Kochi Yuta
Laboratory for Autoimmune Diseases, Center for Genomic Medicine, RIKEN.
Nihon Rinsho Meneki Gakkai Kaishi. 2010;33(2):48-56. doi: 10.2177/jsci.33.48.
Rheumatoid arthritis (RA) is a complex mutifactorial autoimmune disease. As anti-citrullinated peptide antibodies (ACPA) exhibit unique specificity for RA, breakdown of immunological tolerance to citrullinated self-proteins is considered to be a key feature of RA pathogenesis. While environmental factors such as smoking and viral infections have been implicated in the pathogenesis, recent genome-scans for RA have unraveled multiple genetic factors involved in RA. Some of these genetic factors may specifically contribute to the tolerance breakdown of RA. For instance, PADI4 gene encoding an enzyme that converts arginine residues to citrullines may enhance the production of auto-antigens. These citrullinated proteins are then presented to helper T-cells via HL-DR molecule on the antigen presenting cells, where specific HLA-DRB1 alleles encoding "shared-epitope" have significant relevance to RA. On the other hand, genes regulating the activity of lymphocytes such as PTPN22 and FCRL3 may influence auto-reactivity of individual lymphocytes. Taken together, combination of these genetic factors accelerates autoimmune response in RA.
类风湿关节炎（RA）是一种复杂的多因素自身免疫性疾病。由于抗瓜氨酸化肽抗体（ACPA）对RA具有独特的特异性，对瓜氨酸化自身蛋白的免疫耐受破坏被认为是RA发病机制的关键特征。虽然吸烟和病毒感染等环境因素与发病机制有关，但最近针对RA的全基因组扫描揭示了多个参与RA的遗传因素。其中一些遗传因素可能特别促成了RA的耐受破坏。例如，编码将精氨酸残基转化为瓜氨酸的酶的PADI4基因可能会增强自身抗原的产生。然后，这些瓜氨酸化蛋白通过抗原呈递细胞上的HL-DR分子呈递给辅助性T细胞，其中编码“共享表位”的特定HLA-DRB1等位基因与RA有显著相关性。另一方面，调节淋巴细胞活性的基因，如PTPN22和FCRL3，可能会影响单个淋巴细胞的自身反应性。综上所述，这些遗传因素的组合加速了RA中的自身免疫反应。
