Reduced Tregs in Peripheral Blood of PCOS Patients – a Consequence of Aberrant Il2 Signaling

Krishna, Meera B.; Joseph, Annu; Subramaniam, Anand G.; Gupta, Aditya; Pillai, Sathy M.; Laloraya, Malini

doi:10.1210/jc.2014-2401

Cited by 41 publications

(50 citation statements)

References 51 publications

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“…Earlier reports had shown that iNOS derived NO regulates mouse oocyte maturation [37] as well as NO-Treg generation [38]. We have recently reported lowered Tregs in PCOS [39] and thus our observed low iNOS expression assumes larger significance as it would add to the burden of reduced FOXP3 expression further compromising Treg generation. eNOS expression has been shown in PBMC especially in neutrophils and monocytes [40, 41].…”

Section: Discussionmentioning

confidence: 58%

“…Niedbala et al have reported NO• to induce CD4 + CD25 + Foxp3 - regulatory T cells (NO• - Tregs) with suppressive properties in peripheral blood [38]. In our previous study we showed that peripheral pool of PCOS women contained low T-regulatory cells (Tregs) [39]. This is a strong implication that lowered NOS activity on account of decreased iNOS/eNOS expression in PBMC of PCOS patients contributes to decreased NO•-Tregs and exacerbates Treg depletion due to lowered FOXP3.…”

Section: Discussionmentioning

confidence: 99%

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Impaired Arginine Metabolism Coupled to a Defective Redox Conduit Contributes to Low Plasma Nitric Oxide in Polycystic Ovary Syndrome

Krishna

Joseph

Thomas

et al. 2017

Cell Physiol Biochem

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Background: Though oxidative stress is associated with Polycystic Ovary Syndrome (PCOS), the status of nitric oxide is still unclear. Nitric Oxide (NO) plays pivotal roles in many physiological functions which are compromised in PCOS. Our recent study reveals lowered T-regulatory cells (Tregs) in PCOS, and Treg generation is known to be regulated by NO levels. However concrete evidences are lacking on mechanisms modulating NO levels under PCOS. Methods: This is a retrospective case-control cohort study, comprised of PCOS women (N=29) and normal menstruating women as controls (N=20). We analysed NOx (nitrite+nitrate) and hydrogen peroxide (H₂O₂) concentrations, transcript levels of endothelial nitric oxide synthase (eNOS)/inducible nitric oxide synthase (iNOS) and arginine modulators, hydrogen peroxide regulators in the cohort. Results: PCOS women showed reduced plasma NOx(nitrate+nitrite) and H₂O₂ compared to controls. We report reduction in transcript levels of iNOS/NOS2 and eNOS/NOS3 in PCOS peripheral blood. The transcripts involved in arginine bioavailability: Argininosuccinate lyase (ASL), Solute Carrier Family1, member 7 (SLC7A1) and Arginase 1 (ARG1) and Asymmetric Dimethyl Arginine (ADMA) metabolism: Protein arginine methyltransferase 1 (PRMT1) and Dimethylarginine dimethylaminohydrolase 2 (DDAH2) also showed differential expression. H₂O₂ concentration in PCOS women was also found to be reduced. The reduction can be attributed to increase in catalase levels as a consequence of the body’s effort to alleviate the oxidative burden in the system. Conclusion: Our study advocates that PCOS women have lowered NO due to reduced iNOS/eNOS expression, low H₂O₂, high ADMA synthesis and reduced arginine bioavailability. An in-depth analysis of redox biology of PCOS to open up potential therapeutic strategies is highly recommended.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Impaired Arginine Metabolism Coupled to a Defective Redox Conduit Contributes to Low Plasma Nitric Oxide in Polycystic Ovary Syndrome

Krishna

Joseph

Thomas

et al. 2017

Cell Physiol Biochem

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“…Indeed, a decrease of Tregs is related to the occurrence of spontaneous abortion [86], unexplained recurrent abortions [87], and preeclampsia [88]. In addition, the number of Tregs in the peripheral blood of PCOS patients was shown to be lower than that of controls [89]. Therefore, the Th17/Tregs ratio would increase, leading to a chronic inflammatory state in the ovary and throughout the body.…”

Section: Regulatory T Cells (Tregs)mentioning

confidence: 99%

Immunophenotypic Profiles in Polycystic Ovary Syndrome

Pang

et al. 2020

Mediators of Inflammation

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Polycystic ovary syndrome (PCOS) a long-known endocrinopathy and one of the most common endocrine-reproductivemetabolic disorders in women, which can lead to infertility. Although the precise etiology remains unclear, PCOS is considered as a complex genetic trait, with a high degree of heterogeneity. Besides, hormones and immune cells, including both innate and adaptive immune cells, are reportedly a cross talk in PCOS. Chronic low-grade inflammation increases autoimmune disease risk. This proinflammatory condition may, in turn, affect vital physiological processes that ultimately cause infertility, such as ovulation failure and embryo implantation. Here, we review the accumulating evidence linking PCOS with inflammatory status providing an overview of the underlying hormone-mediated dysregulation of immune cells. We mainly focus on the correlational evidence of associations between immune status in women and the increased prevalence of PCOS, along with the specific changes in immune responses. Further recognition and exploration of these interactions may help elucidate PCOS pathophysiology and highlight targets for its treatment and prevention.

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“…Moreover, reduced capability of Treg generation has been found to lead to PCOS in humans and estrogen exposed PCOS mouse model. [ 8 ] CTLA4, a specific Treg markers, is an important costimulatory molecule indulged in playing suppressive function of Treg cells. Therefore, CTLA4 is supposed to affect the immune response and play roles in the pathogenesis of PCOS.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, both mouse models and human study results demonstrated that reduced capability of Treg generation may possibly lead to PCOS. [ 8 ] And cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) is a specific marker of Treg and can compete with CD28 to bind to CD80 and CD86 on antigen-presenting cells, such as macrophages. Through blocking the engagement of CD28 on T cells, CTLA4 can prevent T-cell activation, and thereby reducing the levels of interferon-γ, interleukin (IL)-6, and IL-1β.…”

Section: Introductionmentioning

confidence: 99%

Genetic association of CTLA4 gene with polycystic ovary syndrome in the Chinese Han population

Li²,

et al. 2018

Medicine

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Reduced Tregs in Peripheral Blood of PCOS Patients – a Consequence of Aberrant Il2 Signaling

Abstract: The study suggests that women with PCOS have reduced Tregs due to an inherent hyporesponsiveness to IL2, which is unable to activate STAT5B and reduce FOXP3 expression. IL2-based therapeutic strategies can ameliorate complications in PCOS by suppressing the AKT/PIK3 arm.

Cited by 41 publications

References 51 publications

Impaired Arginine Metabolism Coupled to a Defective Redox Conduit Contributes to Low Plasma Nitric Oxide in Polycystic Ovary Syndrome

Impaired Arginine Metabolism Coupled to a Defective Redox Conduit Contributes to Low Plasma Nitric Oxide in Polycystic Ovary Syndrome

Immunophenotypic Profiles in Polycystic Ovary Syndrome

Genetic association of CTLA4 gene with polycystic ovary syndrome in the Chinese Han population

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