C‐Reactive Protein (CRP) and Autoimmune Disease: Facts and Conjectures

Abstract

C-reactive protein (CRP) is a blood component comprised of five identical subunits with a combined molecular mass of 110 kDa; in the presence of Ca þ þ it binds phosphocholine (PC) with high affinity. Ligand-bound CRP activates complement and the protein reportedly binds various Fc receptors. Coincident with a now decade-long resurgence in clinical interest in associations of CRP with disease, our laboratory has been investigating the biology of CRP in vivo using human CRP transgenic mice (CRPtg). At that time we confirmed that CRP affects a host defense function mediated at least in part through the elimination of pathogens. Less appreciated and not as well understood as CRP's ability to bind antigen and aid in the elimination of microbes, is its known ability to bind autoantigens and presumed capacity to promote clearance of apoptotic cells. These latter properties of CRP have long been suspected to contribute to homeostasis and to autoimmune disease. In this article we review and update the evidence generated in CRPtg by our group and in vitro by others' that indicates CRP is more than just an antimicrobial molecule and convenient marker of inflammation-rather, it protects against autoimmunity. A mechanistic hypothesis is presented to account for this cause-and-effect relationship.

Inefficient clearance of dying cells in patients with SLE: anti-dsDNA autoantibodies, MFG-E8, HMGB-1 and other players

“…CRP was reduced in serum of mice with high rates of apoptotic cells [100]. In CRP transgenic mice in which high rates of splenic and intestinal apoptosis were induced, the amounts of apoptotic cells were significantly decreased compared to wildtype [100]. In addition, it has been shown that CRP inhibits antibody response to phosphocholine-containing epitopes [101] and the inflammatory potential of LPS in transgenic mice.…”

The pattern recognition receptor PTX3 is recruited at the synapse between dying and dendritic cells, and edits the cross-presentation of self, viral, and tumor antigens

“…[38][39][40] They are required for the clearance of chromatin and cell debris [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] and for effective protection against autoimmunity. 3,[42][43][44][45][46][47][48] This function is in apparent contrast with the involvement of pentraxins in protection against extracellular bacteria or fungi. 3 The mechanisms by which pentraxins on the one hand restrict the activation of autoreactive lymphocytes and on the other promote antimicrobial immunity are not yet characterized.…”

C-reactive protein haplotype is associated with high PSA as a marker of metastatic prostate cancer but not with overall cancer risk

“…The known ligands for CRP are chromatin, histones, fibronectin, laminin and small nuclear ribonuclear particles (Stein et al, 2000). The ability of CRP to bind nuclear antigens, as well as its ability to increase the clearance of host apoptotic and necrotic cells, has led to the theory that CRP may prevent autoimmunity (Szalai, 2004). According to a recent systemic review of the association between serum CRP and cancer, CRP concentrations are usually higher in patients with cancer than in healthy controls, but the association seems to be site specific (Heikkila et al, 2007).…”