Inflammatory/Immune Markers

IL-6

1

Description
Interleukin-6 (IL-6) is a protein produced throughout the body as part of the immune response. IL-6 is one of a class of immune system regulators called cytokines that serve a variety of immune functions in response to acute illness or injury. As a pro-inflammatory cytokine, IL-6 is involved in activating inflammatory pathways. IL-6 is always present in the body in small amounts (<1-2 ug/mL), and concentration varies by time of day. However, in periods of immune activation, blood levels of IL-6 increase quickly, reaching as high as 40 times normal levels. IL-6 levels also rise with advancing age and are related to a variety of chronic conditions.

Significance of Measurement
Blood level of IL-6 is known to rise with advancing age in humans, and the dysregulation of IL-6 may be a contributing factor to many of the diseases of aging. Chronic conditions associated with high IL-6 include include osteoporosis, arthritis, type 2 diabetes, certain cancers, Alzheimer's disease (see Scholz, 1996; Papanicolaou, 1998). High levels of IL-6 are also related to cardiovascular disease, heart attack, and stroke (Kannel et al., 1987; Kuller et al., 1991, 1996; Mendall et al., 1996; Ridker et al., 1997; Tracy et al., 1995, 1997). In the elderly, high IL-6 levels result in an increased risk of functional disability and functional decline (Cohen et al., 1997; Ferrucci et al., 1999; Reuben et al., 2002), cognitive decline (Weaver et al., 2002), and mortality (Harris et al., 1999; Reuben et al., 2002).

The association of IL-6 with cardiovascular disease is related to the central role this cytokine plays in promoting the production of C-reactive protein (CRP), an important risk factor for myocardial infarction (Kiechl, et al., 2001; Ridker et al., 1997).

Method of Measurement
Blood serum sample is required. In the MacArthur Study an enzyme-linked immunosorbent assay (ELISA) test was used to measure interleukin-6 (IL-6) levels (High Sensitivity Quantikine kit, R&D Systems, Minneapolis, MN). In the Whitehall Study, IL-6 was assayed using a commercial high-sensitivity, 2-site, enzyme-linked immunosorbent assay kit.

References
· Cohen, H., Pieper, C., Harris, T., Rao, K.M., & Currie, M. (1997). Plasma IL-6: An indicator of functional disability in community dwelling elderly. Journal of Gerontology: Medical Sciences, 52A, M201-M208.
· Ferrucci, L., Harris, T.B., Guralnick, J.M., Tracy, R.P., Corti, M.C., Cohen, H.J., et al. (1999). Serum IL-6 level and the development of disability in older persons. Journal of the American Geriatrics Society, 47, 639-646.
· Harris, T.B., Ferrucci, L., Tracy, R.P., Corti, M.C., Wacholder, S., Ettinger, W.H. et al. (1999). Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. American Journal of Medicine, 106, 506-512.
· Kannel, W., Wolf, P., Castelli, W., & D’Agostino, R. (1987). Fibrinogen and risk of cardiovascular disease: The Framingham Study. Journal of the American Medical Association, 258, 1183-1186.
· Kiechl, S., Egger, G., Mayr, M., Wiedermann, C.J., Bonora, E., Oberhollenzer, F., et al. (2001). Chronic infections and the risk of carotid artherosclerosis: Prospective results from a large population study. Circulation, 103, 1064-1070.
· Kuller, L., Eichner, J., Orchard, T., Grandits, G., McCallum, L., & Tracy, R. (1991). The relation between serum albumin levels and risk of coronary heart disease in the Multiple Risk Factor Intervention Trial. American Journal of Epidemiology, 134, 1266-1277.
· Kuller, L., Tracy, R., Shaten, J., & Meilahn, E. (1996). Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. American Journal of Epidemiology, 144, 537-547.
· Mendall, M., Patel, P., Ballam, L., Strachan, D., & Northfield, T. (1996). C-reactive protein and its relation to cardiovascular risk factors: A population based cross sectional study. British Medical Journal, 312, 1049-1050.
· Papanicolaou, D.A., Wilder, R.L., Manolagas, S.C. & Chrousos, G.P. (1998). The pathophysiologic roles of interleukin-6 in human disease. Annals of Internal Medicine, 128, 127-137.
· Reuben, D.B., Cheh, A.I., Harris, T., Ferrucci, L., Rowe, J., Tracy, R., et al. (2002). Peripheral blood markers of inflammation predict mortality and functional decline in high-functioning community-dwelling older persons. Journal of the American Geriatrics Society, 50, 638-644.
· Ridker, P.M., Cushman, M., Stampfer, M.J., Tracy, R.P. & Hennekens, C.H. (1997). Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. The New England Journal of Medicine, 336, 973-979.
· Scholz, W. (1996). Interleukin 6 in diseases: Cause or cure? Immunopharmacology, 31, 131-150.
· Tracy, R., Bovill, E., Yanez, D., Psaty, B., Fried, L., Heiss, G., et al. (1995). Fibrinogen and factor VIII, but not fact VII, are associated with measures of subclinical cardiovascular disease in the elderly: Results from the Cardiovascular Health Study. Arteriosclerosis, Thrombosis and Vascular Biology, 15, 1269-1279.
· Tracy, R., Lemaitre, R., Psaty, B., Ives, D., Evans, R., Cushman, M., et al. (1997). Relationship of C-reactive protein to risk of cardiovascular disease in the elderly: Results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arteriosclerosis, Thrombosis and Vascular Biology, 17, 1121-1127.
· Weaver, J.D., Huang, M.H., Albert, M., Harris, T., Rowe, J.W., & Seeman, T.E. (2002). Interleukin-6 and risk of cognitive decline. Neurology, 59, 371-378.

C-reactive protein

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Description
C-Reactive Protein (CRP) is an acute phase response protein that indicates blood levels of inflammation. CRP levels rise as part of the immune response to infection and injury and may be elevated due to chronic conditions, like diabetes, psoriasis and asthma (http://labtestsonline.org/understanding/analytes/crp/sample.html).

C-reactive protein is considered one of the best measures of the acute phase response to an infectious disease or other cause of tissue damage and inflammation. The level of CRP can jump a thousand-fold in response to inflammation. It drops relatively quickly as soon as the inflammation passes (http://labtestsonline.org/understanding/analytes/crp/sample.html).

Significance of Measurement
A high level of CRP in the blood suggests an acute infection or inflammation. A blood level above 10 mg/dL is considered indicative of acute illness.

High levels of CRP may also serve as an indicator of several conditions, including rheumatoid arthritis, rheumatic fever, tuberculosis, pneumonia, and lupus. CRP levels are also related to hormone levels in women, so that higher CRP can be detected during the last half of pregnancy and in women using oral contraceptives or hormone replacement therapy.

Recently, research has suggested that moderate levels of CRP, particularly those between 3 and 10 mg/dL (Ridker & Cook, 2004), are related to the development of cardiovascular disease (Danesh et al., 1998, 1999, 2000; Ridker et al., 2000) and cardiac events, including heart attack (Ridker et al., 1997) and stroke (Ridker et al., 2000). Moderate levels of CRP have also been has also been related to arthritis (Sowers et al., 2002), cancer (Erlinger et al., 2004), mortality (Harris et al., 1999; Reuben et al., 2002), physical and cognitive decline (Reuben et al., 2002; Weaver et al., 2000).

Method of Measurement
CRP can be measured with blood samples or blood spots. The CRP test measures the concentration in blood plasma of a special type of protein produced in the liver that is present during episodes of acute inflammation or infection

There is a high sensitivity CRP test (hs-CRP) in addition to the regular CRP test. The hs-CRP measures very low amounts of CRP in the blood and is typically used to assess the level of risk for heart problems. Most hospitals do not perform the high sensitivity CRP test used in research settings
(http://labtestsonline.org/understanding/analytes/crp/sample.html).

References
· Danesh, J., Collins, R., Appleby, P., & Peto, R. (1998). Association of fibrinogen, c-reactive protein, albumin, or leukocyte count with coronary heart disease: Meta-analyses of prospective studies. Journal of the American Medical Association, 270, 1477-1482.
· Danesh, J., Muir, J., Wong, Y., Ward, M., Gallimore, J.R., & Pepys, M.B. (1999). Risk factors for coronary heart disease and acute-phase proteins: A population based study. European Heart Journal, 20, 954-959.
· Danesh, J., Whincup, P., Walker, M., Lennon, L., Thomson, A., Appleby, P., et al (2000). Low grade inflammation and coronary heart disease: Prospective study and updated meta-analysis. British Medical Journal, 321, 199-204.
· Erlinger, T.P., Platz, E.A., Rafai, N., & Helzlsouer, K.J. (2004). C-reactive protein and the risk of incident colorectal cancer. Journal of the American Medical Association, 291, 585-590.
· Harris, T.B., Ferrucci, L., Tracy, R.P., Corti, M.C., Wacholder, S., Ettinger, W.H., et al. (1999). Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. American Journal of Medicine, 106, 506-512.
· Lab Tests Online. (n.d.). C-Reactive Protein. Retrieved March 24, 2005, from http://labtestsonline.org/understanding/analytes/crp/sample.html
· Reuben, D.B., Chen, A.I., Harris, T., Ferrucci, L., Rowe, J., Tracy, R., & Seeman, T. (2002). Peripheral blood markers of inflammation predict mortality and functional decline in high-functioning community-dwelling older persons. Journal of the American Geriatrics Society, 50, 638-644.
· Ridker, P.M., & Cook, N. (2004). Clinical usefulness of very high and very low levels of c-reactive protein across the full range of Framingham Risk Scores. Circulation, 109, 1955-1959.
· Ridker, P.M., Hennekens, C.H., Buring, J.E., & Rifai, N. (2000). C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. New England Journal of Medicine, 342, 836-843.
· Ridker, P.M., Cushman, M., Stampfer, M.J. Tracy, R.P., & Hennekens, C.H. (1997). Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. New England Journal of Medicine, 336, 973-979.
· Sowers, M., Jannausch, M., Stein, E., Jamadar, D., Hochberg, M., & Lachance, L. (2002). C-reactive protein as a biomarker of emergent osteoarthritis. Osteoarthritis & Cartilage, 10, 595-601.
· Weaver, J.D., Huang, M.H., Albert, M., Harris, T., Rowe, J.W., & Seeman, T.E. (2002). Interleukin-6 and risk of cognitive decline. Neurology, 59, 371, 378

Fibrinogen

1

Description
Fibrinogen, also called serum fibrinogen, plasma fibrinogen and factor I, is a protein produced by the liver. Fibrinogen helps stop bleeding by helping the formation of blood clots. During normal blood clotting, fibrinogen is broken down by an enzyme called thrombin into short fragments of fibrin. Thrombin also activates a substance called Factor XIII. Factor XIII helps weave the fibrin fragments into a complex lattice, closing off injured blood-vessel walls. Blood platelets attach to the fibrin fragments, clumping together to form blood clots and stop bleeding.

Significance of Measurement
Fibrinogen has been shown to be strongly predictive of both mortality (Fried et al., 1998) and the onset of cardiovascular disease (Kannel et al., 1987; Patel et al., 1994, 1995; Ridker et al., 1997; Tracy et al., 1995). Fibrinogen is also as important as low levels of HDL cholesterol in predicting cardiovascular disease (de la Serna, 1994).

The relationship between SES and fibrinogen levels has been suggested as the mechanism linking low social status and stress to cardiovascular disease (Brunner et al., 1996; De Boever et al., 1995; Markowe et al., 1985; Wilson et al., 1993).

Method of Measurement
Measured using blood serum or plasma. The NHANES study measured fibrinogen concentration in plasma using the Clauss clotting method. This test method involves measuring the rate of fibrinogen to fibrin conversion in a diluted sample under the influence of excess thrombin. Since under these conditions the fibrinogen content is rate limiting, the clotting time can be used as a measure of the concentration of the fibrinogen and in fact, the clotting time is inversely proportional to the level of fibrinogen in the plasma(http://www.cdc.gov/nchs/data/nhanes/frequency/lab11doc.pdf).

References
· Brunner, E., Smith, G., Marmot, M., Canner, R., Beksinska, M., & O’Brien, J. (1996). Childhood social circumstances and psychosocial and behavioural factors as determinants of plasma fibrinogen. Lancet, 347, 1008-1013.
· De Boever, E., De Bacquer, D., Braeckman, L., Baele, G., Rosseneu, M., & De Backer, G. (1995). Relation of fibrinogen to lifestyles and to cardiovascular risk factors in a working population. International Journal of Epidemiology, 24(5), 915-921.
· de la Serna, G. (1994). Fibrinogen: A new major risk factor for cardiovascular disease: A review of the literature. Journal of Family Practice, 39, 468-477.
· Fried, L., Kronmal, R., Newman, A., Bild, D., Mittelmark, M., Polak, J., et al (1998). Risk factors for 5-year mortality in older adults: The Cardiovascular Health Study. Journal of American Medical Association, 279, 585-592.
· Kannel, W., Wolf, P., Castelli, W., & D’Agostino, R. (1987). Fibrinogen and risk of cardiovascular disease: The Framingham Study. Journal of American Medical Association, 258, 1183-1186.
· Markowe, H., Marmot, M., Shipley, M., Bulpitt, C., Meade, T., Stirling, Y., et al (1985). Fibrinogen: A possible link between social class and coronary heart disease. British Medical Journal, 291, 1312-1314.
· National Center for Health Statistics. (2002). NHANES 1999-2000 public data release file: Laboratory 11- C-reactive protein (CRP), fibrinogen, helicobacter pylori, bone alkaline phosphatase, and urinary N-teleopeptides. Retrieved March 28, 2005, from http://www.cdc.gov/nchs/data/nhanes/frequency/lab11doc.pdf
· Patel, P., Carrington, D., Strachan, D., Leatham, E., Goggin, P., Northfield, T., et al. (1994). Fibrinogen: A link between chronic infection and coronary heart disease. Lancet, 343(8913), 1634-1635.
· Patel, P., Mendall, M., Carrington, D., Strachan, D., Leatham, E., & Molineaux, N. (1995). Association of helicobacter pylori and chlamydia pneumonia infections with coronary heart disease and cardiovascular risk factors. British Medical Journal, 311, 711-714.
· Ridker, P., Cushman, M., Stampfer, M., Tracy, R., & Hennekens, C. (1997). Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. New England Journal of Medicine, 336, 973-979.
· Tracy, R., Bovill, E., Yanez, D., Psaty, B., Fried, L., Heiss, G., et al. (1995). Fibrinogen and factor VIII, but not fact VII, are associated with measures of subclinical cardiovascular disease in the elderly: Results from the Cardiovascular Health Study. Arteriosclerosis, Thrombosis and Vascular Biology, 15, 1269-1279.
· Wilson, T., Kaplan, G., Kauhanen, J., Cohen, R., Wu, M., Salonen, R., et al. (1993). Association between plasma fibrinogen concentration and five socioeconomic indices in the Kuopio Ischemic Heart Disease Risk Factor Study. American Journal of Epidemiology, 137(3), 292-300.

von Willebrand Factor

Immunoglobulins (IgA, IgG,IgE)

CD4

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