Background Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intense itching and recurrent eczematous lesions. Important factors in the etiopathogenesis of AD include genetic predisposition, epidermal barrier dysfunction, immune dysregulation, and gut and skin dysbiosis. Probiotics could be a potential preventive strategy for allergies including AD through immune system modulation as well as enhancement of the epithelial barrier integrity. To further understand the role of probiotics in the management of AD, a Knowledge, Attitude, and Practices (KAP) survey was conducted. Materials and methods A steering committee comprising nine experts formulated consensus recommendations on the role of probiotics in the management of AD and associated flare-ups through the use of the Knowledge, Attitude, and Practices questionnaire while analyzing literature reviews and responses from a national panel consisting of 175 members. The evidence strength and quality were evaluated based on the Agency for Healthcare Research and Quality (AHRQ) criteria. The acceptance of expert opinions as recommendations was considered upon receiving an endorsement from ≥70% of the panelists, as indicated by a Likert scale. Results The national panel emphasized that the improvement in nutritional status, immunomodulatory properties, and beneficial effects on the gastrointestinal (GI) tract and skin support the use of probiotics in AD. The panel agreed that probiotics should be a part of the complementary therapy in the management of AD and associated flare-ups. Mostly, a probiotics supplementation duration of eight to 12 weeks is preferred by dermatologists. Probiotics, when used as an adjuvant therapy, may serve as a strategy to reduce steroid usage or maintenance therapy in high-risk cases with flares. Conclusion A Delphi-mediated KAP response provides a real-life approach to the use of probiotics in the management of AD. It suggests that probiotics could be useful as an adjuvant therapy in the management of AD and associated flare-ups when used along with traditional treatment.

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Conventional immunization methods such as intramuscular injections lack effective mucosal protection against pathogens that enter through the mucosal surfaces. Moreover, conventional therapy often leads to adverse events and compromised immunity, followed by complicated outcomes, leading to the need to switch to other options. Thus, a need to develop safe and effective treatment with long-term beneficial outcomes to reduce the risk of relapse is mandatory. Mucosal vaccines administered across mucosal surfaces, such as the respiratory or intestinal mucosa, to prompt robust localized and systemic immune responses to prevent the public from acquiring pathogenic diseases. Mucosal immunity contains a unique immune cell milieu that selectively identify pathogens and limits the transmission and progression of mucosal diseases, such as allergic dermatitis and inflammatory bowel disease (IBD). It also offers protection from localized infection at the site of entry, enables the clearance of pathogens on mucosal surfaces, and leads to the induction of long-term immunity with the ability to shape regulatory responses. Regulatory T (Treg) cells have been a promising strategy to suppress mucosal diseases. To find advances in mucosal treatment, we investigated the therapeutic effects of intranasal pep27 mutant immunization. Nasal immunization protects mucosal surfaces, but nasal antigen presentation appears to entail the need for an adjuvant to stimulate immunogenicity. Here, a novel method is developed to induce Tregs via intranasal immunization without an adjuvant to potentially overcome allergic diseases and gut and lung inflammation using lung-gut axis communication in animal models. The implementation of the pep27 mutant for these therapies should be preceded by studies on Treg resilience through clinical translational studies on dietary changes.

Giardiasis is a parasitic disease caused by Giardia lamblia (G. lamblia) that affects people worldwide. Still, few studies report on the immunoregulatory effects of the biomolecules of colostrum during interactions with G. lamblia. This study aimed to assess the concentrations of melatonin and cortisol hormones, the percentage of Treg cells, and the levels of cytokines IL-10 and TGF-β in colostrum from mothers who tested positive for the parasite. This cross-sectional study analyzed colostrum samples from 25 puerperal. The samples were tested using an ELISA to determine if they were seropositive for G. lamblia and the type of antibody present (IgM and IgG). Based on the results, the samples were divided into three groups: a control group (N = 10) with no reaction to either IgM or IgG, a group seropositive for IgG (IgG+/IgM-; N = 8), and a group seropositive for IgM (IgM+/IgG-; N = 7). The concentrations of melatonin and cortisol were measured using the ELISA method. Additionally, cytokines IL-10 and TGF-β and immunophenotyping were analyzed using flow cytometry. In the group that tested positive for IgM anti-G. lamblia, the concentration of melatonin was lower. However, in the colostrum from mothers who tested positive for IgG anti-G. lamblia, the level of this hormone had increased. The cortisol levels were similar between the groups, regardless of seropositivity. There was a higher percentage of Treg cells in the colostrum from mothers who tested positive for IgM anti-G. lamblia. TGF-β levels also increased in the colostrum of mothers who tested positive for IgM anti-G. lamblia. In the seronegative group for G. lamblia, there was a positive correlation between melatonin concentration and the percentage of Treg cells. These data suggest that the increase in regulatory cells and cytokines and the reduction in melatonin in colostrum from mothers with recent giardia infection may contribute to the evolution and manifestation of the disease.

BACKGROUND: This study aims to investigate the involvement of acid sphingomyelinase (ASM) in the pathology of dermatomyositis (DM), making it a potential therapeutic target for DM.
METHODS: Patients with DM and healthy controls (HCs) were included to assess the serum level and activity of ASM, and to explore the associations between ASM and clinical indicators. Subsequently, a myositis mouse model was established using ASM gene knockout and wild-type mice to study the significant role of ASM in the pathology and to assess the treatment effect of amitriptyline, an ASM inhibitor. Additionally, we investigated the potential treatment mechanism by targeting ASM both in vivo and in vitro.
RESULTS: A total of 58 DM patients along with 30 HCs were included. The ASM levels were found to be significantly higher in DM patients compared to HCs, with median (quartile) values of 2.63 (1.80-4.94) ng/mL and 1.64 (1.47-1.96) ng/mL respectively. The activity of ASM in the serum of DM patients was significantly higher than that in HCs. Furthermore, the serum levels of ASM showed correlations with disease activity and muscle enzyme levels. Knockout of ASM or treatment with amitriptyline improved the severity of the disease, rebalanced the CD4 T cell subsets Th17 and Treg, and reduced the production of their secreted cytokines. Subsequent investigations revealed that targeting ASM could regulate the expression of relevant transcription factors and key regulatory proteins.
CONCLUSIONS: ASM is involved in the pathology of DM by regulating the differentiation of naive CD4 + T cells and can be a potential treatment target.

BACKGROUND: Immune checkpoint inhibitors, such as anti-programmed cell death-1 (PD-1) and PD-1 ligand-1 (PD-L1) antibodies, have achieved breakthrough results in improving long-term survival rates in lung cancer. Although high levels of PD-L1 expression and tumor mutational burden have emerged as pivotal biomarkers, not all patients derive lasting benefits, and resistance to immune checkpoint blockade remains a prevalent issue. Comprehending the immunological intricacies of lung cancer is crucial for uncovering the mechanisms that govern responses and resistance to immunomodulatory treatments. This study aimed to explore the potential of peripheral immune markers in predicting treatment efficiency among lung cancer patients undergoing PD-1/PD-L1 checkpoint inhibitors.
METHODS: This study enrolled 71 lung cancer patients undergoing PD-1/PD-L1 inhibitor therapy and 20 healthy controls. Immune cell subsets (CD4 + T cells, CD8 + T cells, B cells, NK cells, and NKT cells), phenotypic analysis of T cells and B cells, and PMA/Ionomycin-stimulated lymphocyte function assay were conducted.
RESULTS: Lung cancer patients exhibited significant alterations in immune cell subsets, notably an increased percentage of Treg cells. Post-treatment, there were substantial increases in absolute numbers of CD3 + T cells, CD8 + T cells, and NKT cells, along with heightened HLA-DR expression on CD3 + T and CD8 + T cells. Comparison between complete remission and non-complete remission (NCR) groups showed higher Treg cell percentages and HLA-DR + CD4 + T cells in the NCR group.
CONCLUSIONS: The study findings suggest potential predictive roles for immune cell subsets and phenotypes, particularly Treg cells, HLA-DR + CD4 + T cells, and naïve CD4 + T cells, in evaluating short-term PD-1/PD-L1 therapy efficacy for lung cancer patients. These insights offer valuable prospects for personalized treatment strategies and underscore the importance of immune profiling in lung cancer immunotherapy.

Tumor-infiltrating regulatory T cells (TI-Tregs) elicit immunosuppressive effects in the tumor microenvironment (TME) leading to accelerated tumor growth and resistance to immunotherapies against solid tumors. Here, we demonstrate that poly-(ADP-ribose)-polymerase-11 (PARP11) is an essential regulator of immunosuppressive activities of TI-Tregs. Expression of PARP11 correlates with TI-Treg cell numbers and poor responses to immune checkpoint blockade (ICB) in human patients with cancer. Tumor-derived factors including adenosine and prostaglandin E2 induce PARP11 in TI-Tregs. Knockout of PARP11 in the cells of the TME or treatment of tumor-bearing mice with selective PARP11 inhibitor ITK7 inactivates TI-Tregs and reinvigorates anti-tumor immune responses. Accordingly, ITK7 decelerates tumor growth and significantly increases the efficacy of anti-tumor immunotherapies including ICB and adoptive transfer of chimeric antigen receptor (CAR) T cells. These results characterize PARP11 as a key driver of TI-Treg activities and a major regulator of immunosuppressive TME and argue for targeting PARP11 to augment anti-cancer immunotherapies.

BACKGROUND: Previous studies have shown that peptides encoded by noncoding RNAs (ncRNAs) can be used as peptide drugs to alleviate diseases. We found that microRNA-31 (miR-31) is involved in the regulation of hypertension and that the peptide miPEP31, which is encoded by the primary transcript of miR-31 (pri-miR-31), can inhibit miR-31 expression. However, the role and mechanism of miPEP31 in hypertension have not been elucidated.
METHODS: miPEP31 expression was determined by western blot analysis. miPEP31-deficient mice (miPEP31-/-) were used, and synthetic miPEP31 was injected into Ang II-induced hypertensive mice. Blood pressure was monitored through the tail-cuff method. Histological staining was used to evaluate renal damage. Regulatory T (Treg) cells were assessed by flow cytometry. Differentially expressed genes were analysed through RNA sequencing. The transcription factors were predicted by JASPAR. Luciferase reporter and electrophoretic mobility shift assays (EMSAs) were used to determine the effect of pri-miR-31 on the promoter activity of miPEP31. Images were taken to track the entry of miPEP31 into the cell.
RESULTS: miPEP31 is endogenously expressed in target organs and cells related to hypertension. miPEP31 deficiency exacerbated but exogenous miPEP31 administration mitigated the Ang II-induced systolic blood pressure (SBP) elevation, renal impairment and Treg cell decreases in the kidney. Moreover, miPEP31 deletion increased the expression of genes related to Ang II-induced renal fibrosis. miPEP31 inhibited the transcription of miR-31 and promoted Treg differentiation by occupying the Cebpα binding site. The minimal functional domain of miPEP31 was identified and shown to regulate miR-31.
CONCLUSIONS: miPEP31 was identified as a potential therapeutic peptide for treating hypertension by promoting Treg cell differentiation in vivo. Mechanistically, we found that miPEP31 acted as a transcriptional repressor to specifically inhibit miR-31 transcription by competitively occupying the Cebpα binding site in the pri-miR-31 promoter. Our study highlights the significant therapeutic effect of miPEP31 on hypertension and provides novel insight into the role and mechanism of miPEPs.

BACKGROUND: Mesenchymal stem cells (MSCs) demonstrate a wide range of therapeutic capabilities in the treatment of inflammatory bowel disease (IBD). The intraperitoneal injection of MSCs has exhibited superior therapeutic efficacy on IBD than intravenous injection. Nevertheless, the precise in vivo distribution of MSCs and their biological consequences following intraperitoneal injection remain inadequately understood. Additional studies are required to explore the correlation between MSCs distribution and their biological effects.
METHODS: First, the distribution of human umbilical cord MSCs (hUC-MSCs) and the numbers of Treg and Th17 cells in mesenteric lymph nodes (MLNs) were analyzed after intraperitoneal injection of hUC-MSCs. Subsequently, the investigation focused on the levels of transforming growth factor beta1 (TGF-β1), a key cytokine to the biology of both Treg and Th17 cells, in tissues of mice with colitis, particularly in MLNs. The study also delved into the impact of hUC-MSCs therapy on Treg cell counts in MLNs, as well as the consequence of TGFB1 knockdown hUC-MSCs on the differentiation of Treg cells and the treatment of IBD.
RESULTS: The therapeutic effectiveness of intraperitoneally administered hUC-MSCs in the treatment of colitis was found to be significant, which was closely related to their quick migration to MLNs and secretion of TGF-β1. The abundance of hUC-MSCs in MLNs of colitis mice is much higher than that in other organs even the inflamed sites of colon. Intraperitoneal injection of hUC-MSCs led to a significant increase in the number of Treg cells and a decrease in Th17 cells especially in MLNs. Furthermore, the concentration of TGF-β1, the key cytokine for Treg differentiation, were also found to be significantly elevated in MLNs after hUC-MSCs treatment. Knockdown of TGFB1 in hUC-MSCs resulted in a noticeable reduction of Treg cells in MLNs and the eventually failure of hUC-MSCs therapy in colitis.
CONCLUSIONS: MLNs may be a critical site for the regulatory effect of hUC-MSCs on Treg/Th17 cells and the therapeutic effect on colitis. TGF-β1 derived from hUC-MSCs promotes local Treg differentiation in MLNs. This study will provide new ideas for the development of MSC-based therapeutic strategies in IBD patients.

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.