Zur Problematik der kutanen S. aureus Besiedlung in der atopischen Dermatitis – Untersuchungen zu angeborenen und adaptiven Immunmechanismen -

Atopic dermatitis (AD) is a pruritic and chronic inflammatory skin disorder associated with high IgE titers. The clinical phenotype of disease is the product of genetic susceptibility, immune dysregulation and defects in skin barrier function. Exogenous factors exacerbate the course of pre-existing lesions and it is known that Staphylococcus aureus skin colonization leads to dramatic flare-ups of eczema and affects more than 80% of AD patients. Particularly staphylococcal strains producing superantigens complicate disease through massive T cell activation and induction of specific immune response. Up to now it remains elusive whether defaults within the adaptive immune system render patients prone to recurrent bacterial infections which commonly result from IgG subclass deficiencies. Investigating this issue, unexpectedly highest IgG1 and IgG4 titers were measured in the sera of AD patients colonized by S. aureus. Obviously repeatedly bacterial exposure yielded right the opposite effect and thus specific IgG antibodies appeared to be more inflammatory than protective. Next, IgG responses towards staphylococcal enterotoxin C1 (SEC1) was investigated as many AD patients were colonized by SEC1 producing strains. Interestingly, IgG2 deficiency against this particular superantigen could be detected in ~40% of all enrolled patients. Yet, this patient group was neither characterized by skin colonization with SEC1 producing strains nor by SEC1 specific IgE sensitization. Instead, PBMCs of the anti-SEC1 IgG2 deficient patients produced selectively the TH2 cytokines IL-4 and IL-5 upon SEC1 stimulation implicating the presence of the corresponding specific TH2 cells. This could be due to the toxin itself to activate preferentially T cells bearing BV8S2 elements within the T cell receptor. NKT cells express such a kind of receptor and are considered as main producers of IL-4 thus possibly establishing a specific TH2 micromilieu which could selectively inhibit the synthesis of anti-SEC1 IgG2 antibodies. Patients lacking these antibodies suffered from a severe form of eczema but even when present were not protected against superantigen mediated inflammation. However, anti-SEC1 IgG antibodies could not sufficiently neutralize the corresponding toxin as shown in-vitro which might be responsible for less protection in the end. Susceptibility to S. aureus colonization might be also accompanied by defective innate immune mechanisms. In this regard 11.5% of AD patients were identified as heterozygous carriers of the TLR-2 R753Q mutation which was initially associated with staphylococcal infections. This patient subgroup had a 55% risk to cutaneous S. aureus colonization and was defined by increased disease severity and highest IgE titers. As this mutation has emerged as a novel marker for AD its functional impact was investigated in vitro through transfection of a 50:50 mixture of the TLR-2 wildtype and the generated R753Q mutant constructs in HEK293 cells thus mimicking the heterozygous state. After having confirmed a dose dependency between the amount of transfected receptor and the degree of NFB response heterozygous transfectants showed reduced IL-8 production following stimulation with heat-inactivated S. aureus. So, neutrophilic influx might be affected and therefore promote bacterial survival. In another context it remains largely unknown how staphylococcal components aggravate eczema. As CD4+ T cells predominate in skin lesions one may suggest that these components directly interfere with T cells in a TLR-2 dependent manner. Indeed, activated CD4+ T cells of non-atopic subjects profoundly expressed cell surface TLR-2. Stimulation with lipoteichoic acid yielded down-regulation of this receptor and a similar cytokine profile compared to the non-TLR-2 stimulated T cells. Yet, when stimulated with MALP-2 production of the TH1 cytokines (IL-2, TNF-alpha und IFN-gamma) was further pronounced. Therefore, some staphylococcal components can directly interact with T cells through TLR-2 and may contribute to the pathogenesis and chronification process in AD by augmented secretion of pro-inflammatory cytokines.