The effect of HLA genotype on disease onset and severity in CTLA-4 insufficiency
IntroductionHuman Cytotoxic-T-lymphocyte-antigen-4 (CTLA-4) insufficiency caused by heterozygous germline mutations in CTLA4 is a complex immune dysregulation and immunodeficiency syndrome presenting with reduced penetrance and variable disease expressivity, suggesting the presence of disease modifi...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1447995/full |
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| author | Sara Posadas-Cantera Sara Posadas-Cantera Noriko Mitsuiki Florian Emmerich Virginia Patiño Hanns-Martin Lorenz Olaf Neth Ingunn Dybedal Kjetil Taskén Alejandro A. Schäffer Bodo Grimbacher Bodo Grimbacher Bodo Grimbacher Bodo Grimbacher Laura Gámez-Díaz Laura Gámez-Díaz |
| author_facet | Sara Posadas-Cantera Sara Posadas-Cantera Noriko Mitsuiki Florian Emmerich Virginia Patiño Hanns-Martin Lorenz Olaf Neth Ingunn Dybedal Kjetil Taskén Alejandro A. Schäffer Bodo Grimbacher Bodo Grimbacher Bodo Grimbacher Bodo Grimbacher Laura Gámez-Díaz Laura Gámez-Díaz |
| author_sort | Sara Posadas-Cantera |
| collection | DOAJ |
| description | IntroductionHuman Cytotoxic-T-lymphocyte-antigen-4 (CTLA-4) insufficiency caused by heterozygous germline mutations in CTLA4 is a complex immune dysregulation and immunodeficiency syndrome presenting with reduced penetrance and variable disease expressivity, suggesting the presence of disease modifiers that trigger the disease onset and severity. Various genetic and non-genetic potential triggers have been analyzed in CTLA-4 insufficiency cohorts, however, none of them have revealed a clear association to the disease. Multiple HLA haplotypes have been positively or negatively associated with various autoimmune diseases and inborn errors of immunity (IEI) due to the relevance of MHC in the strength of the T cell responses.MethodsIn this exploratory study, we investigated the association of disease onset, severity and clinical manifestations of CTLA-4 insufficiency with specific HLA class I (A, B and C) and class II (DRB1 and DQB1) alleles in forty-three individuals harboring heterozygous mutations in CTLA4. Twenty-six out of the 43 recruited individuals presented moderate or severe clinical symptoms whereas 17 were completely healthy. HLA frequency analysis, odds ratio analysis and genetic linkage analysis were used.ResultsThe principal statistical analyses showed no positive association between the HLA genotypes analyzed with the disease onset or the disease severity. We found potential risk associations of HLA-DQB1*05:01 and HLA-DRB1*01:02 with respiratory tract involvement and HLA-C*05:01 with affection of the neurological system in the CTLA-4-insufficient patients. Additionally, we found a potential protective association of HLA-DRB1*01:01 with gastrointestinal symptoms.DiscussionEven though, our findings suggest that HLA-A, -B, -C, DRB1, and DQB1 do not contribute to the onset or severity of disease in CTLA-4 insufficiency, certain HLA-alleles may influence the manifestation of specific symptoms. We advocate for further investigation of specific class I and class II HLA alleles as potential disease modifiers in larger clinical cohorts of CTLA-4 insufficiency. |
| format | Article |
| id | doaj-art-25385a1b82ee4b428f6e1c5b2dbdee7b |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| spelling | doaj-art-25385a1b82ee4b428f6e1c5b2dbdee7b2025-01-06T08:15:58ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011510.3389/fimmu.2024.14479951447995The effect of HLA genotype on disease onset and severity in CTLA-4 insufficiencySara Posadas-Cantera0Sara Posadas-Cantera1Noriko Mitsuiki2Florian Emmerich3Virginia Patiño4Hanns-Martin Lorenz5Olaf Neth6Ingunn Dybedal7Kjetil Taskén8Alejandro A. Schäffer9Bodo Grimbacher10Bodo Grimbacher11Bodo Grimbacher12Bodo Grimbacher13Laura Gámez-Díaz14Laura Gámez-Díaz15Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, GermanyInstitute of Medical Microbiology and Hygiene, Medical Center– University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, GermanyInstitute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, GermanyInstitute for Transfusion Medicine and Gene Therapy, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, GermanyImmunology Team, American Insurance, Montevideo, UruguayDivision of Rheumatology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, GermanyPaediatric Infectious Diseases, Rheumatology and Immunology Unit, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, IBiS/Universidad de Sevilla/CSIC, Seville, SpainDepartment of Hematology and Pharmacology, Oslo University Hospital, Oslo, NorwayDepartment of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, NorwayCancer Data Science Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, MD, United StatesInstitute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany0Department of Rheumatology and Clinical Immunology, Medical Center- University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany1CIBSS– Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany2RESIST– Cluster of Excellence 2155 to Hannover Medical School, Satellite Center Freiburg, Freiburg, GermanyInstitute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany1CIBSS– Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, GermanyIntroductionHuman Cytotoxic-T-lymphocyte-antigen-4 (CTLA-4) insufficiency caused by heterozygous germline mutations in CTLA4 is a complex immune dysregulation and immunodeficiency syndrome presenting with reduced penetrance and variable disease expressivity, suggesting the presence of disease modifiers that trigger the disease onset and severity. Various genetic and non-genetic potential triggers have been analyzed in CTLA-4 insufficiency cohorts, however, none of them have revealed a clear association to the disease. Multiple HLA haplotypes have been positively or negatively associated with various autoimmune diseases and inborn errors of immunity (IEI) due to the relevance of MHC in the strength of the T cell responses.MethodsIn this exploratory study, we investigated the association of disease onset, severity and clinical manifestations of CTLA-4 insufficiency with specific HLA class I (A, B and C) and class II (DRB1 and DQB1) alleles in forty-three individuals harboring heterozygous mutations in CTLA4. Twenty-six out of the 43 recruited individuals presented moderate or severe clinical symptoms whereas 17 were completely healthy. HLA frequency analysis, odds ratio analysis and genetic linkage analysis were used.ResultsThe principal statistical analyses showed no positive association between the HLA genotypes analyzed with the disease onset or the disease severity. We found potential risk associations of HLA-DQB1*05:01 and HLA-DRB1*01:02 with respiratory tract involvement and HLA-C*05:01 with affection of the neurological system in the CTLA-4-insufficient patients. Additionally, we found a potential protective association of HLA-DRB1*01:01 with gastrointestinal symptoms.DiscussionEven though, our findings suggest that HLA-A, -B, -C, DRB1, and DQB1 do not contribute to the onset or severity of disease in CTLA-4 insufficiency, certain HLA-alleles may influence the manifestation of specific symptoms. We advocate for further investigation of specific class I and class II HLA alleles as potential disease modifiers in larger clinical cohorts of CTLA-4 insufficiency.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1447995/fullcytotoxic T-lymphocyte antigen 4 (CTLA-4)immune dysregulationinborn errors of immunity (IEI)disease modifiershuman leukocyte antigen (HLA)genetic linkage analysis |
| spellingShingle | Sara Posadas-Cantera Sara Posadas-Cantera Noriko Mitsuiki Florian Emmerich Virginia Patiño Hanns-Martin Lorenz Olaf Neth Ingunn Dybedal Kjetil Taskén Alejandro A. Schäffer Bodo Grimbacher Bodo Grimbacher Bodo Grimbacher Bodo Grimbacher Laura Gámez-Díaz Laura Gámez-Díaz The effect of HLA genotype on disease onset and severity in CTLA-4 insufficiency Frontiers in Immunology cytotoxic T-lymphocyte antigen 4 (CTLA-4) immune dysregulation inborn errors of immunity (IEI) disease modifiers human leukocyte antigen (HLA) genetic linkage analysis |
| title | The effect of HLA genotype on disease onset and severity in CTLA-4 insufficiency |
| title_full | The effect of HLA genotype on disease onset and severity in CTLA-4 insufficiency |
| title_fullStr | The effect of HLA genotype on disease onset and severity in CTLA-4 insufficiency |
| title_full_unstemmed | The effect of HLA genotype on disease onset and severity in CTLA-4 insufficiency |
| title_short | The effect of HLA genotype on disease onset and severity in CTLA-4 insufficiency |
| title_sort | effect of hla genotype on disease onset and severity in ctla 4 insufficiency |
| topic | cytotoxic T-lymphocyte antigen 4 (CTLA-4) immune dysregulation inborn errors of immunity (IEI) disease modifiers human leukocyte antigen (HLA) genetic linkage analysis |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1447995/full |
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