Albani S, Carson D A, Roudier J
Department of Medicine, University of California, San Diego, La Jolla.
Rheum Dis Clin North Am. 1992 Nov;18(4):729-40.
Our experiments have led us to conclude that the rheumatoid arthritis shared epitope may act as a peptide that is important for positive and negative selection of T lymphocytes, that T lymphocytes are skewed by positive selection to recognize epitopes that are similar but not identical to self, and that peptide sequences that are similar to the RA-shared epitope are abundantly expressed by microorganisms that chronically infect most people. This combination of events could partly explain the association of the shared epitope with the severe forms of RA. The hypothesis cannot be tested directly, because we do not postulate that any unique population of autoreactive T cells is expanded in RA; however, the role of positive selection in molding the human T-cell repertoire to exogenous antigens can be tested by mapping T-cell antigenic determinants on the E. coli dnaJ protein or the gp110 protein of EBV in people with different HLA-DR types. Moreover, positive selection models imply that maternal antigens that cross the placenta can influence the T-cell repertoire. Thus, one might expect to find that the frequency of HLA-DR4 in the mothers of patients with RA who themselves lack the DR4 antigen, would be more frequent than predicted by chance alone. As the principles of positive selection are more precisely delineated in animal systems, it should become possible to ascertain more clearly how the shared epitope on HLA-DR molecules enhances the severity of autoimmune reactions; however, RA only occurs in humans; possibly because of the unique inability of human macrophages to replicate. Thus, only the direct analysis of patients can directly reveal the mechanisms of disease pathogenesis.
我们的实验使我们得出结论，类风湿性关节炎共享表位可能作为一种对T淋巴细胞的阳性和阴性选择很重要的肽，T淋巴细胞通过阳性选择而偏向于识别与自身相似但不完全相同的表位，并且与类风湿性关节炎共享表位相似的肽序列在慢性感染大多数人的微生物中大量表达。这些事件的组合可以部分解释共享表位与严重类风湿性关节炎形式之间的关联。该假设无法直接进行检验，因为我们并未假定任何独特的自身反应性T细胞群体在类风湿性关节炎中会扩增；然而，阳性选择在将人类T细胞库塑造为对外源抗原的反应方面所起的作用，可以通过绘制不同HLA - DR类型人群中大肠杆菌dnaJ蛋白或EBV的gp110蛋白上的T细胞抗原决定簇来进行检验。此外，阳性选择模型表明，穿过胎盘的母体抗原可以影响T细胞库。因此，人们可能会发现，自身缺乏DR4抗原的类风湿性关节炎患者的母亲中，HLA - DR4的频率会比仅由偶然因素预测的更为频繁。由于阳性选择的原理在动物系统中得到了更精确的描述，应该有可能更清楚地确定HLA - DR分子上的共享表位如何增强自身免疫反应的严重性；然而，类风湿性关节炎仅发生在人类中；可能是因为人类巨噬细胞具有独特的无法复制的特性。因此，只有对患者的直接分析才能直接揭示疾病发病机制。
