Singh R R, Ebling F M, Sercarz E E, Hahn B H
Department of Medicine/Rheumatology, University of California, Los Angeles 90095, USA.
J Clin Invest. 1995 Dec;96(6):2990-6. doi: 10.1172/JCI118371.
Mechanisms that initiate and maintain autoantibody (autoAb) production in individuals with autoimmune diseases like SLE are poorly understood. Inadequate suppression of autoreactive T cells and/or unusual activation of T and B cells may underlie the persistence of pathogenic autoAbs in lupus. Here, we examine the possibility that in mice with lupus, autoAb molecules may be upregulating their own production by activating self-reactive T cells via their own processed peptides; downregulation of this circuit may decrease autoAb production and delay the development of lupus. We found that before the onset of clinical disease, lupus-prone (NZB/NZW) F1 [BWF1] (but not MHC-matched nonautoimmune mice) developed spontaneous T cell autoimmunity to peptides from variable regions of heavy chains (VH) of syngeneic anti-DNA mAbs but not to peptides from the VH region of an mAb to an exogenous antigen. Tolerizing young BWF1 mice with intravenous injections of autoAb-derived determinants substantially delayed development of anti-DNA antibodies and nephritis and prolonged survival. Thus, in such an autoAb-mediated disease, the presence of autoreactive T cells against VH region determinants of autoAbs may represent an important mechanism involved in the regulation of autoimmunity. Our findings show that tolerizing such autoreactive T cells can postpone the development of an autoimmune disease like SLE.
引发和维持系统性红斑狼疮（SLE）等自身免疫性疾病患者体内自身抗体（autoAb）产生的机制仍知之甚少。自身反应性T细胞抑制不足和/或T细胞与B细胞异常激活可能是狼疮中致病性自身抗体持续存在的原因。在此，我们研究了在狼疮小鼠中，自身抗体分子可能通过自身加工的肽激活自身反应性T细胞来上调自身产生的可能性；下调这一环路可能会减少自身抗体的产生并延缓狼疮的发展。我们发现，在临床疾病发作之前，狼疮易感（NZB/NZW）F1 [BWF1]小鼠（而非MHC匹配的非自身免疫小鼠）对同基因抗DNA单克隆抗体重链可变区（VH）的肽产生了自发性T细胞自身免疫，但对外源性抗原单克隆抗体VH区的肽没有产生自身免疫。通过静脉注射自身抗体衍生的决定簇使年轻的BWF1小鼠产生耐受性，可显著延迟抗DNA抗体和肾炎的发展并延长生存期。因此，在这种自身抗体介导的疾病中，针对自身抗体VH区决定簇的自身反应性T细胞的存在可能是参与自身免疫调节的重要机制。我们的研究结果表明，使这种自身反应性T细胞产生耐受性可以延缓SLE等自身免疫性疾病的发展。
