Unique Mycobacterium tuberculosis-specific blood immune signatures in sarcoidosis: implications for clinical diagnosis
Sarcoidosis is a granulomatous systemic inflammatory disease predominantly affecting lungs. It shares histopathological, clinical and immune features with tuberculosis (TB). There are currently no diagnostic tests to formally identify sarcoidosis; clinicians first need to rule out the presence of other diseases, including TB. We characterized Mycobacterium tuberculosis (Mtb)-specific immune responses in blood of pulmonary sarcoidosis patients in comparison to active tuberculosis (ATB), Mtb-sensitized and non-sensitized healthy controls using flow cytometry and transcriptomics. We found that sarcoidosis was associated with i) a marked reduction in the frequency of antigen-reactive T cells in response to both Mtb peptides and Mtb lysate, ii) increased frequency of monocytes ex vivo and after in vitro stimulation, and iii) increased expression of phagocytic genes compared to Mtb-infected and healthy cohorts. Combination of Mtb-specific T cell and monocyte gene or flow cytometry signatures in Mtb-stimulated PBMC could efficiently distinguish sarcoidosis from ATB with high specificity and sensitivity, and to a lower extent from Mtb-sensitized and non-sensitized healthy controls. These biomarkers offer promising aspects for developing effective diagnostic tests for sarcoidosis, in particular for differential diagnosis from tuberculosis. Overall design: Bulk RNA-seq analysis of sorted CD4 memory T cells and whole PBMC from 60 IGRA-,  48 Sarcoidosis, 59 IGRA+, and 57 ATB subjects following ex vivo stimulation with epitopes specific to Mycobacterium tuberculosis, DMSO control, or a polyclonal (CD3/CD28) positive control.