Title: Autoimmune-prone mice share a promoter haplotype associated with reduced expression and function of the Fc receptor FcγRII
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 [1Vyse T.J. Kotzin B.L. Genetic susceptibility to systemic lupus erythematosus.Annu Rev Immunol. 1998; 16: 261-292Crossref PubMed Scopus (266) Google Scholar, 2Harley J.B. Moser K.L. Gaffney P.M. Behrens T.W. The genetics of human systemic lupus erythematosus.Curr Opin Immunol. 1998; 10: 690-696Crossref PubMed Scopus (133) Google Scholar, 3Van der Pol W-L. Van de Winkel J.G.J. IgG receptor polymorphisms: risk factors for disease.Immunogenetics. 1998; 48: 222-232Crossref PubMed Scopus (203) Google Scholar]. FcRs may be activatory or inhibitory and regulate a variety of immune and inflammatory processes [4Hulett M.D. Hogarth P.M. Molecular basis of Fc receptor function.Adv Immunol. 1994; 57: 1-127Crossref PubMed Scopus (425) Google Scholar, 5Ravetch J.V. Kinet J.P. Fc receptors.Annu Rev Immunol. 1991; 9: 457-492Crossref PubMed Scopus (1253) Google Scholar]. FcγRII (CD32) negatively regulates activation of cells including B cells and macrophages [6Coggeshall K.M. Inhibitory signaling by B cell FcγRIIb.Curr Opin Immunol. 1998; 10: 306-312Crossref PubMed Scopus (123) Google Scholar]. FcγRII-deficient mice are prone to immune-mediated disease [7Takai T. Ono M. Hikida M. Ohmori H. Ravetch J.V. Augmented humoral and anaphylactic responses in FcγRII-deficient mice.Nature. 1996; 379: 346-349Crossref PubMed Scopus (707) Google Scholar, 8Yuasa T. Kubo S. Yoshino T. Ujike A. Matsumura K. Ono M. et al.Deletion of Fcγ receptor IIB renders H-2b mice susceptible to collagen-induced arthritis.J Exp Med. 1999; 189: 187-194Crossref PubMed Scopus (284) Google Scholar, 9Clynes R. Maizes J.S. Guinamard R. Ono M. Takai T. Ravetch J.V. Modulation of complex-induced inflammation in vivo by the coordinate expression of activatory and inhibitory Fc receptors.J Exp Med. 1999; 189: 179-185Crossref PubMed Scopus (324) Google Scholar]. The gene encoding FcγRII, Fcgr2, is contained in genetic susceptibility intervals in mouse models of SLE such as the New Zealand Black (NZB) contribution to the (NZB × New Zealand White (NZW)) F1 strain [1Vyse T.J. Kotzin B.L. Genetic susceptibility to systemic lupus erythematosus.Annu Rev Immunol. 1998; 16: 261-292Crossref PubMed Scopus (266) Google Scholar, 10Morel L. Wakeland E.K. Susceptibility to lupus nephritis in the NZB/W model system.Curr Opin Immunol. 1998; 10: 718-725Crossref PubMed Scopus (60) Google Scholar, 11Vyse T.J. Rozzo S.J. Drake D.G. Izui S. Kotzin B.L. Control of multiple autoantibodies linked with a lupus nephritis susceptibility locus in New Zealand Black mice.J Immunol. 1997; 158: 5566-5574PubMed Google Scholar] and the BXSB strain [12Hogarth M.B. Slingsby J.H. Allen P.J. Thompson E.M. Chandler P. Davies K.A. et al.Multiple lupus susceptibility loci map to chromosome 1 in BXSB mice.J Immunol. 1998; 161: 2753-2761PubMed Google Scholar], and in human SLE [1Vyse T.J. Kotzin B.L. Genetic susceptibility to systemic lupus erythematosus.Annu Rev Immunol. 1998; 16: 261-292Crossref PubMed Scopus (266) Google Scholar, 2Harley J.B. Moser K.L. Gaffney P.M. Behrens T.W. The genetics of human systemic lupus erythematosus.Curr Opin Immunol. 1998; 10: 690-696Crossref PubMed Scopus (133) Google Scholar, 3Van der Pol W-L. Van de Winkel J.G.J. IgG receptor polymorphisms: risk factors for disease.Immunogenetics. 1998; 48: 222-232Crossref PubMed Scopus (203) Google Scholar]. 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 [13Hahn B.H. Animal models of systemic lupus erythematosus.in: Wallace D.J. Hahn B.H. DuBois' lupus erythematosus. Williams and Wilkins, Baltimore, MD1997: 339-382Google Scholar]) 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 FcγRII-deficient mice, and is therefore likely to play an important role in the pathogenesis of SLE and possibly diabetes.