Rheumatoid arthritis occurs most often in people who express HLA-DR molecules containing a five aa “shared epitope” in the β chain. These MHCII molecules preferentially bind citrullinated peptides formed by posttranslational modification of arginine. Citrullinated peptide:HLA-DR complexes may act as arthritis-initiating neo-antigens for CD4+ T cells. Here, we used fluorophore-conjugated HLA-DR tetramers containing citrullinated peptides from human cartilage intermediate layer protein, fibrinogen, vimentin, or enolase 1 to track cognate CD4+ T cells. Immunization of HLA-DR transgenic mice with citrullinated peptides from vimentin or enolase 1 failed to cause any expansion of tetramer-binding cells, whereas immunization with citrullinated peptides from cartilage intermediate layer protein or fibrinogen elicited some expansion. The expanded tetramer-binding populations, however, had lower T helper 1 and higher regulatory T cell frequencies than populations elicited by viral peptides. These results indicate that HLA-DR–bound citrullinated peptides are not neo-antigens and induce varying degrees of immune tolerance that could pose a barrier to rheumatoid arthritis.

中文翻译：

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瓜氨酸肽特异的 CD4+ T 细胞库显示了免疫耐受的证据

类风湿性关节炎最常发生在表达 β 链中包含 5 个氨基酸“共享表位”的 HLA-DR 分子的人群中。这些 MHCII 分子优先结合精氨酸翻译后修饰形成的瓜氨酸肽。瓜氨酸肽：HLA-DR 复合物可能充当 CD4+ T 细胞的关节炎引发新抗原。在这里，我们使用含有来自人软骨中间层蛋白、纤维蛋白原、波形蛋白或烯醇酶 1 的瓜氨酸肽的荧光团缀合的 HLA-DR 四聚体来追踪同源 CD4+ T 细胞。用来自波形蛋白或烯醇化酶1的瓜氨酸肽免疫HLA-DR转基因小鼠未能引起四聚体结合细胞的任何扩增，而用来自软骨中间层蛋白或纤维蛋白原的瓜氨酸肽免疫引起一些扩增。然而，与病毒肽诱导的群体相比，扩大的四聚体结合群体具有较低的 T 辅助细胞 1 和较高的调节性 T 细胞频率。这些结果表明，HLA-DR 结合的瓜氨酸肽不是新抗原，并且会诱导不同程度的免疫耐受，从而可能对类风湿性关节炎形成屏障。