Environmental triggers and susceptibility factors in idiopathic granulomatous diseases.

Our understanding of the pathophysiology of granulomatous diseases has increased substantially during the past few years. However, despite many environmental agents (particularly of infectious origin) capable of inducing granulomatous inflammation, we do not know why only a small percentage of exposed individuals develop the disease, suggesting that a particular trigger results in overtly recognizable phenotypes only when the appropriate genetic trait also occurs. This review focuses on a research area that has been intensively investigated recently, and reports evidence for an individual predisposition to develop pulmonary granulomatous diseases of unknown origin, specifically sarcoidosis, Blau syndrome, and systemic vasculitides. Recent findings reinforce the hypothesis that transmissible agents, particularly mycobacteria, may be causative in some sarcoidosis cases, but the matter remains controversial due to the inability to consistently isolate microorganisms in pathological specimens. Whatever the etiology, future studies should focus on specific disease phenotypes to identify more homogeneous populations for analysis. This approach proved to be fruitful in both sarcoidosis and Wegener granulomatosis, suggesting that stratification of data by clinical phenotypes may discover genetic associations that analysis of disease susceptibility alone would fail to detect. Unraveling how genetic risk factors and environmental triggers interact to determine the disease is challenging but will inevitably have an impact on both diagnostic and therapeutic strategies in granulomatous lung diseases.