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Structure
Superantigens are medium sized 22-29 kDa
globular compact proteins. Crystal structures: ellipsoidal proteins with characteristic two domain protein folding. Have sites for binding MHC II and TCRs.
Structure
Two-domain folding pattern and architecture
(N and C terminal domains and helix in the center of the molecule)
the oligosaccharide/oligonucleotide fold Long -helix that diagonally spans the center of the molecule COOH terminal globular domain
Structure
The N terminal domain:
Hydrophobic residues in solvent exposed regions Determines the lethality of the toxin.
Structure
Each superantigen possesses slightly different
binding modes when it interacts with MHC class II molecules or the T-cell receptor.
Special characters
Presence of disulphide loop formed by the
cystinyl residues (except in TSST I) in the N terminal domain [emetic properties of the enterotoxins]. TSST-I: no extrastructural characters=> cleaved by
pepsin.
SE and SPE: extrastructural characters like: Lengthy amino terminal [resist the peptide digestion in the stomach => Staphylococcal food poisoning]. Emetic property: cystinyl residues.
Normally..
However,..
The unique feature of superantigen is that it
bypasses the antigen processing mechanism and specifically binds to TCR v segment and forms a trimolecular complex along with major histocompatibility complex class II.
Mechanism of action.
Superantigens bind to MHC class II molecules of
antigen presenting cells and V region of T-cell receptor in a non-antigen-specific manner. Stimulation of large number of T cells resulting in cell activation, differentiation, proliferation, and production of cytokines involved in various inflammatory processes.
Activation
endothelial injury [toxic shock syndrome]. of IL- 6, GM-CSF and E-selectin elicit proinflammatory and prothrombic responses [Kawasaki syndrome].
Direct Effects
Th cells: IL-1, IL-2, IL-6, TNF-, Macrophage
Inflammatory protein, Macrophage chemoattractant protein. Fever, rash, multi organ failure, coma & death. IL-10 [non responsive memory cells]: Deletion of activated T. INF : prolonged SAg exposure, induces auto immunity[Kawasaki disease] MHC cross-linking: up-regulates apoptosis.
Indirect Effects
Mitogenic activity.
Monocytic cell activation & release of large
amounts of TNF-: tissue necrosis Induce gastrointestinal toxicity and cause emesis: by SAg produced by bacteria causing food poisoning [SE and SPE].
peptide during the normal T cell activation (A) and during superantigenic activation by staphylococcal enterotoxins (B). The latter can be inhibited by polyclonal antibodies such as anti-SEB hyperimmune serum as shown in (C).
Indirect Effects
Monocytic cell activation and release of large
amounts of TNF- leading to tissue necrosis. Emesis: by SAg produced by bacteria causing food poisoning. Induction of gastrointestinal toxicity and emesis.
Consequences
Shock: massive release of cytokines.
Immunosupression: uncoordinated activation of