Allelic-Dependent Expression of an Activating Fc Receptor on B Cells Enhances Humoral Immune Responses

作者：Li Xinrui; Wu Jianming; Ptacek Travis; Redden David T; Brown Elizabeth E; Alarcon Graciela S; Ramsey Goldman Rosalind; Petri Michelle A; Reveille John D; Kaslow Richard A; Kimberly Robert P^*; Edberg Jeffrey C

来源：Science Translational Medicine, 2013, 5(216): 216ra175.

DOI：10.1126/scitranslmed.3007097

B cells are pivotal regulators of acquired immune responses, and recent work in both experimental murine models and humans has demonstrated that subtle changes in the regulation of B cell function can substantially alter immunological responses. The balance of negative and positive signals in maintaining an appropriate B cell activation threshold is critical in B lymphocyte immune tolerance and autoreactivity. Fc gamma RIIb (CD32B), the only recognized Fc gamma receptor on B cells, provides immunoglobulin G (IgG)-mediated negative modulation through a tyrosine-based inhibition motif, which down-regulates B cell receptor-initiated signaling. These properties make Fc gamma RIIb a promising target for antibody-based therapy. We report the discovery of allele-dependent expression of the activating Fc gamma RIIc on B cells. Identical to Fc gamma RIIb in the extracellular domain, Fc gamma RIIc has a tyrosine-based activation motif in its cytoplasmic domain. In both human B cells and B cells from mice transgenic for human Fc gamma RIIc, Fc gamma RIIc expression counterbalances the negative feedback of Fc gamma RIIb and enhances humoral responses to immunization in mice and to BioThrax vaccination in a human anthrax vaccine trial. Moreover, the FCGR2C-ORF allele is associated with the risk of development of autoimmunity in humans. Fc gamma RIIc expression on B cells challenges the prevailing paradigm of unidirectional negative feedback by IgG immune complexes via the inhibitory Fc gamma RIIb, is a previously unrecognized determinant in human antibody/autoantibody responses, and opens the opportunity for more precise personalized use of B cell-targeted antibody-based therapy.

• 出版日期2013-12-18
• 单位西北大学