Phenotypes and Endotypes in Sarcoidosis: Unraveling Prognosis and Disease Course

Sarcoidosis is a multi-system granulomatous disease of unknown etiology. In genetically susceptible individuals, the precipitating factors generate, via immunity mechanisms, a host granulomatous response. The granuloma, for unknown reasons thus far, may resolve or may persist and lead to organ damage and fibrosis. Infectious agents, occupational exposure, obesity, smoking and genetic factors are implicated in the pathogenesis of sarcoidosis. Macrophages are important in granuloma formation, and their M1/M2 phenotype is associated with the prognosis of the disease. CD4⁺ T helper cells play a central role in the pathogenesis of sarcoidosis. The major contributors appear to be Th1 and Th17.1 cells, whose microenvironmental behavior is dictated by the secretions of macrophages and dendritic cells. Higher levels of Th1 and Th17.1 cells are associated with chronic disease and resistance to corticosteroid treatment. In recent years, advances in the phenotyping of sarcoidosis with the help of HRCT, PET-CT and lung function tests have provided us with a better understanding of the disease. Genetic phenotyping performed by the GenPhenReSa consortium and the SAGA study has led to the recognition of new, distinct phenotypes. The reconstitution of dysregulated autophagy through persistent m-TORC-1 pathways may be a new treatment target in sarcoidosis.