Mycobacterium tuberculosis-specific blood immune signatures distinguish sarcoidosis from tuberculosis disease

Sarcoidosis is a granulomatous systemic inflammatory disease predominantly affecting the lungs. It shares histopathological, clinical, and immune features with tuberculosis (TB). There are currently no diagnostic tests to formally identify sarcoidosis; instead, there is a need first to rule out the presence of other diseases, including TB. We hypothesized that Mycobacterium tuberculosis (Mtb)-specific immune signatures differ between sarcoidosis and TB. We characterized T-cell and monocyte signatures after Mtb antigen in vitro stimulation in the blood of patients with sarcoidosis compared to patients with TB disease and Mtb-sensitized and nonsensitized healthy controls using flow cytometry and transcriptomics on bulk PBMCs and sorted CD4 memory T cells. We found that sarcoidosis was associated with (1) a marked reduction in frequencies of antigen-reactive T cells in response to both Mtb peptides and Mtb lysate, (2) increased frequencies of monocytes, and (3) increased expression of monocyte-associated phagocytic genes compared to TB disease and Mtb-sensitized and nonsensitized healthy cohorts. A combination of Mtb peptide-specific T-cell and monocyte gene or flow cytometry signatures in Mtb peptide-stimulated PBMCs distinguished sarcoidosis from TB disease with high accuracy (area under the curve [AUC] = 0.91 and 0.96 for gene and flow cytometry signatures, respectively) and also distinguished sarcoidosis from Mtb-sensitized and nonsensitized healthy controls combined (AUC = 0.91 and 0.90 for gene and flow cytometry signatures, respectively). These findings highlight biological features that effectively distinguish sarcoidosis from TB and healthy populations and can be considered for the development of an optimized diagnostic method for sarcoidosis.