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Cytotoxic CD4+ T lymphocytes may induce endothelial cell apoptosis in systemic sclerosis
Takashi Maehara, … , Dinesh Khanna, Shiv Pillai
Takashi Maehara, … , Dinesh Khanna, Shiv Pillai
Published January 28, 2020
Citation Information: J Clin Invest. 2020;130(5):2451-2464. https://doi.org/10.1172/JCI131700.
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Research Article Autoimmunity Immunology

Cytotoxic CD4+ T lymphocytes may induce endothelial cell apoptosis in systemic sclerosis

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Abstract

Systemic sclerosis (SSc) is an autoimmune fibrotic disease whose pathogenesis is poorly understood and lacks effective therapies. We undertook quantitative analyses of T cell infiltrates in the skin of 35 untreated patients with early diffuse SSc and here show that CD4+ cytotoxic T cells and CD8+ T cells contribute prominently to these infiltrates. We also observed an accumulation of apoptotic cells in SSc tissues, suggesting that recurring cell death may contribute to tissue damage and remodeling in this fibrotic disease. HLA-DR–expressing endothelial cells were frequent targets of apoptosis in SSc, consistent with the prominent vasculopathy seen in patients with this disease. A circulating effector population of cytotoxic CD4+ T cells, which exhibited signatures of enhanced metabolic activity, was clonally expanded in patients with systemic sclerosis. These data suggest that cytotoxic T cells may induce the apoptotic death of endothelial and other cells in systemic sclerosis. Cell loss driven by immune cells may be followed by overly exuberant tissue repair processes that lead to fibrosis and tissue dysfunction.

Authors

Takashi Maehara, Naoki Kaneko, Cory A. Perugino, Hamid Mattoo, Jesper Kers,, Hugues Allard-Chamard, Vinay S. Mahajan, Hang Liu, Samuel J.H. Murphy, Musie Ghebremichael, David Fox, Aimee S. Payne, Robert Lafyatis, John H. Stone, Dinesh Khanna, Shiv Pillai

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Figure 5

Endothelial cells expressing HLA class II are a frequent target of apoptosis in SSc tissues.

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Endothelial cells expressing HLA class II are a frequent target of apopt...
(A) Representative multicolor immunofluorescence images showing CD31-expressing endothelial cells (orange) with cCasp-3 staining (green) in SSc. (B) Relative proportions of apoptotic cCasp-3+endothelial cells (red) and nonendothelial apoptotic cells (green) in SSc tissues (n = 35). (C) CD4+ (red) and GZMA+ (purple) CD4+ CTLs accumulate in the vicinity of CD31+ (orange) endothelial cells in SSc tissues. (D) Representative multicolor immunofluorescence image showing a GZMA-expressing (purple) CD4+ CTL (white arrows) in close proximity to a cCasp-3+ endothelial cell (yellow arrow). Red arrow highlights GZMA visible within the apoptotic endothelial cell. (E) Percentages of HLA+ cells among CD31+ cells in SSc (n = 35) and control skin (n = 10). (F) Multicolor immunofluorescence images of cCasp-3+ (green) and HLA-DR+ (red) endothelial cells (orange and indicated by arrows) in SSc, but not in control skin. Data are presented as mean ± SEM. *P < 0.05 by Mann-Whitney U test.

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