Multiple Molecular Pathways Discriminate Sarcoidosis From TB Granulomas

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Abstract Introduction: Sarcoidosis and tuberculosis (TB) patients abnormally respond to Mycobacterium tuberculosis (M.tb) antigens to form granulomas. Based on a transcriptomic analysis, we sought to determine if molecular pathways associated with granuloma formation in response to M.tb antigens fundamentally differ in sarcoidosis and latent TB infection (LTBI). Methods: PBMCs were obtained from TB naïve sarcoidosis (n = 6) and LTBI patients (n = 4), who had negative and positive interferon gamma release assays, respectively. PBMCs were immediately treated with polystyrene beads covalently coated with purified protein derivative (PPD) of M.tb, and cultured in RPMI medium for 7 days, at which time granuloma-like structures typically form. AmpliSeq Human Gene Expression kit was used to assess differential expression (DE) of genes from RNA derived from the granulomas. DE genes were identified, and the imputed biological implications of the DE genes were then assessed using pathway and upstream regulator modules in Ingenuity Pathway Analysis® and network analysis using protein-protein interactome data in NetworkAnalyst. Results: Despite the formation of histologically similar appearing granulomas 7 days after exposure to PPD-coated beads, we observed large differences in gene expression (5,103 DE genes based on false discovery rate-adjusted p < 0.05 and > 2-fold change) in granulomas derived from sarcoidosis compared to LTBI PMBCs. Ingenuity Pathway Analysis® identified multiple pro-inflammatory pathways (e.g., neutrophil degranulation, phagosome, S100, Toll-like receptor related) engaged during sarcoidosis granuloma formation, whereas senescence blocking pathways (DNA and histone methylation, DNA/telomere repair) were suppressed. Sarcoidosis granulomas also exhibit enhanced iron uptake pathways (e.g., CD163 mediated) and enhanced activation of MMPs, predicted to promote tissue remodeling. Upstream regulator and network analyses provided additional context for biological interpretation of differences in transcriptional profiles of granulomas derived from sarcoidosis compared to latent LTBI PMBCs. Figure 1 demonstrates top enriched canonical pathways with FDR-adjusted p < 0.05 and Z-scores > 3.5 (reflecting activation) or < -3.5 (reflecting inhibition). Conclusions: In response to identical M.tb antigen challenge, the genomic profiles of sarcoidosis and LTBI granulomas are dramatically different, emphasizing the unique characteristics of sarcoidosis immune response. These differences, with additional consideration of epigenetic and senescence mechanisms, may partially explain the typical adult onset of sarcoidosis and the potentially novel role played by the neutrophil degranulation pathway. The full implications in terms of TB infection susceptibility, tissue remodeling and other disease manifestations remain to be determined.

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