Gene expression profiles in granuloma tissue reveal novel diagnostic markers in sarcoidosis

Abstract

Sarcoidosis is an immune-mediated multisystem disease characterized by the formation of non-caseating granulomas. The pathogenesis of sarcoidosis is unclear, with proposed infectious or environmental antigens triggering an aberrant immune response in susceptible hosts. Multiple pro-inflammatory signaling pathways have been implicated in mediating macrophage activation and granuloma formation in sarcoidosis, including IFN-γ/STAT-1, IL-6/STAT-3, and NF-κB. It is difficult to distinguish sarcoidosis from other granulomatous diseases or assess disease severity and treatment response with histopathology alone. Therefore, development of improved diagnostic tools is imperative. Herein, we describe an efficient and reliable technique to classify granulomatous disease through selected gene expression and identify novel genes and cytokine pathways contributing to the pathogenesis of sarcoidosis. We quantified the expression of twenty selected mRNAs extracted from formalin-fixed paraffin embedded (FFPE) tissue (n=38) of normal lung, suture granulomas, sarcoid granulomas, and fungal granulomas. Utilizing quantitative real-time RT-PCR we analyzed the expression of several genes, including IL-6, COX-2, MCP-1, IFN-γ, T-bet, IRF-1, NOX2, IL-33, Eotaxin-1 and revealed differential regulation between suture, sarcoidosis, and fungal granulomas. This is the first study demonstrating that quantification of target gene expression in FFPE tissue biopsies is a potentially effective diagnostic and research tool in sarcoidosis.

Induction of Pulmonary Granuloma Formation byPropionibacterium acnesIs Regulated by MyD88 and Nox2

“…In our P. acnes-driven model of granuloma formation, Cybb 2/2 mice had dramatically increased granuloma formation ( Figure 5A), with no defect in neutrophil recruitment ( Figure E6), demonstrating that a lack of phagosome NADPH oxidasemediated bacterial clearance increased granuloma formation. Interestingly, others have observed an increase in Nox2 (CybB) messenger RNA in tissue biopsy specimens from sarcoidosis-specific granulomas (48). These data are also consistent with the results of a recent unbiased genome-wide association study identifying Rab23, a component of bacterial killing mediated through phagolysosome fusion, as a risk factor for sarcoidosis (49).…”

Aqueous Tear Deficiency Increases Conjunctival Interferon-γ (IFN-γ) Expression and Goblet Cell Loss

“…[17][18][19] It is also involved in granuloma formation. 20 Elevated IFN-c expression has been identified in a number of autoimmune diseases, including systemic lupus erythematosis, Sjögren syndrome, inflammatory bowel disease, and multiple sclerosis. 15,21,22 We have reported that exposure of the mouse ocular surface to desiccating stress increased IFN-c production by NK and Th1 cells in the conjunctiva.…”

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

“…CXCL9, a STAT1-dependent gene that is a T-cell chemoattractant, promotes granuloma formation and is likely to be an important mediator of pulmonary granulomatous inflammation [34][35][36]. The observation that peripheral blood gene expression profiling can be used to assess pulmonary granulomatous syndromes raises the possibility that diagnostic or prognostic markers could be developed for clinical use [37][38][39]. However, given the immunological similarities between sarcoidosis and CBD, the present study suggests that developing expression profiles that reliably discriminate the two entities will be a significant challenge.…”