title: IgM exacerbates glomerular disease progression in complement-induced glomerulopathy.
abstract: Although glomerular immunoglobulin M (IgM) deposition occurs in a variety of glomerular diseases, the mechanism of deposition and its clinical significance remain controversial. Some have theorized IgM becomes passively trapped in areas of glomerulosclerosis. However, recent studies found that IgM specifically binds damaged glomeruli. Therefore, we tested whether natural IgM binds to neo-epitopes exposed after insults to the glomerulus and exacerbates disease in mice deficient in the complement regulatory protein factor H; a model of non-sclerotic and nonimmune-complex glomerular disease. Immunofluorescence microscopy demonstrated mesangial and capillary loop deposition of IgM, whereas ultrastructural analysis found IgM deposition on endothelial cells and subendothelial areas. Factor H-deficient mice lacking B cells were protected from renal damage, as evidenced by milder histologic lesions on light and electron microscopy. IgM, but not IgG, from wild-type mice bound to cultured murine mesangial cells. Furthermore, injection of purified IgM into mice lacking B cells bound within the glomeruli and induced proteinuria. A monoclonal natural IgM-recognizing phospholipids also bound to glomeruli in vivo and induced albuminuria. Thus, our results indicate specific IgM antibodies bind to glomerular epitopes and that IgM contributes to the progression of glomerular damage in this mouse model of non-sclerotic glomerular disease.
authors.affiliation: Division of Nephrology, Department of Medicine, University of Wisconsin Madison, Madison, Wisconsin, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Panzer
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Laskowski
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Renner
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Liudmila
authors.initials: L
authors.lastname: Kulik
authors.affiliation: Department of Pathology, University Hospital Dubrava, Zagreb, Croatia.
authors.forename: Danica
authors.initials: D
authors.lastname: Ljubanovic
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Kendra M
authors.initials: KM
authors.lastname: Huber
authors.affiliation: Department of Pathology, University of Wisconsin Madison, Madison, Wisconsin, USA.|Pathology and Laboratory Services, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, USA.
authors.forename: Weixiong
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College, London, UK.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Pickering
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: V Michael
authors.initials: VM
authors.lastname: Holers
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Thurman
mesh_terms: D000419:Albuminuria / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000918:Antibody Specificity; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D003167:Complement Activation; D017242:Complement Factor H / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D000939:Epitopes; D005921:Glomerulonephritis / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013997:Time Factors
chemical_list: D000939:Epitopes; D007075:Immunoglobulin M; D017242:Complement Factor H