The Complex Role of C-Reactive Protein in Systemic Lupus Erythematosus

Abstract

C-reactive protein (CRP) is well-known as a sensitive albeit unspecific biomarker of inflammation. In most rheumatic conditions, the level of this evolutionarily highly conserved pattern recognition molecule conveys reliable information regarding the degree of ongoing inflammation, driven mainly by interleukin-6. However, the underlying causes of increased CRP levels are numerous, including both infections and malignancies. In addition, low to moderate increases in CRP predict subsequent cardiovascular events, often occurring years later, in patients with angina and in healthy individuals. However, autoimmune diseases characterized by the Type I interferon gene signature (e.g., systemic lupus erythematosus, primary Sjögren's syndrome and inflammatory myopathies) represent exceptions to the general rule that the concentrations of CRP correlate with the extent and severity of inflammation. In fact, adequate levels of CRP can be beneficial in autoimmune conditions, in that they contribute to efficient clearance of cell remnants and immune complexes through complement activation/modulation, opsonization and phagocytosis. Furthermore, emerging data indicate that CRP constitutes an autoantigen in systemic lupus erythematosus. At the same time, the increased risks of cardiovascular and cerebrovascular diseases in patients diagnosed with systemic lupus erythematosus and rheumatoid arthritis are well-established, with significant impacts on quality of life, accrual of organ damage, and premature mortality. This review describes CRP-mediated biological effects and the regulation of CRP release in relation to aspects of cardiovascular disease and mechanisms of autoimmunity, with particular focus on systemic lupus erythematosus.

Keywords: C-reactive protein; acute-phase protein; autoimmunity; cardiovascular risk; inflammation; organ damage; systemic lupus erythematosus.

Figure 1

Differences in C-reactive protein (CRP) levels among patients with systemic lupus erythematosus (SLE) stratified based on the presence of detectable interleukin 6 (IL-6) levels, Type I interferon (IFN) gene signature, and CRP-lowering gene polymorphism (rs1205), respectively. All patients had a low disease activity but could be serologically active at sampling. Bars indicate median values. Dots represent individual values. Data shown in the figure were adopted from Enocsson et al. [115], with permission from Frontiers Media, 2021 (Creative Commons Attribution licence, version 4.0).

Figure 2

Immunoregulatory effects of pentameric C-reactive protein (pCRP) and monomeric CRP (mCRP) in the context of systemic lupus erythematosus (SLE) and cardiovascular disease. Dissociation of pCRP to mCRP will take place in inflammatory conditions and at cell surfaces and results in local immunoregulatory effects. The biological properties of mCRP partly overlaps the pCRP effects but is generally ascribed a more active and proinflammatory profile. CRP binds to and opsonizes dying cells and cell remnants, which facilitates phagocytosis via Fc-receptor binding. Furthermore, CRP activates classical complement activation via its binding to C1q, resulting in increased opsonization by C3b. Recruitment of Factor H will however limit progression of the complement cascade to membrane attack complex formation. Increased levels of CRP can therefore contribute to efficient clearance of potential autoantigens and thus, be beneficial in autoimmune conditions. The ability of CRP to facilitate immune complex elimination further implies a protective role of CRP in autoimmune diseases. However, increased Type I IFN activity, frequently observed in patients with SLE, inhibits CRP production, which theoretically could increase the autoantigen burden and disease activity. Proatherogenic and protrombotic effects of CRP are attributed to its stimulation of endothelial cells, neutrophils and platelets.