title: Epistatic suppression of fatal autoimmunity in New Zealand black bicongenic mice.
abstract: Numerous mapping studies have implicated genetic intervals from lupus-prone New Zealand Black (NZB) chromosomes 1 and 4 as contributing to lupus pathogenesis. By introgressing NZB chromosomal intervals onto a non-lupus-prone B6 background, we determined that: NZB chromosome 1 congenic mice (denoted B6.NZBc1) developed fatal autoimmune-mediated kidney disease, and NZB chromosome 4 congenic mice (denoted B6.NZBc4) exhibited a marked expansion of B1a and NKT cells in the surprising absence of autoimmunity. In this study, we sought to examine whether epistatic interactions between these two loci would affect lupus autoimmunity by generating bicongenic mice that carry both NZB chromosomal intervals. Compared with B6.NZBc1 mice, bicongenic mice demonstrated significantly decreased mortality, kidney disease, Th1-biased IgG autoantibody isotypes, and differentiation of IFN-γ-producing T cells. Furthermore, a subset of bicongenic mice exhibited a paucity of CD21(+)CD1d(+) B cells and an altered NKT cell activation profile that correlated with greater disease inhibition. Thus, NZBc4 contains suppressive epistatic modifiers that appear to inhibit the development of fatal NZBc1 autoimmunity by promoting a shift away from a proinflammatory cytokine profile, which in some mice may involve NKT cells.
authors.affiliation: Arthritis Center of Excellence, Toronto Western Research Institute, Toronto, Ontario M5T 2S8, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: Loh
authors.forename: Evelyn
authors.initials: E
authors.lastname: Pau
authors.forename: Ginette
authors.initials: G
authors.lastname: Lajoie
authors.forename: Timothy T
authors.initials: TT
authors.lastname: Li
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Baglaenko
authors.forename: Yui-Ho
authors.initials: YH
authors.lastname: Cheung
authors.forename: Nan-Hua
authors.initials: NH
authors.lastname: Chang
authors.forename: Joan E
authors.initials: JE
authors.lastname: Wither
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000235:genetics; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D002478:Cells, Cultured; D004843:Epistasis, Genetic; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007074:Immunoglobulin G / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology* / Q000503:physiopathology; D008181:Lupus Nephritis / Q000235:genetics* / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D020297:Mice, Congenic; D008814:Mice, Inbred NZB; D055611:Natural Killer T-Cells / Q000276:immunology*; D011110:Polymorphism, Genetic; D017464:Receptors, Complement 3d / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D055610:Antigens, CD1d; D001323:Autoantibodies; D007074:Immunoglobulin G; D017464:Receptors, Complement 3d; D007371:Interferon-gamma