- Paper Report
- Open Access
Fc?RIIB knockout develops B lymphocytes loss of self tolerance
- Ali Hajeer1
© Current Science Ltd 2000
- Published: 10 September 2000
- Animal model
Fc?Rs can activate or inhibit the cellular responses by sending opposing signals upon activation by immune complexes. Fc?RIIB belongs to the inhibitory group; it can inhibit and limit the threshold of immune complex activation of both B lymphocytes and macrophages, possibly by recruiting the inhibitory phosphatase SHP-1. It may also contribute to the maintenance of tolerance during affinity maturation by deleting the low affinity, self-reactive lymphocytes from the germinal centres. Both activating and inhibitory Fc?Rs can modify the development and progression of autoimmune diseases by influencing B lymphocytes and/or macrophages. This study aimed to investigate the role of Fc?RIIB in the development of spontaneous autoimmune disease in the mouse.
The original RIIB-/- 129Sv/B6 mouse was healthy, but after seven generations of backcrossing the RIIB-/- B6 mice were losing weight, and showed dehydration and reduced viability. RIIB-/- BALB/c mice on the other hand were healthy and had a life span comparable to that of the wild type. Proteinurea had developed in 90% of the RIIB-/- B6 mice by 9 months, as well as very high antinuclear antibody (ANA) titres (>1:1000) with homogenous nuclear staining, and both anti-DNA and anti-chromatin antibodies. Interestingly, these mice did not develop any of the common autoantibodies such as anti-Sm, cardiolipin or myeloperoxidase antibodies. None of the BALB/c RIIB-/- animals developed proteinurea or autoantibodies. Pathologically, the RIIB-/- B6 mice suffered from a severe multi-organ inflammatory disease. The lungs and kidneys revealed systemic vasculitis with inflammatory cell infiltration. The kidneys showed evidence of glomerulonephritis (extensive glomerular sclerosis, hypercellularity and mesangial thickening) suggesting an ongoing chronic inflammatory disease. Bone marrow transfer experiments suggested that the autoimmune phenotype of the RIIB-/- B6 mouse was dependent upon the deficiency of the RIIB in the B lymphocytes but not in macrophages.
The original Fc?RIIB knockout (RIIB-/-) was generated on the 129SV/B6-hybrid background and was subsequently backcrossed on BALB/c and C57BL/6 (B6) background for 12 generations. Deposition of immune complexes was detected by fluorescein-conjugated anti-mouse IgG antibodies. Anti-DNA was determined by ELISAand ANAs were detected on Hep-2 cells with fluorescein-conjugated anti-mouse IgG antibodies.
Jiang Y, Hirose S, Abe M, Sanokawa-Akakura R, Ohtsuji M, Mi X, Li N, Xiu Y, Zhang D, Shirai J, Hamano Y, Fujii H, Shirai T: Polymorphisms in IgG Fc receptor IIB regulatory regions associated with autoimmune susceptibility. Immunogenetics 2000, 51:429-435 (PubMed abstract).