Hypothesis: Sarcoidosis is a STAT1-mediated disease

Abstract

Immunologic pathways involved in sarcoidosis pathogenesis are largely unknown. We hypothesized that patients with sarcoidosis have characteristic mRNA profiles. Microarray analysis of gene expression was done on peripheral blood (12 patients,12 controls), lung (6 patients, 6 controls) and lymph node (8 patients, 5 controls). Comparing peripheral blood from patients with sarcoidosis to controls, 872 transcripts were upregulated and 1039 were downregulated at ≥ 1.5-fold change and a significant q value. Several transcripts associated with interferon and STAT1 were upregulated. Lung and lymph node analyses also showed dramatic increases in STAT1 and STAT1-regulated chemokines. Granulomas in lymph nodes of patients with sarcoidosis expressed abundant STAT1 and phosphorylated STAT1. STAT1 might play an important role in sarcoidosis. This novel hypothesis unites seemingly disparate observations with regard to sarcoidosis including implication of a casual role for interferons, a suspected infectious trigger, TH1 predominating lymphocytes in bronchoalveolar lavage, and the association with hypercalcemia.

Longitudinal analysis of sarcoidosis blood transcriptomic signatures and disease outcomes

“…It is notable that our IFN signature was predominantly driven by STAT1 and STAT2 expression in sarcoidosis peripheral blood, as this finding supports prior studies showing that STAT1 may play an important role in disease pathogenesis [19,20]. Using microarray gene network analyses and immunohistochemical staining of granulomas, ROSENBAUM et al [20] previously demonstrated that STAT1 signalling is strongly upregulated in peripheral blood (n512), and lung and lymph node tissues. CROUSER et al [19] similarly confirmed an increase in STAT1-related networks in sarcoidosis lung biopsies.…”

“…Unexpectedly, the IFN-inducible chemokine CXCL9 gene (factor 7) was not intercorrelated with the other IFN-related genes in factor 1. We had particular interest in CXCL9 (factor 7), as CXCL9 is upregulated in gene network analyses of sarcoidosis organ tissues [19,20], and we and others have previously shown that serum protein levels of this chemokine are upregulated in sarcoidosis [15,21]. In summary, factor analysis of the qPCR results provided confirmation of the IFN, pattern recognition and TCR pathways in a separate replicate cohort, and additionally demonstrated a separate factor for CXCL9.…”

Beryllium disease and sarcoidosis: still besties after all these years?

“…Their data also provided evidence for the functional importance of JAK signalling in PBMCs from CBD patients by demonstrating beryllium-induced STAT1 phosphorylation as well as a reduction in beryllium-induced lymphocyte proliferation using a JAK2 inhibitor. These data accord with similar findings in sarcoidosis, where the STAT1 pathway has been shown to be the dominant gene expression feature in both granulomatous tissue [23] and peripheral blood [25]. Canonical signalling through the JAK/STAT pathway is necessary for transcription of numerous gene products (e.g.…”

Molecular profiling and gene expression analysis in cutaneous sarcoidosis: The role of interleukin-12, interleukin-23, and the T-helper 17 pathway

“…The tissue level transcriptomic data demonstrate that the molecular profile of CS is similar to that reported for pulmonary sarcoidosis. 15,16 As such, although the initiating factor of the disease resulting in involvement of a given organ may differ, there is commonality in the biological pathways that are dysregulated in systemic sarcoidosis. A molecular disease profile was also measurable in whole blood, with the IFN-g pathway significantly dysregulated, which independently confirms recent data on the molecular profile of sarcoidosis in whole blood.…”