Published online before print June 15, 2009

This Article Full Text Full Text (PDF) All Versions of this Article: ajpath.2009.081159v1 175/1/107    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Guo, S. Articles by Alpers, C. E. Search for Related Content PubMed PubMed Citation Articles by Guo, S. Articles by Alpers, C. E.

(American Journal of Pathology. 2009;175:107-118.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.081159

Deletion of Activating Fc Receptors Does Not Confer Protection in Murine Cryoglobulinemia-Associated Membranoproliferative Glomerulonephritis

Shunhua Guo^*, Anja S. Mühlfeld, Tomasz A. Wietecha^*, Carine J. Peutz-Kootstra, Jolanta Kowalewska^*, Kenneth Yi^*, Min Spencer^*, Warangkana Pichaiwong^*, Falk Nimmerjahn, Kelly L. Hudkins^* and Charles E. Alpers^*

From the Department of Pathology,^* University of Washington, Seattle, Washington; Division of Nephrology, University of Aachen, Aachen, Germany; the Department of Pathology, Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, Netherland; and the Laboratory of Molecular Genetics and Immunology, Rockefeller University, New York, New York

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