Autoimmune-prone mice share a promoter haplotype associated with reduced expression and function of the Fc receptor FcγRII

NR Pritchard, AJ Cutler, S Uribe, SJ Chadban, Bernard J Morley, KGC Smith

Research output: Contribution to journalArticle

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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 [1-3]. FcRs may be activatory or inhibitory and regulate a variety of Immune and inflammatory processes [4,5]. FcγRII (CD32) negatively regulates activation of cells including B cells and macrophages [6]. FcγRII-deficient mice are prone to immune mediated disease [7-9]. The gene encoding Fc gamma RII, 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 [1-3]. 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 FcγRII on macrophages and activated B cells and with hyperactive macrophages resembling those of Fc gamma RII-deficient mice, and is therefore likely to play an important role in the pathogenesis of SLE and possibly diabetes.
Original languageEnglish
Pages (from-to)227-230
Number of pages4
JournalCurrent Biology
Volume10
Issue number4
DOIs
Publication statusPublished - 15 Feb 2000

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