Human C-reactive protein (CRP) is the classical acute phase plasma protein, the circulating concentration of which increases rapidly and dramatically in response to almost all forms of tissue injury, infection and inflammation.
Structure. CRP belongs to the evolutionarily conserved pentraxin family of plasma proteins, is encoded by a single gene on chromosome 1 and shows no structural polymorphism. The CRP molecule comprises 5 identical non-covalently associated 206 residue non-glycosylated single chain subunits arranged with cyclic pentameric symmetry in a disc-like configuration. The flattened ?-jelly roll fold of each protomer is characteristic of the lectin fold superfamily, with one face bearing the calcium dependent ligand binding pocket by which CRP recognises its ligands. In the presence of the ubiquitous in vivo concentration of extracellular calcium, human CRP is exceptionally stable both to dissociation into protomers and to proteolysis. CRP is also a stable analyte in serum or plasma and precise reproducible commercial automated assays are widely available, all standardised on the WHO International Reference Standard.
Metabolism. Circulating CRP is overwhelmingly synthesised by hepatocytes under transcriptional regulation via the pro-inflammatory cytokine cascade, including IL-6, IL-1 and TNF. It has been suggested that CRP may also be produced by other cell types, including adipocytes, but the evidence is limited. The plasma t½ of circulating CRP in humans is very constant at about 19 h under all conditions so that the sole determinant of the plasma concentration is the synthesis rate.
Baseline values. The median plasma concentration in healthy European and European American adults is about 0.8 mg/l, but there are significant ethnic differences, for example the median is around 0.1 mg/l, among Japanese in Japan. Lowest values are around 0.05 mg/l but the CRP concentration can exceed 500 mg/l in the acute phase response, a 10,000 fold range. Baseline values in healthy individuals are very stable at a level specific for each subject but even in the absence of any clinical signs or symptoms there are occasional spikes, and in cross sectional studies among general US populations about a third have values of 310 mg/l. About 50% of the variance in baseline CRP values is genetically determined; the most important other determinant is obesity, especially central abdominal fat, with which baseline CRP concentration is closely associated independently of genetic influences. CRP values are also associated with the known causative risk factors for coronary heart disease: smoking, metabolic syndrome, diabetes, hypertension and lack of physical exercise, as well as with low socio-economic class and with an extremely wide range of cardiovascular and non-cardiovascular medical conditions. Increased baseline CRP is significantly prognostic for all cause mortality and apparently reflects, non-specifically, metabolic and/or cellular distress in the broadest sense.
Acute phase response. Most significant forms of pathology, including trauma, tissue necrosis, infection, inflammation and malignant neoplasia are associated with major acute phase responses of CRP in which there is generally a close correlation in each individual between disease severity and CRP concentration. A few diseases, in particular systemic lupus erythematosus and related collagen diseases, ulcerative colitis and leukaemia, are associated with modest or even absent CRP responses, for reasons which are not known, but intercurrent infection in these conditions does stimulate major CRP production. These observations underpin the considerable utility of CRP in clinical practice. However it is essential to recognise that the CRP response is not specific, and that CRP values can never be diagnostic and can be interpreted only at the ?bedside? together with all other clinical and laboratory information.
Ligand binding. The defining functional property of CRP is its calcium dependent capacity to bind specific ligands, the highest affinity interaction being with phosphocholine. CRP binds many compounds that contain phosphocholine, although the ligand groups must be appropriately available. Thus CRP binds to plasma membranes of damaged and dead cells but not to healthy cells, and to modified LDL and oxidised or lysophospholipids but not to their native or unmodified counterparts. Phosphocholine is very widely distributed in endogenous compounds and in extrinsic substances derived from micro-organisms, parasites and plants, and a high proportion of germline immunoglobulin genes encode antiphospocholine specificity. The capacity to recognise and respond appropriately to molecules containing phosphocholine may thus be of pivotal biological significance. CRP also recognises a variety of other materials, including small nuclear ribonucleoprotein particles, various polyanions and some carbohydrates, all via the same calcium dependent ligand binding pocket that binds phosphocholine.
Functional effects & functions? Human CRP bound to its macromolecular ligands, or when aggregated itself, potently activates the classical complement pathway via C1q. Bound human CRP also binds factor H and may thereby regulate complement activation. In a further analogy to antibodies, human CRP efficiently precipitates soluble ligands and agglutinates particulate ligands. It is therefore possible that, like antibodies, human CRP may contribute to host defence against pathogens, to beneficial scavenging of endogenous ligands, and also to pro-inflammatory processes that exacerbate tissue damage. There are experimental observations suggesting these roles and others for CRP in animal models but none are unequivocally compelling, largely because there are important structural, functional and behavioural differences between CRP in different species, and because of the inescapable limitations of human CRP functioning in a xenogeneic in vivo milieu. Also mice express very little CRP themselves and no CRP gene deletion has yet been performed. A wide range of direct effects of human CRP on cells in vitro have been described but these are controversial and not supported by in vivo evidence. No human deficiency state has yet been reported, and no specific in vivo inhibitor of CRP has yet been deployed, so despite assertions to the contrary, neither the normal physiological functions of human CRP nor its possible role in pathology are yet definitively known.
Any in vivo function proposed for human CRP must be compatible with the speed of the CRP response and the huge differences between baseline values and those seen during the acute phase response. These considerations argue strongly against suggestions that CRP is likely to be involved in modulation of the cytokine cascade, coagulation pathways, vascular tone or endothelial function.
Cardiovascular disease comprises markedly different types of pathology: atherosclerosis, the lifelong process caused by LDL cholesterol; atherothrombosis or another catastrophic acute event that causes arterial occlusion; and ischemic infarction of the tissue supplied by an occluded artery. The levels of tissue damage and inflammation and the concentrations of CRP associated with these different pathologies, differ by orders of magnitude and should not be confused or conflated with each other.
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