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The Lupus‐Associated Fcγ Receptor IIb–I232T Polymorphism Results in Impairment in the Negative Selection of Low‐Affinity Germinal Center B Cells Via c‐Abl in Mice
Author(s) -
Jhou JyunPei,
Yu IShing,
Hwai Haw,
Chen ChihShan,
Chen PeiLung,
Tzeng ShiangJong
Publication year - 2018
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.40555
Subject(s) - germinal center , systemic lupus erythematosus , polymorphism (computer science) , receptor , microbiology and biotechnology , immunology , biology , medicine , genetics , antibody , b cell , genotype , gene , disease
Objective Fcγ receptor II b (Fcγ RII b) is an essential negative regulator of B cells that blocks B cell receptor ( BCR ) signaling and triggers c‐Abl–dependent apoptosis of B cells. Fcγ RII b‐deficient mice display splenomegaly with expansion of B cells, leading to lupus. Fcγ RII b‐I232T is a hypofunctional polymorphism associated with lupus susceptibility in humans, an autoimmune disease linked to diminished deletion of autoreactive B cells. In the context of the Fcγ RII b‐I232T polymorphism, we investigated the role of Fcγ RII b in the deletion of low‐affinity germinal center ( GC ) B cells, an important mechanism for preventing autoimmunity. Methods We generated Fcγ RII b 232T/T mice to mimic human Fcγ RII b‐I232T carriers and immunized mice with chicken gamma globulin ( CGG )–conjugated NP , a T cell–dependent antigen, to examine the response of GC B cells. Results Compared to wild‐type ( WT ) mice, Fcγ RII b 232T/T mice showed increased numbers of low‐affinity NP ‐specific IgG and NP ‐specific B cells and plasma cells; additionally, the expression of a somatic mutation (W33L) in their V H 186.2 genes encoding high‐affinity BCR was reduced. Notably, Fcγ RII b 232T/T mice had a higher number of GC light zone B cells and showed less apoptosis than WT mice, despite having equivalent follicular helper T cell numbers and function. Moreover, phosphorylation of c‐Abl was reduced in Fcγ RII b 232T/T mice, and treatment of WT mice with the c‐Abl inhibitor nilotinib during the peak of GC response resulted in reduced affinity maturation reminiscent of Fcγ RII b 232T/T mice. Conclusion Our findings provide evidence of a critical role of Fcγ RII b/c‐Abl in the negative selection of GC B cells in Fcγ RII b 232T/T mice. Importantly, our findings indicate potential benefits of up‐regulating Fcγ RII b expression in B cells for treatment of systemic lupus erythematosus.