Hahn B H, Singh R R, Ebling F M
Department of Medicine at the University of California-Los Angeles, 90095-1670, USA.
Lupus. 1998;7(5):307-13. doi: 10.1191/096120398678920145.
Young NZB/NZW F1 (BWF1) mice develop T cell repertoires that are spontaneously stimulated by peptides derived from the VH regions of BWF1 J558-encoded autoantibodies (autoAb) to DNA, but not to VH region peptides of a J558-encoded antibody to an exogenous antigen. Immunization of young BWF1 mice with selected Ig-derived peptides accelerates anti-DNA production and nephritis, and immune tolerance induction to a combination of these determinants delays anti-DNA production and disease onset. To further characterize this immunoregulatory circuitry, we asked whether this phenomenon of spontaneous T cell activation by VH region peptides is restricted to anti-DNA Ab of the VH J558 family, and what are the charge and structural attributes of these T cell determinants? We studied spontaneous T cell proliferative responses to peptides derived from an autoAb to DNA constructed from VH 7183 and found that it contains several T cell determinants. Both charge and size of certain amino acids (AA) within each peptide seemed to be important. Peptides containing arginine (R) or glutamic acid (E) were more likely to be T cell determinants than peptides without those AA; replacement of charged AA with uncharged AA abolished T cell recognition of a peptide. We previously reported that some Abs to DNA are enriched in R in their VH; pathogenic BWF1 IgG anti-DNA are enriched in positively and negatively charged AA in VH regions. Therefore, we speculate that peptides from natural IgM autoAb may initially activate BWF1 T cells, and as somatic mutations of Ig occur, charged AA introduced into V regions increase the number of T cell determinants, thus favoring upregulation of pathogenic Ab subsets. Therefore, in predisposed individuals, the ability of T cells to recognize more charged T cell determinants in autoAb may be one mechanism promoting development of disease.
年轻的新西兰黑/新西兰白 F1（BWF1）小鼠会形成 T 细胞库，该细胞库会被源自 BWF1 J558 编码的抗 DNA 自身抗体（自身抗体）VH 区域的肽自发刺激，但不会被 J558 编码的抗外源性抗原抗体的 VH 区域肽刺激。用选定的 Ig 衍生肽免疫年轻的 BWF1 小鼠会加速抗 DNA 产生和肾炎，而对这些决定簇组合的免疫耐受诱导会延迟抗 DNA 产生和疾病发作。为了进一步表征这种免疫调节回路，我们询问 VH 区域肽自发激活 T 细胞的这种现象是否仅限于 VH J558 家族的抗 DNA 抗体，以及这些 T 细胞决定簇的电荷和结构属性是什么？我们研究了对由 VH 7183 构建的抗 DNA 自身抗体衍生肽的自发 T 细胞增殖反应，发现它包含几个 T 细胞决定簇。每个肽内某些氨基酸（AA）的电荷和大小似乎都很重要。含有精氨酸（R）或谷氨酸（E）的肽比不含这些 AA 的肽更有可能成为 T 细胞决定簇；用不带电荷的 AA 替换带电荷的 AA 会消除 T 细胞对肽的识别。我们之前报道过，一些抗 DNA 抗体在其 VH 中富含 R；致病性 BWF1 IgG 抗 DNA 在 VH 区域富含带正电荷和负电荷的 AA。因此，我们推测来自天然 IgM 自身抗体的肽可能最初激活 BWF1 T 细胞，并且随着 Ig 发生体细胞突变，引入 V 区域的带电荷 AA 会增加 T 细胞决定簇的数量，从而有利于致病性抗体亚群的上调。因此，在易感个体中，T 细胞识别自身抗体中更多带电荷 T 细胞决定簇的能力可能是促进疾病发展的一种机制。
