Molecular Mechanisms that Staphylococcal Superantigens Contribute to the Persistence and Exacerbation of Allergic Skin Inflammation in Atopic Dermatitis
Date Issued
2004
Date
2004
Author(s)
Lin, Yu-Tsan
DOI
zh-TW
Abstract
The skin of atopic dermatitis (AD) patients exhibits a striking susceptibility to colonization and infection with Staphylococcus aureus, which can secrete various exotoxins including staphylococcal enterotoxin B (SEB) being the most common. These exotoxins are superantigens. They may penetrate the skin barrier, stimulate T cells bearing the specific variable region of beta chain of T cell receptor (TCRVbeta), and contribute to the persistence and exacerbation of allergic skin inflammation in AD.
The objective of this study was to clarify the molecular mechanisms that staphylococcal superantigens (SsAgs) contribute to the persistence and exacerbation of allergic skin inflammation in AD. The specific aims were to 1) compare serum staphylococcal enterotoxin A (SEA)-specific IgE and SEB-specific IgE levels among AD patients, patients with respiratory allergy without AD, and healthy subjects; 2) investigate the correlation between serum SEA-specific IgE or SEB-specific IgE levels and AD severity or previous skin infections; 3) determine whether there are differences between AD patients and healthy subjects in SEB-induced activation, proliferation, cytokine production, chemokine receptor expression, apoptosis, caspase-3 activation, and changes of anti-apoptotic protein Bcl-2 and Bcl-2 mRNA levels of SEB-reactive (TCRVbeta3+ or Vbeta12+ or Vbeta17+) CD4+ T cells; 4) investigate the effect of exogenously added interleukin-4 (IL-4) on SEB-induced apoptosis, caspase-3 activation, and changes of Bcl-2 and Bcl-2 mRNA levels in SEB-reactive CD4+ T cells from healthy subjects; 5) investigate the effect of inhibition of endogenous IL-4 by using anti-IL-4 neutralizing antibodies (Abs) on SEB-induced apoptosis, caspase-3 activation, and changes of Bcl-2 and Bcl-2 mRNA levels in SEB-reactive CD4+ T cells from AD patients.
Serum SEA-specific IgE and SEB-specific IgE levels were determined by enzyme immunoassay. By using immunofluorescence and Annexin V staining followed by flow cytometric analysis and real-time polymerase chain reaction, we analyzed peripheral blood mononuclear cells with or without SEB stimulation in the presence or absence of recombinant IL-4 or anti-IL-4 neutralizing Abs.
We found that AD patients had higher serum SsAg-specific IgE levels than patients with respiratory allergy without AD and healthy subjects. There were positive correlations between serum SsAg-specific IgE levels and AD severity. These findings suggest that SsAgs play the role of allergens and thus may induce the production of functionally-relevant SsAg-specific IgE Abs in AD patients. However, there was no correlation between serum SsAg-specific IgE levels and previous skin infections. About the sequential responses of CD4+ T cells induced by SsAg stimulation, both activation and proliferation of CD4+ T cells were similar in AD patients and healthy subjects. However, SsAgs induced production of interferon-gamma (type 1 T helper cell (Th1) cytokine) in CD4+ T cells from healthy subjects and IL-4 (type 2 T helper cell (Th2) cytokine) in those from AD patients. SsAgs induced up-regulation of chemokine receptor CXCR3+ cells in CD4+ T cells from healthy subjects and CCR4+ cells in those from AD patients. CD4+ T cells from AD patients were more resistant to SsAg-induced decrease of Bcl-2, caspase-3 activation, and apoptosis than those from healthy subjects. Moreover, exogenously added IL-4 inhibited SsAg-induced decrease of Bcl-2, caspase-3 activation, and apoptosis in CD4+ T cells from healthy subjects. Inhibition of endogenous IL-4 increased SsAg-induced decrease of Bcl-2, caspase-3 activation, and apoptosis in CD4+ T cells from AD patients. These findings suggest that following SsAg stimulation, IL-4 produced by CD4+ T cells in AD patients can inhibit SsAg-induced caspase-3 activation and apoptosis of CD4+ T cells through inhibiting SsAg-induced decrease of Bcl-2. This may impair deletion of SsAg-activated T cells and resolution of allergic skin inflammation.
The results of this study may clarify the molecular mechanisms that SsAgs contribute to the persistence and exacerbation of allergic skin inflammation in AD, which is important for exploring the specific therapy and prevention of AD. In clinical application, this study suggests that the determination of serum SsAg-specific IgE levels may provide important information in the follow-up and therapy of AD patients. Early and aggressive antibiotic treatment of skin infection or exacerbated AD to prevent SsAg exposure of skin T cells is helpful to disease control of AD.
Subjects
金黃色葡萄球菌超級抗原
異位性皮膚炎
介白質-4
細胞凋亡
atopic dermatitis
staphylococcal superantigen
interleukin-4
apoptosis
Type
other
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