Allergic bronchopulmonary aspergillosis (ABPA), a pulmonary hypersensitivity disease mediated by an allergic response to Aspergillus fumigatus (A. fumigatus), occurs preferentially in disease conditions with an impaired pulmonary immunity, especially in cystic fibrosis (CF) and allergic asthma (Stevens 2000). In CF patients ABPA is diagnosed in about 10-15% of patients and frequently leads to acute worsening of the respiratory status. The pathophysiological mechanisms underlying the link between CF and ABPA are poorly understood (Knutsen 2002, 2003). ABPA is characterized by a strong Th2 immune response. Increasing evidence suggests that in CF patients and CFTR-/- mice the immune response is shifted towards a Th2 phenotype (Moss 2000, Allard 2006, Knutsen 2003). In addition, chronic infection with the CF-prototypic pathogen Pseudomonas aeruginosa (P. aeruginosa) modulates the pulmonary immune response in CF patients towards Th2 immunity (Hartl 2006). Favored by this underlying immune deviation, A. fumigatus is believed to further drive the pulmonary and systemic immune response in CF patients towards an overhelming and robust Th2 phenotype, resulting in clinically active ABPA disease. Accordingly, the majority of T cell clones in ABPA patients are Th2 cells (Chauhan 1996; Knutsen 1994) and Th2 cytokines and chemokines are highly increased in the lung fluids and the circulation of ABPA patients compared to non-ABPA CF patients and healthy controls (Hartl 2006, Walker 1994). Besides T cells, B cells from ABPA patients are more sensitive towards IL-4 stimulation (Knutsen 2004). The manifestation of clinically active ABPA is further supposed to be influenced by the underlying genotype. Accordingly, six different HLA-DR alleles (Chauhan 1996, 1997) and polymorphisms in the IL-4α receptor chain (Knutsen 2006) and in the collagen region of surfactant protein A2 (Saxena 2003) have been associated with the occurrence of ABPA. Recently, increased serum levels of the Th2 chemokines thymus- and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) were found in two different ABPA CF patient cohorts (Hartl 2006; Latzin 2007). Serum levels of TARC were highly increased in ABPA patients compared to several CF and non-CF control groups and were useful both cross-sectionally and longitudinally to discriminate ABPA from A. fumigatus colonization and sensitization and to indicate ABPA exacerbations in the clinical course of CF. Based on these studies, TARC serum levels may be useful as future biomarkers for ABPA in CF patients. Despite these intriguing insights into the immunological links between ABPA and CF, more experimental and clinical studies are needed to understand the relevance of these mechanisms for monitoring and treating ABPA in CF patients.
Full conference title:
3rd Advances Against Aspergillosis
- AAA 3rd (2008)