Follicular exclusion of autoreactive B cells requires FcgammaRIIb.
In non-autoimmune mice, the 3H9 transgenic Ig heavy chain can pair with endogenous Iglambda1 light chains to generate B cells with specificity for DNA. These autoreactive cells are actively regulated in vivo, as indicated by the exclusion of lambda1 cells from the splenic B cell follicle and the absence of auto-antibody production. To study the role of Fcgamma receptor IIb (FcgammaRIIb) in peripheral B cell tolerance, FcgammaRIIb(-/-) mice were crossed with C57BL/6 mice bearing a site-directed knock-in of the 3H9 transgene. 3H9FcgammaRIIb(-/-) mice become autoreactive, lose the follicular exclusion of anti-DNA B cells and instead have lambda1 B cells located within splenic germinal centers. They have increased frequencies of splenic auto-antibody-producing cells and elevated titers of IgG anti-DNA auto-antibody. The data implicate an FcgammaRIIb-dependent checkpoint that can exclude autoreactive B cells from splenic follicles. By restricting their participation in germinal center reactions, this putative checkpoint helps attenuate the production of potentially pathogenic auto-antibodies. The data further suggest that this FcgammaRIIb-dependent regulation is B cell autonomous.
Paul
Elahna
E
Department of Pediatrics, Harvard Medical School, Boston, MA, USA. epaul@partners.org
Nelde
Annette
A
Verschoor
Admar
A
Carroll
Michael C
MC
D000367:Age Factors; D000818:Animals; D000974:Antibodies, Antinuclear / Q000032:analysis / Q000097:blood / Q000235:genetics / Q000276:immunology; D017152:Antibodies, Antiphospholipid / Q000032:analysis / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000276:immunology; D005260:Female; D018858:Germinal Center / Q000166:cytology / Q000276:immunology; D018398:Homeodomain Proteins / Q000032:analysis / Q000235:genetics; D007072:Immunoglobulin D / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D007146:Immunoglobulin lambda-Chains / Q000032:analysis; D016130:Immunophenotyping; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017464:Receptors, Complement 3d / Q000032:analysis; D017455:Receptors, IgE / Q000032:analysis; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology*; D017634:Self Tolerance / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D053668:Syndecan-1 / Q000032:analysis
C442826:3H9 protein, mouse; D000974:Antibodies, Antinuclear; D017152:Antibodies, Antiphospholipid; C499172:Fcgr2b protein, mouse; D018398:Homeodomain Proteins; D007072:Immunoglobulin D; D007075:Immunoglobulin M; D007146:Immunoglobulin lambda-Chains; D017464:Receptors, Complement 3d; D017455:Receptors, IgE; D017452:Receptors, IgG; C508242:Sdc1 protein, mouse; D053668:Syndecan-1; C064658:RAG-1 protein