Recognition and functional activation of the human IgA receptor (Fc RI) by C-reactive protein

Structural Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2011; 108(12):4974-9. DOI: 10.1073/pnas.1018369108
Source: PubMed


C-reactive protein (CRP) is an important biomarker for inflammatory diseases. However, its role in inflammation beyond complement-mediated pathogen clearance remains poorly defined. We identified the major IgA receptor, FcαRI, as a ligand for pentraxins. CRP recognized FcαRI both in solution and on cells, and the pentraxin binding site on the receptor appears distinct from that recognized by IgA. Further competitive binding and mutational analysis showed that FcαRI bound to the effector face of CRP in a region overlapping with complement C1q and Fcγ receptor (FcγR) binding sites. CRP cross-linking of FcαRI resulted in extracellular signal-regulated kinase (ERK) phosphorylation, cytokine production, and degranulation in FcαRI-transfected RBL cells. In neutrophils, CRP induced FcαRI surface expression, phagocytosis, and TNF-α secretion. The ability of CRP to activate FcαRI defines a function for pentraxins in inflammatory responses involving neutrophils and macrophages. It also highlights the innate aspect of otherwise humoral immunity-associated antibody receptors.

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Available from: Terry Du Clos, Oct 05, 2015
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    • "The continuous increase in binding signal suggests that after the initial binding to the antigen, a continued non-typical binding and/or aggregation of Ig-fLCs to the chip surface occurred. Notably, such non-saturating binding kinetics were also reported for binding of C-reactive protein to FcαRI [24]. Taken together, the different binding assays consistently support earlier observations that Ig-fLCs bind specifically and with sufficient strength to antigen [7], [25]. "
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    ABSTRACT: Beside the production of complete immunoglobulins IgG, IgE, IgA, IgM and IgD, consisting of tetrameric heterodimers of immunoglobulin heavy and light chains, B cells also secrete immunoglobulin free light chains (Ig-fLC). Previous studies showed that Ig-fLCs are able to induce immediate hypersensitivity reactions. It is apparent that recognition and binding of antigen are crucial steps in the onset of these inflammatory responses. In this study, the binding characteristics of Ig-fLC to antigen were further investigated using various biochemical approaches. In addition, we investigated whether antigen-mediated crosslinking of Ig-fLC is required to initiate allergic skin inflammation in vivo. Our study shows that binding of Ig-fLCs to antigen can be measured with different experimental setups. Surface plasmon resonance analysis showed real-time antigen binding characteristics. Specific antigen binding by Ig-fLCs was further detected using immunoblotting and ELISA. Using the ELISA-based assay, a binding affinity of 76.9±3.8 nM was determined for TNP-specific Ig-fLC. Antigen-induced ear swelling in mice passively sensitized with trinitrophenol-specific Ig-fLC was inhibited when multivalent antigen was combined with excess of monovalent antigen during challenge. We conclude that Ig-fLCs are able to interact with antigen, a prerequisite for antigen-specific cellular activation. In analogy to antigen-specific Fc receptor-induced mast cell activation, crosslinking of Ig-fLCs is necessary to initiate a local allergic response.
    PLoS ONE 07/2012; 7(7):e40986. DOI:10.1371/journal.pone.0040986 · 3.23 Impact Factor
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    ABSTRACT: C-reactive protein (CRP) is a prototypic human acute phase reactant composed of five identical subunits. Emerging evidence indicates that CRP is not merely a predictor of cardiovascular disease, but may also be a direct mediator. However, the diverse and sometimes contradictory activities of CRP have considerably hampered the attempts to define the exact role of CRP in atherogenesis. Here, we review the multiple layers of regulation of CRP’s structure and function, highlighting how local inflammation conditions, such as the abundance of damaged cell membranes and redox homeostasis, can tip the balance of the pro- and anti-inflammatory activities of CRP. We propose that the highly controlled interplay between different structural conformations of CRP underlies its intrinsic property as a fine modulator of inflammation and atherogenesis.
    Chinese Science Bulletin 05/2012; 58(14). DOI:10.1007/s11434-012-5591-3 · 1.58 Impact Factor
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    ABSTRACT: Monocyte-derived, fibroblast-like cells called fibrocytes are associated with fibrotic lesions. The plasma protein serum amyloid P component (SAP; also known as pentraxin-2, PTX2) inhibits fibrocyte differentiation in vitro, and injections of SAP inhibit fibrosis in vivo. SAP is a member of the pentraxin family of proteins that includes C-reactive protein (CRP; PTX1) and pentraxin-3 (PTX3). All three pentraxins are associated with fibrosis, but only SAP and CRP have been studied for their effects on fibrocyte differentiation. We find that compared to SAP and CRP, PTX3 promotes human and murine fibrocyte differentiation. The effect of PTX3 is dependent on FcγRI. In competition studies, the fibrocyte-inhibitory activity of SAP is dominant over PTX3. Binding competition studies indicate that SAP and PTX3 bind human FcγRI at different sites. In murine models of lung fibrosis, PTX3 is present in fibrotic areas, and the PTX3 distribution is associated with collagen deposition. In lung tissue from pulmonary fibrosis patients, PTX3 has a widespread distribution, both in unaffected tissue and in fibrotic lesions, whereas SAP is restricted to areas adjacent to vessels, and absent from fibrotic areas. These data suggest that the relative levels of SAP and PTX3 present at sites of fibrosis may have a significant effect on the ability of monocytes to differentiate into fibrocytes.
    PLoS ONE 03/2015; 10(3):e0119709. DOI:10.1371/journal.pone.0119709 · 3.23 Impact Factor
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