A Shift in the Balance of Regulatory T and T Helper 17 Cells in Rheumatic Heart Disease

Baş, Hatice; Baser, Kazim; Yavuz, Emine; Bolayır, Hasan Ata; Yaman, Belma; Ünlü, Serkan; Çengel, Atiye; Bagriacik, Emin Umit; Yalçın, Rıdvan

doi:10.2310/jim.0000000000000023

Cited by 46 publications

(28 citation statements)

References 43 publications

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“…Although less is known about T H 17 cell responses in RHD, T H 17 cells are important in GAS infections and have been identified in nasopharyngeal and tonsillar lymphoid tissues in streptococcal infection animal models 128–130 . In ARF and RHD, elevated numbers of T H 17 cells, high IL-17A levels and decreased T regulatory cells were reported in peripheral blood 131 . IL-17 triggers effective immune responses against extracellular bacteria, such as promoting neutrophil responses 132,133 .…”

Section: Mechanisms/pathophysiologymentioning

confidence: 99%

Acute rheumatic fever and rheumatic heart disease

Carapetis

Beaton

Cunningham

et al. 2016

Nat Rev Dis Primers

421

418

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Acute rheumatic fever (ARF) is the result of an autoimmune response to pharyngitis caused by infection with group A Streptococcus. The long-term damage to cardiac valves caused by ARF, which can result from a single severe episode or from multiple recurrent episodes of the illness, is known as rheumatic heart disease (RHD) and is a notable cause of morbidity and mortality in resource-poor settings around the world. Although our understanding of disease pathogenesis has advanced in recent years, this has not led to dramatic improvements in diagnostic approaches, which are still reliant on clinical features using the Jones Criteria, or treatment practices. Indeed, penicillin has been the mainstay of treatment for decades and there is no other treatment that has been proven to alter the likelihood or the severity of RHD after an episode of ARF. Recent advances — including the use of echocardiographic diagnosis in those with ARF and in screening for early detection of RHD, progress in developing group A streptococcal vaccines and an increased focus on the lived experience of those with RHD and the need to improve quality of life — give cause for optimism that progress will be made in coming years against this neglected disease that affects populations around the world, but is a particular issue for those living in poverty.

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Section: Mechanisms/pathophysiologymentioning

confidence: 99%

Acute rheumatic fever and rheumatic heart disease

Carapetis

Beaton

Cunningham

et al. 2016

Nat Rev Dis Primers

421

418

View full text Add to dashboard Cite

show abstract

“…The differentiation of Th17 cells plays a critical role in the development of autoimmune diseases, such as rheumatic heart disease (RHD) (10). TGF-b regulates Th17 cells at a low concentration, and IL-6 promotes Th17 skewing (11,12).…”

mentioning

confidence: 99%

Cutting Edge: Ubiquitin-Specific Protease 4 Promotes Th17 Cell Function under Inflammation by Deubiquitinating and Stabilizing RORγt

Yang

Han

et al. 2015

The Journal of Immunology

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RORγt is a key transcription factor that controls the development and function of inflammatory Th17. The mechanisms that regulate RORγt stability remain unclear. We report that Th17 cells highly express the deubiquitinase ubiquitin-specific protease (USP)4, which is essential for maintaining RORγt and Th17 cell function. Inhibition of the catalytic activity of USP4 with vialinin A, a compound derived from Chinese traditional medicine, dampened Th17 differentiation. USP4 interacted and deubiquitinated K48-linked polyubiquitination of RORγt, thereby promoting RORγt function and IL-17A transcription. Interestingly, TGF-β plus IL-6 enhanced USP4-mediated deubiquitination of RORγt. Moreover, USP4 and IL-17 mRNA, but not RORγt mRNA, were significantly elevated in CD4+ T cells from patients with rheumatic heart disease. Thus, USP4 could be a novel therapeutic target for the treatment of Th17-modulated autoimmune diseases.

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“…Several studies have shown that Th17 cells and related cytokines mediate in ammatory responses and autoimmune responses [9][10][11]. Studies by Bas et al showed that both the ratio of Th17/Treg cells and the level of IL-17A in patients with RHD were signi cantly increased than those in the control group [12]. Similar results were found in RHD animal models using Lewis rats [13].…”

mentioning

confidence: 57%

The intervention of S1PR1/STAT3 signaling pathway by inhibiting the expression of STAT3 attenuates the valvular damage due to rheumatic heart disease

Xian¹,

Chen²,

Yi-ming³

et al. 2020

Preprint

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Background Rheumatic heart disease (RHD) is a social health problem that affects many patients every year, but its pathogenesis is still unclear. Recent studies have found that the sphingosine 1-phosphate receptor 1 (S1PR1)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is activated during the development of valvular damage caused by RHD. STAT3 plays an important role in the differentiation of CD4 + T cells into T helper 17 (Th17) cells, and Th17 cell-related cytokines are involved in the development of RHD. In this work, we investigated whether altering the S1PR1/STAT3 signaling pathway by inhibiting the expression of STAT3 attenuates valvular damage due to RHD. Methods Inactivated Group A streptococci (GAS) and complete Freund’s adjuvant (CFA) were used to establish the RHD rat model. STAT3-small interfering RNA (STAT3-siRNA) was used to directly inhibit the expression of STAT3 in the heart. Histological examination was used to evaluate the degree of inflammation and fibrosis in valve tissues. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were used to detect the levels of interleukin (IL)-6 and IL-17 in serum and valve tissue. Reverse transcription-quantitative PCR (RT-qPCR) was used to detect the mRNA expression of S1PR1 and STAT3. Western blotting (WB) and immunohistochemistry were used to detect the protein expression of S1PR1, STAT3, phosphorylated (p-) STAT3, retinoic acid-related orphan receptor gamma T (RORγt). Results The expression of S1PR1 in valve tissues of RHD model rats was decreased. The degree of valvular inflammation and fibrosis of RHD model rats was increased. The levels of IL-6 and IL-17 in valves and serum of RHD model rats were increased as well as an increase of p-STAT3 in valve tissues. Inhibition of STAT3 by STAT3-siRNA decreased STAT3 expression and reduced the total amount of p-STAT3, resulting in decreased expression of IL-6, IL-17 and RORγt in valves and serum and reduced valvular inflammatory response and fibrosis. Conclusions These results suggest that inhibiting the expression of STAT3 in the heart may reduce the valvular damage caused by rheumatic heart disease.

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A Shift in the Balance of Regulatory T and T Helper 17 Cells in Rheumatic Heart Disease

Abstract: The results indicated that high TH17/Treg ratio exists inrheumatic MVD. This imbalance may play a role in the pathogenesis, and TH17/Treg balance may be a promising therapeutic approach in RHD.

Cited by 46 publications

References 43 publications

Acute rheumatic fever and rheumatic heart disease

Acute rheumatic fever and rheumatic heart disease

Cutting Edge: Ubiquitin-Specific Protease 4 Promotes Th17 Cell Function under Inflammation by Deubiquitinating and Stabilizing RORγt

The intervention of S1PR1/STAT3 signaling pathway by inhibiting the expression of STAT3 attenuates the valvular damage due to rheumatic heart disease

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