Abstract
Associations between human leukocyte antigen (HLA) and susceptibility to systemic autoimmune diseases have been reported. The predisposing alleles are variable among ethnic groups and/or diseases. On the other hand, some HLA alleles are associated with resistance to systemic autoimmune diseases, including systemic sclerosis, systemic lupus erythematosus and rheumatoid arthritis. Interestingly, DRB1*13 alleles are the protective alleles shared by multiple autoimmune diseases. DRB1*13:01 allele is protective in European populations and DRB1*13:02 in Japanese. Because alleles in multiple HLA loci are in strong linkage disequilibrium, it is difficult to determine which of the protective alleles is functionally responsible for the protective effects. Thus far, association studies suggested that DRB1*13:02 represents at least one of the causally associated protective factors against multiple systemic autoimmune diseases in the Japanese population. The protective effect of DRB1*13 alleles appears to overcome the predisposing effect of the susceptible alleles in heterozygous individuals of DRB1*13 and the susceptible allele. A gene dosage effect was observed in the associations of DRB1*13:02 with the protection from systemic autoimmune diseases; thus homozygous individuals are more effectively protected from the systemic autoimmune diseases than heterozygotes. DRB1*13:02 also confers protection against organ-specific autoimmune diseases and some infectious diseases. Several hypotheses can be proposed for the molecular mechanisms of the protection conferred by DRB1*13, some of which can explain the dominant effect of DRB1*13 molecules over the susceptible alleles, but the actual protective function of DRB1*13 requires further study. Understanding of the protective mechanisms of DRB1*13 may lead to the identification of targets for the curative treatment of systemic autoimmune diseases.
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Acknowledgements
The study was supported by Grants-in-Aid for Scientific Research (B, C) (26293123, 22591090, 15K09543, 16K15154) and for Young Scientists (B) (24791018) from the Japan Society for the Promotion of Science, Health and Labour Science Research Grants from the Ministry of Health, Labour, and Welfare of Japan, the Practical Research Project for Allergic Diseases and Immunology from Japan Agency for Medical Research and Development, Grants-in-Aid for Clinical Research from National Hospital Organization, Research Grants from Daiwa Securities Health Foundation, Research Grants from Japan Research Foundation for Clinical Pharmacology, Research Grants from The Nakatomi Foundation, Research Grants from Takeda Science Foundation, Research Grants from Mitsui Sumitomo Insurance Welfare Foundation, Research Grants from Kato Memorial Trust for Nambyo Research, Bristol-Myers K.K. RA Clinical Investigation Grant from Bristol-Myers Squibb Co. and research grants from the following pharmaceutical companies: Abbott Japan Co., Ltd., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsuibishi Tanabe Pharma Corporation, Merck Sharp and Dohme Inc., Pfizer Japan Inc., Takeda Pharmaceutical Company Limited, and Teijin Pharma Limited. The funders had no role in study design, data collection and analysis, decision to publish or preparing the manuscript.
Author contributions
Conceived and designed the experiments: HF, NT, and ST; performed the experiments: HF, SO, and AK; analyzed the data: HF, contributed reagents/materials/analysis tools: HF, KS, AH, and ST; wrote the manuscript: HF, NT, and ST.
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HF has the following conflicts, and the following funders are supported wholly or in part by the indicated pharmaceutical companies. The Japan Research Foundation for Clinical Pharmacology is run by Daiichi Sankyo, the Takeda Science Foundation is supported by an endowment from Takeda Pharmaceutical Company and the Nakatomi Foundation was established by Hisamitsu Pharmaceutical Co., Inc. The Daiwa Securities Health Foundation was established by Daiwa Securities Group Inc. and Mitsui Sumitomo Insurance Welfare Foundation was established by Mitsui Sumitomo Insurance Co., Ltd. HF received honoraria from Ajinomoto Co., Inc., Daiichi Sankyo Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Company, Luminex Japan Corporation Ltd. and Ayumi Pharmaceutical Corporation. ST was supported by research grants from the pharmaceutical companies: Abbott Japan Co., Ltd., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Merck Sharp and Dohme Inc., Pfizer Japan Inc., Takeda Pharmaceutical Company Limited, and Teijin Pharma Limited. ST received honoraria from Asahi Kasei Pharma Corporation, Astellas Pharma Inc., AbbVie GK., Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation and Pfizer Japan Inc. NT was supported by SENSHIN Medical Research Foundation, which is supported by an endowment from Mitsubishi Tanabe Pharma Corporation, and received honoraria from Eisai Co., Ltd., Daiichi Sankyo Co., Ltd. and Asahi Kasei Corporation. The other authors declare no financial or commercial conflict of interest.
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Furukawa, H., Oka, S., Tsuchiya, N. et al. The role of common protective alleles HLA-DRB1*13 among systemic autoimmune diseases. Genes Immun 18, 1–7 (2017). https://doi.org/10.1038/gene.2016.40
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DOI: https://doi.org/10.1038/gene.2016.40
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