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 [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.

Overlapping BXSB congenic intervals, in combination with microarray gene expression, reveal novel lupus candidate genes

“…Furthermore, expression profiling does not readily identify functional changes in proteins. However, differential expression undoubtedly underlies some susceptibility loci 14,15,35 and the determination of differentially regulated pathways may aid the identification of any primary functional variant.…”

Association of a transmembrane polymorphism of Fcγ receptor IIb (FCGR2B) with systemic lupus erythematosus in Taiwanese patients

“…The important role of Fc␥RIIb in the development of autoimmune diseases has been firmly established in mouse models (11)(12)(13)(14)(15)(16). Fc␥RIIb-deficient mice display augmented humoral immune responses and are susceptible to the development of autoimmune phenotypes (10,11).…”

Expression of the autoimmune Fcgr2b NZW allele fails to be upregulated in germinal center B cells and is associated with increased IgG production

“…7 Several lupus-prone strains show reduced FcgRIIB levels attributed to a promoter region polymorphism for NZB, BXSB and MRL. 8,9 However, using B6.Sle1/NZW and NZW mice, we have recently shown that failed upregulation of FcgRIIB on GC B cells is not associated with the promoter region polymorphism, but rather with additional polymorphisms in the putative regulatory regions 3 and 4 in the third intron shared by both NZB and NZW alleles. 10 A direct demonstration of the involvement of FcgRIIB in lupus pathogenesis was dramatically demonstrated in both the NZM2410 and BXSB models, in which full disease abrogation was achieved by partial restoration of FcgRIIB expression on hematopoeitic cells.…”