C-Reactive Protein (C-RP)
PKGhatak, MD
In an article published in the Journal of Experimental Medicine in 1930, William S. Tillett and Thomas Francis Jr described a serological reaction with a molecule of pneumococcus. A more clear picture emerged from the authors, Abernathy and Avery, in 1941 from their work on the serology of pneumococcal infection describing a flocculation reaction with C-polysaccharide of pneumococcus and a plasma protein. That protein is now known as C-Reactive Protein.
Chemistry of C-RP.
C-RP is a member of the Pentraxin family of proteins. Pentraxin is a ring shaped planer symmetry protein, with a hole in the center, like a doughnut. This structure gives a high degree of stability to the molecule and resists enzymatic attacks. The name pentraxin came from the Greek Penta Ragos meaning five berries. The molecular weight of C-RP is 115,135 Daltons and each molecule is composed of five identical non-glycosylated polypeptide subunits, each contains 206 amino acid residues. Not more than 15 sugar units are present in each C-RP molecule, but the glucose molecule is not one of them. The amino acids, asparagine, serine, threonine, hydroxylysine, and hydroxyproline are the only 5 amino acids present, in repeats in a C-RP molecule. The glycosidic linkage between carbohydrate and protein occur more frequently through oxygen rather than nitrogen.
Site of biosynthesis.
Hepatocytes synthesize C-RP when Interleukin 6 (IL-6) is released from the damaged cells into the blood and IL-6 is carried to the liver. IL-1 beta enhances IL-6 response in the synthesis of C-RP. The C-RP levels may go up 1000 times from a low normal blood level, 0 to 8 mg/L. Protein molecules are synthesized elsewhere; an enzyme Glycosyltransferase, specific for each type of sugar molecule, catalyzes the attachment of the sugar to the protein moiety.
Plasma level of C-RP.
Normal plasma levels of C-RP are between 0 to 8 mg/L. The half-life of C-RP is 19 hrs. and remains constant under all conditions of health and health and disease. The concentration in plasma is solely determined by the rate of synthesis by hepatocytes under IL-6 stimulus which reflects the intensity of the pathological processes. Once the IL-6 levels fall, the CRP synthesis stops and plasma levels return to the base level in 24 -48 hrs. This property of C-RP makes it an ideal acute-phase protein for-
Screening physical illness.
Monitoring the response to treatment
Detecting any intercurrent infection in immunosuppressed patients
Highly sensitive C-RP (hs-CRP).
More than 30 years ago, researchers noticed lower than normal levels of CRP can be quantified and used in clinical medicine for cardiovascular risk assessment and prediction of future events. High-sensitive CRP determination is an immunoassay and is reported as mg /L. Interpretation of results of hs-CPR is as follows-
1.hsCRP less than 1mg/L is not associated with any acute cardiovascular event and does not have increased incidence when followed for 20 years.
hs-CPR 1 to 3 mg/L is a medium risk factor for Coronary events, Stokes and PAD ( peripheral arterial disease).
hs-CRP over 3 mg/L results should be considered a risk factor for the diseases listed in No2., only if other causes of a more common condition like Rheumatoid arthritis, SBE (subacute bacterial endocarditis), or periodontal disease, etc. is eliminated by repeating hs-CPR a week later.
A few special features of C-RP.
Ligand binding molecules.
C-RP has the highest affinity for phosphocholine residue. It binds readily with small molecules of ribonuclear proteins. C-RP binds with histone, apoptotic cells (programmed cell death) and oxidized LDL (low density lipoprotein).
Complement Activation.
C-RP-ligand complex binds with the C1q complement of the classic pathway. In the process complements C1, C3 and C4 are completely used up. This complex only minimally activates C3 complement and do not activate complements of alternate pathway C5 to C9. The outcome of activities is the initial innate response to tissue injury or infection and promotes the opsonization of cellular debris from the inflammation site and stimulates healing.
Autoimmune disease.
The first reported evidence came from works on the blood of Rheumatoid Arthritis (RA) patients.
C-RP deposits are present in the nuclei of the cells of the synovial membrane. The intensity of RA correlates well with plasma C-RP levels and has replaced ESR (erythrocyte sedimentation rate) for monitoring of disease activities and follow up of patients under treatment. Ulcerative colitis shows a similar pattern. But SLE (systemic lupus erythematosus), Scleroderma and Polymyositis show no close relationship with plasma levels of C-RP and disease activity. This is explained on the basis of the works of certain patients who are unusually susceptible to pneumococcal infection and have very low C-RP in plasma. They have a polymorphism of the gene which encodes Guanine and Thymine ( G &T) nucleotides in the Intron of the gene which accounts for a low plasma C-RP level.
Kidney.
C-RP binds with the immune complex deposited on the basement membrane of the glomeruli in several varieties of glomerulonephritis. In an acute renal transplant rejection episode, C-RP binds with renal tubular epithelial cells and endothelial cells of the peritubular capillaries in the kidney interstitium.
A short summary of the C-RP function.
C-RP is an acute phase protein, though not specific for any particular disease, never the less is a useful clinical tool for the determination of the disease activities and follow up.
C-RP activates the classic complement pathway and has an inhibitory effect on the activation of the alternate complement pathway.
hs-CRP is a predictor of the future coronary event. Prognostic indicator of Cardiovascular events, Strokes and PAD (peripheral arterial) disease.
Taken from NIH publication.
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