OBJECTIVE: Despite the importance of interleukin-13 (IL-13) in systemic sclerosis (SSc) and other fibrotic diseases, its mechanisms of action are not understood. We have reported that excessive amounts of IL-13 are produced by peripheral blood effector CD8+ T cells from patients with diffuse cutaneous SSc (dcSSc). The aim of the present study was to establish the molecular basis of IL-13 dysregulation in the pathogenesis of SSc. METHODS: Quantitative polymerase chain reaction analysis and intracellular staining were used to study the transcription factors that control naive peripheral blood CD8+ T cell differentiation into type 1 and type 2 cytokine-secreting cells. Intracellular staining revealed that GATA-3 levels in freshly isolated naive CD8+ T cells correlated with specific clinical manifestations. We therefore assessed the effects of GATA-3 inhibition on IL-13 production in CD8+ T cells from the SSc patients. RESULTS: Freshly isolated naive peripheral blood CD8+ T cells expressed high levels of GATA-3 and failed to down-regulate IL-13 production when cultured under type 1-skewing conditions, but maintained adequate levels of interferon-γ production. Cellular GATA-3 levels were significantly higher in patients with dcSSc and early inflammatory disease. Silencing of GATA-3 with small interfering RNA significantly reduced IL-13 production by CD8+ T cells, demonstrating a causal relationship between GATA-3 and IL-13. CONCLUSION: These results provide important new insights into SSc pathogenesis and suggest that increased GATA-3 expression in CD8+ T cells could be a highly relevant biomarker of immune dysfunction in patients with dcSSc. GATA-3 could be a novel therapeutic target for this currently incurable disease.
OBJECTIVE: Despite the importance of interleukin-13 (IL-13) in systemic sclerosis (SSc) and other fibrotic diseases, its mechanisms of action are not understood. We have reported that excessive amounts of IL-13 are produced by peripheral blood effector CD8+ T cells from patients with diffuse cutaneous SSc (dcSSc). The aim of the present study was to establish the molecular basis of IL-13 dysregulation in the pathogenesis of SSc. METHODS: Quantitative polymerase chain reaction analysis and intracellular staining were used to study the transcription factors that control naive peripheral blood CD8+ T cell differentiation into type 1 and type 2 cytokine-secreting cells. Intracellular staining revealed that GATA-3 levels in freshly isolated naive CD8+ T cells correlated with specific clinical manifestations. We therefore assessed the effects of GATA-3 inhibition on IL-13 production in CD8+ T cells from the SSc patients. RESULTS: Freshly isolated naive peripheral blood CD8+ T cells expressed high levels of GATA-3 and failed to down-regulate IL-13 production when cultured under type 1-skewing conditions, but maintained adequate levels of interferon-γ production. Cellular GATA-3 levels were significantly higher in patients with dcSSc and early inflammatory disease. Silencing of GATA-3 with small interfering RNA significantly reduced IL-13 production by CD8+ T cells, demonstrating a causal relationship between GATA-3 and IL-13. CONCLUSION: These results provide important new insights into SSc pathogenesis and suggest that increased GATA-3 expression in CD8+ T cells could be a highly relevant biomarker of immune dysfunction in patients with dcSSc. GATA-3 could be a novel therapeutic target for this currently incurable disease.
Authors: Eva Billerbeck; Rachael N Labitt; Kevin Vega; Natalia Frias-Staheli; Marcus Dorner; Jing W Xiao; Charles M Rice; Alexander Ploss Journal: Immunology Date: 2014-10 Impact factor: 7.397
Authors: Gang Li; Adriana T Larregina; Robyn T Domsic; Donna B Stolz; Thomas A Medsger; Robert Lafyatis; Patrizia Fuschiotti Journal: J Invest Dermatol Date: 2016-12-22 Impact factor: 8.551
Authors: Sandra Cascio; Thomas A Medsger; William F Hawse; Simon C Watkins; Christine Milcarek; Larry W Moreland; Robert A Lafyatis; Patrizia Fuschiotti Journal: J Allergy Clin Immunol Date: 2017-11-15 Impact factor: 10.793