Distinct and Separable Roles of the Complement System in Factor H-Deficient Bone Marrow Chimeric Mice with Immune Complex Disease

Abnormal Immune Complex Processing and Spontaneous Glomerulonephritis in Complement Factor H-Deficient Mice with Human Complement Receptor 1 on Erythrocytes

“…Interestingly, a similar CFH for CR1 switch appears to occur in the mouse podocyte as well (24). Hence, in CSS, CFH 2/2 mice have greater deposition of ICs, yet in these circumstances, GN does not ensue unless CfH is absent in plasma, illustrating the importance of fluid-phase, and presumably local glomerular, C regulation in this model system (21).…”

“…Moreover, the presence of human CR1 on mouse Es alone could not account for the excessive glomerular ICs. Whereas the lack of CFH on platelets appears to contribute to glomerular IC deposition (21), there was a marked difference in glomerular ICs in CR1 hu Tg/CFH 2/2 mice compared with CFH 2/2 mice. Thus, the lack of plasma and platelet CFH and the presence of human CR1 in CR1 hu Tg/CFH 2/2 mice were not complete explanations for our findings of excessive glomerular ICs.…”

“…Because of unrestricted alternative pathway C activation, CFH 2/2 mice have low plasma C3 levels (17,24), which was also true of CR1 hu Tg/CFH 2/2 mice. Yet, C3 appeared to be activated on ICs in CR1 hu Tg/CFH 2/2 mice, presumably reflecting the balance of low C3 available for classical pathway activation, yet enhanced amplification through the alternative C pathway, as also appears to occur in glomeruli in mice lacking plasma CFH (21). Related to this is the finding of lower quantities of Eassociated C3 in CR1 hu Tg/CFH 2/2 mice compared with CR1 hu Tg mice.…”

“…The spontaneous disease in CFH 2/2 mice requires C5 (but not C6) and C factor I, presumably to generate proinflammatory C5a and to create iC3b as ligand for b2-integrins on inflammatory cells, respectively (18,20,21). Whereas C57BL/6 CFH 2/2 mice have no evident glomerular disease, and wild type C57BL/6 are resistant to developing GN in chronic serum sickness *Department of Medicine and (CSS) induced by repetitive immunization with heterologous apoferritin, all C57BL/6 CFH 2/2 mice develop GN in CSS (22).…”

Decay-accelerating factor but not CD59 limits experimental immune-complex glomerulonephritis

“…[59][60][61] Factor H is also important in the CSS model of ICGN, as it leads to C3b inactivation in the glomerular capillary wall, a key factor to dampen inflammation in this model. 10,62 Taking all available information together, it appears that DAF and CFH are relevant to C3 activation in glomerular capillary wall cellular and non-cellular sites, respectively.…”