Diversity of acute phase proteins

There is considerable diversity among acute phase proteins with respect to the concentrations attained, their structures, their behavior in different species and in different diseases. The concentration of a plasma protein depends on the balance between its secretion rate and its clearance rate. The availability of the protein for a particular function is the important factor in physiological and pathophysiological situations, rather than simply its serum concentration measured ex vivo. Increased availability can exist by virtue of increased production and yet be disguised by increased utilization or clearance so that plasma levels are normal or even decreased. Definition of acute phase proteins solely on the behavior of their plasma levels, while easy and convenient, is thus superficial and clearly misses important patterns of metabolic regulation of plasma proteins.

Among the acute phase proteins the increases vary between one- and twofold, for example, for some complement components, through up to five- to tenfold, for example for some clotting factors and proteinase inhibitors, and up to 1000-fold or more for CRP and SAA. CRP and SAA are trace constituents of normal plasma and are the most dramatic acute phase reactants increasing very rapidly to peak levels which may be up to 3000 times normal at about 48 h after an acute event. Persistently high levels may occur in chronic active disease processes, but with effective therapy or spontaneous resolution they fall to normal with a half-time as fast as 24-30 h. In contrast, all other acute phase proteins respond more slowly, taking days to reach their peak values, and also falling much more slowly, reflecting clearance and catabolic half-lives of days rather than hours. Furthermore, unlike most other acute phase proteins, there seems to be little effect of disease processes on the clearance or catabolism of CRP and SAA. The synthesis rate, which reflects the intensity of the pathology which induced their production, is thus the most important or even sole determinant of their plasma levels. For all these reasons these two acute phase proteins are the most useful for clinical purposes in humans.

Acute phase proteins are structurally extremely diverse. Most are glycoproteins produced predomin antly, though not exclusively, by hepatocytes. The extent and heterogeneity of glycosylation is often significantly increased during the acute phase response, apparently under the influence of the stimulatory cytokines. However, CRP and SAA are not glycosylated. SAA, unlike all the other acute phase proteins, is an apolipoprotein associated with high density lipoprotein, and unlike CRP, which shows no polymorphism, SAA is highly polymorphic. There are several sets of genes for SAA, including some which are predominantly expressed in tissues other than liver and and the products of which are not significantly present in the plasma. There are also differences in the responses of different SAA genes to different acute phase stimuli. The importance of this diversity is not clear since the normal function of SAA, and its role in acute phase situations, are not known. However, SAA is the precursor of AA protein which forms the fibrils in reactive systemic, AA-type amyloidosis, a serious and usually fatal complication of chronic persistent infections and inflammatory disorders.

While the profile of acute phase plasma proteins is broadly similar across species there are nonetheless important differences. For example, SAP is a major acute phase reactant only in the mouse, and there are many other differences in normal levels and acute phase behavior of other members of the pentraxin family of proteins to which it belongs. While these differences may be important for the usefulness of particular proteins as markers in clinical or experimental situations, they may not reflect, as has been pointed out above, the underlying metabolic regulation. On the other hand, some species differences are clearly of physiological and pathophysiological importance. Thus, although rats have a gene for a homolog of SAA, the expression of which is regu lated as an acute phase protein, the product docs not appear as a plasma lipoprotein and rats never get AA amyloidosis. This contrasts with the behavior of SAA in all other mammals and birds which have been studied.

Finally, even within a species there is diversity in the acute phase response to different stimuli, to different disease processes and between different individuals. This has been most extensively studied in the case of CRP and SAA responses in humans, in whom there is a small number of serious inflammatory or tissue-damaging disorders characterized by absent or minimal acute phase production of these proteins. These exceptional disorders include systemic lupus erythematosus, dermatomyositis, Sjogren's disease, scleroderma, ulcerative colitis and leukemia, in all of which only a minority of patients have more than modest elevations of CRP or SAA concentration.

even in the face of extensive and active disease. Other acute phase proteins are produced, apparently normally, and if these patients acquire a significant intercurrent infection they then mount major acute phase responses of CRP and SAA. These phenomena are of considerable clinical value but the underlying mechanisms, whether of macrophage response, cytokine production or hepatocyte response are not known. In the great majority of other diseases in which CRP and SAA levels are greatly increased, the levels attained closely reflect the extent and activity of the pathological process in each individual, and serial monitoring provides valuable objective and quantitative information about the natural history of the disorder or its response to treatment. However, while there is usually a good general correlation between disease activity and CRP/SAA concentration there may nonetheless be considerable variation between the acute phase protein levels seen in different individuals with apparently comparable degrees of clinical activity. These variations are due partly to difficulties in clinical assessment of disease activity but mostly to genuine interindividual differences in the acute phase response.

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