Infante A J, Thompson P A, Krolick K A, Wall K A
Department of Pediatrics, University of Texas Health Science Center, San Antonio 78284-7810.
J Immunol. 1991 May 1;146(9):2977-82.
C57BL/6 (B6) mice respond to immunization with acetylcholine receptor (AChR) from Torpedo californica as measured by T cell proliferation, antibody production, and the development of muscle weakness resembling human myasthenia gravis. The congenic strain B6.C-H-2bm12 (bm12), which differs from B6 by three amino acid substitutions in the beta-chain of the MHC class II molecule I-A, develops a T cell proliferative response but does not produce antibody or develop muscle weakness. By examining the fine specificity of the B6 and bm12 T cell responses to AChR by using T cell clones and synthetic AChR peptides, we found key differences between the two strains in T cell epitope recognition. B6 T cells responded predominantly to the peptide representing alpha-subunit residues 146-162; this response was cross-reactive at the clonal level to peptide 111-126. Based on the sequence homology between these peptides and the T cell response to a set of truncated peptides, the major B6 T cell epitope was determined to be residues 148-152. The cross-reactivity of peptides 146-162 and 111-126 could also be demonstrated in vivo. Immunization of B6 mice with either peptide primed for T cell responses to both peptides. In contrast, immunization of bm12 mice with peptide 111-126 primed for an anti-peptide response, which did not cross-react with 146-162. Peptide-reactive T cells were not elicited after immunization of bm12 mice with 146-162. These results define a major T cell fine specificity in experimental autoimmune myasthenia gravis-susceptible B6 mice to be directed at alpha-subunit residues 148-152. T cells from disease-resistant bm12 mice fail to recognize this epitope but do recognize other portions of AChR. We postulate that alpha-148-152 is a disease-related epitope in murine experimental autoimmune myasthenia gravis. In this informative strain combination, MHC class II-associated determinant selection, rather than Ag responsiveness per se, may play a major role in determining disease susceptibility.
通过T细胞增殖、抗体产生以及类似人类重症肌无力的肌肉无力的发展来衡量,C57BL/6(B6)小鼠对来自加州电鳐的乙酰胆碱受体(AChR)免疫有反应。同基因品系B6.C-H-2bm12(bm12)与B6的区别在于MHC II类分子I-A的β链中有三个氨基酸替换,它产生T细胞增殖反应,但不产生抗体也不出现肌肉无力。通过使用T细胞克隆和合成AChR肽来检测B6和bm12 T细胞对AChR的精细特异性,我们发现这两个品系在T细胞表位识别上存在关键差异。B6 T细胞主要对代表α亚基残基146 - 162的肽有反应;这种反应在克隆水平上与肽111 - 126有交叉反应。基于这些肽之间的序列同源性以及对一组截短肽的T细胞反应,确定主要的B6 T细胞表位为残基148 - 152。肽146 - 162和111 - 126的交叉反应性在体内也能得到证实。用这两种肽中的任何一种免疫B6小鼠都会引发对两种肽的T细胞反应。相比之下,用肽111 - 126免疫bm12小鼠会引发抗肽反应,该反应与146 - 162无交叉反应。用146 - 162免疫bm12小鼠后不会引发肽反应性T细胞。这些结果确定了在实验性自身免疫性重症肌无力易感的B6小鼠中主要的T细胞精细特异性是针对α亚基残基148 - 152。来自抗病性bm12小鼠的T细胞无法识别这个表位,但能识别AChR的其他部分。我们推测α - 148 - 152是小鼠实验性自身免疫性重症肌无力中的一个疾病相关表位。在这个信息丰富的品系组合中,MHC II类相关决定簇选择而非抗原反应性本身可能在决定疾病易感性方面起主要作用。