title: Deletion of IgG-switched autoreactive B cells and defects in Fas(lpr) lupus mice.
abstract: During a T cell-dependent Ab response, B cells undergo Ab class switching and V region hypermutation, with the latter process potentially rendering previously innocuous B cells autoreactive. Class switching and hypermutation are temporally and anatomically linked with both processes dependent on the enzyme, activation-induced deaminase, and occurring principally, but not exclusively, in germinal centers. To understand tolerance regulation at this stage, we generated a new transgenic mouse model expressing a membrane-tethered gamma2a-reactive superantigen (gamma2a-macroself Ag) and assessed the fate of emerging IgG2a-expressing B cells that have, following class switch, acquired self-reactivity of the Ag receptor to the macroself-Ag. In normal mice, self-reactive IgG2a-switched B cells were deleted, leading to the selective absence of IgG2a memory responses. These findings identify a novel negative selection mechanism for deleting mature B cells that acquire reactivity to self-Ag. This process was only partly dependent on the Bcl-2 pathway, but markedly inefficient in MRL-Fas(lpr) lupus mice, suggesting that defective apoptosis of isotype-switched autoreactive B cells is central to Fas mutation-associated systemic autoimmunity.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Djemel
authors.initials: D
authors.lastname: Aït-Azzouzene
authors.forename: Dwight H
authors.initials: DH
authors.lastname: Kono
authors.forename: Rosana
authors.initials: R
authors.lastname: Gonzalez-Quintial
authors.forename: Louise J
authors.initials: LJ
authors.lastname: McHeyzer-Williams
authors.forename: Min
authors.initials: M
authors.lastname: Lim
authors.forename: Dilki
authors.initials: D
authors.lastname: Wickramarachchi
authors.forename: Tobias
authors.initials: T
authors.lastname: Gerdes
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Gavin
authors.forename: Patrick
authors.initials: P
authors.lastname: Skog
authors.forename: Michael G
authors.initials: MG
authors.lastname: McHeyzer-Williams
authors.forename: David
authors.initials: D
authors.lastname: Nemazee
authors.forename: Argyrios N
authors.initials: AN
authors.lastname: Theofilopoulos
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018089:Superantigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D007074:Immunoglobulin G; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018089:Superantigens; D019014:fas Receptor; C052617:Bcl2 protein, mouse