The classical pentraxins, C-reactive protein (CRP) and serum amyloid P component (SAP) are serum proteins of the innate immune system, and are relevant to many human diseases involving inflammation, tissue damage and autoimmunity We have now found a completely novel interaction of pentraxins with the leukocyte receptors for IgA, Fc1RI (CD89). The functional consequences of CRP and SAP binding to CD89 and their role in immunological processes are unknown. Pentraxins bind to both microbial pathogens and endogenous antigens involved in the stimulation of autoimmunity. It is likely that the interaction of CRP and SAP with CD89 plays a role in the uptake and processing of these diverse ligands. In addition, CRP in the absence of ligand has inhibitory effects on monocyte and macrophage activation and inflammation. The goals of the proposed studies are to characterize the structural basis of the pentraxin-CD89 interaction, to determine the functional effects of multivalent and monovalent binding of pentraxins to cells expressing CD89, and to use CD89 transgenic (Tg) mice to determine the role of CRP-CD89 interaction in vivo in regulation of inflammation. The findings will define a new interaction between innate immune molecules and Fc receptors that regulate the inflammatory response. The overall objective of the project is to determine how CRP interacts with a newly defined receptor on myeloid cells and to define the functional consequences of this interaction.
Specific Aims :
Specific Aim 1. To define the interaction of SAP and CRP with CD89. The focus of this aim is the complete characterization of the interaction of CRP and SAP with CD89 with respect to affinity, stoichiometry, kinetics and structure. Binding of CRP and SAP to CD89 in the cell membrane will be examined by quantitative fluorescence microscopy. Solution of the pentraxin-CD89 complex will be a primary goal.
Specific aim 2. To define the functional consequences of CRP and SAP interaction with CD89. We will define the signaling pathways induced by CRP in CD89-transfected rat basophilic leukemia (RBL) cells that result in activation and inhibition of degranulation in these cells. We will then examine the role of CD89 in uptake of pentraxin-opsonized microbes and whether CD89 contributes to inhibitory effects of CRP on monocytes.
Specific Aim 3. To evaluate the effect of CRP-CD89 interaction in different mouse models of inflammatory diseases. We have shown that CRP induces protection in nephrotoxic nephritis (NTN), immune thrombocytopenia (ITP) and other immune complex diseases through interaction with Fc3RI on macrophages. Monovalent targeting of CD89 has a similar suppressive effect in NTN and unilateral ureteral obstruction (UUO) models. We will use CD89tg/CD64-/- mice to study the ability of CRP to suppress inflammation by interaction with CD89.
We have identified a novel interaction between the pentraxins (C-reactive protein and serum amyloid P component) of the innate immune system and CD89, the major human receptor for IgA antibodies. Both CRP and IgA play major roles in host defense and inflammation. The proposed studies will define the role of CRP and CD89 in cell responses and treatment of inflammatory diseases. These studies may lead to novel therapies for a variety of human autoimmune, infectious and inflammatory disease.
| Lu, Jinghua; Marjon, Kristopher D; Mold, Carolyn et al. (2014) Pentraxins and IgA share a binding hot-spot on Fc?RI. Protein Sci 23:378-86 |
| Mold, Carolyn; Clos, Terry W Du (2013) C-reactive protein inhibits plasmacytoid dendritic cell interferon responses to autoantibody immune complexes. Arthritis Rheum 65:1891-901 |
| Lu, Jinghua; Marjon, Kristopher D; Mold, Carolyn et al. (2012) Pentraxins and Fc receptors. Immunol Rev 250:230-8 |
| Lu, Jinghua; Marjon, Kristopher D; Marnell, Lorraine L et al. (2011) Recognition and functional activation of the human IgA receptor (FcalphaRI) by C-reactive protein. Proc Natl Acad Sci U S A 108:4974-9 |
