Hyper-IgE syndromes: key to understand Staphylococcus aureus immune defense and associated allergy

尽管进行了大量的研究，但关于宿主对金黄色葡萄球菌的防御及其对过敏性疾病的影响仍存在许多问题。金黄色葡萄球菌感染的抗生素耐药性和过敏性疾病的稳步上升是世界范围内的政治卫生保健问题。高免疫球蛋白综合征(HIEs)是一种与严重形式的特应性皮炎重叠的原发免疫缺陷，表现为反复出现的金黄色葡萄球菌皮肤和呼吸道感染、湿疹和血清IgE升高。针对由STAT3基因突变引起的常染色体显性遗传性HIEs，我们希望了解金黄色葡萄球菌毒力因子、金黄色葡萄球菌特异性的Ig G和Ig E以及上皮细胞在宿主抵抗金黄色葡萄球菌中的作用。因此，金黄色葡萄球菌的病原体和毒素将从特应性皮炎和HIES患者中分离、鉴定并与临床和免疫学表现(如特异性抗体产生)相关联。上皮细胞在金黄色葡萄球菌免疫防御和变态反应性疾病中的作用目前还不清楚。聚焦于STAT3信号通路，我们将评估HIE和特应性皮炎患者的原代上皮细胞与健康对照组和转基因上皮细胞模型之间的物理上皮屏障，抗菌因子的调节，以及暴露于金黄色葡萄球菌后的Th细胞分化。此外，还将评估Th2或Th17细胞环境的影响。我们期望获得关于STAT3-IL17轴在金黄色葡萄球菌免疫中的作用以及如何有益地影响这一轴的详细信息。

There are still lots of questions in regards to host defense against Staphylococcus aureus and its impact on allergic disease despite intensive research. Antibiotic resistance of S. aureus infections and a steady rise of allergic diseases are political health care issues world-wide. Hyper-IgE syndromes (HIES) are primary immunodeficiencies which overlap with severe forms of atopic dermatitis presenting with recurrent S. aureus skin and respiratory infections, eczema and elevated serum-IgE. Focused on autosomal dominant HIES which is caused by mutations in the gene STAT3, we want to understand the role of S. aureus virulence factors, specific S. aureus IgG and IgE, and the epithelium in host defense against S. aureus. Therefore S. aureus pathogens and toxins will be isolated from atopic dermatitis and HIES patients, characterized, and correlated to the clinical and immunological presentation such as specific antibody production. The contribution of the epithelium in in S. aureus immune defense and allergic diseases is currently not well understood. Focused on the STAT3 signaling pathway we will assess primary epithelial cells of HIES and atopic dermatitis patients versus healthy controls and genetically modified epithelial cell models regarding physical epithelial barrier, regulation of antimicrobial factors, and Th cell differentiation after exposure to S. aureus. Furthermore, the influence of a Th2- or Th17-cell milieu will be assessed. We expect to obtain detailed information about the role of the STAT3-IL17 axis in immunity against S. aureus and how to beneficially influence this axis.