Allergic bronchopulmonary aspergillosis in asthma and cystic fibrosis

Abstract

Allergic bronchopulmonary aspergillosis (ABPA) is a Th2 hypersensitivity lung disease in response to Aspergillus fumigatus that affects asthmatic and cystic fibrosis (CF) patients. Sensitization to A. fumigatus is common in both atopic asthmatic and CF patients, yet only 1-2% of asthmatic and 7-9% of CF patients develop ABPA. ABPA is characterized by wheezing and pulmonary infiltrates which may lead to pulmonary fibrosis and/or bronchiectasis. The inflammatory response is characterized by Th2 responses to Aspergillus allergens, increased serum IgE and eosinophilia. A number of genetic risks have recently been identified in the development of ABPA. These include HLA-DR and HLA-DQ, IL-4 receptor alpha chain (IL-4RA) polymorphisms, IL-10-1082GA promoter polymorphisms, surfactant protein A2 (SP-A2) polymorphisms, and cystic fibrosis transmembrane conductance regulator gene (CFTR) mutations. The studies indicate that ABPA patients are genetically at risk to develop skewed and heightened Th2 responses to A. fumigatus antigens. These genetic risk studies and their consequences of elevated biologic markers may aid in identifying asthmatic and CF patients who are at risk to the development of ABPA. Furthermore, these studies suggest that immune modulation with medications such as anti-IgE, anti-IL-4 and/or IL-13 monoclonal antibodies may be helpful in the treatment of ABPA.

Figure 1

Proposed immunopathogenesis of ABPA. In the pathogenesis of ABPA, A. fumigatus proteases have a direct effect on bronchial epithelia causing epithelial cell damage with subsequent stimulation of cytokines and chemokines. Aspergillus proteins are processed via HLA-DR2/DR5 bearing dendritic cells that skew the Th0 response to a Th2 response. Th2 cytokines stimulate IgE synthesis and eosinophil activation. This leads to an eosinophilic inflammatory in the bronchial airways. Abbreviations: Af: Aspergillus fumigates, Asp fx: Aspergillus fumigatus proteins, APC: antigen presenting cell, MBP: major basic protein, ECP: eosinophil cationic protein, EDN: eosinophil derived neurotoxin, VLA: very late activation antigen, VCAM: vascular cell adhesion molecule, CxCR and CCR: chemokines receptors, MCO: monocyte chemotactic protein, sCD23: soluble CD23, cyst-LT: cysteinyl leukotriene.