C-reactive protein (CRP) is an acute phase serum protein which is produced rapidly in response to inflammation. Numerous studies have shown that CRP has protective properties in acute inflammation, infection and autoimmune dieseases however the mechanism is not understood. Cellular receptors that interact with CRP are Fc gamma receptors (FcR) which we identified. We have demonstrated the role of both activating anf inhibitory FcR interacting with CRP to protect mice frrom endotoxin shock, autoimmune disease and immune complex mediated disease. A recent paper using an adoptive transfer system demonstrated that suppression of immune thrombocytopenia purpura (IIP) was mediated by intravenous immunoglobulin (IVIg) possibly by regulating FcR. We found that CRP treated spleen cells transferred suppression of mice developing ITP through interactions with FcR on the donor cell. We propose to study the mechanism by which this suppression is taking place. Our hypothesis is that CRP-activated macrophages suppress immune ITP by inhibiting FcR-mediated phagocytosis in recipient mice. We propose that the transfer of suppression depends on a soluble factor(s) and that phagocytosis by target macrophages is decreased due to increased expression of the regulatory receptor, Fc gamma Rllb. This hypothesis will be addressed by specific aims proposed. The specfic aims are: 1. To develop an in vitro system in which CRP-induced suppressive macrophages modulate the phagocytic activity and FcR expression of target macrophages, and 2. To determine whether cell-cell contact or soluble mediators are responsible for suppression of phagocytosis in the in vitro model of ITP. In this proposed study we will identiy the mechanism by which suppression is induced in the target cell and what souble mediators are responsible for suppresion. The long term goal is to determine if the immunosuppressive properties of CRP, observed in ITP, can be oberved in human immune complex mediated diseases.
| 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 |
| 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 |
