title: The Yaa locus and IFN-α fine-tune germinal center B cell selection in murine systemic lupus erythematosus.
abstract: Male NZW/BXSB.Yaa (W/B) mice express two copies of TLR7 and develop pathogenic autoantibodies, whereas females with only one copy of TLR7 have attenuated disease. Our goal was to analyze the regulation of the autoantibody response in male and female W/B mice bearing the autoreactive site-directed H chain transgene 3H9. Serum anti-dsDNA Abs appeared in males at 12 wk, and most had high-titer IgG anti-dsDNA and anti-cardiolipin Abs and developed >300 mg/dl proteinuria by 8 mo. Females had only low-titer IgG anti-cardiolipin Abs, and none developed proteinuria by 1 y. Males had a smaller marginal zone than females with a repertoire that was distinct from the follicular repertoire, indicating that the loss of marginal zone B cells was not due to diversion to the follicular compartment. Vk5-43 and Vk5-48, which were rare in the naive repertoire, were markedly overrepresented in the germinal center repertoire of both males and females, but the VJ junctions differed between males and females with higher-affinity autoreactive B cells being selected into the germinal centers of males. Administration of IFN-α to females induced anti-cardiolipin and anti-DNA autoantibodies and proteinuria and was associated with a male pattern of junctional diversity in Vk5-43 and Vk5-48. Our studies are consistent with the hypothesis that presence of the Yaa locus, which includes an extra copy of Tlr7, or administration of exogenous IFN-α relaxes the stringency for selection in the germinal centers resulting in increased autoreactivity of the Ag-driven B cell repertoire.
authors.affiliation: Center for Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Manhasset, NY 11030;
authors.forename: Ioana
authors.initials: I
authors.lastname: Moisini
authors.forename: Weiqing
authors.initials: W
authors.lastname: Huang
authors.forename: Ramalingam
authors.initials: R
authors.lastname: Bethunaickan
authors.forename: Ranjit
authors.initials: R
authors.lastname: Sahu
authors.forename: Peta-Gay
authors.initials: PG
authors.lastname: Ricketts
authors.forename: Meredith
authors.initials: M
authors.lastname: Akerman
authors.forename: Tony
authors.initials: T
authors.lastname: Marion
authors.forename: Martin
authors.initials: M
authors.lastname: Lesser
authors.forename: Anne
authors.initials: A
authors.lastname: Davidson
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D001666:Binding Sites, Antibody; D002454:Cell Differentiation / Q000276:immunology*; D005260:Female; D056426:Genetic Loci / Q000276:immunology*; D018858:Germinal Center / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D016130:Immunophenotyping; D016898:Interferon-alpha / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008814:Mice, Inbred NZB; D008817:Mice, Mutant Strains; D015398:Signal Transduction / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D001323:Autoantibodies; C554329:Ifna1 protein, mouse; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7