Hannover Medical School, Hanover, Germany
- Hannover Medical School, Cluster of Excellence RESIST (EXC 2155), Hanover, Germany
| | - Torsten Witte
- Department of Rheumatology and Immunology, Hannover Medical School, Hanover, Germany
- Hannover Medical School, Cluster of Excellence RESIST (EXC 2155), Hanover, Germany
| | - Reinhold Ernst Schmidt
- Department of Rheumatology and Immunology, Hannover Medical School, Hanover, Germany
- Hannover Medical School, Cluster of Excellence RESIST (EXC 2155), Hanover, Germany
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Sanyoura M, Lundgrin EL, Subramanian HP, Yu M, Sodadasi P, Greeley SAW, MacLeish S, Del Gaudio D. Novel compound heterozygous LRBA deletions in a 6-month-old with neonatal diabetes. Diabetes Res Clin Pract 2021; 175:108798. [PMID: 33845048 PMCID: PMC11056189 DOI: 10.1016/j.diabres.2021.108798] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 04/07/2021] [Indexed: 11/23/2022]
Abstract
We report a 6-month-old boy with antibody-positive insulin-dependent diabetes mellitus. Sequencing identified compound heterozygous deletions of exon 5 and exons 36-37 in LRBA. At three years, he has yet to exhibit any other immune symptoms. Genetic testing of LRBA is warranted in patients with neonatal diabetes, even without immune dysregulation.
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Affiliation(s)
- May Sanyoura
- Department of Human Genetics, The University of Chicago, 5841 S. Maryland Ave., G701, Chicago, IL 60637, USA
| | - Erika L Lundgrin
- Division of Pediatric Endocrinology and Metabolism, University Hospitals Rainbow Babies & Children's Hospital, 11100 Euclid Ave., Cleveland, OH 44106, USA
| | - Hari Prasanna Subramanian
- Department of Human Genetics, The University of Chicago, 5841 S. Maryland Ave., G701, Chicago, IL 60637, USA
| | - Min Yu
- Department of Human Genetics, The University of Chicago, 5841 S. Maryland Ave., G701, Chicago, IL 60637, USA
| | - Priscilla Sodadasi
- Department of Human Genetics, The University of Chicago, 5841 S. Maryland Ave., G701, Chicago, IL 60637, USA
| | - Siri Atma W Greeley
- Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago, 5841 S. Maryland Ave., MC 1027, Chicago, IL 60637, USA
| | - Sarah MacLeish
- Division of Pediatric Endocrinology and Metabolism, University Hospitals Rainbow Babies & Children's Hospital, 11100 Euclid Ave., Cleveland, OH 44106, USA
| | - Daniela Del Gaudio
- Department of Human Genetics, The University of Chicago, 5841 S. Maryland Ave., G701, Chicago, IL 60637, USA.
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Boz V, Valencic E, Girardelli M, Pin A, Gàmez-Diaz L, Tommasini A, Lega S, Bramuzzo M. Case Report: Refractory Autoimmune Gastritis Responsive to Abatacept in LRBA Deficiency. Front Immunol 2021; 12:619246. [PMID: 33717114 PMCID: PMC7952427 DOI: 10.3389/fimmu.2021.619246] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 02/04/2021] [Indexed: 12/19/2022] Open
Abstract
Primary immunodeficiency (PID) with immune dysregulation may present with early onset gastrointestinal autoimmune disorders. When gastrointestinal autoimmunity is associated with multiple extraintestinal immune system dysfunction the diagnosis of PID is straightforward. However, with the advent of next generation sequencing technologies, genetic defects in PID genes have been increasingly recognized even when a single or no extraintestinal signs of immune dysregulation are present. A genetic diagnosis is especially important considering the expanding armamentarium of therapies designed to inhibit specific molecular pathways. We describe a boy with early-onset severe, refractory autoimmune gastritis and biallelic mutations in the LRBA gene causing a premature STOP-codon who was successfully treated with CTLA4-Ig, abatacept, with long term clinical and endoscopic remission. The case underscores the importance to consider a monogenetic defect in early onset autoimmune disorders, since the availability of targeted treatments may significantly improve patient prognosis.
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Affiliation(s)
- Valentina Boz
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Erica Valencic
- Department of Pediatrics, Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”, Trieste, Italy
| | - Martina Girardelli
- Department of Pediatrics, Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”, Trieste, Italy
| | - Alessia Pin
- Department of Pediatrics, Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”, Trieste, Italy
| | - Laura Gàmez-Diaz
- Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg im Breisgau, Germany
| | - Alberto Tommasini
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
- Department of Pediatrics, Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”, Trieste, Italy
| | - Sara Lega
- Department of Pediatrics, Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”, Trieste, Italy
| | - Matteo Bramuzzo
- Department of Pediatrics, Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”, Trieste, Italy
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Abstract
Primary immune regulatory disorders (PIRDs) are a group of diseases belonging to inborn errors of immunity. They usually exhibit lymphoproliferation, autoimmunities, and malignancies, with less susceptibility to recurrent infections. Unlike classical primary immune deficiencies, in autoimmune manifestations, such as cytopenias, enteropathy can be the first symptom of diseases, and they are typically resistant to treatment. Increasing awareness of PIRDs among specialists and a multidisciplinary team approach would provide early diagnosis and treatment that could prevent end-organ damage related to the diseases. In recent years, many PIRDs have been described, and understanding the immunological pathways linked to these disorders provides us an opportunity to use directed therapies for specific molecules, which usually offer better disease control than known classical immunosuppressants. In this review, in light of the most recent literature, we will discuss the common PIRDs and explain their clinical symptoms and recent treatment modalities.
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Affiliation(s)
- Burcu Kolukısa
- Marmara University Faculty of Medicine, Division of Pediatric Allergy and Immunology, İstanbul, Turkey,İstanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, İstanbul, Turkey,The Işıl Berat Barlan Center for Translational Medicine, İstanbul, Turkey
| | - Safa Barış
- Marmara University Faculty of Medicine, Division of Pediatric Allergy and Immunology, İstanbul, Turkey,İstanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, İstanbul, Turkey,The Işıl Berat Barlan Center for Translational Medicine, İstanbul, Turkey
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47
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Amini L, Greig J, Schmueck-Henneresse M, Volk HD, Bézie S, Reinke P, Guillonneau C, Wagner DL, Anegon I. Super-Treg: Toward a New Era of Adoptive Treg Therapy Enabled by Genetic Modifications. Front Immunol 2021; 11:611638. [PMID: 33717052 PMCID: PMC7945682 DOI: 10.3389/fimmu.2020.611638] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 12/24/2020] [Indexed: 12/27/2022] Open
Abstract
Regulatory Tcells (Treg) are essential components of peripheral immune homeostasis. Adoptive Treg cell therapy has shown efficacy in a variety of immune-mediated diseases in preclinical studies and is now moving from phase I/IIa to larger phase II studies aiming to demonstrate efficacy. However, hurdles such as in vivo stability and efficacy remain to be addressed. Nevertheless, preclinical models have shown that Treg function and specificity can be increased by pharmacological substances or gene modifications, and even that conventional T cells can be converted to Treg potentially providing new sources of Treg and facilitating Treg cell therapy. The exponential growth in genetic engineering techniques and their application to T cells coupled to a large body of knowledge on Treg open numerous opportunities to generate Treg with "superpowers". This review summarizes the genetic engineering techniques available and their applications for the next-generation of Super-Treg with increased function, stability, redirected specificity and survival.
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Affiliation(s)
- Leila Amini
- BIH Center for Regenerative Therapies (BCRT) and Berlin Center for Advanced Therapies (BeCAT), Charité-Universitätsmedizin Berlin and Berlin Institute of Health (BIH), Berlin, Germany
| | - Jenny Greig
- INSERM, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France
| | - Michael Schmueck-Henneresse
- BIH Center for Regenerative Therapies (BCRT) and Berlin Center for Advanced Therapies (BeCAT), Charité-Universitätsmedizin Berlin and Berlin Institute of Health (BIH), Berlin, Germany
| | - Hans-Dieter Volk
- BIH Center for Regenerative Therapies (BCRT) and Berlin Center for Advanced Therapies (BeCAT), Charité-Universitätsmedizin Berlin and Berlin Institute of Health (BIH), Berlin, Germany
| | - Séverine Bézie
- INSERM, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France
| | - Petra Reinke
- BIH Center for Regenerative Therapies (BCRT) and Berlin Center for Advanced Therapies (BeCAT), Charité-Universitätsmedizin Berlin and Berlin Institute of Health (BIH), Berlin, Germany
| | - Carole Guillonneau
- INSERM, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France
| | - Dimitrios L. Wagner
- BIH Center for Regenerative Therapies (BCRT) and Berlin Center for Advanced Therapies (BeCAT), Charité-Universitätsmedizin Berlin and Berlin Institute of Health (BIH), Berlin, Germany
| | - Ignacio Anegon
- INSERM, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France
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48
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Bacchetta R, Weinberg K. Thymic origins of autoimmunity-lessons from inborn errors of immunity. Semin Immunopathol 2021; 43:65-83. [PMID: 33532929 PMCID: PMC7925499 DOI: 10.1007/s00281-020-00835-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Accepted: 12/22/2020] [Indexed: 12/16/2022]
Abstract
During their intrathymic development, nascent T cells are empowered to protect against pathogens and to be operative for a life-long acceptance of self. While autoreactive effector T (Teff) cell progenitors are eliminated by clonal deletion, the intrathymic mechanisms by which thymic regulatory T cell (tTreg) progenitors maintain specificity for self-antigens but escape deletion to exert their regulatory functions are less well understood. Both tTreg and Teff development and selection result from finely coordinated interactions between their clonotypic T cell receptors (TCR) and peptide/MHC complexes expressed by antigen-presenting cells, such as thymic epithelial cells and thymic dendritic cells. tTreg function is dependent on expression of the FOXP3 transcription factor, and induction of FOXP3 gene expression by tTreg occurs during their thymic development, particularly within the thymic medulla. While initial expression of FOXP3 is downstream of TCR activation, constitutive expression is fixed by interactions with various transcription factors that are regulated by other extracellular signals like TCR and cytokines, leading to epigenetic modification of the FOXP3 gene. Most of the understanding of the molecular events underlying tTreg generation is based on studies of murine models, whereas gaining similar insight in the human system has been very challenging. In this review, we will elucidate how inborn errors of immunity illuminate the critical non-redundant roles of certain molecules during tTreg development, shedding light on how their abnormal development and function cause well-defined diseases that manifest with autoimmunity alone or are associated with states of immune deficiency and autoinflammation.
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Affiliation(s)
- Rosa Bacchetta
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Lokey Stem Cell Research Building 265 Campus Drive, West Stanford, CA, 94305, USA.
- Center for Definitive and Curative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
| | - Kenneth Weinberg
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Lokey Stem Cell Research Building 265 Campus Drive, West Stanford, CA, 94305, USA
- Center for Definitive and Curative Medicine, Stanford University School of Medicine, Stanford, CA, USA
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Consonni F, Favre C, Gambineri E. IL-2 Signaling Axis Defects: How Many Faces? Front Pediatr 2021; 9:669298. [PMID: 34277517 PMCID: PMC8282996 DOI: 10.3389/fped.2021.669298] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 05/31/2021] [Indexed: 11/13/2022] Open
Abstract
CD25, Signal transducer and activator of transcription 5B (STAT5B) and Forkhead box P3 (FOXP3) are critical mediators of Interleukin-2 (IL-2) signaling pathway in regulatory T cells (Tregs). CD25 (i.e., IL-2 Receptor α) binds with high affinity to IL-2, activating STAT5B-mediated signaling that eventually results in transcription of FOXP3, a master regulator of Treg function. Consequently, loss-of-function mutations in these proteins give rise to Treg disorders (i.e., Tregopathies) that clinically result in multiorgan autoimmunity. Immunodysregulation, Polyendocrinopathy Enteropathy X-linked (IPEX), due to mutations in FOXP3, has historically been the prototype of Tregopathies. This review describes current knowledge about defects in CD25, STAT5B, and FOXP3, highlighting that these disorders both share a common biological background and display comparable clinical features. However, specific phenotypes are associated with each of these syndromes, while certain laboratory findings could be helpful tools for clinicians, in order to achieve a prompt genetic diagnosis. Current treatment strategies will be outlined, keeping an eye on gene editing, an interesting therapeutic perspective that could definitely change the natural history of these disorders.
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Affiliation(s)
- Filippo Consonni
- Anna Meyer Children's Hospital, University of Florence, Florence, Italy
| | - Claudio Favre
- Division of Pediatric Oncology/Hematology, Meyer University Children's Hospital, Florence, Italy
| | - Eleonora Gambineri
- Division of Pediatric Oncology/Hematology, Meyer University Children's Hospital, Florence, Italy.,Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
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50
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Grover P, Goel PN, Piccirillo CA, Greene MI. FOXP3 and Tip60 Structural Interactions Relevant to IPEX Development Lead to Potential Therapeutics to Increase FOXP3 Dependent Suppressor T Cell Functions. Front Pediatr 2021; 9:607292. [PMID: 33614551 PMCID: PMC7888439 DOI: 10.3389/fped.2021.607292] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 01/05/2021] [Indexed: 12/21/2022] Open
Abstract
Regulatory T (Treg) cells play a role in the maintenance of immune homeostasis and are critical mediators of immune tolerance. The Forkhead box P3 (FOXP3) protein acts as a regulator for Treg development and function. Mutations in the FOXP3 gene can lead to autoimmune diseases such as Immunodysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome in humans, often resulting in death within the first 2 years of life and a scurfy like phenotype in Foxp3 mutant mice. We discuss biochemical features of the FOXP3 ensemble including its regulation at various levels (epigenetic, transcriptional, and post-translational modifications) and molecular functions. The studies also highlight the interactions of FOXP3 and Tat-interacting protein 60 (Tip60), a principal histone acetylase enzyme that acetylates FOXP3 and functions as an essential subunit of the FOXP3 repression ensemble complex. Lastly, we have emphasized the role of allosteric modifiers that help stabilize FOXP3:Tip60 interactions and discuss targeting this interaction for the therapeutic manipulation of Treg activity.
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Affiliation(s)
- Payal Grover
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Peeyush N Goel
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Ciriaco A Piccirillo
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada.,Program in Infectious Diseases and Immunology in Global Health, The Research Institute of the McGill University Health Centre, Montréal, QC, Canada.,Centre of Excellence in Translational Immunology (CETI), Montréal, QC, Canada
| | - Mark I Greene
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
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