Chesnutt M S, Finck B K, Killeen N, Connolly M K, Goodman H, Wofsy D
Department of Medicine, Department of Veterans Affairs Medical Center, San Francisco, California 94121, USA.
Clin Immunol Immunopathol. 1998 Apr;87(1):23-32. doi: 10.1006/clin.1997.4492.
MRL/lpr mice spontaneously develop an autoimmune disease with features of systemic lupus erythematosus. They also develop a lymphoproliferative disorder characterized by a massive accumulation of double-negative (DN) T cells that lack both CD4 and CD8. To clarify the role of CD4 in autoimmunity and lymphoproliferation in these mice, CD4-deficient MRL/lpr mice were generated. CD4-deficient MRL/lpr mice developed massive expansion of DN T cells in the blood, spleen, and lymph nodes, which significantly exceeded the degree of lymphoproliferation in CD4-expressing control MRL/lpr mice. Despite this lymphoproliferation, CD4-deficient MRL/lpr mice produced little, if any, antibodies to double-stranded DNA, and they had prolonged survival relative to CD4-expressing littermates. However, they eventually developed moderately severe nephritis, characterized by immunoglobulin and complement deposition in glomeruli, vasculitis, and renal infiltration by CD8+ T cells. These findings indicate that (1) lymphoproliferation in MRL/lpr mice does not require the expression of CD4; (2) autoantibody production in MRL/lpr mice is dependent on the expression of CD4 and not on the accumulation of DN T cells; and (3) the development of nephritis in MRL/lpr mice involves both CD4-dependent and CD4-independent mechanisms.
MRL/lpr小鼠会自发发展出一种具有系统性红斑狼疮特征的自身免疫性疾病。它们还会发展出一种淋巴细胞增生性疾病，其特征是大量缺乏CD4和CD8的双阴性（DN）T细胞积累。为了阐明CD4在这些小鼠自身免疫和淋巴细胞增生中的作用，构建了CD4缺陷型MRL/lpr小鼠。CD4缺陷型MRL/lpr小鼠的血液、脾脏和淋巴结中DN T细胞大量扩增，其程度显著超过表达CD4的对照MRL/lpr小鼠的淋巴细胞增生程度。尽管有这种淋巴细胞增生，但CD4缺陷型MRL/lpr小鼠几乎不产生（如果有产生的话）抗双链DNA抗体，并且相对于表达CD4的同窝小鼠，它们的存活期延长。然而，它们最终发展出中度严重的肾炎，其特征是肾小球中有免疫球蛋白和补体沉积、血管炎以及CD8 + T细胞浸润肾脏。这些发现表明：（1）MRL/lpr小鼠的淋巴细胞增生不需要CD4的表达；（2）MRL/lpr小鼠自身抗体的产生依赖于CD4的表达，而不依赖于DN T细胞的积累；（3）MRL/lpr小鼠肾炎的发展涉及CD4依赖和CD4非依赖机制。
