Clonal anergy

For the use of "anergy" in thermodynamics, see Exergy.

Anergy is a term in immunobiology that describes a lack of reaction by the body's defense mechanisms to foreign substances, and consists of a direct induction of peripheral lymphocyte tolerance. An individual in a state of anergy often indicates that the immune system is unable to mount a normal immune response against a specific antigen, usually a self-antigen. Lymphocytes are said to be anergic when they fail to respond to their specific antigen. Anergy is one of three processes that induce tolerance induction, modifying the immune system to prevent self-destruction (the others being clonal deletion and immunoregulation).^[1]

Mechanism

This phenomenon was first described in B lymphocytes by Gustav Nossal and termed "Clonal Anergy." The clones of B lymphocytes in this case can still be found alive in the circulation, but are very ineffective at mounting immune responses. Later Ronald Schwartz and Marc Jenkins described a similar process operating in the T lymphocyte. Many viruses (HIV being the most extreme example) seem to exploit the immune system's use of tolerance induction to evade the immune system, though the suppression of specific antigens is done by fewer pathogens (notably Mycobacterium leprae).^[2]

At the cellular level, the term "anergy" defines the inability of an immune cell to mount a complete response against its target. In the immune system, circulating cells called lymphocytes form a primary army that defends the body against pathogenic viruses, bacteria and parasites. There are two major kinds of lymphocytes - the T lymphocyte and the B lymphocyte. Among the millions of lymphocytes in the human body, only a few actually are specific for any particular infectious agent. At the time of infection, these few cells must be recruited and allowed to multiply rapidly. This process - called "clonal expansion" - allows the body to quickly mobilise an army of clones, as and when required. This clonal army then combats the pathogen until the body is free of the infection. Following clearance of the infection, the clones that are no longer needed die away naturally.

However, a small number of the body's army of lymphocytes are able to react with proteins that are normally present in a healthy body. The clonal expansion of those cells can lead to autoimmune diseases, wherein the body attacks itself. In order to prevent this process, lymphocytes possess an intrinsic quality-control mechanism. This machinery shuts down the lymphocytes' ability to expand, if the trigger for the expansion turns out to be the body's own protein. T-cell anergy can arise when the T-cell does not receive appropriate co-stimulation in the presence of specific antigen recognition.^[2] B-cell anergy can be induced by exposure to soluble circulating antigen, and is often marked by a downregulation of surface IgM expression and partial blockade of intracellular signaling pathways.^[2]

Clinical significance

Anergy may be taken advantage of for therapeutic uses. The immune response to grafting of transplanted organs and tissues could be minimized without weakening the entire immune system— a side effect of immunosuppressive drugs like cyclosporine. Anergy may also be used to induce activated lymphocytes to become unresponsive with autoimmune diseases like diabetes mellitus, multiple sclerosis and rheumatoid arthritis.^[1] Likewise, preventing anergy in response to a tumoral growth may help in anti-tumor responses.^[3]

Testing

The "Multitest Mérieux" or "CMI Multitest" system (Multitest IMC, Istituto Merieux Italia, Rome, Italy) has been used as a general test of the level of cellular immunity. It is an intradermal test of skin reactivity (similar to tuberculin tests) in which a control (glycerol) is used with seven antigens of bacterial or fungal origin (tetanus toxoid, tuberculin, diphtheria, streptococcus, candida, trichophyton, and proteus). In this test reactions are categorized according to the number of antigens provoking a response and the summed extent of the skin response to all seven antigens. Here anergy is defined as a region of skin reactivity of 0-1 mm, hypoergy as a reaction of 2–9 mm in response to fewer than three antigens, normoergy as a reaction of 10–39 mm or to three or more antigens, and hyperergy for a reaction of 40 mm or more.^[4][5][6]

References

1. ^ ^{a b} Schwartz, Ronald H. (1993). "T Cell Anergy". Scientific American 269 (2): 61–71. 
2. ^ ^{a b c} Janeway, Charles; Travers, Paul; Walport, Mark; Shlomchik, Mark (2001). Immunobiology; Fifth Edition. New York and London: Garland Science. ISBN 0-8153-4101-6. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=imm.TOC&depth=10. 
3. ^ Saibil, Samuel D.; Deenick, Elissa K.; Ohashi, Pamela S. (2007). "The sound of silence: modulating anergy in T lymphocytes". Current Opinion in Immunology 19 (6): 658–664. doi:10.1016/j.coi.2007.08.005. PMID 17949964. 
4. ^ Müller, Nicole; Schneider, Th; Zeitz, M; Marth, Th (2001). "Whipple's disease: new aspects in pathogenesis and diagnoses". Acta Endoscopica 31: 243–253. http://documents.irevues.inist.fr/bitstream/2042/7452/1/actaend_2001_3_243-253.pdf. 
5. ^ Spornraft, P.; Fröschl, M.; Ring, J.; Meurer, M.; Goebel, F.-D.; Ziegler-Heitbrock, H.W.L.; Riethmüller, G.; Braun-Falco, O. (1988). "T4/T8 ratio and absolute T4 cell numbers in different clinical stages of Kaposi's sarcoma in AIDS". British Journal of Dermatology 139: 1–9. http://www.rethinkingaids.com/portals/0/TheCD/S/spo.pdf. 
6. ^ De Flora, S.; Grassi, C.; Carati, L. (1997). "Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment". Eur Respir J 10 (7): 1535–1541. doi:10.1183/09031936.97.10071535. PMID 9230243. http://erj.ersjournals.com/cgi/reprint/10/7/1535.pdf. 

Further reading

• Jenkins, Marc K. (February 1992). "The role of cell division in the induction of clonal anergy". Immunology Today 13 (2): 69–73. doi:10.1016/0167-5699(92)90137-V. PMID 1349483. 

External links

• MeSH Clonal+anergy