title: Deletion of activating Fcgamma receptors does not confer protection in murine cryoglobulinemia-associated membranoproliferative glomerulonephritis.
abstract: Many types of glomerulonephritis are initiated by the deposition of immune complexes, which induce tissue injury via either engagement of Fc receptors on effector cells or via complement activation. Four murine Fcgamma receptors (FcgammaRs) have been identified at present. Ligand binding to FcgammaRI, III, and IV induces cell activation via the immunoreceptor tyrosine-based activation motif on the common gamma chain (FcRgamma). In this study, FcRgamma chain knockout (FcRgamma(-/-)) mice were crossed with thymic stromal lymphopoietin transgenic (TSLPtg) mice, which develop cryoglobulinemic membranoproliferative glomerulonephritis (MPGN). Female mice were studied at 30 and 50 days of age, when MPGN is in early and fully developed stages, respectively. Both TSLPtg and TSLPtg/FcRgamma(-/-) mice developed MPGN with massive glomerular immune deposits, mesangial cell proliferation, extensive mesangial matrix accumulation, and macrophage influx. TSLPtg/FcRgamma(-/-) mice had more glomerular immune complex deposits and higher levels of circulating cryoglobulins, IgG2a, IgG2b, and IgM, compared with TSLPtg mice. TSLPtg and TSLPtg/FcRgamma(-/-) mice developed similar levels of proteinuria. These results demonstrated that deletion of activating FcgammaRs does not confer protection in this model of immune complex-mediated MPGN. The findings contradict accepted paradigms on the role of activating FcgammaRs in promoting features of glomerulonephritis as seen in other model systems. We speculate engagement of FcgammaRs on cells such as monocytes/macrophages may be important for the clearance of deposited immune complexes and extracellular matrix proteins.
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Shunhua
authors.initials: S
authors.lastname: Guo
authors.forename: Anja S
authors.initials: AS
authors.lastname: Mühlfeld
authors.forename: Tomasz A
authors.initials: TA
authors.lastname: Wietecha
authors.forename: Carine J
authors.initials: CJ
authors.lastname: Peutz-Kootstra
authors.forename: Jolanta
authors.initials: J
authors.lastname: Kowalewska
authors.forename: Kenneth
authors.initials: K
authors.lastname: Yi
authors.forename: Min
authors.initials: M
authors.lastname: Spencer
authors.forename: Warangkana
authors.initials: W
authors.lastname: Pichaiwong
authors.forename: Falk
authors.initials: F
authors.lastname: Nimmerjahn
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Hudkins
authors.forename: Charles E
authors.initials: CE
authors.lastname: Alpers
mesh_terms: D000818:Animals; D003449:Cryoglobulinemia / Q000150:complications* / Q000276:immunology; D005260:Female; D005455:Fluorescent Antibody Technique; D015432:Glomerulonephritis, Membranoproliferative / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017452:Receptors, IgG / Q000172:deficiency* / Q000235:genetics
chemical_list: D017452:Receptors, IgG