title: BAFF/APRIL inhibition decreases selection of naive but not antigen-induced autoreactive B cells in murine systemic lupus erythematosus.
abstract: BAFF inhibition is a new B cell-directed therapeutic strategy for autoimmune disease. Our purpose was to analyze the effect of BAFF/APRIL availability on the naive and Ag-activated B cell repertoires in systemic lupus erythematosus, using the autoreactive germline D42 H chain (glD42H) site-directed transgenic NZB/W mouse. In this article, we show that the naive Vκ repertoire in both young and diseased glD42H NZB/W mice is dominated by five L chains that confer no or low-affinity polyreactivity. In contrast, glD42H B cells expressing L chains that confer high-affinity autoreactivity are mostly deleted before the mature B cell stage, but are positively selected and expanded in the germinal centers (GCs) as the mice age. Of these, the most abundant is VκRF (Vκ16-104*01), which is expressed by almost all IgG anti-DNA hybridomas derived from the glD42H mouse. Competition with nonautoreactive B cells or BAFF/APRIL inhibition significantly inhibited selection of glD42H B cells at the late transitional stage, with only subtle effects on the glD42H-associated L chain repertoire. However, glD42H/VκRF-encoded B cells were still vastly overrepresented in the GC, and serum IgG anti-DNA Abs arose with only a slight delay. Thus, although BAFF/APRIL inhibition increases the stringency of negative selection of the naive autoreactive B cell repertoire in NZB/W mice, it does not correct the major breach in B cell tolerance that occurs at the GC checkpoint.
authors.affiliation: Center for Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors.forename: Weiqing
authors.initials: W
authors.lastname: Huang
authors.forename: Ioana
authors.initials: I
authors.lastname: Moisini
authors.forename: Ramalingam
authors.initials: R
authors.lastname: Bethunaickan
authors.forename: Ranjit
authors.initials: R
authors.lastname: Sahu
authors.forename: Meredith
authors.initials: M
authors.lastname: Akerman
authors.forename: Dan
authors.initials: D
authors.lastname: Eilat
authors.forename: Martin
authors.initials: M
authors.lastname: Lesser
authors.forename: Anne
authors.initials: A
authors.lastname: Davidson
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D053264:B-Cell Activating Factor / Q000037:antagonists & inhibitors*; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D018985:Epitopes, B-Lymphocyte / Q000276:immunology*; D005260:Female; D007108:Immune Tolerance / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008814:Mice, Inbred NZB; D008822:Mice, Transgenic; D011828:Radiation Chimera / Q000276:immunology; D053303:Transmembrane Activator and CAML Interactor Protein / Q000037:antagonists & inhibitors; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000037:antagonists & inhibitors*
chemical_list: D053264:B-Cell Activating Factor; D018985:Epitopes, B-Lymphocyte; C491959:Tnfsf13 protein, mouse; C505720:Tnfsf13b protein, mouse; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13
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