Abnormal immune complex processing and spontaneous glomerulonephritis in complement factor H-deficient mice with human complement receptor 1 on erythrocytes.
Complement receptor 1 (CR1) on human erythrocytes (Es) and complement factor H (CFH) on rodent platelets perform immune adherence, which is a function that allows the processing of immune complexes (ICs) bearing C3 by the mononuclear phagocyte system. Similar immune adherence occurs in the glomerular podocyte by CR1 in humans and CFH in rodents. As a model for human IC processing, we studied transgenic mice lacking CFH systemically but with human CR1 on Es. These CR1(hu)Tg/CFH(-/-) mice spontaneously developed proliferative glomerulonephritis, which was accelerated in a chronic serum sickness model by active immunization with heterologous apoferritin. ICs containing Ag, IgG and C3 bound to Es in CR1(hu)Tg/CFH(-/-) mice. In this setting, there was increased IC deposition in glomeruli, attributable to the presence of CR1 on Es, together with the absence of CFH on platelets and podocytes. In the absence of plasma CFH, the accumulated ICs activated complement, which led to spontaneous and chronic serum sickness-induced proliferative glomerulonephritis. These findings illustrate the complexities of complement-dependent IC processing by blood cells and in the glomerulus, and the importance of CFH as a plasma complement regulator.
Alexander
Jessy J
JJ
Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Hack
Bradley K
BK
Jacob
Alexander
A
Chang
Anthony
A
Haas
Mark
M
Finberg
Robert W
RW
Quigg
Richard J
RJ
D000818:Animals; D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003167:Complement Activation / Q000235:genetics / Q000276:immunology; D017242:Complement Factor H / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015432:Glomerulonephritis, Membranoproliferative / Q000097:blood / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007105:Immune Complex Diseases / Q000097:blood / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050199:Podocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011499:Protein Processing, Post-Translational / Q000235:genetics / Q000276:immunology*; D017463:Receptors, Complement 3b / Q000097:blood* / Q000235:genetics; D012713:Serum Sickness / Q000097:blood / Q000235:genetics / Q000276:immunology; D012720:Severity of Illness Index
C509991:CR1 protein, human; D017463:Receptors, Complement 3b; D017242:Complement Factor H