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FcRIIB Deficiency Leads to Autoimmunity and a Defective Response to Apoptosis in Mrl-MpJ Mice¹

Tracy L. McGaha^2,*, Mikael C. I. Karlsson and Jeffrey V. Ravetch

^* Department of Medicine, Section of Nephrology and Kidney Transplantation and Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19140; Department of Medicine, The Karolinska Institute, Stockholm, Sweden; and Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York 10021

Data suggests that modulation of FcRIIB expression represents a significant risk factor for the development of autoimmunity. In this study, we investigated this notion in mice that possess genetics permissible for the development of autoimmunity. To this end, Mrl-MpJ Fcgr2b–/– mice were monitored for the development of autoreactivity. We found that FcRIIB deficiency led to chronic B cell activation associated with increased germinal center and plasma cell accumulation in the spleen. Likewise, Mrl-MpJ Fcgr2b–/– mice exhibited significant serum IgG reactivity against DNA. We further analyzed the IgG isotype contribution to the anti-dsDNA response and found increases in all subtypes with the exception of IgG3. In particular, we found large increases in IgG1 and IgG2b autoreactivity correlating with significant increases in immune complex deposition and kidney pathology. Finally, we found dendritic cells derived from Mrl-MpJ Fcgr2b–/– mice greatly increased IL-12 expression upon coincubation with apoptotic thymocytes compared with wild-type controls. The results indicate that FcRIIB is an important regulator of peripheral tolerance and attenuation of the inhibitory signal it provides enhances autoimmune disease on susceptible backgrounds. Additionally, the data indicates FcRIIB function has a significant impact on APC activity, suggesting a prominent role in dendritic cell activity in response to interaction with particulate autoantigens.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health (to J.V.R.) and a national research service award (to T.L.M.).

² Address correspondence and reprint requests to Dr. T. L. McGaha, Temple University School of Medicine, Medical Office Building Room 340, 3322 North Broad Street, Philadelphia, PA 19140. E-mail address: tmcgaha{at}temple.edu

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; IC, immune complex; GC, germinal center; PC, plasma cell; DC, dendritic cell; BMDC, bone marrow-derived dendritic cell; PNA, peanut agglutinin; GBM, glomerular basement membrane; PAS, Periodic acid Schiff reagent; NMS, normal mouse serum; AMS, autoimmune mouse serum; LD, linkage disequilibrium; SAP, serum amyolid P.