title: Autoimmune-prone mice share a promoter haplotype associated with reduced expression and function of the Fc receptor FcgammaRII.
abstract: Human autoimmune diseases thought to arise from the combined effects of multiple susceptibility genes include systemic lupus erythematosus (SLE) and autoimmune diabetes. Well-characterised polygenic mouse models closely resembling each of these diseases exist, and genetic evidence links receptors for the Fc portion of immunoglobulin G (FcR) with their pathogenesis in mice and humans [1] [2] [3]. FcRs may be activatory or inhibitory and regulate a variety of immune and inflammatory processes [4] [5]. FcgammaRII (CD32) negatively regulates activation of cells including B cells and macrophages [6]. FcgammaRII-deficient mice are prone to immune-mediated disease [7] [8] [9]. The gene encoding FcgammaRII, Fcgr2, is contained in genetic susceptibility intervals in mouse models of SLE such as the New Zealand Black (NZB) contribution to the (NZB x New Zealand White (NZW)) F1 strain [1] [10] [11] and the BXSB strain [12], and in human SLE [1] [2] [3]. We therefore sequenced Fcgr2 and identified a haplotype defined by deletions in the Fcgr2 promoter region that is present in major SLE-prone mouse strains (NZB, BXSB, SB/Le, MRL, 129 [13]) and non-obese diabetic (NOD) mice but absent in control strains (BALB/c, C57BL/6, DBA/2, C57BL/10) and NZW mice. The autoimmune haplotype was associated with reduced cell-surface expression of FcgammaRII on macrophages and activated B cells and with hyperactive macrophages resembling those of FcgammaRII-deficient mice, and is therefore likely to play an important role in the pathogenesis of SLE and possibly diabetes.
authors.affiliation: Department of Medicine, Cambridge Institute of Medical Research, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Box 139, Cambridge, CB2 2XY, UK.
authors.forename: N R
authors.initials: NR
authors.lastname: Pritchard
authors.forename: A J
authors.initials: AJ
authors.lastname: Cutler
authors.forename: S
authors.initials: S
authors.lastname: Uribe
authors.forename: S J
authors.initials: SJ
authors.lastname: Chadban
authors.forename: B J
authors.initials: BJ
authors.lastname: Morley
authors.forename: K G
authors.initials: KG
authors.lastname: Smith
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics*; D001402:B-Lymphocytes / Q000378:metabolism; D001483:Base Sequence; D015870:Gene Expression; D006239:Haplotypes; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008213:Lymphocyte Activation; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D017452:Receptors, IgG / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D017452:Receptors, IgG