Session Type: Poster Session (Tuesday)
Session Time: 9:00AM-11:00AM
Background/Purpose: Sarcoidosis (SD) is a granulomatous inflammatory disease with a heterogenous presentation and no definite etiology. SD usually begins in the lungs, skin, or lymph nodes but can involve other organs such as the heart and lacrimal glands. A better understanding of pathogenesis can pave new therapeutic avenues.
Methods: We employed the STARGEO platform to tag samples from the Gene Expression Omnibus and performed three separate meta-analyses on 216 peripheral blood (216 SD vs 271 healthy), bronchoalveolar lavage (BAL; 21 SD vs 20 healthy), and lacrimal gland (22 SD vs 14 healthy) samples. We then analyzed the signature in Ingenuity Pathway Analysis.
Results: Lacrimal gland analysis revealed Th1 and Th2 activation and T helper cell differentiation as top canonical pathways. IFNG, TGFB1, and TNF were top upstream regulators. ADAMDEC1 was our top upregulated gene and is essential for dendritic cell differentiation. Additionally, we found upregulation of the metalloproteinase MMP12. MMP12 and ADAMDEC1 are potential markers of pulmonary SD activity and may be implicated in lacrimal glad involvement. GBP5, activator of the NLRP3 inflammasome, and osteopontin, associated in T cells in SD granulomas, were upregulated. Genes expressing antimicrobial peptides in secretions, such as HTN1 and STATH, were downregulated.
Blood analysis revealed TH1 activation, IFN, EIF2, TREM1, and pattern recognition receptor signaling as top canonical pathways. IRF7, IFNa, STAT1, and IFNL1 were top upstream regulators. We found upregulation of classical complement pathway related genes such as FCGR1B and SERPING1. Additionally, CARD17, regulator of IL1B, was upregulated and has activity linked to granulomatosis disease. The recently described transcription factor and immune regulator BATF2 was upregulated. Lastly, there was downregulation of TRABD2A, a metalloprotease and negative regulator or Wnt signaling.
BAL analysis revealed “role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis” as the top canonical pathway, with TP53, hepatocyte growth factor, ERBB2, CTNNB1, and E2F7 as top upstream regulators. We found upregulation of sprout family gene SPRY2, a negative feedback regulator of tyrosine kinases. Additionally, there was downregulation of phospholipase D1, a regulator of signal transduction.
Conclusion: Sarcoidosis is a complex and likely multifactorial disease process. Our results emphasized the role of innate immune cell and Wnt activity in SD, among other signaling pathways, and suggest potential biomarkers and therapeutic targets. This approach to data analysis illustrates the importance of studying affected target organs to determine active pathways that are unique.
To cite this abstract in AMA style:Aljabban J, Syed S, Syed S, Adapa N, Hasan L, Allarakhia Z, Hadley D, Aljabban M, Jarjour W. Multi-Organ System Meta-Analytic Approach to Investigating Sarcoidosis [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/multi-organ-system-meta-analytic-approach-to-investigating-sarcoidosis/. Accessed April 17, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/multi-organ-system-meta-analytic-approach-to-investigating-sarcoidosis/