Hohlfeld R, Toyka K V, Tzartos S J, Carson W, Conti-Tronconi B M
Proc Natl Acad Sci U S A. 1987 Aug;84(15):5379-83. doi: 10.1073/pnas.84.15.5379.
Myasthenia gravis is a human disease caused by an autoimmune response against the nicotinic acetylcholine receptor (AcChoR). Since the molecular structure of AcChoR is well known, myasthenia gravis is an excellent system for studying the recognition of a complex membrane antigen in the human immune system. Human T-helper (TH) cell lines reactive to the AcChoR were isolated from four myasthenic patients by selection with native AcChoR from Torpedo californica. The selected TH cells could efficiently recognize native and fully denatured AcChoR. The vast majority of the TH-stimulating AcChoR epitopes were located on the denatured alpha subunit of AcChoR. Antibody competition experiments using a panel of rat anti-AcChoR monoclonal antibodies showed that 39-45% of the autoantibodies present in the sera of these same patients bound to the conformation-sensitive "main immunogenic region" (MIR), also located on the alpha subunit. However, AcChoR-induced stimulation of the T cells could not be inhibited with up to 20-fold molar excess of different rat anti-MIR monoclonal antibodies. These results suggest that the Torpedo AcChoR alpha subunit contains conformation-insensitive epitopes that play a role in the autosensitization of TH cells and that seem to be physically separated from the MIR. The specificity of the TH cell response may contribute to directing the B-cell response to other alpha-subunit determinants, such as the MIR itself.
重症肌无力是一种由针对烟碱型乙酰胆碱受体（AcChoR）的自身免疫反应引起的人类疾病。由于AcChoR的分子结构已为人所知，重症肌无力是研究人类免疫系统中复合膜抗原识别的理想系统。通过用来自加州电鳐的天然AcChoR进行筛选，从四名重症肌无力患者中分离出了对AcChoR有反应的人类辅助性T（TH）细胞系。所选的TH细胞能够有效识别天然和完全变性的AcChoR。绝大多数刺激TH细胞的AcChoR表位位于AcChoR变性的α亚基上。使用一组大鼠抗AcChoR单克隆抗体进行的抗体竞争实验表明，这些患者血清中39%-45%的自身抗体与同样位于α亚基上的构象敏感“主要免疫原区”（MIR）结合。然而，高达20倍摩尔过量的不同大鼠抗MIR单克隆抗体并不能抑制AcChoR诱导的T细胞刺激。这些结果表明，电鳐AcChoRα亚基含有构象不敏感表位，这些表位在TH细胞的自身致敏中起作用，并且似乎与MIR在物理上是分开的。TH细胞反应的特异性可能有助于将B细胞反应导向其他α亚基决定簇，如MIR本身。
