The Biologic Structure and Function of CRP
Tillet and Francis first discovered CRP in 1930 at Rockefeller University while examining the serum of adult patients diagnosed with acute pneumococcal pneumonia. They observed a precipitation reaction between CRP and the C-polysaccharide cell wall of the pneumococcal bacteria. This reaction later was determined to be the result of CRP binding to C-polysaccharide in the presence of calcium, forming CRP-ligand complexes.[29,30,31,32,33,34] CRP's unique binding characteristics have led to the identification of elevated CRP levels in over 70 different infectious and noninfectious disorders associated with acute and chronic inflammatory disorders in adults, children, and infants.[12,29,35]
Understanding the biochemical structure and function of CRP is important to ensure appropriate use. CRP is a member of the pentraxin family of proteins, which are nonspecific, acute-phase reactant proteins composed of 5 identical 23-kDa polypeptide subunits arranged in a cyclic pentameter shape.[30,31,33,34] Each of these subunits (Fig 1) contains one binding site for a phosphocholine molecule and 2 binding sites for calcium.[30,31,32,33,34]
Pentameter structure of CRP, including calcium and phosphocholine binding sites. These sites enable CRP to recognize and bind to a variety of microorganisms, cellular debris, and nuclear material from damaged cells. Data from Kushner.
These binding sites allow CRP to recognize and bind to a variety of biologic substrates, including phosphocholine and phospholipid components of damaged cell walls and chromatin and nuclear antigens resulting in the formation of CRP-ligand complexes.[13,30,31,32,33] CRP-ligand complexes can activate the complement system, thereby facilitating phagocytosis and the removal of materials released from damaged cells as well as potentially toxic materials from invading microorganisms.[31,32,33,36] CRP-ligand complexes also bind directly to neutrophils, macrophages, and other phagocytic cells, stimulating an inflammatory response and the release of cytokines.[31,32] Figure 2 illustrates the functions of CRP within the immune system.
Key functions of CRP within the innate immune system include the ability to (1) recognize and bind to phosphocholine exposed in damaged cell walls and found in many bacteria, fungi, and parasites; (2) act like an opsonin, marking bacteria, damaged cell walls, and nuclear debris for phagocytosis; (3) bind to Cl, the first component of the classical pathway of the complement system that triggers phagocytic activity; and (4) bind to polymorphonuclear leukocytes (PMNs) and monocytes, which stimulate the production of inflammatory cytokines. Data from DuClos.
The fetus is able to produce CRP and other acute-phase reactant proteins as early as 4 to 5 weeks of gestation.[10,12] Paired mother and infant sampling shows that CRP does not cross the placenta, and although maternal risk factors can exert an effect on the fetus, there is no correlation between maternal and infant CRP levels at birth.[37,38,39,40]
An acute-phase inflammatory response occurs as the human body mounts a systemic response to tissue injury caused by infectious, noninfectious, chemical, physical, or immunologic toxins.[32,33,34] CRP, serum amyloid A, haptoglobin, and fibrinogen are all positive acute-phase proteins regulated by cytokines, which are known to increase by at least 25% during the inflammatory response. Interleukin-1 (IL-1), interleukin-6 (IL-6), and tissue necrosis factor (TNF)- are the major cytokines that stimulate the liver to synthesize CRP and other positive acute-phase proteins (Fig 3).[32,33]
Stimulation and synthesis of positive acute-phase reactants during inflammation. Inflammation caused by infection or tissue damage stimulates the circulating inflammation-associated cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF)-. These cytokines stimulate hepatocytes to increase the synthesis and release of positive acute-phase proteins, including CRP. IL-6 is the major cytokine stimulus for CRP production.
CRP is the most sensitive of the acute-phase proteins, with levels rising as much as 1,000-fold during the acute inflammatory processes.[29,32,34] Levels begin to rise within 4 to 6 hours of the onset of signs of infection or tissue injury and peak 24 to 48 hours later. They rapidly disappear as the infection or inflammatory process resolves.[11,22,23,26]
The degree of CRP response or rise in serum may be dependent on the amount of tissue damage present. For example, elevated CRP levels from 150 to 350 mg/L have been reported in cases of invasive bacterial meningitis, whereas smaller rises from 20 to 40 mg/L occur in acute viral infections and from noninfectious causes.[29,41] CRP is a useful serum marker to assess and monitor the presence, severity, and course of the inflammatory response in infectious and noninfectious disorders, including acute myocardial infarction, angina, malignancies, rheumatoid arthritis, inflammatory bowel disease, burns, and trauma, and after surgical procedures.[29,35,41,42]
Adv Neonatal Care. 2003;3(1) © 2003 W.B. Saunders
Cite this: The Role of C-Reactive Protein in the Evaluation and Management of Infants With Suspected Sepsis - Medscape - Feb 01, 2003.