STAT1 signaling in sarcoidosis granulomas and its association with organ-specific clinical course

Background The clinical course of sarcoidosis, a systemic disease of unknown etiology, varies from spontaneous resolution to progressive multi-organ dysfunction. To clarify the pathogenesis, omics-based analyses of patient samples have been conducted. However, analyses of mechanisms underlying granuloma development and persistence related to disease progression remain limited. This study aimed to identify immunological events within sarcoidosis granulomas and to explore their association with the subsequent clinical course of the affected organs. Methods Laser-microdissected granuloma and non-granuloma regions from lung tissues of five patients were analyzed using RNA sequencing, followed by differential gene expression and pathway analyses. Immunohistochemistry for pSTAT1 and pSTAT3 was performed on pulmonary and extrapulmonary tissues from 20 patients; organ-specific analyses were subsequently performed in 30 specimens from 15 corticosteroid-naïve patients. Associations between granuloma pSTAT1 positivity and organ-specific clinical course were assessed using an unadjusted Mann–Whitney U test and a logistic generalized estimating equation model accounting for multiple specimens from the same patient. Results Comparative analysis identified 1,129 differentially expressed genes between granuloma and non-granuloma regions. The granuloma region showed high expression of IFN-γ–STAT1 pathway-related genes. Immunohistochemical analysis revealed that pSTAT1-positive nuclei were consistently observed within granuloma lesions in all organs. Higher granuloma pSTAT1 positivity was observed in organs with subsequent disease progression. In the unadjusted analysis, pSTAT1 positivity was significantly higher in progressive than in stable/improved specimens ( P = 0.030). In a logistic generalized estimating equation model accounting for within-patient clustering, each 10-percentage-point increase in pSTAT1 positivity was associated with higher odds of subsequent organ-specific progression (OR, 2.86; 95% CI, 0.94–8.76), although the association did not reach statistical significance after small-sample correction ( P = 0.062). Conclusions IFN-γ–STAT1 signaling was activated within sarcoidosis granulomas, and higher granuloma pSTAT1 positivity was observed in organs with progressive clinical courses in this exploratory cohort. These findings support further investigation of granuloma-localized STAT1 signaling in larger prospective studies. Trial registration number Not applicable.