Superantigens

On the other hand, EFN-a may also be involved in the activation of autoreactive T-cells as has been proposed for type I diabetes. An DFN-a inducible superantigen, encoded by the truncated envelope gene of a human endogenous retrovirus and specifically activating V 37 T-cells, has been detected in pancreatic lesions from type I diabetes patients, infiltrated by V 37 T-cells. Since IFN-a expression could be detected in pancreatic (3 cells in conceit with persistent viral infections, there is a clear link between viral infections and autoimmunity via IFN-a-stimulated superantigen expression. 

Bacterial or viral proteins linking T-cell receptors and MHC molecules through simultaneous interaction with the constant domains of all MHC class II molecules and of T-cell receptor (3-chains. Hence, superantigens are polyclonal T-cell activators most likely involved in the development of autoimmune diseases. 

Coutant, K.D. et al., Modulation of the activity of human monocyte-derived dendritic cells by chemical haptens, a metal allergen, and a staphylococcal superantigen, Toxicol. Sci., 52, 189, 1999. 

TCDD) induces Fas-dependent activation-induced cell death in superantigen primed T cells, Arch. Toxicol., 76, 570, 2002. 

Akdis M, Simon HU, Weigl L, Kreyden O, Blaser K, Akdis AC Skin homing CLA-F CD8+ T cells respond to superantigen and contribute to eosinophilia and IgE production in atopic dermatitis. J Immunol 1999 163 466-475. 

Table 1. Interaction between T cells and MHC class II + cells by staphylococcal superantigens leads to numerous inflammatory reactions in the skin... 

Microorganism Activate T Lymphocytes and Bystander Cells in the Skin in Atopic Dermatitis An important strategy by which S. aureus exacerbates atopic dermatitis is by secreting exotoxins. Some of them function as superantigens, which stimulate activation of T cells and major histocompatibility (MHC) class II + APC or keratinocytes, which express MHC class II upon activation. Many effects on T lymphocytes and other cells are elicited by superantigens (table 1). 

In addition, some patients with atopic dermatitis produce specific IgE antibodies directed against staphylococcal superantigens, which correlate with skin disease severity. Superantigens have been shown to penetrate into the dermis and higher doses have been shown to induce cutaneous inflammation when applied onto the skin. Low doses which do not induce visible clinical inflammation are still able to amplify aeroal-lergen-induced patch test responses [14]. 

T regulatory cells in atopic dermatitis and subversion of their activity by superantigens. J Allergy Clin Immunol 2004 113 756-763. 

The First Step Toward Superantigen-Based Intoxication Binding to Major... 

The Second Step Toward Superantigen-Based Intoxication T-Cell Receptor... 

Mode of action Activation of macrophages/monocytes release of endogenous mediators such as lipids from arachidonic acid, reduced oxygen species, proteins 1. Pore formation in cell membranes 2. Enzymatic modification of specific substrates in the cytosol of host cells (AB-type toxins) 3. Superantigen stimulation of the immune system... 

Over the past 20 years, the S. aureus SEs and TSST-1 have been called superantigens . This term was first proposed in the late 1980s by Marrack and Kappler to describe microbial (bacterial or viral) proteins that activate large numbers of specific T cells versus conventional antigens. Table 3 lists the various superantigens, and their diverse microbial sources, known to date. Ey definition, interactions of superantigens with cells of the... 

Table 3 Superantigens found in diverse bacteriai and virai forms...

The staphylococcal superantigens initially bind to conserved elements on major histocompatibility complex class II molecules with relatively high affinity (A(i 10 mol 1 ). These receptors are found in abundance, throughout the body, on antigen-presenting cells such as macrophages and monocytes. However, each toxin... 

Finally, a recent paper by Gunther et aL shows that SEK uniquely binds to the T-cell receptor (human V/35.1) through a 15 amino-acid loop (q 3-/38) not evident in other superantigens, except for those in the same toxin grouping (e.g., SET). Surface plasmon resonance studies reveal a 6 (tmol binding affinity of SEK for V/35.1, which fits the range for other SEs when used in this technique. 

The coupling of superantigen—major histocompatibility complex class II to T-cell receptor swifdy results in cell-signaling cascades. ° These staphylococcal toxins can increase levels of phosphatidyl inositol from quiescent T cells, such as other mitogens, as well as elicit intracellular Ca movement that activates the protein kinase C (PKC) pathway important for interleukin-2 (IL-2) expression. " IL-2 is intimately linked to T-cell proliferation. In addition to the PKC pathway, the protein tyrosine kinase (PTK) pathway is also activated by superantigens, leading to elevated expression of various proinflammatory cytokines. Staphylococcal superantigens also potently activate transcriptional factors NF-/IB (nuclear factor kappa B) and AP-1 (activator protein-1), which subsequently elicit the synthesis of proinflammatory cytokines. " " ... 

Ironically, SE or TSST-1 concentrations that cause T-cell proliferation do not always correlate with receptor affinity. For instance, SEE binds HLA-DR with 100-fold lower affinity relative to the very similarly structured SEA however, SEE stimulates T-cell proliferation to equivalent levels as SEA. The dose-response curves for cytokine and chemokine production in vitro by staphylococcal superantigen-stimulated cells are also very similar despite differences in affmity/specificity for major histocompatibility complex class II and T-cell receptor V/3 molecules. Overall, these observations suggest that the biological effects of staphylococcal superantigens are induced at rather low, nonsaturating occupancy rates not readily classified by typical biokinetics. 

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