title: IgM contributes to glomerular injury in FSGS.
abstract: Glomerular IgM and C3 deposits frequently accompany idiopathic FSGS and secondary glomerulosclerosis, but it is unknown whether IgM activates complement, possibly contributing to the pathogenesis of these diseases. We hypothesized that IgM natural antibody binds to neoepitopes exposed in the glomerulus after nonimmune insults, triggering activation of the complement system and further injury. We examined the effects of depleting B cells, using three different strategies, on adriamycin-induced glomerulosclerosis. First, we treated wild-type mice with an anti-murine CD20 antibody, which depletes B cells, before disease induction. Second, we evaluated adriamycin-induced glomerulosclerosis in Jh mice, a strain that lacks mature B cells. Third, we locally depleted peritoneal B cells via hypotonic shock before disease induction. All three strategies reduced deposition of IgM in the glomerulus after administration of adriamycin and attenuated the development of albuminuria. Furthermore, we found that glomerular IgM and C3 were detectable in a subset of patients with FSGS; C3 was present as an activation fragment and colocalized with glomerular IgM, suggesting that glomerular IgM may have bound a cognate ligand. Taken together, these results suggest that IgM activates the complement system within the glomerulus in an animal model of glomerulosclerosis. Strategies that reduce IgM natural antibody or that prevent complement activation may slow the progression of glomerulosclerosis.
authors: Department of Medicine, School of Medicine, University of Colorado Denver, Aurora, Colorado 80045, USA.
authors: Derek
authors: D
authors: Strassheim
authors: Brandon
authors: B
authors: Renner
authors: Sarah
authors: S
authors: Panzer
authors: Richard
authors: R
authors: Fuquay
authors: Liudmila
authors: L
authors: Kulik
authors: Danica
authors: D
authors: Ljubanović
authors: V Michael
authors: VM
authors: Holers
authors: Joshua M
authors: JM
authors: Thurman
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D001402:B-Lymphocytes / Q000276:immunology; D003167:Complement Activation; D003176:Complement C3 / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity; D005923:Glomerulosclerosis, Focal Segmental / Q000209:etiology / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D006801:Humans; D007113:Immunity, Innate; D007075:Immunoglobulin M / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000276:immunology; D008212:Lymphocyte Depletion / Q000379:methods; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D000069283:Rituximab
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D003176:Complement C3; D007075:Immunoglobulin M; D000069283:Rituximab; D004317:Doxorubicin
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