The acute phase response and C-reactive protein

The acute phase response—trauma, tissue necrosis, infection, inflammation, and malignant neoplasia induce a complex series of nonspecific systemic, physiological, and metabolic responses including fever, leucocytosis, catabolism of muscle proteins, greatly increased de novo synthesis and secretion of a number of ‘acute phase’ plasma proteins, and decreased synthesis of albumin, transthyretin, and high- and low-density lipoproteins. The altered plasma protein concentration profile is called the acute phase response. All endothermic animals mount a similar response, suggesting that it may have survival value, and increased availability of proteinase inhibitors, complement, clotting, and transport proteins presumably enhances host resistance, minimizes tissue injury, and promotes regeneration and repair.

Acute phase proteins—these are mostly synthesized by hepatocytes, in which transcription is controlled by cytokines including interleukin 1, interleukin 6, and tumour necrosis factor. The circulating concentrations of complement proteins and clotting factors increase by up to 50 to 100%; some of the proteinase inhibitors and α₁-acid glycoprotein can increase three- to fivefold; but C-reactive protein and serum amyloid A protein (an apolipoprotein of high-density lipoprotein particles) are unique in that their concentrations can change by more than 1000-fold.

C-reactive protein (CRP)—this consists of five identical, nonglycosylated, noncovalently-associated polypeptide subunits. It binds to substances which contain phosphocholine, including phospholipids, some plasma lipoproteins, and the plasma membranes of damaged cells, also to small nuclear ribonucleoprotein particles when these are exposed in dead or damaged cells. By activating the classical complement pathway after binding to ligand it can trigger the inflammatory, opsonizing, and complex-solubilizing activities of the complement system, perhaps thereby protecting against infection with organisms that express phosphocholine (e.g. pneumococci and Haemophilus influenzae) and aiding in recognition and ‘scavenging’ of cellular debris.

Clinical features—(1) determination of CRP in serum or plasma is the most useful marker of the acute phase response in most inflammatory and tissue damaging conditions. It is a stable analyte, easy to measure, and has proven value in monitoring therapeutic responses. (2) Acute phase proteins may be harmful in some circumstances. Sustained increased production of serum amyloid A protein can lead to the deposition of AA-type, reactive systemic amyloid, a serious and usually fatal condition that can complicate chronic infective and inflammatory diseases. CRP, through its capacity to activate complement, can exacerbate ischaemic (and possibly also other forms) of tissue damage.