Increased Sensitivity to IL-4 in Patients with Allergic Bronchopulmonary Aspergillosis

Abstract

Background: Allergic bronchopulmonary aspergillosis (ABPA) is characterized by a heightened Th2 CD4+ T cell response to Aspergillus fumigatus allergens and a hyper-IgE state compared to atopic asthmatic and cystic fibrosis patients without ABPA. We hypothesized that one reason for this response is increased sensitivity to IL-4 in ABPA, resulting in increased expression of CD23 and CD86, leading to a positive amplification mechanism which increases Th2 CD4+ T cell responses. Methods: Peripheral blood mononuclear cells isolated from 10 ABPA, 9 atopic, and 8 nonatopic subjects and stimulated for 48 h with varying concentrations of rIL-4 ranging from 0.1 to 50 ng/ml. The percentages of CD23+ and CD86+ B cells and the number of CD23+ molecules on CD20+ and CD86+CD20+ B cells were quantified by flow cytometry. Results: Total serum IgE levels were elevated in ABPA patients compared to atopic and nonatopic controls. At day 0 prior to culture, CD23 molecules per CD20+ B cell were significantly elevated in ABPA patients compared to atopic and to nonatopic patients. CD23 molecules per CD20+ B cell in ABPA and atopic patients decreased after 48 h in culture without IL-4 added and were similar. With IL-4 stimulation, ABPA patients had significantly increased rates of CD23 expression per B cell compared to atopic and nonatopic subjects (p < 0.001). Furthermore, ABPA had significantly increased numbers of CD23+ molecules per B cell and CD86+ B cell following IL-4 stimulation compared to atopic and nonatopic patients. Both ABPA and atopic patients at day 0 prior to culture had increased expression of CD86+ and CD23+CD86+ B cells compared to nonatopic patients. After 48 h in culture without IL-4, the percentages of CD86+ and CD23+CD86+ B cells decreased in ABPA and atopic patients. After stimulation with IL-4, ABPA patients had significant upregulation of CD23+CD86+ B cells compared to atopic and nonatopic patients. Similarly, the number of CD23 molecules per CD86+CD20+ B cell was significantly upregulated following IL-4 stimulation in ABPA patients compared to atopic and to nonatopic subjects. Conclusions: This is the first study to demonstrate that ABPA patients have increased sensitivity to IL-4 stimulation compared to other atopic individuals, such that ABPA > atopic >> nonatopic patients. The B cells from ABPA patients were significantly more sensitive to IL-4 stimulation compared to atopic and nonatopic patients with upregulation of CD23 and CD86 expression. ABPA subjects had increased CD86+ and CD23+CD86+ B cell expression on day 0 prior to culture and with upregulation of CD23+ molecules on CD86+CD20+ B cells. IL-4 also stimulated upregulated CD86+ expression on B cells in atopic patients with little effect on nonatopic patients. This study supports the premise that IL-4, IL-4Rα and CD86 are central targets in the treatment of ABPA and atopic disease.