Systemic and local lymph node inflammation at disease onset in sarcoidosis patients.

Background: Sarcoidosis is a chronic granulomatous disease of unknown origin, and the potential involvement of microorganisms has long been debated. We conducted the present study to explore the role of microorganisms at the onset of the disease using shotgun sequencing on lymph node samples. Methods: We conducted a prospective cohort study of adult patients admitted for sarcoidosis in the department of internal medicine from a tertiary referral university hospital in France (ClinicalTrials.gov identifier NCT05916638). Plasma and tissue samples were collected from sarcoidosis patients prior to the initiation of treatment. Plasma controls were healthy individuals. Tissue sample controls were patients with metastatic adenocarcinoma who underwent lymph node biopsy procedures for cancer staging. Results: Plasma samples were collected from 19 patients with sarcoidosis and 10 control subjects. Of the 45 proteins studied using a multiplex quantification assay, the levels of 29 were significantly higher in the sarcoidosis patients. Of these, C-X-C motif chemokine ligand 9, lymphotoxin-α and tumour necrosis factor were also significantly upregulated at the mRNA level in affected tissues. Unbiased transcriptomic analysis of lymph node tissue revealed enrichment of the interferon (IFN)-γ signalling pathway, the interleukin (IL)-2-STAT5 pathway and the IL-6-JAK-STAT3 pathway in sarcoidosis patients. Shotgun sequencing of the lymph nodes showed no evidence of bacteria, fungi, viruses or parasites in the sarcoidosis samples. Conclusion: Our findings challenge the long-held belief that sarcoidosis is caused by a microorganism. The activation of the JAK-STAT and IFN-γ signalling pathways in sarcoidosis tissue indicates that JAK inhibitors could be used to treat the condition.