Genetic variability of T cell responses in Hypersensitivity Pneumonitis identified using the BXD genetic reference panel.

Hypersensitivity pneumonitis is an interstitial lung disease that may progress to fibrosis and significant risk of death. It develops following repeated exposures to inhaled environmental antigens; however, a fraction of the exposed population develops disease suggesting that host genetics contribute to disease susceptibility. In this study we have used the BXD family of mice with the (SR) model of HP to investigate the role of genetics in HP susceptibility. The BXD family is derived from a B6 mother and D2 father and have been used to map susceptibility loci to numerous diseases. B6, D2 and BXD progeny strains were exposed to SR for three weeks and the development of HP was monitored. The B6 and D2 strains developed alveolitis, however, the cellular composition was neutrophilic in D2 and more lymphocytic in B6. Hematoxylin and eosin staining of lung sections revealed lymphoid aggregates in B6 lungs, whereas, D2 exhibited a neutrophilic infiltration. Twenty-eight BXD strains of mice were tested, and the results reveal significant heritable variation for numbers of CD4 or CD8 T cells in the airspaces. There was significant genetic variability for lymphoid aggregates and alveolar wall thickening. We mapped a significant QTL on chromosome 18 for CD8 CD69 T cells that includes -an excellent candidate gene associated with epithelial-mesenchymal transition that is upregulated in lungs of strains with HP. These results demonstrate that the BXD family is a valuable and translationally relevant model to identify genes contributing to the disease and to devise early and effective interventions.