Pathophysiological mechanisms involved in acute and chronic hypersensitivity pneumonitis

Abstract

Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) characterized by a bronchoalveolar inflammation usually caused by the inhalation of avian and fungal proteins. The immunopathological pathways involved in the disease after antigen exposure are still unknown. In addition, the diagnosis of HP remains challenging because of the absence of a gold standard. In fact, HP patients are diagnosed on the basis of a combination of clinical, imaging and laboratory findings. In this context, YKL-40 and KL-6 are two promising biomarkers that may play an important role in the management of HP diagnosis. Moreover, to establish correct HP diagnosis, identification of the triggering antigen is an essential step. To achieve this, specific IgG antibody determination is a useful technique. In addition, the environmental detection of the causative antigen will help to control complete antigen avoidance, which is crucial to preventing disease progression and to improving respiratory symptoms in patients with HP. However, in clinical practice, no methods are currently available for directly measuring antigen exposure in the environment. This PhD thesis aims to assess the immunopathological pathways that are activated in HP, and to improve diagnostic accuracy and prognosis in patients. The first study focuses on the cellular immune response and the cytokine pattern involved in a murine model of bird-related HP (BRHP). This study contends that in the first stages of BRHP there is a mixed Th1/Th2 immune response with increased levels of type 2-related dendritic cells, an eosinophilic inflammation, reduced levels of B cells and secretion of type 1 and type 2 cytokines such as TNF-[Alfa] and IL-13. With progression of BRHP, although there is a Th1 response with IFN-[Gamma], IL-1[Beta] and IL-12 secretion, the levels of cytokines seem to indicate a switch towards a Th2/Th17 mixed response with increased levels of IL-5, IL-6 and IL-23. The second study (Article 1) aims to determine the role of KL-6 and YKL-40 as biomarkers in the diagnosis and prognosis of patients with HP. This study demonstrates that both serum KL-6 and YKL-40 levels seem to be capable of distinguishing HP patients from healthy individuals and from patients with idiopathic pulmonary fibrosis (IPF) at a range of 346 - 1441 U/ml and 55 - 121 ng/ml respectively. In addition, serum KL-6 may also be a predictor of HP disease progression because of its negative correlation with TLC and DLCO at 12 months of follow-up. The objective of the third study is to evaluate the degree of sensitization to avian and fungal antigens and the potential risk of developing HP in a cohort of urban pest surveillance and control service workers. A high degree of sensitization to avian and fungal antigens is observed in the study population. In particular, workers involved in nest pruning have higher levels of specific parakeet and mucor IgGs and lower DLCO/VA (alveolar volume) values. In addition, this study identifies Ig Lambda chain and Apolipoprotein A-I as candidate proteins for distinguishing patients with HP from workers exposed to pigeons. The last study (Article 2) focuses on the development and validation of a sensitive sandwich enzyme link immunoassay (ELISA) technique and a rapid immunochromatographic test (ICT) to detect pigeon antigens in environmental air samples. This study demonstrates that there is a good correlation between the two assays, although the ELISA method has a broader range for quantifying pigeon antigen. Even so, this study concludes that the ICT is rapid, simple to use and a valid alternative.