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, 10, 2061

The Complex Association of FcγRIIb With Autoimmune Susceptibility


The Complex Association of FcγRIIb With Autoimmune Susceptibility

J Sjef Verbeek et al. Front Immunol.


FcγRIIb is the only inhibitory Fc receptor and controls many aspects of immune and inflammatory responses. The observation 19 years ago that Fc γ RIIb -/- mice generated by gene targeting in 129 derived ES cells developed severe lupus like disease when backcrossed more than 7 generations into C57BL/6 background initiated extensive research on the functional understanding of this strong autoimmune phenotype. The genomic region in the distal part of Chr1 both in human and mice in which the Fc γ R gene cluster is located shows a high level of complexity in relation to the susceptibility to SLE. Specific haplotypes of closely linked genes including the Fc γ RIIb and Slamf genes are associated with increased susceptibility to SLE both in mice and human. Using forward and reverse genetic approaches including in human GWAS and in mice congenic strains, KO mice (germline and cell type specific, on different genetic background), knockin mice, overexpressing transgenic mice combined with immunological models such as adoptive transfer of B cells from Ig transgenic mice the involved genes and the causal mutations and their associated functional alterations were analyzed. In this review the results of this 19 years extensive research are discussed with a focus on (genetically modified) mouse models.

Keywords: Fcgamma receptor IIB; SLE; autoimmue disease; mouse model; reverse genetics; systemic lupus erythematosus.


Figure 1
Figure 1
Physical map of the sub-telomeric region of mouse chromosome 1. The upper horizontal line represents a 40 Mb genomic region including the 129 derived FcγRIIb flanking region present in the original FγRIIb129-/- mouse, backcrossed more than 7 generations into C57BL/6 background. This FcγRIIb flanking region spans at a minimum the distance between the microsatellite markers D1Mit34 and D1Mit150 [horizontal black bar; (98)]. The lower horizontal line represents a magnification of the 3.8 Mb subregion located between microsatellite markers D1Mit36 and D1Mit206 showing a detailed map of the FcγR and Slam family gene clusters within this region. In addition, below the line, the location of all other coding genes in this region is shown according to the NCBI database. At the bottom, the congenic fragments present in the different FcγRIIb−/− and Slamf129 C57BL/6 congenic strains, described in the text, are depicted as horizontal bars.
Figure 2
Figure 2
Epistasis between the FcγRIIb KO alleles and the Sle16 (Slam129) and Yaa autoimmune susceptibility loci resulting in lupus-like disease in C57BL/6 mice. Epistatic interactions are indicated as dotted arrows. The FcγRIIb flanking Sle16 genomic region contains the autoimmunity associated Slamf129 haplotype 2 gene cluster (see Figure 1). (1) Rahman et al. (108); (2) Espéli et al. (11); (3) Boross et al. (109); (4) Li et al. (110); (5) Bygrave et al. (111); (6) Bolland and Ravetch (112); (7) Bolland et al. (113); (8) Kanari et al. (98). The increasing severity of autoimmune disease in the different mouse models is depicted on top.

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