Szalai Alexander J, Weaver Casey T, McCrory Mark A, van Ginkel Frederik W, Reiman Rachael M, Kearney John F, Marion Tony N, Volanakis John E
The University of Alabama at Birmingham.
Arthritis Rheum. 2003 Jun;48(6):1602-11. doi: 10.1002/art.11026.
Human C-reactive protein (CRP) binds apoptotic cells and alters blood clearance of injected chromatin in mice. To test whether CRP participates in the pathogenesis of systemic lupus erythematosus (SLE), we examined disease development in lupus-prone (NZB x NZW)F(1) (NZB/NZW) mice expressing a human CRP transgene (hCRPtg/BW).
Mortality was monitored, proteinuria was determined by dipstick, and serum levels of human CRP and anti-double-stranded DNA (anti-dsDNA) were determined by enzyme-linked immunosorbent assay in NZB/NZW and hCRPtg/BW mice. Thin sections of kidneys were analyzed by immunofluorescence microscopy to compare deposition of IgG, IgM, C3, and human CRP, and electron microscopy was used to reveal differences in ultrastructure. In situ hybridization was performed to detect human CRP messenger RNA expression.
The hCRPtg/BW mice had less proteinuria and longer survival than NZB/NZW mice. They also had lower IgM and higher IgG anti-dsDNA titers than NZB/NZW mice, although the differences were transient and small. In hCRPtg/BW mice, accumulation of IgM and IgG in the renal glomeruli was delayed, reduced, and more mesangial than in NZB/NZW mice, while end-stage accumulation of IgG, IgM, and C3 in the renal cortex was prevented. There was less glomerular podocyte fusion, basement membrane thickening, mesangial cell proliferation, and occlusion of capillary lumens in hCRPtg/BW mice, but dense deposits in the mesangium were increased. With disease progression in hCRPtg/BW mice, there was little rise in the plasma CRP level, but CRP in the kidneys became increasingly apparent due to local, disease-independent, age-related expression of the transgene.
In hCRPtg/BW mice, CRP protects against SLE by increasing blood and mesangial clearance of immune complexes and by preventing their accumulation in the renal cortex.
人C反应蛋白（CRP）可结合凋亡细胞并改变小鼠体内注射染色质的血液清除率。为了测试CRP是否参与系统性红斑狼疮（SLE）的发病机制，我们检测了表达人CRP转基因（hCRPtg/BW）的狼疮易感（NZB×NZW）F1（NZB/NZW）小鼠的疾病发展情况。
监测NZB/NZW和hCRPtg/BW小鼠的死亡率，通过试纸条检测蛋白尿，并采用酶联免疫吸附测定法测定人CRP和抗双链DNA（抗dsDNA）的血清水平。通过免疫荧光显微镜分析肾脏薄片，以比较IgG、IgM、C3和人CRP的沉积情况，并利用电子显微镜揭示超微结构的差异。进行原位杂交以检测人CRP信使核糖核酸的表达。
hCRPtg/BW小鼠的蛋白尿少于NZB/NZW小鼠，生存期更长。它们的IgM水平低于NZB/NZW小鼠，抗dsDNA IgG滴度高于NZB/NZW小鼠，尽管差异是短暂且微小的。在hCRPtg/BW小鼠中，肾小球中IgM和IgG的积累延迟、减少，且比NZB/NZW小鼠更多地积聚在系膜中，同时肾脏皮质中IgG、IgM和C3的终末期积累得到了预防。hCRPtg/BW小鼠的肾小球足细胞融合、基底膜增厚、系膜细胞增殖和毛细血管腔阻塞较少，但系膜中的致密沉积物增加。随着hCRPtg/BW小鼠疾病的进展，血浆CRP水平几乎没有升高，但由于转基因的局部、与疾病无关的年龄相关表达，肾脏中的CRP变得越来越明显。
在hCRPtg/BW小鼠中，CRP通过增加免疫复合物的血液和系膜清除率以及防止它们在肾脏皮质中积累来预防SLE。
