C-Reactive Protein: Clinical Relevance and Interpretation

Excerpt

C-reactive protein (CRP), first identified by Tillett and Francis in 1930, derives its name from its reaction with the C carbohydrate antigen in the capsule of Streptococcus pneumoniae during acute inflammation. CRP is a pentameric protein synthesized by the liver in response to inflammation, with a molecular weight of approximately 115 kDa. This substance exhibits a characteristic "jelly-like lectin fold."

CRP typically consists of 5 identical subunits arranged into a cyclic pentamer around a central pore. However, the protein exists in 2 primary isoforms: the pentameric form (pCRP) and the monomeric form (mCRP). PCRP is the circulating form under normal conditions and is primarily anti-inflammatory. Meanwhile, mCRP arises during inflammation and has pro-inflammatory effects.

The transition between these 2 forms occurs when pCRP dissociates into monomers, typically in response to tissue damage or other inflammatory stimuli. This structural shift is significant as mCRP exhibits pro-inflammatory properties, such as platelet activation, leukocyte recruitment, and endothelial dysfunction, which contribute to the pathogenesis of various diseases, including cardiovascular conditions. These structural and functional differences underscore CRP's dual role in inflammation, both as a mediator of anti-inflammatory responses and a promoter of inflammatory processes during pathological conditions.

CRP functions as an acute-phase reactant, primarily induced by interleukin 6 acting on the hepatic gene responsible for CRP transcription during inflammatory or infectious processes. Studies have explored the potential link between CRP dysregulation in the clearance of apoptotic cells and cellular debris and the onset of systemic lupus erythematosus (SLE), though definitive evidence is currently lacking. Animal models of alveolitis have demonstrated protective effects of CRP in lung tissue, where it reduces neutrophil-mediated alveolar damage and protein leakage into the lungs.

This protein plays a role in recognizing and facilitating the clearance of foreign pathogens and damaged cells by binding to phosphocholine, phospholipids, histones, chromatin, and fibronectin (see Image. C-Reactive Protein Isoforms and Their Phosphocholine Complexes). CRP activates the classical complement pathway and engages phagocytic cells via Fc receptors, expediting the removal of apoptotic cells, necrotic debris, and pathogens.

Pathologic activation can occur in autoimmune processes when CRP binds to autoantibodies that expose phosphocholine residues. This mechanism contributes to disease in conditions such as idiopathic thrombocytopenic purpura. In certain contexts, CRP-mediated complement activation may exacerbate tissue damage through downstream inflammatory cytokine release.

Unlike the erythrocyte sedimentation rate, which indirectly reflects inflammation, CRP levels change rapidly in response to inflammatory stimuli. CRP concentrations increase acutely and decline promptly once the underlying trigger resolves. Chronic elevation may indicate ongoing inflammation from persistent infections or inflammatory arthritides, such as rheumatoid arthritis.

Numerous conditions can elevate CRP levels, including both acute and chronic processes, whether infectious or noninfectious. Markedly elevated CRP concentrations most commonly reflect infection, representing an example of pathogen-associated molecular pattern (PAMP) recognition. Trauma can also induce a significant elevation of CRP through the alarmin response.

More modest CRP increases often arise from a broader spectrum of stimuli, including sleep disturbances, periodontal disease, or low-grade systemic inflammation. Higher CRP levels correlate with reduced engagement in light physical activity or moderate-to-vigorous physical activity, as well as increased sedentary time.