Rosenberg J S, Oshima M, Atassi M Z
Verna and Marrs McLean Department of Biochemistry, Baylor College of Medicine, Houston, TX 77030, USA.
J Immunol. 1996 Oct 1;157(7):3192-9.
We have previously mapped the T and B cell epitopes on the alpha-subunit of acetylcholine receptor (AChR) in human myasthenia gravis (MG) and in experimental autoimmune MG-susceptible (C57BL/6 (B6)) and nonsusceptible mouse strains. In addition to regions recognized by both T and B cells, the AChR alpha-subunit has regions that are recognized solely by T cells. An exclusive T cell epitope within residues alpha 146-162 of Torpedo californica (t), tAChR, plays an important role in experimental autoimmune MG pathogenesis in B6 mice. To study its function, we established, from tAChR-primed B6 mice, two t alpha 146-162-specific T cell lines (P14Th) which comprised Th2-type cells because they secreted IL-4 but not IL-2. P14Th did not recognize the corresponding region on mouse (m) AChR (m alpha 146-162). They caused in vitro differentiation of tAChR-primed B cells into plasma cells that secreted anti-AChR Abs directed, in decreasing order, against the following tAChR alpha regions: t alpha 122-138 > t alpha 134-150 > t alpha 45-60 > t alpha 170-186 > t alpha 56-71. Little or no Ab response could be detected against peptides t alpha 182-198 or t alpha 146-162 itself. The major enhancement was in the Abs against region t alpha 122-150 (spanning the t alpha 122-138/t alpha 134-150 overlap) that is involved in ACh binding. These Abs cross-reacted completely with m alpha 122-150, the corresponding region on mAChR. Therefore, t alpha 146-162-specific T cells, although unable to recognize m alpha 146-162, are nevertheless pathogenic because they help B cells responding to a tAChR region that is conserved in mAChR and involved in ACh binding. These Abs cross-react with the corresponding effector-binding region of mAChR, thereby disrupting the normal physiologic function of the mouse receptor.
我们之前已绘制出人类重症肌无力（MG）以及实验性自身免疫性MG易感（C57BL/6（B6））和非易感小鼠品系中乙酰胆碱受体（AChR）α亚基上的T细胞和B细胞表位。除了T细胞和B细胞都识别的区域外，AChRα亚基还有仅被T细胞识别的区域。加州电鳐（t）tAChR的α146 - 162残基内的一个独特T细胞表位在B6小鼠的实验性自身免疫性MG发病机制中起重要作用。为研究其功能，我们从用tAChR免疫的B6小鼠中建立了两个tα146 - 162特异性T细胞系（P14Th），它们属于Th2型细胞，因为它们分泌IL - 4但不分泌IL - 2。P14Th不识别小鼠（m）AChR上的相应区域（mα146 - 162）。它们在体外使经tAChR免疫的B细胞分化为浆细胞，这些浆细胞分泌抗AChR抗体，其针对以下tAChRα区域的反应强度递减：tα122 - 138 > tα134 - 150 > tα45 - 60 > tα170 - 186 > tα56 - 71。针对肽段tα182 - 198或tα146 - 162本身几乎检测不到或没有抗体反应。主要增强的是针对参与ACh结合的tα122 - 150区域（跨越tα122 - 138/tα134 - 150重叠区）的抗体。这些抗体与mAChR上的相应区域mα122 - 150完全交叉反应。因此，tα146 - 162特异性T细胞虽然无法识别mα146 - 162，但仍具有致病性，因为它们帮助B细胞对mAChR中保守且参与ACh结合的tAChR区域作出反应。这些抗体与mAChR的相应效应器结合区域交叉反应，从而破坏小鼠受体的正常生理功能。
