Superantigens in disease

Bacterial superantigens have been implicated as a causative agent in several acute pathological conditions, including food poisoning, toxic shock associated with staphylococcal sepsis, the toxic shock syndrome, scalded skin syndrome and scarlet fever. A common feature of these diseases is massive systemic immunoactivation, as reflected by high serum levels of TNFa, II.-1, IL-6 and IFNy. Associated toxic shock is likely, at least in part, to be due to excessive release of cytokines.

SAgs are believed to be involved in the pathogenesis of some viruses. The MMTV retrovirus is secreted in the milk of infected mice and infects B cells of lactating pups. MMTV SAgs presented on infected B cells induce V(3-specific T cell activation. The T-B cell interactions support proliferation of infected B cells, facilitating perpetuation and spreading of the virus. The involvement of similar SAg encoding retroviruses in human disease remains to be shown. SAgs are also implicated in the pathogenesis of rabies virus. This is supported by the fact that T cells expressing TCR-V|36 are expanded in rabies-infected mice, and mice lacking V(36 T cells are difficult to infect. The immunostimulatory properties of SAgs may lead to a breakdown of tolerance and favor development of autoimmune responses. In Kawasaki syndrome, a cause of acquired heart disease in children, general immunoactivation with expansion of T cells expressing TCR-V(32 and 8 and high systemic levels of IFNy is frequently observed. IFNy induces expression of MHC class II molecules on aortic endothelial cells, which is believed to facilitate SAg-dependent destruction of these cells. Staphylococcus strains producing TSST-1 have been implicated as a major causative agent. In a number of autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, autoimmune thyroiditis and psoriasis, a skewed pattern of V|3 usage has been observed. Moreover, it has been shown that SEs and possibly Mycoplasma arthritidis mitogen induce and exacerbate autoimmune disease in various experimental models. This has suggested to a number of investigators that SAgs may be involved in modulating human autoimmune disease. However, no firm evidence is present to support a role for SAg in the initiation or perpetuation of chronic inflammatory diseases.

The potent immunostimulating properties of SAgs have recently been exploited for immunotherapy of cancer. Recombinant fusion proteins between tumor reactive monoclonal antibody fragments and SAgs mutated to reduce MHC class II binding have been used successfully to treat experimental tumors. Such tumor-specific SAgs localized to the tumor and were able to induce massive infiltration in tumors of T cells actively producing TNFa and IFNy, and resulted in apparent cure of animals in the absence of systemic toxicity.

See also: Antigen presentation via MHC class II molecules; Anergy, T cell; Clonal deletion; Cytokines; Septic shock; Staphylococcus, infection and immunity; T cell receptor, recognition by; T lymphocyte activation.

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