Recent evidence suggests that pentraxins interact with Fc receptors raising the possiblity of cross interaction between the complement and the Fc receptor mediated pathways. We are investigating the interaction between SAP/CRP and Fc receptors and determine the structure of their complex. We have recently determined the crystal structure of human SAP in complex with FcRIIa. The 1:1 receptor-SAP recognition is predominantly mediated through the interactions of the ridge helix from two separate SAP protomers with the D1 and D2 domains of the Fc receptor. The complex structure between human SAP and FcRIIa reveals a diagonally bound receptor on each SAP pentamer. Mutational analysis suggests a conserved receptor recognition among pentraxins. The shared binding site for SAP and IgG results in their competition to FcR binding and the inhibition of immune complex-mediated phagocytosis by soluble pentraxins. These results establish the role of innate pentraxins in the FcgR pathway, and have novel therapeutic implications for autoimmune diseases.Unexpectedly, the SAP binding site on FcRIIa overlaps partially with the IgG binding site on the receptor. The solution-based binding experiments confirmed that SAP and CRP competed against IgG for the binding to FcRs. Solutuion binding experiments showed that pentraxins recognize various FcRs and activate FcR-mediated phagocytosis and cytokine secretion. Moreover, soluble SAP and CRP inhibited significantly the immune complex-mediated phagocytosis, indicating a regulatory function for this family of plasma proteins. The result highlights the importance of pentraxins in interfacing between the innate and humoral immunities and suggests new therapeutic applications for pentraxins in autoimmune diseases. We recently identified the major IgA receptor, FcRI as a ligand for pentraxins. We conclude through competitive binding and mutational analysis that CRP binds to a distinct site on FcRI from that of IgA, and that the recognition involves the effector face of CRP in a region overlapping with its C1q and FcR binding site. Furthermore, CRP crosslinking of FcRI resulted in ERK phosphorylation, degranulation and cytokine production in FcRI transfected RBL cells. In neutrophils, CRP binding induced FcRI surface expression and TNF- secretion, and CRP-opsonized bacteria triggered phagocytosis. The impact of this work is two folds. First, the discovery that pentraxins activate FcRI reveals a novel function for pentraxins in inflammation. It implicates a potential pentraxin-mediated synergistic activation of various Fc receptors in neutrophil and macrophage-mediated inflammatory responses. This is particular so since neutrophils and macrophages are the first responders of infection and inflammation. Second, our finding also highlights the innate aspect of antibody receptors that are mediators of humoral immunity. As pentraxins, such as CRP, are acute phase proteins whose expressions are upregulated during infections, we are investigating the potential role of CRP in Fc receptor activations during parasitic and viral infections.

Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2013
Total Cost
$392,868
Indirect Cost
City
State
Country
Zip Code
Lu, Jinghua; Sun, Peter D (2014) A rapid and rational approach to generating isomorphous heavy-atom phasing derivatives. FEBS J 281:4021-8
Lu, Jinghua; Yu, Yadong; Zhu, Iowis et al. (2014) Structural mechanism of serum amyloid A-mediated inflammatory amyloidosis. Proc Natl Acad Sci U S A 111:5189-94
Lu, Jinghua; Marnell, Lorraine L; Marjon, Kristopher D et al. (2008) Structural recognition and functional activation of FcgammaR by innate pentraxins. Nature 456:989-92