UNASSIGNED: Hashimoto\'s thyroiditis (HT), a chronic autoimmune disorder impacting thyroid function, is a growing public health concern. The relationship between Treg cells and HT has been extensively studied, with Treg cells considered crucial in suppressing HT progression. However, these studies have mainly been observational, limiting our understanding of Treg cells\' impact on HT risk. Leveraging large datasets, we utilized Mendelian randomization (MR) analysis to examine the causal association between Treg cell biomarkers and HT, providing additional validation for these relationships.
UNASSIGNED: Comprehensive two-sample Mendelian randomization analysis was performed to determine the causal association between Treg cells signatures and HT in this study. Based on publicly available genetic data, we explored causal associations between 165 Treg cells signatures and HT risk.
UNASSIGNED: The European cohort study has identified five Treg cell phenotypes that causally protect against HT risk. Resting Treg %CD4 (OR = 0.975, 95% CI = 0.954~0.998, P = 0.030); CD4 on resting Treg (OR = 0.938, 95% CI = 0.882~0.997, P = 0.041; CD28- CD8dim %CD8dim (OR = 0.983, 95% CI = 0.969~0.998, P = 0.030); CD25 on CD39+ resting Treg (OR = 0.926, 95% CI = 0.864~0.991, P = 0.026); 5) CD28 on activated & secreting Treg (OR = 0.969, 95% CI = 0.942~0.996, P = 0.025). The Asian cohort study has identified four Treg cell phenotypes negatively correlated with the risk of HT. CD25hi %T cell (OR = 0.635, 95% CI = 0.473~852, P = 0.002); CD4 Treg %CD4 (OR = 0.829, 95% CI = 0.687~1.000, P = 0.050); CD127-CD8br %T cell (OR = 0.463, 95% CI =0.311~0.687, P< 0.001); CD3 on resting Treg (OR = 0.786, 95% CI = 0.621~0.994, P = 0.044).
UNASSIGNED: Our study has demonstrated the close connection between Treg cells and HT by genetic means, thus providing foundational basis for future research.

Dermatomyositis (DM)/polymyositis (PM) is a systemic autoimmune disease characterized by proximal limb muscle with high morbidity and mortality and poor prognosis mediated by immune dysfunction; its etiology is unknown. DM/PM patients are at excessive risk of interstitial lung disease (ILD) and a higher risk of death. However, the role of circulating lymphocyte subsets, which play a pivotal role in occurrence and progression of DM/PM and ILD, respectively, remains unclear in DM/PM patients with ILD.
Demographic characteristics, general data, and peripheral lymphocyte levels measured by flow cytometry were collected and analyzed in 47 DM/PM patients with ILD, 65 patients without ILD, and 105 healthy controls (HCs).
The most important first symptom of DM/PM patients is rash. Compared with non-ILD patients, the levels of neutrophil/lymphocyte ratio (NLR), systemic inflammatory response index (SIRI) were significantly higher and the levels of C reactive protein (CRP) were significantly lower in patients with ILD. Compared with HCs, DM/PM patients, with or without ILD, had decreased absolute counts of T, CD4 + T, CD8 + T, natural killer (NK), helper T (Th) 1, Th2, Th17, and regulatory T (Treg)cells. The fewest Th1 and Treg cells and the the lowest CD8 + T and Th1 cells percentages were seen in peripheral blood of patients with ILD. Longer duration, decreased lymphocyte/monocyte ratio (LMR)levels and CD8 + T and Th1 cells proportions, and fewer circulating Treg cells were independent risk factors for DM/PM with ILD.
The identification of peripheral blood T lymphocyte subsets, especially Treg cells, and blood count in DM/PM appears to be useful in the comprehensive assessment of clinical lung involvement.

During pregnancy, the maternal immune system is challenged to tolerate a semi-allogenic fetus. A proinflammatory profile has been linked to adverse pregnancy outcomes and poor placental development. In this study, the authors evaluated the number of circulating Tregs and Th17 cells in a group of patients diagnosed with preeclampsia(PE) and fetal growth restriction(FGR).
Prospective longitudinal observational study where peripheral blood lymphocyte subsets were analyzed in a cohort of pregnant patients with PE, FGR, and a control group of healthy pregnant women.
The diagnosis of PE was associated with a significative higher number of circulating Th17 cells and a significative relative reduction in the Treg cell count. This proinflammatory profile was also expressed in the evolution of the Th17/ CD4+CD25highFOXP3+ Treg ratio. In the FGR group, the Th17 cell count was significantly higher during the third trimester of pregnancy. This proinflammatory profile was also expressed in the evolution of the Th17/ CD4+CD25highFOXP3+ Treg ratio. When we compare the immunological profiles of patients with PE and FGR we observed a higher number of proinflammatory Th17 cells and a significative lower number of Treg cells in PE patients. This is particularly expressed in the differences found between the Th17/ CD4+CD25highFOXP3+ Treg ratios of these two groups. Discussion/Conclusion Our data showed a that a proinflammatory profile and a relative excess of Th17 cells was associated with the diagnosis of PE and FGR. A more exuberant systemic proinflammatory profile present in the PE patients is absent in patients with FGR without preeclampsia.

Asthma is a common chronic inflammatory disease of the airway. Intestinal flora, a significant risk factor for asthma, has become a widespread concern in the pathogenesis of asthma. To review the literature related to intestinal flora in asthma, summarize research direction, and report trends, this study used CiteSpace to perform bibliometric statistics and analysis on the research papers of intestinal flora and asthma collected in the Web of science core collection from 2001 to 2021. Eventually, a total of 613 articles were included. The results demonstrated that research on gut flora and asthma continued to heat up, with article numbers increasing, especially in the last decade. Moreover, analysis of the keywords showed that the research topics of intestinal flora and asthma range from confirming the link between intestinal flora and asthma to investigating mechanisms and then to asthma treatment. According to the summary of research hotspots, we expand on three emerging issues that require attention in the intestinal flora and asthma research, including (regulatory T)Treg cells, probiotics, and chain fatty acid. Evidence illustrated that Treg cells play a crucial role in the pathogenesis of asthma caused by dysbiosis of the gut flora. Furthermore, in contrast to probiotic supplements, which do not reduce the risk of developing asthma, short-chain fatty acids supplements do. Overall, the research direction in the field of intestinal flora and asthma has recently evolved from macro to micro with depth broadened. As a robust scientific evaluation, our study provided a comprehensive overview of the area, particularly for research focus, which could more precisely direct scholars on future research and clinical diagnosis, therapy, and individualized prevention.

The principal goal of the study was to verify the concept of pharmacological induction of Foxp3+CD25+CD4+ T regulatory (Treg) cells which will additionally be characterized by a highly suppressive phenotype, i.e., by extensive CD25 and CD39 expression and IL-10 and TGF-β production. Stimulated and unstimulated murine lymphocytes were exposed to IL-27, teriflunomide (TER), and all trans retinoic acid (ATRA) alone and to their combinations. The study demonstrated that: (a) IL-27 alone induced CD39 expression on Treg cells and the generation of Tr1 cells; (b) TER alone induced Foxp3-expressing CD4+ T cells and up-regulated density of CD25 on these cells; TER also induced the ability of Treg cells to TGF-β production; (c) ATRA alone induced CD39 expression on Treg cells. The experiments revealed a strong superadditive effect between IL-27 and ATRA with respect to increasing CD39 expression on Treg cells. Moreover, IL-27 and ATRA in combination, but not alone, induced the ability of Treg cells to IL-10 production. However, the combination of IL-27, TER, and ATRA did not induce the generation of Treg cell subset with all described above features. This was due to the fact that TER abolished all listed above desired effects induced by IL-27 alone, ATRA alone, and their combination. IL-27 alone, ATRA alone, and their combination affected TER-induced effects to a lesser extent. Therefore, it can be concluded that in the aspect of pharmacological induction of Treg cells with a highly suppressive phenotype, the triple combination treatment with TER, IL-27, and ATRA does not provide any benefits over TER alone or dual combination including IL-27 and ATRA.

Natural killer (NK) cells play a crucial role in the anti-tumor transaction through cytolytic activity with the help of proportionate expression of their activating receptors (ARs) and inhibitory receptors (IRs). The proliferation, differentiation, and effector\'s functions of NK cells were affected and regulated by CD4+CD25+ regulatory T (Treg) cells through the NKG2D receptor expressed on NK cells. It has not yet been established whether Treg cells also affects the expression and functions of other receptors of NK cell. Moreover, the effect of cyclophosphamide (CYP) treatment on the expression and functions of AR and IR receptors of NK cells regulated by Treg cells during cancer progression is not clearly understood. Therefore, we have used the metronomic dose of CYP and anti-CD25 and anti-TGF-β to inhibit the effects of Treg cells in DL-induced tumor microenvironment and analyze the expression of ARs and IRs on NK cells and the FoxP3 level on Treg cells. It was observed that treatment of CYP and blocking antibodies not only affects the functions of tumor-associated NK cells (TANK cells) by modulating the expression of ARs and IRs in DL-induced tumor microenvironment, but also downregulates the functions of Treg cells. The findings of our study supported and suggested that the use of CYP in combination with other therapeutic approaches will effectively reduce tumor growth directly and/or indirectly by modulating the NK cell-mediated immune response of the host.

HIV infection and the prolonged use of antiretroviral therapy (ART) contribute to persistent inflammation and immune deregulation in people living with HIV/AIDS (PLWHA). Propolis is a bee product with plenty of biological properties, including immunomodulatory and anti-inflammatory action. This work aimed to evaluate possible changes in the immune/inflammatory response in PLWHA under ART after propolis intake. Asymptomatic PLWHA were double-blindly randomized into parallel groups receiving propolis (500 mg/day, n = 20) for 3 months or placebo (n = 20). Plasma cytokines (TNF-α, IL-2, IL-4, IL-6, IL-10 and IL17) were evaluated by cytometric bead array; cytokine production by PBMC (IFN-γ, IL-5, IL-17, IL-10, IL-1β, IL-18, and IL-33) was assessed by ELISA; gene expression (T-bet, GATA-3, RORγt and Foxp3) was determined by RT-qPCR, and cell proliferation was analysed by flow cytometry using CFSE staining. The average of gender, age, CD4+/CD8+ T cell count, time of diagnosis and treatment were similar in both groups. No differences were observed in cytokine levels nor in inflammasome activation. However, Pearson\'s correlation showed that IL-10 was directly correlated to CD4+ T cell count and inversely to IFN-γ after treatment with propolis. Foxp3 expression and lymphocyte proliferation increased in the propolis group. Data suggested that daily propolis consumption may improve the immune response and decrease the inflammatory status in asymptomatic PLWHA under ART.

T regulatory (Treg) cells play a critical role in the maintenance of self-tolerance, as well as in inhibition of inflammation and exaggerated immune response against exogenous antigens. They develop in the thymus (tTreg cells) but also may be generated at the peripheral tissues, including tumor microenvironment (pTreg cells), or induced in vitro in the presence of transforming growth factor (TGF)-β (iTreg cells). Since tTreg cells constitute a minor fraction of peripheral blood lymphocytes in physiological conditions, an alternative way to obtain high number of functional Treg cells for therapeutic purposes is their generation in vitro from conventional T cells. In our studies, we compared effectiveness of several pharmacological agents with suggested immunomodulatory effects on Treg development (rapamycin, prednisolone, inosine pranobex, glatiramer acetate, sodium butyrate, and atorvastatin) to optimize Treg-inducing protocols. All but one (atorvastatin) immunomodulators augmented induction of polyclonal Treg cells in cultures. They were effective both in increasing the number of CD4+CD25highFoxp3high cells and Foxp3 expression. Rapamycin and prednisolone were found the most effective. Both drugs prolonged also phenotypic stability of Treg cells and induced fully active Treg cells in a functional assay. In the assay, prednisolone appeared superior versus rapamycin. The results, on the one hand, may be helpful in planning optimal protocols for generation of Treg cells for clinical application and, on the other hand, shed some light on mechanisms of the immunomodulatory activity of some tested agents observed in vivo.

The main aims of this study were: (1) to investigate whether a blockade of the interaction between the receptor activator of nuclear factor-κB (NF-ĸB) ligand (RANKL) and its receptor RANK may have potential as a novel therapeutic strategy for allergic asthma; (2) to compare the efficacies of the blockade of RANKL/RANK interaction as well as the blockade of NF-κB inhibitor kinase (IKK) and of NF-κB translocation to the nucleus, also in comparison with glucocorticosteroid treatment, in terms of the development of a mouse model of allergic airway inflammation (AAI) and accompanying immune response. The blockade of each of the targets fully prevented the development of AAI. All the tested therapeutic strategies seemed to have a certain advantage over glucocorticosteroids with regard to counteracting the development of AAI. Prevention of the activation and clonal expansion of CD4+ effector T (Teff) cells in the mediastinal lymph nodes (MLNs) constitutes a fundamental event underlying the anti-asthmatic effect induced by the blockade of IKK, NF-κB translocation or of RANKL/RANK interaction. The results indicate that attenuation of the CD11b+CD103-CD11chigh dendritic cell response in the MLNs is an initial but not the main mechanism responsible for this effect. In turn, the direct anti-proliferative action on CD4+ Teff cells seems to constitute the chief mechanism responsible for the anti-asthmatic effect of all the tested therapeutic strategies. A clinical implication is that local inhibition of RANKL/RANK interaction achieved via inhalatory administration of a RANKL antagonist can be considered as a novel therapeutic strategy in treatment of allergic asthma.

Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined.
This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors.
Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed.
We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS.
Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.