Session Type: Poster Session (Monday)
Session Time: 9:00AM-11:00AM
Background/Purpose: The CD4+ T cell subset driving the pathogenesis of systemic sclerosis (SSc) remains poorly understood. Many different CD4+ T cell subsets have been implicated, but previous studies on SSc have typically not used quantitative multi-color approaches on tissue biopsies. We have previously reported on the expansion of CD4+ cytotoxic T lymphocytes (CD4+CTLs) in the blood of SSc patients. Furthermore, CD4+CTLs are implicated in the pathogenesis of another autoimmune fibrotic disease, IgG4-related disease. We sought to quantify CD4+CTLs and other CD4+ T cell subsets in untreated SSc tissues from patients with diffuse cutaneous SSc (dcSSc).
Methods: Multi-color immunofluorescence was used to quantify CD4+ T cell subsets in 350 skin sections of thirty-five patients with early dcSSc enrolled in the ASSET trial (placebo-controlled trial of abatacept vs. placebo in early dcSSc, clinicaltrials.gov NCT02161406). Paired blood samples from 18 of these patients, along with 9 additional SSc blood samples recruited through the Massachusetts General Hospital (MGH), were used to quantify frequencies of, examine the TCR repertoire and explore the transcriptomes of circulating CD4+CTLs. All patient samples from the ASSET trial and 6 of 9 of the subjects recruited through the MGH were untreated at the time of collection. Twenty age-matched healthy donors and 19 non-fibrotic sarcoidosis patient samples were used as blood controls, while 10 skin samples from healthy donors were used as tissue controls.
Results: CD4+CTLs were expanded in the blood of SSc patients, showed marked clonal-restriction by TCR repertoire analysis and the magnitude of expansion correlated with the degree of tissue fibrosis. The transcriptomes of CD4+ CTLs from SSc patients enriched for gene sets suggesting enhanced metabolic activity, cell survival, and conditioning by both type 1 and type 2 interferons. Quantitative multi-color immunofluorescence revealed that TH1, TH2, and TFH cells are relatively rare populations in SSc tissues, comparable to those observed in normal skin, whereas CD4+CTLs are prominent and represent the most abundant CD4+ T cell subset in most dcSSc skin biopsies. Many of these cells synthesized IL-1β suggesting that they have been reactivated in tissues. We observed and quantified prominent activated caspase-3 staining, particularly in endothelial cells, and many endothelial cells upregulated MHC class II molecules in dcSSc skin biopsies.
Conclusion: The low abundance of infiltrating TH1, TH2, and TFH cells in the skin of SSc subjects suggests that these CD4+ T cells are unlikely to be of pathogenic significance in this disease. In contrast, activated, clonally-expanded and tissue infiltrating CD4+CTLs likely drive the pathogenesis of SSc. The prominent accumulation of apoptotic HLA class II expressing endothelial cells in the lesions of these patients suggests that recurring immune mediated endothelial cell apoptosis may contribute to tissue damage and remodeling in this fibrotic disease. (Supported by Autoimmune Centers of Excellence awards from the NIAID to SP, DK, DF and JS)
To cite this abstract in AMA style:Maehara T, Perugino C, Kaneko N, Mattoo H, Kers J, Allard-Chamard H, Mahajan V, Liu H, Murphy S, Ghebremichael M, Tuncay Y, Della Torre E, Liang L, Montesi S, Wallace Z, Fox D, Lafyatis R, Stone J, Khanna D, Pillai S. Clonally Expanded CD4+ Cytotoxic T Cells, Endothelial Cell Apoptosis and the Pathogenesis of Early Systemic Sclerosis [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/clonally-expanded-cd4-cytotoxic-t-cells-endothelial-cell-apoptosis-and-the-pathogenesis-of-early-systemic-sclerosis/. Accessed December 4, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/clonally-expanded-cd4-cytotoxic-t-cells-endothelial-cell-apoptosis-and-the-pathogenesis-of-early-systemic-sclerosis/