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In the first paper [[10]], the epidemiologic, clinical, and immunological features of CVID-associated giardiasis are reviewed, evidencing that patients with giardiasis more commonly have reduced IgA levels and lower levels of switched memory B cells. 35566429 12 Pieniawska-'Smiech K., Kuraszewicz A., Sado J., 'Smiech K., Lewandowicz-Uszy'nska A. Assessment of COVID-19 Incidence and the Ability to Synthesise Anti-SARS-CoV-2 Antibodies of Paediatric Patients with Primary Immunodeficiency. The atypical presentation of IEI is also the main focus of the paper by Morawska et al., which explores the spectrum of atopic manifestations in patients with selective IgA deficiency (sIgAD). This work analyzes the most common autoimmune manifestations in patients with antibody deficiencies, combined immunodeficiencies, and immune dysregulation disorders, and also introduces some specific monogenic entities that are used as a paradigm of "druggable" IEI. [Extracted from the article]

This document is an editorial published in the journal Frontiers in Immunology. It discusses the role of adaptive immunity in atherosclerosis, a condition that contributes to acute cardiovascular events. The editorial highlights the importance of chronic inflammation in atherosclerosis and the potential for new intervention strategies. It also explores the use of new immunological techniques to study the role of the adaptive immune system in the development, progression, and regression of atherosclerosis. The document includes summaries of several research papers that investigate different aspects of adaptive immunity in atherosclerosis, including T cell and B cell responses. Overall, the editorial provides an overview of the latest findings in this field and serves as a valuable resource for researchers interested in studying adaptive immunity in atherosclerosis. [Extracted from the article]

This article explores the role of T helper cells in autoimmune diseases and the need for more effective treatment strategies. The authors specifically focus on autoreactive CD4+ T helper cells, particularly the T follicular helper subset, which promote the production of autoantibodies. They also discuss the imbalance between pathogenic peripheral T helper cells and tissue-resident Tregs in autoimmune diseases. The article highlights the importance of further research to develop targeted therapies for controlling autoimmune diseases. Additionally, the document provides a summary of various studies and reviews on the role of T helper cells in specific autoimmune diseases, aiming to contribute to the understanding of T cell involvement and potential therapeutic targets. [Extracted from the article]

The article offers information on the challenges and advancements in hematopoietic stem cell transplantation (HCT) over the past 50 years, as chronicled through key papers in the JCI. Topics include the curative potential of HCT for various hematologic diseases, the challenges of allogeneic HCT such as relapse and graft-versus-host disease (GVHD), and the immunologic complexities underlying these challenges.

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease that affects nearly 3.41 million people globally, with 90% of the cases affecting women of childbearing age. SLE is a complex disease due to the interplay of various immunological pathways and mechanisms. This scoping review aims to highlight the latest research findings on the therapeutic mechanisms of action of EVs in SLE. Relevant research articles were identified using the PRISMA framework from databases such as PubMed/MEDLINE (National Library of Medicine), Scopus (Elsevier), and Web of Science: Core Collection (Clarivate Analytics) from July 2023 to October 2023. Eleven studies met the inclusion criteria and thus were included in this scoping review. The findings showed that EVs have therapeutic effects on ameliorating the disease progression of SLE. EVs can reduce the pro-inflammatory cytokines and increase the anti-inflammatory cytokines. Moreover, EVs can increase the levels of regulatory T cells, thus reducing inflammation. EVs also have the potential to regulate B cells to alleviate SLE and reduce its adverse effects. The scoping review has successfully analysed the therapeutic potential in ameliorating the disease progression of SLE. The review also includes prospects to improve the effects of EVs further to increase the therapeutic effects on SLE. [ABSTRACT FROM AUTHOR]

This article, titled "Editorial: Pathogenic roles of T cells in autoimmunity," explores the role of T cells in autoimmune diseases. The immune system has mechanisms in place to prevent self-reactive T and B lymphocytes from causing autoimmune diseases, but these mechanisms are imperfect. Helper T cells, specifically CD4 T cells, play a crucial role in the development of autoimmune diseases. The article discusses the different subsets of helper T cells and their functions, as well as the potential for targeting pathogenic T cells in the treatment and prevention of autoimmune diseases. The research topic also includes papers on the pathogenic roles of T cells in specific autoimmune diseases such as vitiligo, idiopathic inflammatory myopathies, and primary Sjogren Syndrome. [Extracted from the article]

Summary: The immune system plays a critical role in protecting the host against infection but is subject to numerous levels of control that are necessary to prevent pathological, tissue-damaging responses. Inappropriate inflammatory immune responses to self-antigens, innocuous commensal microorganisms, or environmental antigens can lead to chronic, debilitating, and degenerative diseases. Regulatory T cells have an essential, non-redundant, and dominant function in preventing pathological immune responses, as shown by the development of systemic fatal autoimmunity in humans and animals with a genetic deficiency in regulatory T cells. In addition to controlling immune responses, there is a growing understanding that regulatory T cells also contribute directly to tissue homeostasis by promoting tissue regeneration and repair. For these reasons, the prospect of enhancing regulatory T-cell numbers and/or function in patients represents an appealing therapeutic opportunity with potential applications in many diseases, including some where the pathological role of the immune system has only recently been recognized. Approaches to enhance regulatory T cells are now starting to be explored in clinical studies in humans. This review series brings together papers highlighting the Treg-enhancing approaches that are most advanced clinically and examples of therapeutic opportunities based on our growing understanding of regulatory T-cell functions. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) are crucial for preserving tolerance in the body, rendering Treg immunotherapy a promising treatment option for both organ transplants and autoimmune diseases. Presently, organ transplant recipients must undergo lifelong immunosuppression to prevent allograft rejection, while autoimmune disorders lack definitive cures. In the last years, there has been notable advancement in comprehending the biology of both antigen-specific and polyclonal Tregs. Clinical trials involving Tregs have demonstrated their safety and effectiveness. To maximize the efficacy of Treg immunotherapy, it is essential for these cells to migrate to specific target tissues, maintain stability within local organs, bolster their suppressive capabilities, and ensure their intended function's longevity. In pursuit of these goals, the utilization of biomaterials emerges as an attractive supportive strategy for Treg immunotherapy in addressing these challenges. As a result, the prospect of employing biomaterial-enhanced Treg immunotherapy holds tremendous promise as a treatment option for organ transplant recipients and individuals grappling with autoimmune diseases in the near future. This paper introduces strategies based on biomaterial-assisted Treg immunotherapy to enhance transplant medicine and autoimmune treatments.

Dendritic cells (DCs) are essential orchestrators of immune responses and represent potential targets for immunomodulation in autoimmune diseases. Human amniotic fluid secretome is abundant in immunoregulatory factors, with extracellular vesicles (EVs) being a significant component. However, the impact of these EVs on dendritic cells subsets remain unexplored. In this study, we investigated the interaction between highly purified dendritic cell subsets and EVs derived from amniotic fluid stem cell lines (HAFSC‐EVs). Our results suggest that HAFSC‐EVs are preferentially taken up by conventional dendritic cell type 2 (cDC2) through CD29 receptor‐mediated internalization, resulting in a tolerogenic DC phenotype characterized by reduced expression and production of pro‐inflammatory mediators. Furthermore, treatment of cDC2 cells with HAFSC‐EVs in coculture systems resulted in a higher proportion of T cells expressing the regulatory T cell marker Foxp3 compared to vehicle‐treated control cells. Moreover, transfer of HAFSC‐EV‐treated cDC2s into an EAE mouse model resulted in the suppression of autoimmune responses and clinical improvement. These results suggest that HAFSC‐EVs may serve as a promising tool for reprogramming inflammatory cDC2s towards a tolerogenic phenotype and for controlling autoimmune responses in the central nervous system, representing a potential platform for the study of the effects of EVs in DC subsets. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) are essential for maintaining immune homeostasis by serving as negative regulators of adaptive immune system effector cell responses. Reduced production or function of Tregs has been implicated in several human autoimmune diseases. The cytokine interleukin 2 plays a central role in promoting Treg differentiation, survival, and function in vivo and may therefore have therapeutic benefits for autoimmune diseases. mRNA‐6231 is an investigational, lipid nanoparticle‐encapsulated, mRNA‐based therapy that encodes a modified human interleukin 2 mutein fused to human serum albumin (HSA‐IL2m). Herein, we report the development of a semi‐mechanistic kinetic‐pharmacodynamic model to quantify the relationship between subcutaneous dose(s) of mRNA‐6231, HSA‐IL2m protein expression, and Treg expansion in nonhuman primates. The nonclinical kinetic‐pharmacodynamic model was extrapolated to humans using allometric scaling principles and the physiological basis of pharmacological mechanisms to predict the clinical response to therapy a priori. Model‐based simulations were used to inform the dose selection and design of the first‐in‐human clinical study (NCT04916431). The modeling approach used to predict human responses was validated when data became available from the phase I clinical study. This validation indicates that the approach is valuable in informing clinical decision‐making. [ABSTRACT FROM AUTHOR]

Immune evasion contributes to cancer growth and progression. Cancer cells have the ability to activate different immune checkpoint pathways that harbor immunosuppressive functions. The programmed death protein 1 (PD-1) and programmed cell death ligands (PD-Ls) are considered to be the major immune checkpoint molecules. The interaction of PD-1 and PD-L1 negatively regulates adaptive immune response mainly by inhibiting the activity of effector T cells while enhancing the function of immunosuppressive regulatory T cells (Tregs), largely contributing to the maintenance of immune homeostasis that prevents dysregulated immunity and harmful immune responses. However, cancer cells exploit the PD-1/PD-L1 axis to cause immune escape in cancer development and progression. Blockade of PD-1/PD-L1 by neutralizing antibodies restores T cells activity and enhances anti-tumor immunity, achieving remarkable success in cancer therapy. Therefore, the regulatory mechanisms of PD-1/PD-L1 in cancers have attracted an increasing attention. This article aims to provide a comprehensive review of the roles of the PD-1/PD-L1 signaling in human autoimmune diseases and cancers. We summarize all aspects of regulatory mechanisms underlying the expression and activity of PD-1 and PD-L1 in cancers, including genetic, epigenetic, post-transcriptional and post-translational regulatory mechanisms. In addition, we further summarize the progress in clinical research on the antitumor effects of targeting PD-1/PD-L1 antibodies alone and in combination with other therapeutic approaches, providing new strategies for finding new tumor markers and developing combined therapeutic approaches. [ABSTRACT FROM AUTHOR]

CD4+CD25hiCD127lo/−FOXP3+ regulatory T cells (Tregs) play a key role in preventing autoimmunity. In autoimmune type 1 diabetes (T1D), adoptive transfer of autologous polyclonal Tregs has been shown to be safe in adults in phase 1 clinical trials. We explored factors contributing to efficacy of autologous polyclonal expanded Tregs (expTregs) in a randomized phase 2 multi-center, double-blind, clinical trial (Sanford/Lisata Therapeutics T-Rex phase 2 trial, ClinicalTrials.gov NCT02691247). One hundred ten treated children and adolescents with new-onset T1D were randomized 1:1:1 to high-dose (20 × 106 cells/kilogram) or low-dose (1 × 106 cells/kilogram) treatments or to matching placebo. Cytometry as well as bulk and single-cell RNA sequencing were performed on selected expTregs and peripheral blood samples from participants. The single doses of expTregs were safe but did not prevent decline in residual β cell function over 1 year compared to placebo (P = 0.94 low dose, P = 0.21 high dose), regardless of age or baseline C-peptide. ExpTregs were highly activated and suppressive in vitro. A transient increase of activated memory Tregs was detectable 1 week after infusion in the high-dose cohort, suggesting effective transfer of expTregs. However, the in vitro fold expansion of expTregs varied across participants, even when accounting for age, and lower fold expansion and its associated gene signature were linked with better C-peptide preservation regardless of Treg dose. These results suggest that a single dose of polyclonal expTregs does not alter progression in T1D; instead, Treg quality may be an important factor. Editor's summary: Regulatory T cells (Tregs) are important in immune tolerance. Infusion of autologous polyclonal Tregs, first expanded in vitro to increase their numbers, has been investigated for safety in small clinical studies, however usefulness of this therapy for type 1 diabetes (T1D) remains unclear. Bender et al. report that a phase 2 randomized trial of a single dose of expanded Tregs showed no efficacy in preserving C-peptide, an indicator of β cell function, in early-onset T1D. This negative in vivo result comes despite the suppressive capacity of the expanded Tregs in vitro, and will inform future studies of the role of polyclonal Tregs in T1D. —Catherine Charneski [ABSTRACT FROM AUTHOR]

The immune system is meant to protect against invading microbes. Although this system is effective against many microbes, some can use molecular mimicry to turn the immune system against the host and activate autoimmune responses. The resulting autoimmunity has significant implications for public health and healthcare costs. It is well known that regulatory T cells (Tregs) are crucial for self-tolerance and that their function is impaired after exposure to self-antigens or antigens with molecular mimicry, leading to the activation of autoimmune responses. How molecular mimicry disrupts Tregs in this manner remains under debate. This review contributes to the field of the pathogenesis of autoimmunity by proposing that purinergic signaling in the lymph nodes, with extracellular ATP, ADP, and adenosine as ligands, plays a pivotal role in this process. Repeated or high-dose microbial infection causes the release of large amounts of extracellular ATP sufficient to reach the threshold of extracellular ATP levels for activating P2X7 purinergic receptors (P2X7Rs) on dendritic cells and Tregs. This hampers the ability of Tregs to suppress autoimmune responses. Crucially, P2X7Rs are activated at very high extracellular ATP levels, thus only after repeated or highdose infection with microbes. Arguably, in contrast to the rapid elimination of microbes with foreign antigens, the clearance of invading microbes that employ molecular mimicry requires the activation of P2X7Rs at the expense of self-tolerance. Because all processes required to activate autoimmune responses occur in secondary lymphoid organs, this article hypothesizes that, contrary to current convention, microbes do not need to enter organs to initiate autoimmunity. However, some types of microbes can prevent P2X7R-induced Treg disruption by converting extracellular ATP to adenosine, mitigating autoimmune responses resulting in chronic diseases with less severe inflammation. The proposed hypothesized mechanism has potential implications for the understanding and treatment of autoimmune disorders. [ABSTRACT FROM AUTHOR]

The occurrence of many autoimmune diseases takes root on the disrupted balance among Treg cells, Teff cells, etc. Low-dose interleukin-2 (IL-2) cytokine demonstrates promising clinical efficacy in the expansion of Treg cells and the treatment of autoimmune diseases. However, its clinical application is hindered by the small therapeutic index and short half-life. Previous studies have shown that non-covalent complex of human IL-2 and anti-IL-2 antibody biases cytokine activity towards Treg cells and extends IL-2's half-life. The clinical translation of such complex is non-trivial. In this study, we discover an anti-human IL-2 antibody and engineer a covalently-linked single-agent fusion of human IL-2 and its antibody that selectively expands Treg cells and exhibits superior disease control activity in animal models of ulcerative colitis and systemic lupus erythematosus, with proper safety profile and good developability. These studies pave the road for its clinical development in diverse autoimmune diseases. A single-agent fusion of human IL-2 and antiIL-2 antibody is discovered and engineered to selectively expand regulatory T cells and to treat autoimmune diseases. [ABSTRACT FROM AUTHOR]

The regulatory T (Treg) cells constitute a functionally defined subpopulation of T cells that modulate the immune system and maintain immune tolerance through suppression of the development of autoimmune responses to self-antigens and allergic reactions to external antigens. Reduction in the number or function of Treg cells has been suggested as a key immune abnormality underlying the development of autoimmune and allergic diseases. In vitro studies have demonstrated that purified polyvalent immunoglobulin G (IgG) from multiple healthy blood donors can exert immunomodulatory effects on Treg cells. Incubation of polyvalent human IgG with purified CD4+CD25high T cells increased the intracellular expression of interleukin (IL)-10. Intravenous administration of polyvalent human IgG induced significant expansions of CD4+ Foxp3+ Treg cells and clinical improvements in patients with autoimmune diseases. In human clinical trials, intramuscular administration of autologous total IgG significantly increased the percentage of IL-10-producing CD4+ Treg cells in the peripheral blood of healthy subjects and provided significant clinical improvements in patients with atopic dermatitis. These results suggest a clinical usefulness of polyvalent IgG-induced activation of Treg cells in human subjects. This review proposes a new hypothesis for immune tolerance mechanism by integrating the pre-existing “idiotypic network theory” and “Treg cell theory” into an “anti-idiotypic Treg cell theory.” Based on this hypothesis, an “active anti-idiotypic therapy” for allergic and autoimmune diseases using autologous polyvalent IgG (as immunizing antigens) is suggested as follows: (1) Intramuscular or subcutaneous administration of autologous polyvalent IgG produces numerous immunogenic peptides derived from idiotypes of autologous IgG through processing of dendritic cells, and these peptides activate anti-idiotypic Treg cells in the same subject. (2) Activated anti-idiotypic Treg cells secrete IL-10 and suppress Th2 cell response to allergens and autoimmune T cell response to selfantigens. (3) These events can induce a long-term clinical improvements in patients with allergic and autoimmune diseases. Further studies are needed to evaluate the detailed molecular mechanism underlying polyvalent IgG-induced Treg cell activation and the clinical usefulness of this immunomodulatory therapy for autoimmune and allergic diseases. [ABSTRACT FROM AUTHOR]

Low-dose interleukin-2 (IL-2) regulates the homeostasis of CD4+ T cells by modulating the proportions of effector and regulatory T cells, thus reducing disease activity in patients with systemic lupus erythematosus (SLE). However, to date, no research has been carried out on the efficacy of low-dose IL-2 for treating autoimmune thyroid disease (AITD). The aim of this study was to observe the effects of IL-2 on AITD patients with concurrent SLE, and explore potential mechanism of action. A retrospective analysis was conducted on 29 SLE patients with concurrent AITD. Among them, 11 patients were in IL-2 therapy group and 18 patients without IL-2 treatment were considered as control group. Two groups had similar disease activities and were treated with comparable regular strategy. Free triiodothyronine (FT3), free thyroxine (FT4), thyroxine(T4), triiodothyronine(T3), thyroid stimulating hormone (TSH), thyroglobulin antibody (TG-Ab), thyroid peroxidase antibody (TPO-Ab) levels and immune cell subgroups were measured. After receiving low-dose IL-2 therapy, the TG-Ab and TPO-Ab levels decreased drastically (TG-Ab p = 0.008, TPO-Ab p = 0.007), and the majority of the AITD patients became seronegative, while there was no discernible change in control group. In IL-2 group, percentage of CD4+ T cells showed a significant increase after treatment (p = 0.029), with an upward trend in the ratio of regulatory T (Treg) cells to follicular helper T (Tfh) cells (Treg/Tfh). The percentage as well as absolute count of B cells demonstrated a decreasing trend. Low-dose IL-2 may downregulate the levels of TG-Ab and TPO-Ab by modulating the immune balance of Treg/Tfh and B-cells, providing new avenue for clinical treatment of AITD. Low-dose IL-2 could decrease the levels of TG-Ab and TPO-Ab in AITD with concurrent SLE patients. Low-dose IL-2 may regulate Treg/Tfh balance and B-cells to ameliorate TG-Ab and TPO-Ab. Low-dose IL-2 provides a new avenue for AITD clinical treatment. [ABSTRACT FROM AUTHOR]

Autoimmunity and its associated diseases have been the primary area of focus in research in the past decade; however, several mechanisms are still left unclear. Autoimmune diseases are idiopathic and currently, there are hardly any genetic tools available to predict who is at risk of developing them. With the advancement of artificial intelligence, it could be possible to predict the potential emergence of autoimmune disorders. This review article discusses the disease classification and relevant causes, including environmental, biological, and genetic factors. Additionally, it explores certain mechanisms where the T-regulatory cells fail and lead to disease development. The article delves into the etiology to illustrate how autoimmune diseases could develop in a person as well as therapeutic approaches are also discussed. With the development of multiplex technologies, it is easier to detect autoantibodies in blood while cytokines and chemokines can give a breakthrough in diagnosis and novel therapeutics for these diseases. [ABSTRACT FROM AUTHOR]

Introduction: Regulatory T cell (Treg)-targeting cancer immunotherapy aims to transiently deplete Treg cells in the tumor microenvironment, without affecting effector T cells (Teff), thus both enhancing anti-tumor activity and avoiding autoimmunity. This study evaluated whether adding E7777 (a new formulation of denileukin diftitox [DD]) improved the efficacy of anti-PD-1 antibody therapy. DD is a recombinant protein containing the hydrophobic and catalytic portions of diphtheria toxin fused to full-length human IL-2. E7777 has the same amino acid sequence and brief circulatory half-life as DD, but with greater purity and potency. Methods: Subcutaneous syngeneic murine solid tumor models (colon cancer CT-26 and liver cancer H22) were used to evaluate safety, efficacy, and overall survival with E7777 and anti-PD-1 antibodies, each administered as monotherapy or in concurrent or sequential combination. In Experiment 1, treatments were compared to assess anti-tumor activity at various time points, with tumors excised and dissociated and tumor leukocytes characterized. In Experiment 2, tumor growth, response, and overall survival were characterized for 100 days following a 3-week treatment. Results: E7777 administered in combination with anti-PD-1 led to significantly increased anti-tumor activity and durable, extended overall survival compared to either treatment alone. In both tumor models, the Treg cell infiltration induced by anti-PD-1 treatment was counterbalanced by co-treatment with E7777, suggesting potential synergistic activity. Combination therapy showed the most favorable results. Treatment with E7777 was safe and well-tolerated. Discussion: Combined E7777 and anti-PD-1 therapy was well tolerated and more effective than monotherapy with either drug. [ABSTRACT FROM AUTHOR]

The autoimmune reaction against the beta cells of the pancreatic islets in type 1 diabetes mellitus (T1DM) patients is active in prediabetes and during the development of the clinical manifestation of T1DM, but it decreases within a few years of the clinical manifestation of this disease. A key role in the pathogenesis of T1DM is played by regulatory T cell (Treg) deficiency or dysfunction. Immune interventions, such as potential therapeutic applications or the induction of the Treg-cell population in T1DM, will be important in the development of new types of treatment. The aim of this study was to evaluate innovative immune interventions as treatments for T1DM. After an evaluation of full-length papers from the PubMed database from 2010 to 2021, 20 trials were included for the final analysis. The analysis led to the following conclusions: Treg cells play an important role in the limitation of the development of T1DM, the activation or application of Tregs may be more effective in the early stages of T1DM development, and the therapeutic use of Treg cells in T1DM is promising but requires long-term observation in a large group of patients. [ABSTRACT FROM AUTHOR]

The cytokine interleukin-2 (IL-2) has the potential to treat autoimmune disease but is limited by its modest specificity toward immunosuppressive regulatory T (Treg) cells. IL-2 receptors consist of combinations of α, β, and γ chains of variable affinity and cell specificity. Engineering IL-2 to treat autoimmunity has primarily focused on retaining binding to the relatively Treg-selective, high-affinity receptor while reducing binding to the less selective, low-affinity receptor. However, we found that refining the designs to focus on targeting the high-affinity receptor through avidity effects is key to optimizing Treg selectivity. We profiled the dynamics and dose dependency of signaling responses in primary human immune cells induced by engineered fusions composed of either wild-type IL-2 or mutant forms with altered affinity, valency, and fusion to the antibody Fc region for stability. Treg selectivity and signaling response variations were explained by a model of multivalent binding and dimer-enhanced avidity—a combined measure of the strength, number, and conformation of interaction sites—from which we designed tetravalent IL-2–Fc fusions that had greater Treg selectivity in culture than do current designs. Biasing avidity toward IL2Rα with an asymmetrical multivalent design consisting of one α/β chain–binding and one α chain–binding mutant further enhanced Treg selectivity. Comparative analysis revealed that IL2Rα was the optimal cell surface target for Treg selectivity, indicating that avidity for IL2Rα may be the optimal route to producing IL-2 variants that selectively target Tregs. Editor's summary: The cytokine IL-2 activates cells that either perpetuate or suppress immune system activity, making cell selectivity critical for its use in immunotherapy. Orcutt-Jahns et al. used a model of binding and signaling dynamics to design a series of IL-2 variants with enhanced selectivity for immunosuppressive regulatory T cells. Versions that leveraged multivalent binding to the α chain of the heterotrimeric IL-2 receptor were more selective for regulatory T cells than were current IL-2 therapeutics. This approach may yield IL-2 variants that are more effective at treating autoimmune diseases. –Leslie K. Ferrarelli [ABSTRACT FROM AUTHOR]

Introduction: Excretory/secretory products (ESPs) derived from helminths have been reported to effectively control allergic inflammation, which have better therapeutic prospects than live parasite infections. However, it remains unknown whether ESPs from schistosome eggs can protect against allergies, despite reports alleging that schistosome infection could alleviate disordered allergic inflammation. Method: In the present study, we investigated the protective effects of ESPs from Schistosoma japonicum eggs (ESP-SJE) on asthmatic inflammation. Firstly, we successfully established an allergic airway inflammation model in mice by alum-adjuvanted ovalbumin (OVA) sensitization and challenge. ESP-SJE were administered intraperitoneally on days -1 and 13 (before sensitization), on day 20 (before challenge), and on days 21–24 (challenge phase). Results: The results showed that ESP-SJE treatment significantly reduced the infiltration of inflammatory cells, especially eosinophils into the lung tissue, inhibited the production of the total and OVA-specific IgE during OVA-sensitized and -challenged phases, respectively, and suppressed the secretion of Th2-type inflammatory cytokines (IL-4). Additionally, ESP-SJE treatment significantly upregulated the regulatory T cells (Tregs) in the lung tissue during OVA challenge. Furthermore, using liquid chromatography-mass spectrometry analysis and Treg induction experiments in vitro, we might identify nine potential therapeutic proteins against allergic inflammation in ESP-SJE. The targets of these candidate proteins included glutathione S-transferase, egg protein CP422 precursor, tubulin alpha-2/alpha-4 chain, actin-2, T-complex protein 1 subunit beta, histone H₄, whey acidic protein core region, and molecular chaperone HtpG. Conclusion: Taken together, the results discussed herein demonstrated that ESP-SJE could significantly alleviate OVA-induced asthmatic inflammation in a murine model, which might be mediated by the upregulation of Treg in lung tissues that may be induced by the potential modulatory proteins. Therefore, potential proteins in ESP-SJE might be the best candidates to be tested for therapeutic application of asthma, thus pointing out to a possible new therapy for allergic airway inflammation. Author summary: Asthma, especially atopic asthma, one of the most common chronic, non-communicable diseases in children and adults, which is characterized by variable respiratory symptoms and variable airflow limitation. As the rapid rising of allergy and asthma rates, it seriously affects the quality of people's life. Asthma is a consequence of complex gene-environment interactions with heterogeneity in clinical presentation. Recent years, A leading theory is the "hygiene hypothesis", which suggests that the decreasing incidence of infections in western countries is the origin of the increasing incidence of allergic diseases. Following this lead, abundant experimental studies have proved that helminth infection can down-regulate host's immunopathology in allergies. Further, helminth-derived excretory/secretory products (ESPs) have been reported to effectively control allergic inflammation, which have better therapeutic prospects than live parasite infections. Schistosome act as a wide-spread and one of the best illustrated helminths. Present study investigated that ESPs from Schistosoma japonicum eggs (ESP-SJE) could effectively alleviate OVA-induced allergic airway inflammation in a murine model, and nine potential modulatory proteins for Treg induction that might to be vital to inhibit asthmatic inflammation from ESP-SJE were predicated by mass spectrum analysis. The significance of our research is in founding a new way to explore schistosome-derived molecules alleviating asthma, which may allow the development of a model that will greatly enhance our understanding of the interaction between atopic asthma and helminth parasites, further facilitate the discovery of a better candidates to be tested for therapeutic application of asthma, thus pointing out to a possible new therapy for allergic disease or other autoimmune disease. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS), a T-cell-mediated autoimmune disease that affects the central nervous system (CNS), is characterized by white matter demyelination, axon destruction, and oligodendrocyte degeneration. Ivermectin, an anti-parasitic drug, has anti-inflammatory, anti-tumor, and antiviral properties. However, to date, there are no in-depth studies on the effect of ivermectin on the function effector of T cells in murine experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Here, we conducted in vitro experiments and found that ivermectin inhibited the proliferation of total T cells (CD3+) and their subsets (CD4+ and CD8+ T cells) as well as T cells secreting the pro-inflammatory cytokines IFN-γ and IL-17A; ivermectin also increased IL-2 production and IL-2Rα (CD25) expression, which was accompanied by an increase in the frequency of CD4+CD25+Foxp3+ regulatory T cells (Treg). Importantly, ivermectin administration reduced the clinical symptoms of EAE mice by preventing the infiltration of inflammatory cells into the CNS. Additional mechanisms showed that ivermectin promoted Treg cells while inhibiting pro-inflammatory Th1 and Th17 cells and their IFN-γ and IL-17 secretion; ivermectin also upregulated IL-2 production from MOG35–55-stimulated peripheral lymphocytes. Finally, ivermectin decreased IFN-γ and IL-17A production and increased IL-2 level, CD25 expression, and STAT5 phosphorylation in the CNS. These results reveal a previously unknown etiopathophysiological mechanism by which ivermectin attenuates the pathogenesis of EAE, indicating that it may be a promising option for T-cell-mediated autoimmune diseases such as MS. [ABSTRACT FROM AUTHOR]

Existing therapeutics for autoimmune diseases remain problematic due to low efficacy, severe side effects, and difficulties to reach target tissues. Herein, we design multifunctional fusion nanovesicles that can target lesions for the treatment of autoimmune skin diseases. The grapefruit‐derived exosome‐like nanovesicles (GEVs) with anti‐inflammatory and antioxidant effects are first encapsulated with CX5461, an immunosuppressant with anti‐proliferative properties to form GEV@CX5461. In order to enhance therapeutic efficiency and safety, GEV@CX5461 are then fused with CCR6+ nanovesicles derived from membranes of engineered gingiva‐derived mesenchymal stem cells (GMSCs). The resulting FV@CX5461 not only maintain the bioactivity of GEVs, CX5461, and GMSC membranes but also home to inflamed tissues rich in chemokine CCL20 through the chemotaxis function of CCR6 on FVs. Moreover, FV@CX5461 reduce the secretion of inflammatory factors, calm down Th17 cell activation, and induce Treg cell infiltration. Finally, impressive therapeutic efficiency in both psoriasis and atopic dermatitis disease models is demonstrated using FV@CX5461 to reshape the unbalanced immune microenvironment. A nanotherapeutic drug delivery strategy is developed using fusion nanovesicles derived from plant and animal cells with high clinical potential. [ABSTRACT FROM AUTHOR]

Considering the large number of individuals who have already been infected and may have reinfection, the post-infection effects of COVID-19 are of great importance for clinical practice and predicting disease trends. However, our understanding of the potential long-term effects, particularly on immunity, after recovering from COVID-19 remains limited. The aim of this study was to investigate the abnormal immunological factors that contribute to the prolonged immunological effects of COVID-19. Two groups of patients were enrolled in the study, including 11 individuals with various autoimmune diseases (AIDs) and 16 patients diagnosed with systemic lupus erythematosus (SLE). Detailed clinical symptoms were closely monitored, and peripheral mononuclear cells were analyzed using flow cytometry. The clinical status was evaluated using the SLE Disease Activity Index (SLEDAI) and the Clinical Global Impressions (CGI) index. The proportions of follicular T helper cells (Tfh) exhibited significant increases in both cohorts (AID: p = 0.03; SLE: p = 0.0008). Conversely, the percentages of Foxp3+ and CD4+ regulatory T cells (Treg) were reduced in patients following COVID-19 infection (AID: p = 0.009, 0.05, resp.; SLE: p = 0.02, 0.0009, resp.). The percentages of Th2 and Th17 cells were significantly increased in SLE patients (p < 0.05). Exacerbated conditions were observed in SLE patients two months after infection (SLEDAI, p < 0.05). Our findings show that COVID-19 infection increases Tfh cells and decreases Treg cells in patients of AIDs, worsening pathogenetic immune status in post-recovery populations. [ABSTRACT FROM AUTHOR]

Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the production of autoantibodies, immune complex deposition, and tissue/organ damage. In this study, we aimed to identify molecular features and signaling pathways associated with SLE severity using RNA sequencing (RNAseq), single-cell RNA sequencing (scRNA-seq), and clinical parameters. Methods: We analyzed transcriptome profiles of 45 SLE patients, grouped into mild (mSLE, SLEDAI ≤ 9) and severe (sSLE, SLEDAI > 9) based on SLE Disease Activity Index (SLEDAI) scores. We also collected clinical data on anti-dsDNA, ANA, ESR, CRP, snRNP, AHA, and anti-Smith antibody status for each patient. Results: By comparing gene expression across groups, we identified 12 differentially expressed genes (DEGs), including 7 upregulated (CEACAM6, UCHL1, ARFGEF3, AMPH, SERPINB10, TACSTD2, and OTX1) and 5 downregulated (SORBS2, TRIM64B, SORCS3, DRAXIN, and PCDHGA10) DEGs in sSLE compared to mSLE. Furthermore, using the CIBERSORT algorithm, we found that Treg cells were significantly decreased in sSLE and negatively correlated with AMPH expression, which was mainly expressed in Treg cells from SLE patients according to public scRNA-seq data (GSE135779). Discussion: Overall, our findings shed light on the molecular mechanisms underlying SLE severity and provide insight into potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Autoimmune diseases (ADs) are characterized by the production of autoreactive lymphocytes, immune responses to self-antigens, and inflammation in related tissues and organs. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is majorly expressed in activated T cells and works as a critical regulator in the inflammatory response. In this review, we first describe the structure, expression, and how the signaling pathways of CTLA-4 participate in reducing effector T-cell activity and enhancing the immunomodulatory ability of regulatory T (Treg) cells to reduce immune response, maintain immune homeostasis, and maintain autoimmune silence. We then focused on the correlation between CTLA-4 and different ADs and how this molecule regulates the immune activity of the diseases and inhibits the onset, progression, and pathology of various ADs. Finally, we summarized the current progress of CTLA-4 as a therapeutic target for various ADs. [ABSTRACT FROM AUTHOR]

The conventional therapeutic approaches to treat autoimmune diseases through suppressing the immune system, such as steroidal and non-steroidal anti-inflammatory drugs, are not adequately practical. Moreover, these regimens are associated with considerable complications. Designing tolerogenic therapeutic strategies based on stem cells, immune cells, and their extracellular vesicles (EVs) seems to open a promising path to managing autoimmune diseases' vast burden. Mesenchymal stem/stromal cells (MSCs), dendritic cells, and regulatory T cells (Tregs) are the main cell types applied to restore a tolerogenic immune status; MSCs play a more beneficial role due to their amenable properties and extensive cross-talks with different immune cells. With existing concerns about the employment of cells, new cell-free therapeutic paradigms, such as EV-based therapies, are gaining attention in this field. Additionally, EVs' unique properties have made them to be known as smart immunomodulators and are considered as a potential substitute for cell therapy. This review provides an overview of the advantages and disadvantages of cell-based and EV-based methods for treating autoimmune diseases. The study also presents an outlook on the future of EVs to be implemented in clinics for autoimmune patients. [ABSTRACT FROM AUTHOR]

Summary: Immune homeostasis is heavily dependent on the action of regulatory T cells (Tregs) which act to suppress the activation of many immune cell types including autoreactive conventional T cells. A body of evidence has shown that Tregs are intrinsically defective in many common autoimmune diseases, and gene polymorphisms which increase the susceptibility of autoimmune disease development have implicated the interleukin-2 (IL-2) signaling pathway as a key dysregulated mechanism. IL-2 is essential for Treg function and survival, and Tregs are highly sensitive to low levels of this cytokine in their environment. This review will revisit the rationale behind using low-dose IL-2 as a therapy to treat autoimmune diseases and evaluate the outcomes of trials to date. Furthermore, novel engineered IL-2 therapies with increased Treg specificity have shown promise in pre-clinical studies and human clinical trials for some agents have begun. Future studies will determine whether low-dose IL-2 or engineered IL-2 therapies can change the course of autoimmune and inflammatory diseases in patients. [ABSTRACT FROM AUTHOR]

Introduction: Autoimmune hepatitis (AIH) is a chronic liver disease caused by a perturbed immune system. The scarcity of short- and long-term immune monitoring of AIH hampered us to comprehend the interaction between immunosuppressive medication and immune homeostasis. Methods and patients: We recruited children with AIH at the time of diagnosis and at the 1st, 3rd, 6th, 12th, 18th, and 24th months of immunosuppression (IS). We also enrolled children with AIH being on IS for >2 years. Children with druginduced liver injury (DILI), and those receiving tacrolimus after liver transplantation (LT), were enrolled as disease/IS control subjects. Healthy children (HC) were also recruited. Peripheral blood mononuclear cells (PBMCs) were isolated from all participants. Healthy liver tissue from adult donors and from livers without inflammation were obtained from children with hepatoblastoma. By using flow cytometry, we performed multi-parametric immune profiling of PBMCs and intrahepatic lymphocytes. Additionally, after IS with prednisolone, tacrolimus, rapamycin, or 6-mercaptopurine, we carried out an in vitro cytokine stimulation assay. Finally, a Lifecodes SSO typing kit was used to type HLA-DRB1 and Luminex was used to analyze the results. Results: Untreated AIH patients had lower total CD8 T-cell frequencies than HC, but these cells were more naïve. While the percentage of naïve regulatory T cells (Tregs) (CD4+FOXP3lowCD45RA+) and regulatory B cells (Bregs, CD20+CD24+CD38+) was similar, AIH patients had fewer activated Tregs (CD4+FOXP3highCD45RA-) compared to HC. Mucosal-associated-invariant-T-cells (MAIT) were also lower in these patients. Following the initiation of IS, the immune profiles demonstrated fluctuations. Bregs frequency decreased substantially at 1 month and did not recover anymore. Additionally, the frequency of intrahepatic Bregs in treated AIH patients was lower, compared to control livers, DILI, and LT patients. Following in vitro IS drugs incubation, only the frequency of IL-10-producing total B-cells increased with tacrolimus and 6MP. Lastly, 70% of AIH patients possessed HLA-DR11, whereas HLA-DR03/ DR07/DR13 was present in only some patients. Conclusion: HLA-DR11 was prominent in our AIH cohort. Activated Tregs and MAIT cell frequencies were lower before IS. Importantly, we discovered a previously unrecognized and long-lasting Bregs scarcity in AIH patients after IS. Tacrolimus and 6MP increased IL-10+ B-cells in vitro. frequency of intrahepatic Bregs in treated AIH patients was lower, compared to control livers, DILI, and LT patients. Following in vitro IS drugs incubation, only the frequency of IL-10-producing total B-cells increased with tacrolimus and 6MP. Lastly, 70% of AIH patients possessed HLA-DR11, whereas HLA-DR03/ DR07/DR13 was present in only some patients. Conclusion: HLA-DR11 was prominent in our AIH cohort. Activated Tregs and MAIT cell frequencies were lower before IS. Importantly, we discovered a previously unrecognized and long-lasting Bregs scarcity in AIH patients after IS. Tacrolimus and 6MP increased IL-10+ B-cells in vitro. [ABSTRACT FROM AUTHOR]

This article aims to explore associated immune indicators of autoimmune thyroid disease (AITD) through a meta-analysis of published case-control studies on newly diagnosed AITD patients, intending to provide some suggestions for research on the mechanisms of AITD. Six electronic databases were searched for case-control studies on newly diagnosed AITD patients from inception to August 15, 2022. A random-effects model was used to calculate the standardized mean difference (SMD), odds ratio (OR), and 95% confidence interval (95% CI). A total of 26 articles were included in this meta-analysis. Patients with newly diagnosed AITD had higher levels of helper T cell 17 (Th17) (Hashimoto's disease (HT): SMD=2.35, 95% CI: 1.98, 2.72; Graves' disease (GD): SMD=1.61, 95% CI: 1.23, 1.98), lower levels of regulatory T cell (Treg) (HT: SMD=–2.04, 95% CI: –2.67, –1.42; GD: SMD=–1.35, 95% CI: –2.11, –0.58), and lower levels of forkhead box P3 (FoxP3) mRNA (HT: SMD=–2.58, 95% CI: –3.12, –2.05; GD: SMD=–2.13, 95% CI: –2.56, –1.70), compared to the healthy population. In addition, the single nucleotide polymorphism rs3761548 and rs3761549 in the promoter region of FoxP3 showed a higher frequency in the comparison of genotype "CT" only in HT patients than in the healthy population (OR=1.66, 95%CI: 1.18, 2.34). In patients with newly diagnosed AITD, the Th17/Treg ratio imbalance may develop AITD. Monitoring Th17 and Treg levels may become an essential tool to assess the organism's immune homeostasis and hopefully guide clinical diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Regulatory CD4+ T (Treg) cells play a key role in the induction of immune tolerance and in the prevention of autoimmune diseases. Treg cells are defined by the expression of transcription factor FOXP3, which ensures proliferation and induction of the suppressor activity of this cell population. In a tumor microenvironment, after transplantation or during autoimmune diseases, Treg cells can respond to various signals from their environment and this property ensures their suppressor function. Recent studies showed that a metabolic signaling pathway of Treg cells are essential in the control of Treg cell proliferation processes. This review presents the latest research highlights on how the influence of extracellular factors (e.g. nutrients, vitamins and metabolites) as well as intracellular metabolic signaling pathways regulate tissue specificity of Treg cells and heterogeneity of this cell population. Understanding the metabolic regulation of Treg cells should provide new insights into immune homeostasis and disorders along with important therapeutic implications for autoimmune diseases, cancer and other immune-system-mediated disorders. [ABSTRACT FROM AUTHOR]

Vitamin D (VD) deficiency is a highly prevalent worldwide phenomenon and is extensively discussed as a risk factor for the development of systemic lupus erythematosus (SLE) and other immune-mediated diseases. In addition, it is now appreciated that VD possesses multiple immunomodulatory effects. This study aims to explore the impact of dietary VD intake on lupus manifestation and pathology in lupus-prone NZB/W F1 mice and identify the underlying immunological mechanisms modulated by VD. Here, we show that low VD intake accelerates lupus progression, reflected in reduced overall survival and an earlier onset of proteinuria, as well higher concentrations of anti-double-stranded DNA autoantibodies. This unfavorable effect gained statistical significance with additional low maternal VD intake during the prenatal period. Among examined immunological effects, we found that low VD intake consistently hampered the adoption of a regulatory phenotype in lymphocytes, significantly reducing both IL-10-expressing and regulatory CD4+ T cells. This goes along with a mildly decreased frequency of IL-10- expressing B cells. We did not observe consistent effects on the phenotype and function of innate immune cells, including cytokine production, costimulatory molecule expression, and phagocytic capacity. Hence, our study reveals that low VD intake promotes lupus pathology, likely via the deviation of adaptive immunity, and suggests that the correction of VD deficiency might not only exert beneficial functions by preventing osteoporosis but also serve as an important module in prophylaxis and as an add-on in the treatment of lupus and possibly other immune-mediated diseases. Further research is required to determine the most appropriate dosage, as too-high VD serum levels may also induce adverse effects, possibly also on lupus pathology. [ABSTRACT FROM AUTHOR]

IL‐17‐producing Th17 cells play an important role in pathogenesis of rheumatoid arthritis (RA). Aberrant immune activation due to an imbalance between Th17 and regulatory T (Treg) cells is associated with the development of RA and other autoimmune diseases. Targeting pathogenic Th17 cells and their associated molecules is emerging as a promising strategy to treat and reverse RA. Here, we demonstrate that IL‐3 inhibits the differentiation of Th17 cells and promotes the development of Treg cells in IL‐2‐dependent manner. In IL‐2 KO mice, we observed that IL‐3 has no effect on differentiation of both Th17 and Treg cells. In addition, IL‐3 decreases pathogenic IL‐17A+TNF‐α+, IL‐17A+IFN‐γ+ and IL‐23R+ Th17 cells, secretion of GM‐CSF and IFN‐γ, and osteoclastogenesis when presented in the culture together with Th17 polarizing cytokines. Mechanistically, IL‐3 regulates the development of Th17 cells through the inhibition of STAT3 phosphorylation. IL‐3 treatment significantly decreases the pathogenic Th17 cell responses and arthritic scores in the mouse model of RA. Importantly, IL‐3 inhibits the differentiation of human Th17 cells. Thus, our results suggest a novel therapeutic role of IL‐3 in the regulation of Th17 cell‐mediated pathophysiology of RA. [ABSTRACT FROM AUTHOR]

Autoimmune diseases have a prevalence of approximately 7 to 9% and are classified as either organ‐specific diseases, including type I diabetes, multiple sclerosis, inflammatory bowel disease and myasthenia gravis, or systemic diseases, including systemic lupus erythematosus, rheumatoid arthritis and Sjögren's syndrome. While many advancements have been made in understanding of the mechanisms of autoimmune disease, including the nature of self‐tolerance and its breakdown, there remain unmet needs in terms of effective and highly targeted treatments. T regulatory cells (Tregs) are key mediators of peripheral tolerance and are implicated in many autoimmune diseases, either as a result of reduced numbers or altered function. Tregs may be broadly divided into those generated in the thymus (tTregs) and those generated in the periphery (pTregs). Tregs target many different immune cell subsets and tissues to suppress excessive inflammation and to support tissue repair and homeostasis: there is a fine balance between Treg cell stability and the plasticity that is required to adjust Tregs' regulatory purposes to particular immune responses. The central role of immunoglobulin E (IgE) in allergic disease is well recognized, and it is becoming increasingly apparent that this immunoglobulin also has a wider role encompassing other diseases including autoimmune disease. Anti‐IgE treatment restores the capacity of plasmacytoid dendritic cells (pDCs) impaired by IgE‐ high‐affinity IgE receptor (FcεR1) cross‐linking to induce Tregs in vitro in atopic patients. The finding that anti‐IgE therapy restores Treg cell homeostasis, and that this mechanism is associated with clinical improvement in asthma and chronic spontaneous urticaria suggests that anti‐IgE therapy may also have a potential role in the treatment of autoimmune diseases in which Tregs are involved. [ABSTRACT FROM AUTHOR]

Type 1 regulatory T (Tr1) cells, in addition to other regulatory cells, contribute to immunological tolerance to prevent autoimmunity and excessive inflammation. Tr1 cells arise in the periphery upon antigen stimulation in the presence of tolerogenic antigen presenting cells and secrete large amounts of the immunosuppressive cytokine IL-10. The protective role of Tr1 cells in autoimmune diseases and inflammatory bowel disease has been well established, and this led to the exploration of this population as a potential cell therapy. On the other hand, the role of Tr1 cells in infectious disease is not well characterized, thus raising concern that these tolerogenic cells may cause general immune suppression which would prevent pathogen clearance. In this review, we summarize current literature surrounding Tr1-mediated tolerance and its role in health and disease settings including autoimmunity, inflammatory bowel disease, and infectious diseases. [ABSTRACT FROM AUTHOR]

Vitiligo is a noncontagious autoimmune skin depigmenting disease. Regulatory T cells (Tregs) play a key role in maintaining peripheral tolerance; however, Tregs' number, suppressive function, and associated suppressive molecules (FOXP3, IL-10, and TGF-β) are found to be reduced in vitiligo patients. Although, the role of Tregs in vitiligo pathogenesis is well established, there are several contrary findings which suggest a controversial role of Tregs in vitiligo. Therefore, to clarify the role of Tregs in vitiligo pathogenesis, we aimed to study Tregs' frequency, suppressive capacity, and associated suppressive molecules (FOXP3, IL-10, and TGF-β) in vitiligo patients through meta-analysis approach. A total of 30 studies involving 1223 vitiligo patients and 1109 controls were included in the study. Pooled results from our meta-analysis suggested significantly reduced Treg cells' frequency in vitiligo patients (p = 0.002). Interestingly, Tregs' suppressive capacity was also significantly reduced in vitiligo patients (p = 0.0002); specifically, Treg-mediated suppression of CD8+T cells was impaired in vitiligo patients (p < 0.00001). Moreover, FOXP3, a key Tregs' transcription factor, was significantly reduced in blood and skin of vitiligo patients (p < 0.00001). Intriguingly, the FOXP3 expression was significantly reduced in the lesional skin as compared to perilesional and nonlesional skin (p = 0.007 and p = 0.04). Furthermore, the expression of key Treg-associated suppressive cytokines IL-10 and TGF-β were significantly reduced in vitiligo patients (p = 0.0005 and p = 0.01). The disease activity-based analysis suggested for reduced Tregs' frequency and FOXP3 expression in active vitiligo patients (p = 0.05 and p = 0.01). We also studied the effect of microRNA-based treatment, narrow band-UVB phototherapy, and Treg-associated treatments on Tregs' frequency, FOXP3, and IL-10 expression. Interestingly, we found increased Tregs' frequency, FOXP3, and IL-10 expression after the treatment (p = 0.007, p < 0.0001, and p = 0.002). Overall, our meta-analysis suggests that the Tregs play a crucial role in pathogenesis and progression of vitiligo, and hence, Treg-based therapeutic interventions could be effective in vitiligo patients. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor receptor–associated factor 3 (TRAF3) is a central regulator of immunity. TRAF3 is often somatically mutated in B cell malignancies, but its role in human immunity is not defined. Here, in five unrelated families, we describe an immune dysregulation syndrome of recurrent bacterial infections, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia. Affected individuals each had monoallelic mutations in TRAF3 that reduced TRAF3 expression. Immunophenotyping showed that patients' B cells were dysregulated, exhibiting increased nuclear factor-κB 2 activation, elevated mitochondrial respiration, and heightened inflammatory responses. Patients had mild CD4+ T cell lymphopenia, with a reduced proportion of naïve T cells but increased regulatory T cells and circulating T follicular helper cells. Guided by this clinical phenotype, targeted analyses demonstrated that common genetic variants, which also reduce TRAF3 expression, are associated with an increased risk of B cell malignancies, systemic lupus erythematosus, higher immunoglobulin levels, and bacterial infections in the wider population. Reduced TRAF3 conveys disease risks by driving B cell hyperactivity via intrinsic activation of multiple intracellular proinflammatory pathways and increased mitochondrial respiration, with a likely contribution from dysregulated T cell help. Thus, we define monogenic TRAF3 haploinsufficiency syndrome and demonstrate how common TRAF3 variants affect a range of human diseases. Turning down TRAF3 revs up B cells: TRAF3 is a cytoplasmic adaptor protein involved in multiple intracellular signal transduction pathways. Rae et al. identified nine individuals with a previously undescribed monogenic immune dysregulatory syndrome caused by a loss-of-function mutation in one of their two TRAF3 alleles. Patients with this newly described TRAF3 haploinsufficiency syndrome exhibited B cell hyperactivity leading to hypergammaglobulinemia and autoimmunity but also displayed increased susceptibility to recurrent bacterial infections. Common human genetic variants of TRAF3 associated with lower gene expression were found to carry an increased risk of autoimmune disease and some B cell malignancies. These findings point to functional impairment of TRAF3 as a shared mechanism leading to B cell dysfunction, hyperactivity, and disease in the presence of either rare loss-of-function germline mutations or much more common genetic variants. [ABSTRACT FROM AUTHOR]

Regulatory T (Treg) cells are required for maintaining self‐tolerance and preventing the development of autoimmune diseases. However, Treg cells are abundant in tumors and suppress antitumor immunity, contributing to tumor development and growth. Thus, the selective deletion of tumor‐infiltrating Treg cells is important for successful Treg cell‐targeted therapies, providing effective antitumor immunity without inducing deleterious autoimmune disorders. Advancements in sequencing technologies have exposed the diversity and heterogeneity of human Treg cells during activation and differentiation, further emphasizing the importance of understanding tumor‐infiltrating Treg cells for the development of Treg cell‐targeted therapies. This review provides an overview of the classification and function of Treg cells and summarizes recent knowledge on the activation and differentiation of Treg cells in the tumor microenvironment. [ABSTRACT FROM AUTHOR]

A failure of central immune tolerance driven by autoantigen specific T regulatory (Treg) cells is a major cause of many autoimmune diseases. Restoration of proper autoantigen Treg specific response holds promise as a highly effective, long-term therapy for a wide variety of autoimmune diseases. Generating autoantigen specific Tregs remains a challenge due to the non-specific nature of most tolerizing agents and the complexities of generating Tregs in vivo. Here we show a new push/pull method for inducing antigen-specific Treg tolerance via induction of tolerogenic dendritic cells (tolDCs). We identified a combination of three tolerogenic drugs, dexamethasone, simvastatin and SC-514, which when used in combination with toll-like-receptor (TLR) agonists induces an active tolDC phenotype. When the tolerogenic combination was packaged into a liposome with a model antigen such as ovalbumin (OVA), these tolDCs induce differentiation of OVA specific Tregs both ex vivo and in vivo. We examined the tolerizing potential of the combination in an experimental autoimmune encephalomyelitis (EAE) disease model. Given the antigen specificity of this technique, this paper presents an attractive preclinical autoimmune therapy. [ABSTRACT FROM AUTHOR]

Introduction. Lupus nephritis (LN) is an autoimmune glomerulonephritis secondary to systemic lupus erythematosus. Commonly, immunosuppressive agents are required for treating LN. However, frequent use of conventional immunosuppressants may produce a variety of side effects. Hence, seeking alternative drugs for treating LN is very important. This report aims to figure out the immunoregulatory efficacy of celastrol (CLT) in LN. Material and methods. A spontaneous in vivo model of LN was established in FasL-deficient B6/gld mice. ELISA was used for analyzing serum creatinine (Scr) and anti-dsDNA levels in mice. IHC staining, immunofluorescence and hematoxylin-eosin and PAS staining were applied to determine renal immunopathology and histology. Cytokine gene levels were assessed using RT-qPCR. CD4+Foxp3+ Treg frequency in murine kidneys, lymph nodes and spleens was determined using flow cytometry analysis. Results. CLT treatment alleviated renal dysfunction and renal injury in LN-prone B6/gld mice. Moreover, CLT reduced CD3+ T cell infiltration and inhibited proinflammatory cytokine expression in renal tissues of B6/gld mice. Importantly, CLT enhanced CD4+FoxP3+ Treg frequency in kidneys, lymph nodes and spleens of B6/gld mice. Conclusions. CLT exerts therapeutic effects on murine LN by improving renal function and immunopathology and inducing CD4+FoxP3+ Tregs. (Folia Histochemica et Cytobiologica 2022, Vol. 60, No. 3, 237-246). [ABSTRACT FROM AUTHOR]

CD4+CD25highFoxp3+ regulatory T-cells (Tregs) are functionally characterized for their ability to suppress the activation of multiple immune cell types and are indispensable for maintaining immune homeostasis and tolerance. Disruption of this intrinsic brake system assessed by loss of suppressive capacity, cell numbers, and Foxp3 expression, leads to uncontrolled immune responses and tissue damage. The conversion of Tregs to a pathogenic pro-inflammatory phenotype is widely observed in immune mediated diseases. However, the molecular mechanisms that underpin the control of Treg stability and suppressive capacity are incompletely understood. This review summarizes the concepts of Treg cell stability and Treg cell plasticity highlighting underlying mechanisms including translational and epigenetic regulators that may enable translation to new therapeutic strategies. Our enhanced understanding of molecular mechanism controlling Tregs will have important implications into immune homeostasis and therapeutic potential for the treatment of immune-mediated diseases. [ABSTRACT FROM AUTHOR]

Activin A, a critical member of the transforming growth factor-β (TGF-β) superfamily, is a pluripotent factor involved in allergies, autoimmune diseases, cancers and other diseases with immune disorder. Similar to its family member, TGF-β, activin A also transmits signals through SMAD2/SMAD3, however, they bind to distinct receptors. Recent studies have uncovered that activin A plays a pivotal role in both innate and adaptive immune systems. Here we mainly focus its effects on activation, differentiation, proliferation and function of cells which are indispensable in the immune system and meanwhile make some comparisons with those of TGF-β. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by demyelinating neuropathy. The etiology of MS is not yet clear and its treatment remains a major medical challenge. While we search for drugs that can effectively treat experimental autoimmune encephalomyelitis (EAE), the animal model of MS, we also hope to further explore its possible pathogenesis. In the present study, we investigated whether methyl butyrate (MB) could alleviate EAE and its potential mechanisms. In EAE mice, we found that administration of MB was effective in alleviating their clinical signs and improving histopathological manifestations of the CNS. In the CNS and intestinal lamina propria, we observed fewer effector T cells, including Th1 and Th17, in the MB-treated group. MB also increased the proportion of regulatory T cells and the secretion of IL-10 in peripheral immune organs. In vitro, MB led to suppression of Th1 cells and promotion of regulatory T cells in their differentiation. Given that MB had no direct effect on Th17 cell differentiation in vitro, we hypothesized that MB suppressed Th17 cells indirectly by inhibiting the secretion of IL-6, which was later confirmed both in vitro and in vivo. In addition, we found that MB treatment upregulated Maf gene expression in mice, which explained its promotion of IL-10 secretion. The above findings suggest that MB may provide new ideas for the study of the mechanism of MS and have positive implications for new drug development. [ABSTRACT FROM AUTHOR]

CD4+ T cell responses to self-antigens are pivotal for immunological self-tolerance. Activation of Foxp3– T-conventional (T-conv) cells can precipitate autoimmune disease, whereas activation of Foxp3+ T-regulatory (T-reg) cells is essential to prevent autoimmune disease. This distinction indicates the importance of the thymus in controlling the differentiation of self-reactive CD4+ T cells. Thymocytes and thymic antigen-presenting cells (APC) depend on each other for normal maturation and differentiation. In this Hypothesis and Theory article, we propose this mutual dependence dictates which self-antigens induce T-reg cell development in the thymic medulla. We postulate self-reactive CD4+ CD8– thymocytes deliver signals that stabilize and amplify the presentation of their cognate self-antigen by APC in the thymic medulla, thereby seeding a niche for the development of T-reg cells specific for the same self-antigen. By limiting the number of antigen-specific CD4+ thymocytes in the medulla, thymocyte deletion in the cortex may impede the formation of medullary T-reg niches containing certain self-antigens. Susceptibility to autoimmune disease may arise from cortical deletion creating a "hole" in the self-antigen repertoire recognized by T-reg cells. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is an autoimmune disease that is characterized by vascular damage and fibrosis. Both clinical manifestations and immunological disturbances are diverse according to the disease duration. Particularly, changes in immunological processes are prominent in the early phase of SSc. The orchestration of several subsets of immune cells promotes autoimmune responses and inflammation, and eventually stimulates pro-fibrotic processes. Many reports have indicated that CD4+ T cells play pivotal roles in pathogenesis in the early phase of SSc. In particular, the pathogenic roles of regulatory T (Treg) cells have been investigated. Although the results were controversial, recent reports suggested an increase of Treg cells in the early phase of SSc patients. Treg cells secrete transforming growth factor-β (TGF-β), which promotes myofibroblast activation and fibrosis. In addition, the dysfunction of Treg cells in the early phase of SSc was reported, which results in the development of autoimmunity and inflammation. Notably, Treg cells have the plasticity to convert to T-helper17 (Th17) cells under pro-inflammatory conditions. Th17 cells secrete IL-17A, which could also promote myofibroblast transformation and fibrosis and contributes to vasculopathy, although the issue is still controversial. Our recent transcriptomic comparison between the early and late phases of SSc revealed a clear difference of gene expression patterns only in Treg cells. The gene signature of an activated Treg cell subpopulation was expanded in the early phase of SSc and the oxidative phosphorylation pathway was enhanced, which can promote Th17 differentiation. And this result was accompanied by the increase in Th17 cells frequency. Therefore, an imbalance between Treg and Th17 cells could also have an important role in the pathogenesis of the early phase of SSc. In this review, we outlined the roles of Treg cells in the early phase of SSc, summarizing the data of both human and mouse models. The contributions of Treg cells to autoimmunity, vasculopathy, and fibrosis were revealed, based on the dysfunction and imbalance of Treg cells. We also referred to the potential development in treatment strategies in SSc. [ABSTRACT FROM AUTHOR]

In order to maintain immunological tolerance to self and non-self antigens, one's T regulatory (Treg) cells play a critical role in the regulation of detrimental inflammation. Treg cells inhibit the immune system in a variety of ways, some of which are contact-dependent and the others are soluble factors. Extracellular vesicles (EVs) are mainly secretory membrane structures that play a pivotal role in intercellular communication in both the local and systemic environments, enabling the transport of proteins, lipids, and nucleic acids between immune and non-immune cells. A number of studies have shown that Treg-derived EVs are specially formulated intercellular exchanging devices capable of regulating immunological responses by producing a cell-free tolerogenic milieu. Some of the processes suggested include miRNA-induced gene shutdown and upmodulation, surface protein activity, and enzyme transfer. Instead of being influenced by external circumstances like Tregs, exosomes' cohesive structure allows them to transmit their charge intact across the blood–brain barrier and deliver it to the target cell with particular receptors. These properties have resulted in the use of Treg-derived EVs' immunomodulatory effects moving beyond laboratory research and into preclinical applications in animal models of a variety of inflammatory, autoimmune, and transplant rejection disorders. However, insufficient evidence has been produced to permit enrollment in human clinical studies. As such, we begin our research by introducing the most potent immunosuppressive elements discovered in Treg-derived EVs elucidating likely mechanisms of action in inhibiting immunological responses. Following that, we address recent research on the potential of suppressive EVs to regulate autoimmune inflammatory responses and improve tissue transplant survival. [ABSTRACT FROM AUTHOR]

The role of CD4 T regulatory cells is well established in peripheral tolerance and the pathogenesis of the murine model and human autoimmune diseases. CD4 T regulatory cells (CD4 Tregs) have been investigated in common variable immunodeficiency (CVID). Recently, additional members have been added to the club of regulatory lymphocytes. These include CD8 T regulatory (CD8 Tregs), B regulatory (Bregs), and T follicular helper regulatory (TFR) cells. There are accumulating data to suggest their roles in both human and experimental models of autoimmune disease. Their phenotypic characterization and mechanisms of immunoregulation are evolving. Patients with CVID may present or are associated with an increased frequency of autoimmunity and autoimmune diseases. In this review, we have primarily focused on the characteristics of CD4 Tregs and new players of the regulatory club and their changes in patients with CVID in relation to autoimmunity and emphasized the complexity of interplay among various regulatory lymphocytes. We suggest future careful investigations of phenotypic and functional regulatory lymphocytes in a large cohort of phenotypic and genotypically defined CVID patients to define their role in the pathogenesis of CVID and autoimmunity associated with CVID. [ABSTRACT FROM AUTHOR]