Structural recognition and functional activation of FcγR by innate pentraxins

Abstract

The classical pentraxins, serum amyloid P component (SAP) and C-reactive protein (CRP), are major acute phase reactants in mouse and man. As shown in this paper, pentraxins recognize various FcγRs, and SAP opsonization activates FcγR-mediated phagocytosis and cytokine secretion. The receptor binding sites for SAP and IgG overlap resulting in competition of IgG binding to FcγR as well as inhibition of immune complex-mediated phagocytosis by soluble pentraxins. The classical pentraxins, serum amyloid P component (SAP) and C-reactive protein (CRP), are major acute phase reactants in mouse and man. It is shown that pentraxins recognize various FcγRs and SAP opsonization activates FcγR-mediated phagocytosis and cytokine secretion. The receptor binding sites for SAP and IgG overlap, resulting in competition of IgG binding to FcγR as well as inhibition of immune complex-mediated phagocytosis by soluble pentraxins. Pentraxins are a family of ancient innate immune mediators conserved throughout evolution. The classical pentraxins include serum amyloid P component (SAP) and C-reactive protein, which are two of the acute-phase proteins synthesized in response to infection1,2. Both recognize microbial pathogens and activate the classical complement pathway through C1q (refs 3 and 4). More recently, members of the pentraxin family were found to interact with cell-surface Fcγ receptors (FcγR) and activate leukocyte-mediated phagocytosis5,6,7,8. Here we describe the structural mechanism for pentraxin’s binding to FcγR and its functional activation of FcγR-mediated phagocytosis and cytokine secretion. The complex structure between human SAP and FcγRIIa reveals a diagonally bound receptor on each SAP pentamer with both D1 and D2 domains of the receptor contacting the ridge helices from two SAP subunits. The 1:1 stoichiometry between SAP and FcγRIIa infers the requirement for multivalent pathogen binding for receptor aggregation. Mutational and binding studies show that pentraxins are diverse in their binding specificity for FcγR isoforms but conserved in their recognition structure. The shared binding site for SAP and IgG results in competition for FcγR binding and the inhibition of immune-complex-mediated phagocytosis by soluble pentraxins. These results establish antibody-like functions for pentraxins in the FcγR pathway, suggest an evolutionary overlap between the innate and adaptive immune systems, and have new therapeutic implications for autoimmune diseases.