Predominant selection of T cells specific for the glycosylated collagen type II epitope (263-270) in humanized transgenic mice and in rheumatoid arthritis
Predominant selection of T cells specific for the glycosylated collagen type II epitope (263-270) in humanized transgenic mice and in rheumatoid arthritis
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DOI：
10.1073/pnas.132254199
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发表时间：
2002-07-23
影响因子：
11.1
通讯作者：
Holmdahl, R
中科院分区：
文献类型：
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作者：
Bäcklund, J;Carlsen, S;Holmdahl, R
风湿性关节炎（RA）与某些MHC II类等位基因相关，并且以关节中的慢性自身免疫反应为特征。使用转基因小鼠表达人DR 4（DRB 1 *0401）和人CD 4，但缺乏内源性MHC II类，我们表明，翻译后糖基化的II型胶原（CII）的影响T细胞的耐受性，这种候选人软骨特异性自身抗原的水平。在这样的小鼠中，人CII的表达导致对人CII的耐受化的鼠T细胞应答。然而，耐受性诱导仍然不完全，优先删除对未修饰的CII 263-270表位的反应，而T细胞对该表位的糖基化变体的识别受到的影响程度较小。在一组严重受累的RA患者（n = 14）中记录了对CII-糖肽的T细胞应答的类似优势。因此，RA T细胞主要识别其糖基化形式的免疫显性CII肽，并可以解释为什么以前一直难以检测RA患者对CII的T细胞应答。
Rheumatoid arthritis (RA) is associated with certain MHC class II alleles and is characterized by a chronic autoimmune response in the joints. Using transgenic mice expressing human DR4 (DRB1*0401) and human CD4, but lacking endogenous MHC class II, we show that posttranslational glycosylation of type II collagen (CII) influences the level of T cell tolerance to this candidate cartilage-specific autoantigen. In such mice, the expression of human CII resulted in a tolerized murine T cell response to human CII. However, tolerance induction remained incomplete, preferentially deleting responses to the nonmodified CII 263-270 epitope, whereas T cell recognition of a glycosylated variant of this epitope was affected to a lesser degree. A similar dominance of T cell responses to CII-glycopeptides was recorded in a cohort of severely affected RA-patients (n = 14). Thus, RA T cells predominantly recognize the immunodominant CII peptide in its glycosylated form and may explain why previously it has been difficult to detect T cell responses to CII in RA patients.