Chronic Disease Association

When S. aureus and group A streptococci are thought of, typically boils and pharyngitis, respectively, come to mind rather than the severe infectious diseases that these organisms can cause. Thus, the lack of great attention to these organisms may have allowed them, unchecked, to cause a myriad of chronic diseases that are recognized but whose microbial origin has not been considered.

Considerable circumstantial evidence suggests that SPEs contribute to rheumatic fever. It has been known since the 1950s that SPEs amplify specifically the cardiotoxicity of other agents, such as streptolysin 0 and endotoxin. All rheumatogenic streptococci thus far tested make SPEs. In contrast, historically well-characterized strains, including strong hyaluronidase producers, that do not cause rheumatic fever do not make SPEs. Finally, SPEs cause very significant T cell proliferation, which may contribute to the autoimmune aspects of the disease. Lymphocytes from rheumatic fever patients respond atypically to SPEs compared with cells from controls. It has been proposed that the massive release of interferon-v as a consequence of the superantigenicity of pyrogenic toxins causes a failure to generate neutralizing antibodies against the toxins. This has been used, for example, to explain why nearly 85% of TSS patients remain susceptible to TSS after recovery from an episode. Thus, it is possible that a human can be assaulted many times by SPEs before formation of protective antibodies and that these assaults progressively lead to damage to the heart. There is fairly convincing evidence that SPEs contribute to or cause guttate psoriasis. Typically, patients have group A streptococcal infection 1-2 weeks prior to onset of psoriasis. Thus far, all strains of streptococci isolated from patients make SPEs. Finally, purified SPE preparations cause keratinocyte proliferation and skin reactivity in rabbits. For several years, investigators have proposed that group A streptococci and S. aureus be considered in attempts to establish the cause of Kawasaki syndrome. Recently, Abe et al. showed that patients with Kawasaki syndrome typically have elevated blood levels ofV{j2- and possibly VtJ8.1containing T cells, suggestive of superantigenic effects. Finally, the symptoms of Kawasaki syndrome overlap with those of TSS and TSLS in many respects.

Thus, efforts to identify the superantigens responsible for the VtJ skewing should continue and should include pyrogenic toxins. M protein from group A streptococci has long been associated with rheumatic fever. Considerable data suggest convincingly that immune cross-reaction at the level of both T cells and B cells, between M protein and heart tissue occurs and may contribute to rheumatic fever. As well, there are many well-recognized rheumatogenic M types. More than 85% of patients with atopic dermatitis are chronically infected with S. aureus. Because pyrogenic toxins directly cause mast cell degranulation and amplify IgEmediated allergic reactions, these toxins may be involved in the pathogenesis of the illness. Also, I developed clinically documented atopic dermatitis, lasting 3-4 months, after accidentally splashing staphylococcal enterotoxin A on my face. Many patients with TSS have symptoms resembling arthritis. Recently, it has been shown that patients with rheumatoid arthritis have a skewing ofV{j TCR. TSST-I has been found to reactivate arthritis established in a rat model of rheumatoid arthritis (unpublished data). Thus, it is possible that superantigens trigger or exacerbate arthritis episodes. In the next few years I anticipate that a large number of other chronic diseases will be linked to microbial superantigens. At that time we will finally gain the necessary respect for the broad impact these products have on humans.