Immune Tolerance and Inflammation in ABPA in Patients with Cystic Fibrosis

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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.