Chronic Inflammation
This is caused by a prolonged persistence of an antigen (a foreign antigen such as a bacterial cell wall resisting phagocytosis) or in some autoimmune disorders where self antigen protein serves as the activating factor of T cells. This activation of T cells contributes to the wasting and tissue damage associated with chronic inflammation. The cytokines tumor necrosis factor and interferon play a crucial role in this. Interferon-gamma, which is secreted by Th cells, activates macrophages to release TNF-alpha by promoting transcription of the TNF-alpha gene and increasing the stability of the TNF-alpha mRNA transcripts. This increase in TNF-alpha leads to cachexia. To see some interesting pictures of chronic inflammation, click any of the highlighted words.

Bacterial Septic Shock
This often fatal disease occurs within a few hours after infection by certain gram negative bacteria including E. coli, P. aeruginosa, and N. meningitidis. The symptoms associated with this disorder are a decrease in blood pressure, fever, diarrhea, and blood clotting in various organs. These are a result of an overproduction of TNF-alpha and IL-1. Monoclonal antibodies to TNF-alpha may provide an effective treatment to this disorder by binding to the free TNF. On the average, $5-10 billion dollars are spent on treatment for bacterial septic shock and 70,000 Americans die from this disorder every year.

Bacterial Toxic Shock
The symptoms of this disease are similar to bacterial septic shock and this disease, too, is caused by an overproduction of tumor necrosis factor. This time, however, it is due to an increased number of T cells responding to a bacterial toxin that acts as a superantigen. Superantigens activate T cells more strongly and in greater numbers that normal antigen. For example, less that 0.01% of T cells respond to a conventional antigen but between 5-25% of T cells respond to a given superantigen. The activation of such a large number of T cells leads to an overproduction of TNF.

Graft vs. Host Disease

This disorder is quite common among bone marrow recipients. In fact, it occurs in 50-70% of these individuals. Before the transplant, the patient's immune system is suppressed and when bone marrow, which has some immunocompetent cells, is introduced an immune response against the host can occur. This happens because the immunocompetent cells of the graft recognize the host self antigens as foreign. An immune response is launched, resulting in the production of TNF which causes cytolytic damage to cells. TNF's role in this has been shown by a study which found that the binding of monoclonal antibodies to TNF eliminated GVHD following bone marrow transplants in mice.


TNF's Role in HIV Infection and AIDS

Elevated leves of cytokines, including both tumor necrosis factors, have been detected in the serum of AIDS patients. This increase in TNF may account for the wasting syndrome associated with these patients. TNF-alpha, along with other cytokines, plays a role in the proliferation of Kaposi's sarcoma cells. Also, in vitro studies have indicated have indicated that this increase in cytokines causes HIV to move out of the latent phase into the lytic phase. They do this by inducing expression of HIV reverse transcriptase in infected monocytes and HIV expression in infected CD4+ T cells.

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