CRP and Anti-CRP Autoantibodies in Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ involvement, production of a wide range of autoantibodies and by formation and tissue deposition of immune complexes in the inflamed organs. In contrast to most systemic inflammatory conditions, and despite raised levels of pro-inflammatory cytokines, SLE flares are rarely reflected by elevated C-reactive protein (CRP), an important acute-phase reactant in man with homologues in vertebrates and several invertebrates. Normally, the circulating concentration of liver-derived CRP rises rapidly in response to infections and tissue injury, and CRP measurement is widely employed as a marker of ongoing inflammation. With sensitive methods, detection of small elevations of CRP is also valuable as a prognostic marker in cardiovascular disease. As a part of the innate immune system, CRP binds certain molecules exposed on the surface of dying cells/apoptotic bodies and on the surface of pathogens and mediates their elimination by uptake in the reticuloendothelial system. CRP also interacts with IgG-containing immune complexes, binds Fc-receptors and activates the complement system via C1q. In murine lupus, CRP has been found to decrease autoantibody levels and increase the survival rates. In this review we discuss possible explanations for, and consequences of, the relative CRP failure in SLE, as well as pathogenetic implications of anti-CRP autoantibodies.

Solid-phase classical complement activation by C-reactive protein (CRP) is inhibited by fluid-phase CRP–C1q interaction

“…We have previously reported the occurrence of autoantibodies to mCRP in SLE [45]. Although this does not explain the deficient CRP-reaction in SLE, it correlates to disease activity and may have relevance to the pathogenetic process [8,46].…”

“…Figure 4a shows the increase in anti-C3c accumulation on top of the serum layer was most dramatic in the s-CRP interval between 4 to 10 mg/L, i.e. levels that in numerous studies have been shown to predict coronary events [8,12]. The largest amounts of anti-C3c bound to surfaces exposed to serum with s-CRP ≈150 mg/L, whereas virtually no anti-C3c bound to surfaces exposed to serum with s-CRP >300 mg/L (Figure 4a).…”

“…Due to its dramatic rise within the initial 24 to 72 hours in response to proinflammatory stimuli or tissue damage, CRP is an important marker of ongoing systemic inflammation [7]. Circulating CRP is essentially derived from hepatocytes, but small amounts may also be produced locally by other cells [8]. The synthesis is mainly regulated at the transcriptional level through IL-6-and IL-1-directed induction of the CRP gene, located on the long arm of chromosome 1, by activation of NF-B and transcriptional factor NF-IL-6/CAAT-enhancer binding protein (C/EBP) family members C/EBP and C/EBP [7,9].…”

“…The calcium-dependent binding of CRP to phosphorylcholine (PC) exposed on bacterial cell walls, damaged cell membranes or apoptotic blebs, offers an explanation to the antibody-like properties of CRP, which is opsonizing by its Fc gamma receptor (FcR) affinity [7,8,10,11]. Minor CRP elevations have been shown to reflect a low-grade vascular inflammation, and to predict coronary events in patients with angina pectoris as well as in apparently healthy subjects [8,12].…”

“…Minor CRP elevations have been shown to reflect a low-grade vascular inflammation, and to predict coronary events in patients with angina pectoris as well as in apparently healthy subjects [8,12]. More substantial elevations of circulating CRP is a useful sign of systemic inflammation, e.g.…”