FcgammaRIIB deficiency leads to autoimmunity and a defective response to apoptosis in Mrl-MpJ mice.
Data suggests that modulation of FcgammaRIIB 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 FcgammaRIIB 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 FcgammaRIIB 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 FcgammaRIIB function has a significant impact on APC activity, suggesting a prominent role in dendritic cell activity in response to interaction with particulate autoantigens.
McGaha
Tracy L
TL
Department of Medicine, Section of Nephrology and Kidney Transplantation, Temple University School of Medicine, Philadelphia, PA 19140, USA. tmcgaha@temple.edu
Karlsson
Mikael C I
MC
Ravetch
Jeffrey V
JV
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology*; D000936:Antigen-Antibody Complex / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D017209:Apoptosis; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D018858:Germinal Center / Q000276:immunology; D007132:Immunoglobulin Isotypes / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D007668:Kidney / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010950:Plasma Cells / Q000276:immunology; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism*; D013154:Spleen / Q000276:immunology
D000974:Antibodies, Antinuclear; D000936:Antigen-Antibody Complex; D015703:Antigens, CD; C080571:Fc gamma receptor IIB; D007132:Immunoglobulin Isotypes; D017452:Receptors, IgG; D018664:Interleukin-12