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

Human autoimmune diseases thought to arise from the combined effects of mul tiple susceptibility genes include systemic lupus erythematosus (SLE) and a utoimmune diabetes. Well-characterised polygenic mouse models closely resem bling each of these diseases exist, and genetic evidence links receptors fo r 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 varie ty of Immune and inflammatory processes [4,5]. Fc gamma RII (CD32) negative ly regulates activation of cells including B cells and macrophages [6]. Fc gamma RII-deficient mice are prone to immune mediated disease [7-9]. The ge ne encoding Fc gamma RII, Fcgr2, is contained in genetic susceptibility Int ervals in mouse models of SLE such as the New Zealand Black (NZB) contribut ion 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 iden tified a haplotype defined by deletions in the Fcgr2 promoter region that i s 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 associ ated with reduced cell-surface expression of Fc gamma RII on macrophages an d activated B cells and with hyperactive macrophages resembling those of Fc gamma RII-deficient mice, and is therefore likely to play an important rol e in the pathogenesis of SLE and possibly diabetes.