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Allelic-dependent expression of an activating Fc receptor on B cells enhances humoral immune responses.

ABSTRACT: 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?RIIb (CD32B), the only recognized Fc? 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?RIIb a promising target for antibody-based therapy. We report the discovery of allele-dependent expression of the activating Fc?RIIc on B cells. Identical to Fc?RIIb in the extracellular domain, Fc?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?RIIc, Fc?RIIc expression counterbalances the negative feedback of Fc?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?RIIc expression on B cells challenges the prevailing paradigm of unidirectional negative feedback by IgG immune complexes via the inhibitory Fc?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.

SUBMITTER: Li X

PROVIDER: S-EPMC3982386 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Allelic-dependent expression of an activating Fc receptor on B cells enhances humoral immune responses.

Li Xinrui X Wu Jianming J Ptacek Travis T Redden David T DT Brown Elizabeth E EE Alarcón Graciela S GS Ramsey-Goldman Rosalind R Petri Michelle A MA Reveille John D JD Kaslow Richard A RA Kimberly Robert P RP Edberg Jeffrey C JC

Science translational medicine 20131201 216

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. FcγRIIb (CD32B), the only recognized Fcγ receptor on B cells, provides immunoglobulin ...[more]

PMID: 24353158

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Project description:C-reactive protein (CRP) is a member of the pentraxin family of proteins. These proteins are highly conserved over the course of evolution being present as far back as 250 million years ago. Mammalian pentraxins are characterized by the presence of five identical non-covalently linked subunits. Each subunit has a structurally conserved site for calcium-dependent ligand binding. The biological activities of the pentraxins established over many years include the ability to mediate opsonization for phagocytosis and complement activation. Pentraxins have an important role in protection from infection from pathogenic bacteria, and regulation of the inflammatory response. It was recognized early on that some of these functions are mediated by activation of the classical complement pathway through C1q. However, experimental evidence suggested that cellular receptors for pentraxins also play a role in phagocytosis. More recent experimental evidence indicates a direct link between pentraxins and Fc receptors. The Fc receptors were first identified as the major receptors for immunoglobulins. The avidity of the interaction between IgG complexes and Fc receptors is greatly enhanced when multivalent ligands interact with the IgG binding sites and activation of signaling pathways requires Fc receptor crosslinking. Human pentraxins bind and activate human and mouse IgG receptors, FcγRI and FcγRII, and the human IgA receptor, FcαRI. The affinities of the interactions between Fc receptors and pentraxins in solution and on cell surfaces are similar to antibody binding to low affinity Fc receptors. Crystallographic and mutagenesis studies have defined the structural features of these interactions and determined the stoichiometry of binding as one-to-one. Pentraxin aggregation or binding to multivalent ligands increases the avidity of binding and results in activation of these receptors for phagocytosis and cytokine synthesis. This review will discuss the structural and functional characteristics of pentraxin Fc receptor interactions and their implications for host defense and inflammation.

Dataset Information

Allelic-dependent expression of an activating Fc receptor on B cells enhances humoral immune responses.

Publications

Allelic-dependent expression of an activating Fc receptor on B cells enhances humoral immune responses.

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