Staphylococcal enterotoxins can reactivate experimental allergic encephalomyelitis.

Abstract

Staphylococcal enterotoxins (SEs) are one member of a unique group of molecules known as superantigens. They are potent T-celi activators and stimulate a large number of T cells bearing specific T-cell-receptor -chain variable regions. It has been proposed that superantigens may trigger autoimmune disorders by stimulation of autoreactive T cells with restricted -chain variable-chain usage. We investigated the effects of SEs B and A (SEB and SEA) on the reactvation of experimental allergic encephalomyelitis, an animal model for multiple sclerosis. We report that SEB can reinduce encephalitis multipl times in PL/J mice that had previously recovered from an acute episode. SEB was also able to induce encephalitis in mice previously immunized with myelin basic protein but did not show clinical signs of dLswe. In addition, it was observed that T cells from PL/J mice that Superantigens such as the staphylococcal enterotoxins (SEs) are among the most powerful T-cell activators known (1-3). Stimulation of T cells by the superantigens occurs first by engaging the class II major histocompatibility complex and then the complex binds to the T-cell receptor (TCR) in a (-chain variable-region (V(3)-specific manner (1, 4). The SEs B and A (SEB and SEA, respectively), employed in this study, have been shown to be specific for murine T cells bearing V(33, -7, and -8.1-8.3 and V(1, -3, -10, -11, and -12, respectively (5). The observation that these enterotoxins can activate T cells based on TCR V gene usage has led to the concept that these antigens may trigger autoimmune disorders (6-9).Experimental allergic encephalomyelitis (EAE) is an animal model of antigen-induced autoimmunity and has been widely studied to gain insight into the inflammatory demyelinating disease multiple sclerosis (MS) (10

Increased CD80(+) B cells in active multiple sclerosis and reversal by interferon beta-1b therapy.

“…1), as well as the elevated number of HLA-DR ϩ and CD71 ϩ monocytes and lymphocytes (Table I), results from an unknown stimulus for immune cell activation (20,(26)(27)(28). During exacerbations, IL-2, IFN-␥, TNF-␣, and TNF-␤ appear in serum, their respective mRNAs are upregulated in MNC (29)(30)(31)(32), and activated cells increase in the peripheral blood (20,29,33).…”

“…IFN-␥ administration causes exacerbations of MS (43). In addition, viral infections induce MS attacks (26,27), superantigens released during bacterial infections reactivate EAE (28), and quinolone antibiotics (a relationship between worsening of the symptoms of MS and ciprofloxacin treatment [Reder, A.T., unpublished data]) sometimes worsen MS symptoms. All three of these activators induce Th1 cytokines, including IFN-␥, which could induce CD40, CD40L, CD80, and CD86 expression, and all three worsen inflammatory brain disease.…”

Superantigen Enhancement of Specific Immunity: Antibody Production and Signaling Pathways

“…The rationale behind the approach was 2-fold. First, we have previously shown that superantigens can exacerbate the autoimmune disorder experimental allergic encephalomyelitis (EAE) in mice primed to MBP (7). Second, mice primed to weak tumor-specific Ags of melanoma cells were prophylactically protected against lethal melanoma with protective immunological memory of Ͼ170 days (8).…”

“…In contrast, T cells that are actively undergoing activation by specific Ag at the time of superantigen stimulation do not become anergized (6,7). This is an important characteristic of superantigens that can potentially be exploited when attempting to enhance specific Ag responses.…”

Expression of bacterial superantigen genes in mice induces localized mononuclear cell inflammatory responses.

“…Accordingly, administration of high doses of SAgs (e.g., SEB) has been used to reduce the severity of several experimental oligoclonal T cell-mediated diseases, including experimental allergic encephalitis (21), spontaneous diabetes mellitus (22), and allergic hypersensitivity (23). Paradoxically, others have found that bacterial SAgs may actually exacerbate certain experimental immune-mediated diseases such as adjuvant arthritis (24) and allergic encephalitis (25). T cells stimulated by SAgs proliferate and release primarily Th1 cytokines (especially interferon-gamma and TNF alpha), and the T cell stimulatory properties of SAgs have also been used successfully to treat experimental cancer in mice (26)(27)(28).…”