Delation of Activating Fcg Receptors Does Not Confer Protection in Murine Cryoglobulinemia-Associated Membranoproliferative Glomerulonephritis

• Published in: The American journal of pathology Vol. 175; no. 1; pp. 107 - 118
• Main Authors: Guo, S, MuehlfeId, A S, Wietecha, T A, Peutz-Kootstra, C J, Kowalewska, J, Yi, K, Spencer, M, Pichaiwong, W, Nimmerjahn, F, Hudkins, K L, Alpers, CE
• Format: Journal Article
• Language: English
• Published: 01.07.2009
• ISSN: 0002-9440
• DOI: 10.2353/ajpath.2009.081159

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 Fcg receptors (FcgRs) have been identified at present. Ligand binding to FcgRI, III, and IV induces cell activation via the immunoreceptor tyrosine-based activation motif on the common g chain (FcRg). In this study, FcRg chain knockout (FcRg super(-/-)) 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/FcRg super(-/-) mice developed MPGN with massive glomerular immune deposits, mesangial cell proliferation, extensive mesangial matrix accumulation, and macrophage influx. TSLPtg/FcRg super(-/-) mice had more glomerular immune complex deposits and higher levels of circulating cryoglobulins, IgG2a, IgG2b, and IgM, compared with TSLPtg mice. TSLPtg and TSLPtg/FcRg super(-/-) mice developed similar levels of proteinuria. These results demonstrated that deletion of activating FcgRs does not confer protection in this model of immune complex-mediated MPGN. The findings contradict accepted paradigms on the role of activating FcgRs in promoting features of glomerulonephritis as seen in other model systems. We speculate engagement of FcgRs on cells such as monocytes/macrophages may be important for the clearance of deposited immune complexes and extracellular matrix proteins.