FcγRIIb differentially regulates pre-immune and germinal center B cell tolerance in mouse and human.
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Several tolerance “checkpoints” exist throughout B cell development to control autoreactive B cells and prevent the generation of pathogenic autoantibodies. FcγRIIb is an Fc receptor that inhibits B cell activation and, if defective, is associated with autoimmune disease. Its impact on specific B cell tolerance checkpoints is unknown. Here we show that reduced expression of FcγRIIb leads to increased deletion and anergy of autoreactive immature B cells, but despite this autoreactive B cells expand in the germinal center and serum autoantibodies are produced, even in response to exogenous non-self antigen. Thus, we show FcγRIIb has opposing effects on pre- and post-immune tolerance checkpoints, and suggest B cell tolerance requires the control of “bystander” germinal center B cells with low or no affinity for the immunization antigen.
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2041-1723
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Wellcome Trust (083650/Z/07/Z)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0514-10109)
Wellcome Trust (200871/Z/16/Z)
Wellcome Trust (106068/Z/14/Z)