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The Lupus-Associated Fc? Receptor IIb-I232T Polymorphism Results in Impairment in the Negative Selection of Low-Affinity Germinal Center B Cells Via c-Abl in Mice.

ABSTRACT: OBJECTIVE:Fc? receptor IIb (Fc?RIIb) is an essential negative regulator of B cells that blocks B cell receptor (BCR) signaling and triggers c-Abl-dependent apoptosis of B cells. Fc?RIIb-deficient mice display splenomegaly with expansion of B cells, leading to lupus. Fc?RIIb-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 Fc?RIIb-I232T polymorphism, we investigated the role of Fc?RIIb in the deletion of low-affinity germinal center (GC) B cells, an important mechanism for preventing autoimmunity. METHODS:We generated Fc?RIIb232T/T mice to mimic human Fc?RIIb-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, Fc?RIIb232T/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 VH 186.2 genes encoding high-affinity BCR was reduced. Notably, Fc?RIIb232T/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 Fc?RIIb232T/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 Fc?RIIb232T/T mice. CONCLUSION:Our findings provide evidence of a critical role of Fc?RIIb/c-Abl in the negative selection of GC B cells in Fc?RIIb232T/T mice. Importantly, our findings indicate potential benefits of up-regulating Fc?RIIb expression in B cells for treatment of systemic lupus erythematosus.


PROVIDER: S-EPMC6221021 | BioStudies | 2018-01-01T00:00:00Z


REPOSITORIES: biostudies

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