Chemokine receptor Ccr2 deficiency reduces renal disease and prolongs survival in MRL/1pr lupus-prone mice
Chemokine receptor Ccr2 deficiency reduces renal disease and prolongs survival in MRL/1pr lupus-prone mice
复制标题
DOI：
10.1681/asn.2005040426
复制
发表时间：
2005-12-01
影响因子：
13.6
通讯作者：
Luckow, B
中科院分区：
文献类型：
--
作者：
de Lema, GP;Maier, H;Luckow, B
MRL/MpJ-Fas（lpr）/J（MRL/lpr）小鼠代表了人系统性红斑狼疮的良好建立的小鼠模型。自发性淋巴细胞增殖突变（lpr）纯合子MRL/lpr小鼠的特征为全身性自身免疫、与异常T细胞增殖相关的大量淋巴结病、脾肿大、高丙种球蛋白血症、关节炎和致死性免疫复合物介导的肾小球肾炎。先前报道了趋化因子（C-C基序）受体2（Ccr 2）的稳态mRNA水平在MRL/lpr小鼠的肾脏中持续增加。为了检查Ccr 2在免疫复合物介导的肾小球肾炎的发生和进展中的作用，产生Ccr 2缺陷型小鼠并将其与MRL/lpr遗传背景回交。Ccr 2缺陷型MRL/lpr小鼠淋巴结病较少，蛋白尿较少，病变评分降低，肾小球和肾小管间质隔室中T细胞和巨噬细胞浸润较少。Ccr 2缺陷型MRL/lpr小鼠的存活时间显著长于MRL/lpr野生型小鼠，尽管两组的肾小球中循环免疫球蛋白水平相似且免疫复合物沉积相当。然而，抗dsDNA抗体水平在不存在Ccr 2的情况下降低。Ccr 2缺陷型MRL/lpr小鼠外周血中CD 8（+）T细胞的频率显著降低。因此，Ccr 2缺陷不仅影响单核细胞/巨噬细胞和T细胞在肾脏中的浸润，而且还影响MRL/lpr小鼠中的全身性T细胞应答。这些数据表明Ccr 2在自身免疫的一般发展和狼疮样疾病的肾脏受累中均起重要作用。这些结果将Ccr 2鉴定为用于治疗狼疮性肾炎的另外的可能靶点。
MRL/MpJ-Fas(lpr)/J (MRL/lpr) mice represent a well-established mouse model of human systemic lupus erythematosus. MRL/lpr mice homozygous for the spontaneous lymphoproliferation mutation (lpr) are characterized by systemic autoimmunity, massive lymphadenopathy associated with proliferation of aberrant T cells, splenomegaly, hypergammaglobulinemia, arthritis, and fatal immune complex-mediated glomerulonephritis. It was reported previously that steady-state mRNA levels for the chemokine (C-C motif) receptor 2 (Ccr2) continuously increase in kidneys of MRL/lpr mice. For examining the role of Ccr2 for development and progression of immune complex-mediated glomerulonephritis, Ccr2-deficient mice were generated and backcrossed onto the MRL/lpr genetic background. Ccr2-deficient MRL/lpr mice developed less lymphadenopathy, had less proteinuria, had reduced lesion scores, and had less infiltration by T cells and macrophages in the glomerular and tubulointerstitial compartment. Ccr2-deficient MRL/lpr mice survived significantly longer than MRL/lpr wild-type mice despite similar levels of circulating immunoglobulins and comparable immune complex depositions in the glomeruli of both groups. Anti-dsDNA antibody levels, however, were reduced in the absence of Ccr2. The frequency of CD8(+) T cells in peripheral blood was significantly lower in Ccr2-deficient MRL/lpr mice. Thus Ccr2 deficiency influenced not only monocyte/ macrophage and T cell infiltration in the kidney but also the systemic T cell response in MRL/lpr mice. These data suggest an important role for Ccr2 both in the general development of autoimmunity and in the renal involvement of the lupus-like disease. These results identify Ccr2 as an additional possible target for the treatment of lupus nephritis.