Immune Tolerance and Inflammation in ABPA in Patients with Cystic Fibrosis

过敏性支气管肺曲霉菌病(ABPA)是一种以喘息为临床特征的过敏性疾病， 影响哮喘和囊性纤维化(CF)患者的肺浸润性病变、支气管扩张和纤维化。在……里面 ABPA患者对多种烟曲霉(Af)抗原的免疫反应导致 Th2应答增强，免疫球蛋白E(IgE)水平升高。在我们的CF中心，ABPA影响7% 然而，在CF人口中，超过30%的人带有Af。我们实验室的初步数据 证明在树突状细胞和巨噬细胞中表达的β-葡聚糖受体Dectin-1是必需的 用于识别膨大的分生孢子；Af的一种形式，在菌丝发育之前。初步数据显示 对于患有ABPA的CF患者的Th2反应，Dectin-1也是必需的。另外，房颤患者 在没有ABPA的情况下定居会导致抗原特异性IL-10反应升高，我们认为这是由于 调节性T细胞反应在这些患者中的发展。根据这些数据，我们假设 ABPA患者需要单核/树突状细胞表达Dectin-1以表达特异性 曲霉菌抗原(即膨大的分生孢子)以及Th2细胞因子的分泌。此外，我们 假设与CF患者相比，APBPA的发生需要Treg细胞的减少 有曲霉菌，但没有ABPA的证据。为了检验这些假设，我们提出了以下建议 特定目标：特定目标1：验证患有ABPA的CF患者需要Dectin-1表达的假设 外周血单核细胞/树突状细胞以及烟曲霉菌与Dectin-1的结合将产生 与非ABPA患者相比，ABPA患者的炎症反应增强。具体目标2： 为了验证患有ABPA的CF患者的T细胞将具有适应性Treg功能降低的假设。 具体目标3.检验针对葡聚糖合成酶的抗真菌药物阻止促炎作用的假设 ABPA患者外周血中Th2细胞因子的诱生。理解 ABPA中的这些反应将增加我们对变态反应与耐受机制的了解 人类受试者。

Allergic bronchopulmonary aspergillosis (ABPA) is an allergic disease characterized clinically by wheezing, pulmonary infiltrates, bronchiectasis, and fibrosis that affects patients with asthma and cystic fibrosis (CF). In patients with ABPA, immunological responses to a variety of Aspergillus fumigatus (Af) antigens result in a heightened Th2 response and an elevated immunoglobulin E (IgE) level. At our CF Center ABPA affects 7% of the CF population however over 30% are colonized with Af. Preliminary data in our laboratory demonstrates that Dectin-1, a beta-glucan receptor expressed in dendritic cells and macrophages is required for recognition of swollen conidia; a form of Af that precedes hyphal development. Preliminary data suggest that Dectin-1 is also required for Th2 response in CF patients with ABPA. Additionally patients with Af colonization without ABPA have elevated antigen specific IL-10 responses which we propose is due the development of regulatory T-cell response in these patients. Based on these data, we hypothesize that CF patients with ABPA require monocyte/dendritic cell expression of dectin-1 for the presentation of specific Aspergillus antigens (namely swollen conidia) as well as for Th2 cytokine elaboration. Moreover, we hypothesize that a decreased in Treg cells is required for development of APBPA compared to CF patients colonized with Aspergillus but no evidence of ABPA. To test these hypotheses, we propose the following specific aims: Specific Aim 1: To test the hypothesis that CF patients with ABPA require Dectin-1 expression on peripheral blood monocytes/dendritic cells and that binding of A. fumigatus to Dectin-1 will produce a heightened inflammatory response in patients with ABPA compared to non-ABPA patients. Specific Aim 2: To test the hypothesis that T cells from CF patients with ABPA will have decreased adaptive Treg function. Specific Aim 3. To test the hypothesis that anti-fungals targeted against glucan synthetase block both proinflammatory and Th2 cytokine induction in peripheral blood of patients with CF with ABPA. Understanding these responses in ABPA will increase our knowledge regarding mechanisms of allergy vs. tolerance in human subjects.