Date: Monday, November 6, 2017
Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
To examine the global gene expression profile in patients with very early diffuse systemic sclerosis (SSc).
Skin biopsies were obtained from patients enrolled in the Prospective Registry for Early Systemic Sclerosis (PRESS). All patients had diffuse cutaneous involvement and disease duration < 2 years. Fifty-seven patients and 33 age-, gender-matched controls were examined by nextGen RNA Sequencing (Depth: 50 million reads, 75 bp length) on Illumina HiSeq 3000 platform. Cell type-specific signature scores were calculated for each patient sample compared to the average score in controls as previously described (Assassi et al. Arthritis Rheum 2015). Gene signatures for 15 cell types present in skin were calculated including: Fibroblasts, keratinocytes, CD4+ and DC8+ T-cells, NK cells, dendritic cells, M1 and M2 macrophages, and B-cells.
The median disease duration was only 1.1 years while median mRSS score was 22. In comparison to controls, 2537 transcripts were differentially expressed (FDR <5%).
An Ingenuity Pathway Analysis revealed that the following top over-represented pathways: Hepatic fibrosis (p= 3.85×10-39), granulocyte adhesion and diapedesis (p=3.11×10-19), leukocyte extravasation signaling (p=2.79×10-16), Th1 and Th2 activation pathway (p=1.44×10-15), agranulocyte adhesion and diapedesis (p=6.56×10-14). The cell-type specific signature score analysis revealed a prominent up-regulation of innate and adaptive immune cell types. The three most frequent activated cell-type signatures were M2 Macrophage (present in 96% of patient samples), fibroblast (93%), and microvascular endothelial cells (91%). Interestingly, the proportion of patient samples with an adaptive immune system signature was much higher than the frequencies observed in our previously published data set (61 SSc patients with mean disease duration of 7.7 years and 36 matched controls). Specifically, CD8+ T cell, CD4+ T cell, and B-cell signatures were present in 67%, 61%, and 67% of samples in the present study whereas those signatures were present in less than 25% of SSc samples with established disease in the previous data set. Figure shows the distribution of signature scores for adaptive immune cell types in the present data set (early diffuse SSc) and previously published study (established SSc).
Skin samples of patients with early diffuse involvement have a prominent adaptive immune signature which is not present in established disease. This finding can have important implications for clinical trials targeting adaptive immune system.
To cite this abstract in AMA style:Assassi S, Khanna D, Hinchcliff M, Steen VD, Hant F, Gordon JK, Shah AA, Ying J, Swindell W, Zheng W, Zhu L, Shanmugam VK, Domsic RT, Castelino FV, Bernstein EJ, Frech TM. Cell Type Specific Gene Expression Analysis of Early Systemic Sclerosis Skin Shows a Prominent Activation Pattern of Innate and Adaptive Immune System in the Prospective Registry for Early Systemic Sclerosis (PRESS) Cohort [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/cell-type-specific-gene-expression-analysis-of-early-systemic-sclerosis-skin-shows-a-prominent-activation-pattern-of-innate-and-adaptive-immune-system-in-the-prospective-registry-for-early-system/. Accessed June 4, 2020.
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