Abstract
Pulmonary involvement occurs in up to 95% of sarcoidosis cases. In this pilot study, we examine lung compartment-specific protein expression to identify pathways linked to development and progression of pulmonary sarcoidosis. We characterized bronchoalveolar lavage (BAL) cells and fluid (BALF) proteins in recently diagnosed sarcoidosis cases. We identified 4,306 proteins in BAL cells, of which 272 proteins were differentially expressed in sarcoidosis compared to controls. These proteins map to novel pathways such as integrin-linked kinase and IL-8 signaling and previously implicated pathways in sarcoidosis, including phagosome maturation, clathrin-mediated endocytic signaling and redox balance. In the BALF, the differentially expressed proteins map to several pathways identified in the BAL cells. The differentially expressed BALF proteins also map to aryl hydrocarbon signaling, communication between innate and adaptive immune response, integrin, PTEN and phospholipase C signaling, serotonin and tryptophan metabolism, autophagy, and B cell receptor signaling. Additional pathways that were different between progressive and non-progressive sarcoidosis in the BALF included CD28 signaling and PFKFB4 signaling. Our studies demonstrate the power of contemporary proteomics to reveal novel mechanisms operational in sarcoidosis. Application of our workflows in well-phenotyped large cohorts maybe beneficial to identify biomarkers for diagnosis and prognosis and therapeutically tenable molecular mechanisms.
Highlights
Sarcoidosis is a multisystem immune-mediated disease of unknown cause with widely variable disease manifestations, severity, and o utcomes[1]
In a large study that utilized SELDI-TOF MS to compare bronchoalveolar lavage (BAL) fluid (BALF) from sarcoidosis subjects with Lofgren’s syndrome and different chest x-ray (CXR) stages of pulmonary sarcoidosis (n = 65) with healthy controls, 40 differentially expressed peaks were identified compared to healthy controls and included 27 peaks that were specific for a particular CXR stage[24]
We examined BAL cells as the inflammatory response is aberrant in sarcoidosis with (a) yet unknown antigen(s) triggering an exuberant dysfunctional immune response with CD4 + T cells, Tregs, high levels of Th1 cytokines TNF-α, IFNγ, and IL-210,33,34, along with inappropriate counter regulatory responses
Summary
Sarcoidosis is a multisystem immune-mediated disease of unknown cause with widely variable disease manifestations, severity, and o utcomes[1]. Prior studies have used protein m icroarrays19,20, 2-dimensional electrophoresis (2DE)[12,21,22,23], and top-down[24] as well as shotgun p roteomics[25,26,27] to examine variable sarcoidosis phenotypes including Lofgren’s syndrome, non-Lofgren’s chest x-ray (CXR) stage I, and stage II/III pulmonary sarcoidosis and compared them to subjects with asthma, IPF, tuberculosis or healthy smoking and non-smoking controls These studies have identified differences in protein spots on 2DE12,21,22, differentially expressed proteins[25,26,28] and possible mechanisms that could explain the development of sarcoidosis[25,26,27]. The differentially expressed proteins mapped to canonical PI3K/ Akt/mTOR signaling, MAP kinase, hypoxia response, and pluripotency-associated transactional factor pathways These studies support rigorous evaluation of well-characterized, clinically-meaningful sarcoidosis phenotypes by contemporary techniques to identify novel mechanisms of sarcoidosis which can provide tenable treatment targets and biomarkers for personalized care. We found significant differences in BALF and cellular proteins between cases and controls and progressive versus non-progressive cases suggesting that this approach may find useful application in larger studies
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