Papillary thyroid cancer (PTC) is the most common type of thyroid malignancy with an increased female incidence ratio. The specific traits of X chromosome inheritance may be implicated in gender differences of PTC predisposition. The aim of this study was to investigate the association of two X-linked genes, Forkhead Box P3 (FOXP3) and Protein Phosphatase 1 Regulatory Subunit 3F (PPP1R3F), with PTC predisposition and gender disparity. One hundred thirty-six patients with PTC and an equal number of matched healthy volunteers were enrolled in the study. Genotyping for rs3761548 (FOXP3) and rs5953283 (PPP1R3F) was performed using polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP). The methylation status of FOXP3 was assessed using the combined bisulfite restriction analysis (COBRA) method. The SPSS software was used for statistical analyses. Gender stratification analysis revealed that the CA and AA genotypes and the A allele of FOXP3 rs3761548 variant are associated with PTC predisposition only in females. Moreover, different methylation status was observed up to the promoter locus of FOXP3 between PTC female patients, carrying the CA and CC genotype, and controls. Both revealed associations may explain the higher PTC incidence in females through reducing FOXP3 expression as reported in immune related blood cells.

BACKGROUND: Chronic idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease characterized by a breakdown of immune tolerance; in ITP, the body\'s immune system mistakenly attacks and destroys platelets. This study aims to investigate the role and underlying mechanisms of FOXP3 in chronic ITP.
METHODS: Flow cytometry was used to detect the proportion of CD4+CD25+FOXP3+ regulatory T cells (Tregs) in CD4+CD25+ T lymphocytes from 20 patients with chronic ITP (CITP), 20 acute ITP (AITP) controls, and 20 healthy individuals.CD4+CD25+ Treg cells were isolated from peripheral blood of patients with CITP using magnetic beads and then treated with phosphate-buffered saline solution or decitabine (a methylation inhibitor) for 48 h. The levels of interleukin-2 (IL-2), IL-10, and transforming growth factor-beta1 (TGF-β1) in the plasma and CD4+CD25+ Treg cells were assessed by Enzyme-linked-immunosorbent serologic assay and quantitative real-time polymerase chain reaction (qRT-PCR). FOXP3 level was measured by qRT-PCR and Western blot analysis. Methylation-specific PCR (MS-PCR) was adopted to detect the status of FOXP3 methylation.
RESULTS: The number of Treg cells and the contents of IL-2, IL-10, and TGF-β1 decreased in patients with CITP, compared to the AITP control group and normal group. FOXP3 expression was reduced and FOXP3 methylation increased in patients with CITP, compared to the AITP control group and normal group. Hypermethylation of FOXP3 promoter led to decrease in FOXP3 level in Treg cells. Inhibition of FOXP3 promoter hypermethylation promoted the secretion of IL-2, IL-10, and TGF-β1 in Treg cells.
CONCLUSIONS: The number of Treg cells in CITP patients decreased, and the hypermethylation of FOXP3 promoter led to reduction of its expression in Treg cells, thus affecting the immune functioning of Treg cells.

Background Hashimoto\'s thyroiditis (HT) is an autoimmune thyroid disease characterized by inflammation and dysfunction of the thyroid gland, resulting in hypothyroidism, it results in impaired thyroid hormone generation and mimics hypothyroidism. The disease involves complex interactions among genetic, environmental, and epigenetic factors, particularly affecting the regulation of T regulatory (Treg) cells, including CD4 + foxp3 + T cells. Treg cells, defined as CD4 + T cells, rely on the expression of the foxp3 transcription factor, which is crucial for their development and differentiation. Disruptions in this regulation can lead to immune dysregulation and potential proinflammatory responses. The study focuses on investigating the impact of dietary patterns on the epigenetic changes in the foxp3 gene, a key player in the development of HT. The primary aim was to evaluate how eliminating gluten and casein proteins from dietary regimens may influence the methylation levels of the foxp3 gene, considering the potential link between these dietary components and the triggering of autoimmune diseases. Methods An epigenetic analysis of the foxp3 gene in HT patients who were strictly following a dietary plan compared with the control group. For the epigenetic study, a methylation analysis experiment was conducted.  Results Our findings revealed a notable reduction in foxp3 gene methylation levels among HT patients who adhered to a diet excluding casein and gluten. The control maintained normal dietary guidelines and showed no significant alterations in methylation levels. Discussion The laboratory values showed a decrease in methylation levels of the foxp3 gene, with statistical significance indicated as *p<0.005, **p<0.001, ***p<0.0001, suggesting a potential enhancement in its expression which could have profound implications for immune system regulation. Disruptions in the foxp3 pathway are crucial in the development of autoimmune disorders, where altered activity hinders the regulation of T cell (Treg) development, ultimately contributing to conditions like HT disease. These findings imply that nutritional interventions, especially for individuals with HT, could potentially be a strategy for mitigating autoimmunity through epigenetic mechanisms.

Fasciolosis is an important economic disease of livestock. There is a global interest in the development of protective vaccines since the current anthelmintic therapy is no longer sustainable. A better knowledge of the host-parasite interaction is needed to design effective vaccines. To date, few studies have evaluated host-parasite interaction by comparing infected and reinfected animals. The present study evaluates the microscopical hepatic lesions in sheep infected and reinfected with Fasciola hepatica during the acute and chronic stages of infection. The histopathological study revealed the presence of necrotizing foci (NF1) associated with larvae migration during the early stages of infection in the primoinfected (PI) and reinfected (RI) groups. In the late stages of infection of the PI group and at the early and late stages of infection in the RI groups, extensive necrotizing/hemorrhagic foci (NF2) were found in the vicinity of enlarged bile ducts, some containing adult flukes, suggesting parasites may have caused NF2 while feeding. The immunohistochemical study revealed an increase in Foxp3+ T cells in both PI and RI groups with respect to the UC group and in the infiltrates adjacent to NF1 in the RI groups with respect to the PI group, suggesting the F. hepatica induce Foxp3 T cell expansion to facilitate parasite survival. In addition, in both the PI and RI groups, and during acute and chronic stages of the infection, a poor expression of iNOS was found accompanied by a strong expression of CD163, suggesting a marked M2 activation of macrophages in the hepatic lesions, which may be related with healing processes, and it also may facilitate parasite survival. The main differences between PI and RI animals were the more severe infiltration of eosinophils and Foxp3+ T cells, whereas RI did not modify M2 activation of macrophages which occurs since the early stages of primoinfection.

Breast cancer poses a global health challenge, yet the influence of ethnicity on the tumor microenvironment (TME) remains understudied. In this investigation, we examined immune cell infiltration in 230 breast cancer samples, emphasizing diverse ethnic populations. Leveraging tissue microarrays (TMAs) and core samples, we applied multiplex immunofluorescence (mIF) to dissect immune cell subtypes across TME regions. Our analysis revealed distinct immune cell distribution patterns, particularly enriched in aggressive molecular subtypes triple-negative and HER2-positive tumors. We observed significant correlations between immune cell abundance and key clinicopathological parameters, including tumor size, lymph node involvement, and patient overall survival. Notably, immune cell location within different TME regions showed varying correlations with clinicopathologic parameters. Additionally, ethnicities exhibited diverse distributions of cells, with certain ethnicities showing higher abundance compared to others. In TMA samples, patients of Chinese and Caribbean origin displayed significantly lower numbers of B cells, TAMs, and FOXP3-positive cells. These findings highlight the intricate interplay between immune cells and breast cancer progression, with implications for personalized treatment strategies. Moving forward, integrating advanced imaging techniques, and exploring immune cell heterogeneity in diverse ethnic cohorts can uncover novel immune signatures and guide tailored immunotherapeutic interventions, ultimately improving breast cancer management.

Since transcription factor Forkhead Box P3 (FoxP3) was identified as a specific regulatory T cell (Treg) marker, researchers have scrutinized its value as a potential novel therapeutic target or a prognostic factor in various types of cancer with inconsistent results. The present analysis was performed to assess the influence of Treg FoxP3 expression on the prognosis of primary melanoma and to evaluate the correlations with various clinicopathological prognostic factors. We analyzed all eligible patients with stage pT3 primary malignant melanomas treated in a tertiary cancer center. Immunohistochemical staining for Treg FoxP3 expression was performed on retrospectively identified paraffin blocks and subsequently correlated with the outcomes of the patients. A total of 81% of the patients presented a positive Treg FoxP3 expression, being correlated with a higher risk of lymph node metastasis, tumor relapse, and death. Moreover, positive expression was statistically associated with a shorter OS. The tumor relapse rate was estimated at 36.7%. A positive expression of Treg FoxP3 and lymph node metastasis were associated with a higher risk of death based on multivariate analysis. Treg FoxP3 expression may be used as an independent prognostic factor in patients with malignant melanoma to evaluate tumor progression and survival.

Foxp3+ regulatory T cells (Foxp3+ Treg) play a role in regulating various types of tumors, but uncertainty still exists regarding the exact mechanism underlying Foxp3+ Treg activation in gastrointestinal malignancies. As of now, research has shown that Foxp3+ Treg expression, altered glucose metabolism, or a hypoxic tumor microenvironment all affect Foxp3+ Treg function in the bodies of tumor patients. Furthermore, it has been demonstrated that post-translational modifications are essential for mature Foxp3 to function properly. Additionally, a considerable number of non-coding RNAs (ncRNAs) have been implicated in the activation of the Foxp3 signaling pathway. These mechanisms regulating Foxp3 may one day serve as potential therapeutic targets for gastrointestinal malignancies. This review primarily focuses on the properties and capabilities of Foxp3 and Foxp3+Treg. It emphasizes the advancement of research on the regulatory mechanisms of Foxp3 in different malignant tumors of the digestive system, providing new insights for the exploration of anticancer treatments.

The induction of immunological tolerance is a promising strategy for managing autoimmune diseases, allergies, and transplant rejection. Tregitopes, a class of peptides, have emerged as potential agents for this purpose. They activate regulatory T cells, which are pivotal in reducing inflammation and promoting tolerance, by binding to MHC II molecules and facilitating their processing and presentation to Treg cells, thereby encouraging their proliferation. Moreover, Tregitopes influence the phenotype of antigen-presenting cells by attenuating the expression of CD80, CD86, and MHC class II while enhancing ILT3, resulting in the inhibition of NF-kappa B signaling pathways. Various techniques, including in vitro and in silico methods, are applied to identify Tregitope candidates. Currently, Tregitopes play a vital role in balancing immune activation and tolerance in clinical applications such as Pompe disease, diabetes-related antigens, and the prevention of spontaneous abortions in autoimmune diseases. Similarly, Tregitopes can induce antigen-specific regulatory T cells. Their anti-inflammatory effects are significant in conditions such as autoimmune encephalomyelitis, inflammatory bowel disease, and Guillain-Barré syndrome. Additionally, Tregitopes have been leveraged to enhance vaccine design and efficacy. Recent advancements in understanding the potential benefits and drawbacks of IVIG and the discovery of the function and mechanism of Tregitopes have introduced Tregitopes as a popular option for immune system modulation. It is expected that they will bring about a significant revolution in the management and treatment of autoimmune and immunological diseases. This article is a comprehensive review of Tregitopes, concluding with the potential of these epitopes as a therapeutic avenue for immunological disorders.

In this study, we identified FOXP3 as a transcription factor for lncRNA SNHG1, which exerts a significant protective role against cardiomyocyte hypertrophy. Through DNA-pull down experiments and ChIP analysis, we confirmed that FOXP3 could bind to the promoter of SNHG1. Luciferase reporter and RT-qPCR experiments validated that FOXP3 overexpression promoted SNHG1 expression in cardiomyocytes. Furthermore, in a model of cardiomyocyte hypertrophy, FOXP3 expression was upregulated, particularly in cardiomyocytes. Functional assays demonstrated that FOXP3 overexpression inhibited cardiomyocyte hypertrophy, while FOXP3 knockdown held the opposite effect. Additionally, we revealed that lncRNA SNHG1 acted as a sponge for miR-182, miR-326, and miR-3918, thereby stabilizing FOXP3 mRNA in cardiomyocytes. The protective role of SNHG1 against cardiomyocyte hypertrophy was found to depend on the presence of FOXP3, forming a positive FOXP3/SNHG1 feedback axis. Moreover, we unveiled this positive FOXP3/SNHG1 feedback axis suppressed cardiomyocyte hypertrophy by negatively regulating Parkin-mediated mitophagy. These findings provide novel insights into the molecular mechanisms underlying cardiomyocyte hypertrophy and offer potential therapeutic targets for related interventions.

UNASSIGNED: Currently, Chronic Obstructive Pulmonary Disease (COPD) has a high impact on morbidity and mortality worldwide. The increase of CD4+, CD8+ cells expressing NF-κB, STAT4, IFN-γ and perforin are related to smoking habit, smoking history, airflow rate, obstruction and pulmonary emphysema. Furthermore, a deficiency in CD4+CD25+Foxp3+ regulatory T cells (Tregs) may impair the normal function of the immune system and lead to respiratory immune disease. On the other hand, the anti-inflammatory cytokine IL-10, produced by Treg cells and macrophages, inhibits the synthesis of several pro-inflammatory cytokines that are expressed in COPD. Therefore, immunotherapeutic strategies, such as Photobiomodulation (PBM), aim to regulate the levels of cytokines, chemokines and transcription factors in COPD. Consequently, the objective of this study was to evaluate CD4+STAT4 and CD4+CD25+Foxp3+ cells as well as the production of CD4+IFN- γ and CD4+CD25+IL-10 in the lung after PBM therapy in a COPD mice model.
UNASSIGNED: We induced COPD in C57BL/6 mice through an orotracheal application of cigarette smoke extract. PMB treatment was applied for the entire 7 weeks and Bronchoalveolar lavage (BAL) and lungs were collected to study production of IFN- γ and IL-10 in the lung. After the last administration with cigarette smoke extract (end of 7 weeks), 24 h later, the animals were euthanized. One-way ANOVA followed by NewmanKeuls test were used for statistical analysis with significance levels adjusted to 5% (p < 0.05).
UNASSIGNED: This result showed that PBM improves COPD symptomatology, reducing the number of inflammatory cells (macrophages, neutrophils and lymphocytes), the levels of IFN-γ among others, and increased IL-10. We also observed a decrease of collagen, mucus, bronchoconstriction index, alveolar enlargement, CD4+, CD8+, CD4+STAT4+, and CD4+IFN-γ+ cells. In addition, in the treated group, we found an increase in CD4+CD25+Foxp3+ and CD4+IL-10+ T cells.
UNASSIGNED: This study suggests that PBM treatment could be applied as an immunotherapeutic strategy for COPD.