Session Information
Date: Sunday, November 12, 2023
Title: Abstracts: Systemic Sclerosis & Related Disorders I: Translational
Session Type: Abstract Session
Session Time: 2:00PM-3:30PM
Background/Purpose: Systemic sclerosis (SSc) is a multiorgan disease characterized by systemic vascular injury, inflammation, and fibrosis. While SSc mainly affects the skin, pulmonary manifestations such as interstitial lung disease (ILD) are the leading cause of morbidity and mortality. Tumor necrosis factor–like cytokine 1A (TL1A) is a membrane costimulatory protein and cytokine that drives multiple inflammatory and fibrotic pathways implicated in SSc. TL1A can induce lung fibrosis and tissue remodeling in mice and can stimulate cellular proliferation and extracellular matrix protein production in human lung fibroblasts. The present study evaluated the expression of TL1A and related pathways in serum, skin, and lung tissue in patients with SSc. An anti-TL1A monoclonal blocking antibody, PRA023, is currently in phase 2 trial for SSc-ILD.
Methods: Soluble TL1A was measured in serum samples from early diffuse (< 2yr; n=58) and late diffuse ( >5yr; n=57) SSc and matched healthy control sera (n=60) (University of Texas cohort). Bulk and single-cell transcriptomic public data from SSc lung and skin were analyzed for gene expression. Gene expression and chromatin accessibility from the same cell were profiled in skin biopsies and peripheral blood mononuclear cells (PBMCs) from patients with SSc with (n=4) and without (n=4) ILD and healthy controls (n=4) using 10X Genomics Chromium Single Cell Multiome technology (University of Michigan cohort). TL1A and its receptor, DR3, proteins were detected in SSc skin (n=15), SSc-ILD (n=5), and healthy control lung tissue (n=5) by immunohistochemistry in both cohorts.
Results: TL1A levels were elevated in late diffuse SSc compared with early diffuse and healthy control sera (p< 0.05). In bulk transcriptomic SSc skin public datasets, Th1, Th2, Th17, and TL1A-induced T cell and fibrosis gene signatures were increased. In the skin, single-cell gene expression and chromatin accessibility analysis showed that TL1A was expressed in myeloid and epithelial cells, while DR3 was expressed on T cells. Differential gene expression analysis between SSc and control skin revealed several genes upregulated in fibroblasts (eg, COL16A1, ELN, PRRX1; p< 0.05) and in myeloid cells (eg, HLA-DRB1, NRP1, SRGN; p< 0.05). TL1A-induced genes were upregulated in myeloid cells and fibroblasts of SSc skin compared with controls (p< 0.001). In donor-matched PBMCs, single-cell gene expression and chromatin accessibility data indicated TL1A expression in myeloid cells, a cell population expanded in SSc, and DR3 expression in T cells. In lung tissue bulk RNA, TL1A gene expression was increased in SSc-ILD compared to healthy controls. In single-cell RNAseq SSc-ILD lung data, TL1A was expressed by myeloid and epithelial cells, while DR3 was expressed by T cells and epithelial and endothelial cells. Although SSc skin showed relatively low levels of TL1A and DR3 protein expression, TL1A and DR3 proteins were relatively abundant in SSc-ILD compared with healthy control lung tissues.
Conclusion: TL1A expression and pathway activity analyses suggest that TL1A may modulate immune and fibrotic pathways in SSc skin and the lung, with higher activity of the pathway in lung tissue compared with the skin.
To cite this abstract in AMA style:
Llewellyn H, Tsoi L, Wu M, Grigaityte K, Wang T, Seibold J, Muñoz-Elias E, Khanna D, Gudjonsson J. Expression of TL1A, Inflammatory, and Fibrotic Pathways in Patients with Diffuse Systemic Sclerosis [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/expression-of-tl1a-inflammatory-and-fibrotic-pathways-in-patients-with-diffuse-systemic-sclerosis/. Accessed .« Back to ACR Convergence 2023
ACR Meeting Abstracts - https://acrabstracts.org/abstract/expression-of-tl1a-inflammatory-and-fibrotic-pathways-in-patients-with-diffuse-systemic-sclerosis/