Kobayashi Takao, Iijima Koji, Radhakrishnan Suresh, Mehta Vinay, Vassallo Robert, Lawrence Christopher B, Cyong Jong-Chol, Pease Larry R, Oguchi Katsuji, Kita Hirohito
Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.
J Immunol. 2009 Feb 15;182(4):2502-10. doi: 10.4049/jimmunol.0802773.
Asthma is thought to result from dysregulated Th2-like airway inflammatory responses to the environment. Although the etiology of asthma is not fully understood in humans, clinical and epidemiological evidence suggest a potential link between exposure to environmental fungi, such as Alternaria, and development and/or exacerbation of asthma. The goal of this project was to investigate the mechanisms of airway Th2 responses by using Alternaria as a clinically relevant model for environmental exposure. Airway exposure of naive animals to an experimental Ag, OVA, or a common allergen, short ragweed pollen, induced no or minimal immune responses to these Ags. In contrast, mice developed strong Th2-like immune responses when they were exposed to these Ags in the presence of Alternaria extract. Extracts of other fungi, such as Aspergillus and Candida, showed similar Th2 adjuvant effects, albeit not as potently. Alternaria stimulated bone marrow-derived dendritic cells (DCs) to express MHC class II and costimulatory molecules, including OX40 ligand, in vitro. Importantly, Alternaria inhibited IL-12 production by activated DCs, and DCs exposed to Alternaria enhanced Th2 polarization of CD4(+) T cells. Furthermore, adoptive airway transfer of DCs, which had been pulsed with OVA in the presence of Alternaria, showed that the recipient mice had enhanced IgE Ab production and Th2-like airway responses to OVA. Thus, the asthma-related environmental fungus Alternaria produces potent Th2-like adjuvant effects in the airways. Such immunogenic properties of certain environmental fungi may explain their strong relationships with human asthma and allergic diseases.
哮喘被认为是由对环境的Th2样气道炎症反应失调所致。尽管人类哮喘的病因尚未完全明确，但临床和流行病学证据表明，接触环境真菌（如链格孢菌）与哮喘的发生和/或加重之间可能存在关联。本项目的目标是利用链格孢菌作为环境暴露的临床相关模型，研究气道Th2反应的机制。将未接触过抗原的动物气道暴露于实验性抗原卵清蛋白（OVA）或常见过敏原短豚草花粉，对这些抗原未诱导或仅诱导了最小的免疫反应。相比之下，当小鼠在链格孢菌提取物存在的情况下接触这些抗原时，会产生强烈的Th2样免疫反应。其他真菌（如曲霉菌和念珠菌）的提取物也显示出类似的Th2佐剂效应，尽管效力稍弱。链格孢菌在体外刺激骨髓来源的树突状细胞（DCs）表达II类主要组织相容性复合体和共刺激分子，包括OX40配体。重要的是，链格孢菌抑制活化DCs产生白细胞介素-12，并且接触链格孢菌的DCs增强了CD4(+) T细胞的Th2极化。此外，将在链格孢菌存在的情况下用OVA脉冲处理过的DCs经气道过继转移，结果显示受体小鼠的IgE抗体产生增加，并且对OVA产生Th2样气道反应。因此，与哮喘相关的环境真菌链格孢菌在气道中产生强大的Th2样佐剂效应。某些环境真菌的这种免疫原性特性可能解释了它们与人类哮喘和过敏性疾病的密切关系。
