Abstract
BackgroundThe significance of a unique inhibitory Fc receptor for IgG, FcγRIIB (RIIB), in the prevention of spontaneous production of autoantibodies remains controversial, due mainly to the fact that the RIIB locus is adjacent to the autoimmune-related SLAM locus harboring the genes coding for signaling lymphocyte activation molecules, making it difficult to isolate the effect of RIIB deletion from that of SLAM in gene-targeted mice. Our objective was to determine the influence of RIIB deletion on the spontaneous development of autoimmune diseases and to compare it with that of potentially pathogenic SLAM.ResultsWe established two congenic C57BL/6 (B6) strains, one with the RIIB deletion and the other with SLAM, by backcrossing 129/SvJ-based RIIB-deficient mice into the B6 genetic background extensively. The RIIB deficiency indeed led to the production and/or accumulation of a small amount of anti-nuclear autoantibodies (ANAs) and to weak IgG immune-complex deposition in glomeruli without any obvious manifestation of lupus nephritis. In contrast, pathogenic SLAM in the B6 genetic background induced ANAs but no IgG immune-complex deposition in the kidneys. Naïve SLAM mice but not RIIB-deficient mice exhibited hyperplasia of splenic germinal centers.ConclusionThe present results clarify the roles of RIIB in preventing production and/or accumulation of a small amount of ANAs, and development of glomerulonephritis. The combined effects of RIIB deletion and pathogenic SLAM can lead to severe lupus nephritis in the B6 genetic background.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-014-0047-y) contains supplementary material, which is available to authorized users.
Highlights
The significance of a unique inhibitory Fc receptor for IgG, FcγRIIB (RIIB), in the prevention of spontaneous production of autoantibodies remains controversial, due mainly to the fact that the RIIB locus is adjacent to the autoimmune-related Signal lymphocyte activation molecule(s) (SLAM) locus harboring the genes coding for signaling lymphocyte activation molecules, making it difficult to isolate the effect of RIIB deletion from that of SLAM in gene-targeted mice
Analysis of a series of microsatellite markers including D1Mit15, 36, and 113 in the vicinities of the Fcgr2b and SLAM loci revealed the successful separation of the RIIB−/− locus and the SLAM haplotype in 129 mice (SLAM129) locus during the backcross (Figure 1A; for details, see Additional file 1: Figure S1 and Additional file 1: Table S1)
We obtained a mouse line with the combined loci, N28 RIIB−/−SLAM129, as a control (Figure 1A and Additional file 1: Figure S1). Both the N28 RIIB−/− (RIIB−/−SENDAI) and N18 SLAM129 mice thrived normally, at least up to 45 weeks after birth, and the RIIB−/−SLAM129 mice did as well despite the fact that female RIIB−/−SLAM129 mice manifested obvious glomerulonephritis, as judged on histology (Figure 1B, see below), RIIB−/− mice produce a small amount of Anti-nuclear antibodies (ANA) To gain an insight into the difference between RIIB−/− and SLAM129 mice, and its relation to autoimmunity, we measured the total IgM and IgG levels in sera from these locusseparated lines and the combined line, RIIB−/−SLAM129, as a control, at the age of 24–28 weeks
Summary
The significance of a unique inhibitory Fc receptor for IgG, FcγRIIB (RIIB), in the prevention of spontaneous production of autoantibodies remains controversial, due mainly to the fact that the RIIB locus is adjacent to the autoimmune-related SLAM locus harboring the genes coding for signaling lymphocyte activation molecules, making it difficult to isolate the effect of RIIB deletion from that of SLAM in gene-targeted mice. RIIB executes important IgG-mediated feedback regulation of cell activation, proliferation and antibody/cytokine production, as demonstrated in different experimental settings using RIIB-deficient (RIIB−/−) mice [13,14,15] In contrast to this well-established feedback regulation, the roles of RIIB in maintaining tolerance and in preventing spontaneous development of autoimmunity, remain uncertain due to the inconsistent phenotypes observed in RIIB−/− mice by different research groups, in terms of the level of ANAs and the severity of lupus nephritis [8,16,17,18]. A recent report [19] pointed out the role of RIIB expressed in liver sinusoidal endothelial cells in the clearance of small size IgG-ICs, so the additional RIIB function of minimizing the level of pathologic IgGICs in the blood should be taken into account
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
