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首页> 外文期刊>Clinical and Experimental Immunology: An Official Journal of the British Society for Immunology >Effects of type II collagen epitope carbamylation and citrullination in human leucocyte antigen (HLA)-DR4(+) monozygotic twins discordant for rheumatoid arthritis
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Effects of type II collagen epitope carbamylation and citrullination in human leucocyte antigen (HLA)-DR4(+) monozygotic twins discordant for rheumatoid arthritis

机译：类风湿性关节炎不一致的人类白细胞抗原（HLA）-DR4（+）单卵双胞胎中II型胶原抗原决定簇氨甲酰化和瓜氨酸化的作用

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摘要

The aim of this study is to investigate the effect of the native, citrullinated or carbamylated type II human collagen T cell- and B cell-epitopes on the adaptive immune response in rheumatoid arthritis (RA). Peripheral blood T and B cells obtained from a human leucocyte D4-related (antigen DR4(-) HLA-DR4)(+) woman with early RA, her healthy monozygotic twin and an unrelated HLA-DR3(+) woman with early RA were analysed for activation (CD154/CD69), apoptosis (annexin/7-aminoactinomycin), cytokine production [interferon (IFN)/interleukin (IL)-17/IL-4/IL-10/IL-6] and functional phenotype (CD45Ra/CCR7) after stimulation with the collagen native T cell epitope (T261-273), the K264 carbamylated T cell epitope (carT261-273), the native B cell epitope (B359-369) or the R360 citrullinated B cell epitope (citB359-369), and the combinations of these. The T cell memory compartment was activated by T cell epitopes in both discordant DR4(+) twins, but not in the DR3(+) RA. The collagen-specific activation of CD4(+) T cells was induced with both the native and carbamylated T cell epitopes only in the RA twin. Both T cell epitopes also induced IL-17 production in the RA twin, but a greater IL-4 and IL-10 response in the healthy twin. Thecitrullinated B cell epitope, particularly when combined with the carbamylated T cell epitope, induced B cell activation and an increased IL-6/IL-10 ratio in the RA twin compared to a greater IL-10 production in the healthy twin. Our data suggest that circulating collagen-specific T and B cells are found in HLA-DR4(+) subjects, but only RA activated cells express co-stimulatory molecules and produce proinflammatory cytokines. Carbamylation and citrullination further modulate the activation and cytokine polarization of T and B cells.
机译：本研究的目的是研究天然，瓜氨酸化或氨基甲酸酯化的II型人胶原T细胞和B细胞表位对类风湿关节炎（RA）适应性免疫反应的影响。从患有早期RA的人类白细胞D4相关（抗原DR4（-）HLA-DR4）（+）妇女，她的健康单卵双胞胎和与早期RA无关的HLA-DR3（+）妇女获得的外周血T和B细胞分别为分析其活化（CD154 / CD69），凋亡（annexin / 7-aminoactinomycin），细胞因子产生[干扰素（IFN）/白介素（IL）-17 / IL-4 / IL-10 / IL-6]和功能表型（CD45Ra / CCR7）用胶原蛋白天然T细胞抗原决定簇（T261-273），K264氨基甲酰化T细胞抗原决定簇（carT261-273），天然B细胞抗原决定簇（B359-369）或R360瓜氨酸化B细胞抗原决定簇（citB359- 369），以及这些的组合。 T细胞表位在两个不一致的DR4（+）双胞胎中都被T细胞表位激活，但在DR3（+）RA中却未被激活。 CD4（+）T细胞的胶原蛋白特异性活化仅在RA双胞胎中被天然T细胞和氨基甲酸酯化T细胞表位所诱导。这两个T细胞表位也诱导了RA双胞胎中IL-17的产生，但是在健康的双胞胎中IL-4和IL-10的应答更大。瓜氨酸化的B细胞表位，特别是与氨甲酰化的T细胞表位组合时，与健康双胞胎中产生更高的IL-10相比，RA双胞胎中诱导了B细胞活化和IL-6 / IL-10比率增加。我们的数据表明，在HLA-DR4（+）受试者中发现了循环胶原特异性T和B细胞，但只有RA激活的细胞表达共刺激分子并产生促炎性细胞因子。氨基甲酸酯化和瓜氨酸化进一步调节T和B细胞的活化和细胞因子极化。

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