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Introduction: Chemokines and their receptors are essential for leukocyte migration to several tissues, including human milk. Here, we evaluated the homing of T and B lymphocyte subsets to breast milk in response to ongoing respiratory infections in the nursing infant. Methods: Blood and mature milk were collected from healthy mothers of nurslings with respiratory infections (Group I) and from healthy mothers of healthy nurslings (Group C). Total lymphocyte, T and B cells, their subset numbers, and the expression of the homing receptors CCR5, CCR6, CCR10, and CXCR3 in these cells were evaluated in milk. Maternal serum and milk chemokine, cytokine, and IgA and IgG antibody levels were also quantified. Results: All milk lymphocyte numbers were greater in Group I than in Group C. All CD4 T-cell subsets expressing CCR5, CCR6, and CXCR3 were higher in Group I. Within the CD8 T-cell subsets, only CCR6 and CXCR3 were higher in Group I, while CCR5 expression was higher in Group I exclusively for activated CD8 T cells. Group I showed greater numbers of all CCR6+ B-cell subsets and CXCR3+ naive B cells and plasma cells than did Group C. Infection of the nurslings promoted increased CCL20, CXCL10, IL-6, IL-8, total IgA, and IgG levels in the milk. Conclusion: Respiratory infections in nursing infants stimulate an increase in cytokines and chemokines in breast milk, facilitating the recruitment and activation of lymphocytes. This process may promote immunological tolerance and help in the maturation of the infant's immune system, providing an additional strategy for passive maternal-infant protection. [ABSTRACT FROM AUTHOR]

Pregnancy failure in the first trimester of cows significantly impacts the efficiency of the dairy industry. As a type I interferon exclusively to ruminants, IFN- τ plays a key role in maternal recognition and immune tolerance of fetuses. Macrophages are the most common immune cells within the ruminant endometrium. Nevertheless, deeply analyzing the mechanisms of IFN- τ regulating macrophage polarization still needs further study. In this study, a notable decline of bta-miR-30b-5p expression via the increase of SOCS1 was observed in uterine tissues of pregnant cows. We then confirmed that the 3′UTR of SOCS1 was to be directly targeted by bta-miR-30b-5p. After that, we demonstrated that this obviously promoted the bovine macrophages (BoMac) polarized to M2 through enhancing SOCS1 expression with the treatment of IFN- τ . Furthermore, we found that SOCS1 restrained the expression of the key proteins p65 and p-P65 in the NF-κB pathway. Causing, the wide range of cross-species activities of IFN- τ , therefore we established a pregnant mouse model for the future confirmation of the above mechanism. The results verified that IFN- τ significantly improved this mechanism and maintained normal pregnancy status in mice, but miR-30b-5p significantly reduced the M2 polarization by inhibiting SOCS1, which activated the NF-κB signaling pathway, and then leading to the failure of embryo implantation. All these results indicated that IFN- τ can regulate immune tolerance during pregnancy by promoting M2 macrophage polarization through inhibiting bta-miR-30b-5p targeting SOCS1 to deactivate the NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Biometallic ions play a crucial role in regulating the immune system. In recent years, cancer immunotherapy has become a breakthrough in cancer treatment, achieving good efficacy in a wide range of cancers with its specificity and durability advantages. However, existing therapies still face challenges, such as immune tolerance and immune escape. Biometallic ions (e.g. zinc, copper, magnesium, manganese, etc.) can assist in enhancing the efficacy of immunotherapy through the activation of immune cells, enhancement of tumor antigen presentation, and improvement of the tumor microenvironment. In addition, biometallic ions and derivatives can directly inhibit tumor cell progression and offer the possibility of effectively overcoming the limitations of current cancer immunotherapy by promoting immune responses and reducing immunosuppressive signals. This review explores the role and potential application prospects of biometallic ions in cancer immunotherapy, providing new ideas for future clinical application of metal ions as part of cancer immunotherapy and helping to guide the development of more effective and safe therapeutic regimens. [ABSTRACT FROM AUTHOR]

Background: There is ongoing debate about the safety and efficacy of epicutaneous immunotherapy (EPIT) in treating food allergies. The systematic review and meta-analysis aimed to evaluate the safety and efficacy of EPIT. Methods: We systematically searched international trial registers (ClinicalTrials.gov), PubMed, Embase, the Cochrane Central of Controlled Trials (CENTRAL), and Web of Science from the inception of the database until June 25, 2023. Two authors independently screened potential studies based on the following criteria: food allergy, epidermal immunotherapy, and randomized controlled trials(RCTs). The risk-of-bias assessment was performed using the Cochrane risk-of-bias 2 (ROB 2) tool. The primary outcomes included desensitization, local adverse events, systemic adverse events, and quality of life. Secondary outcomes included epinephrine utilization, topical medication utilization, and severe adverse events. We assessed certainty of evidence by the GRADE approach. Results: Ten studies involving 1970 participants were included. Ten high-quality RCTs focusing on peanut allergy and cow's milk allergy were included in the analysis. The meta-analysis revealed that EPIT promoted desensitization in patients with food allergy (RR 2.11, 95% CI 1.72–2.58; I2 = 0%, high certainty), particularly in aged ≤ 11 years (RR 3.84, 95% CI 2.39–6.26; I2 = 34%). Additionally, treatment duration ≥ 52 weeks was found to increase immune tolerance (RR 3.37, 95% CI 2.39–4.75; I2 = 13%). Patients who undergo EPIT treatment not only raised the local adverse reactions (RR 1.63, 95% CI 1.10–2.41; I2 = 82%, low certainty) but also raised systemic adverse reactions (RR 1.52, 95% CI 1.01–2.28; I2 = 0%, high certainty). Conclusion: After EPIT treatment, patients with food allergy can effectively increase their immune tolerance to food. However, it also significantly increases mild-to-moderate anaphylaxis. There is limited data on the impact of EPIT on quality of life and other food allergic diseases, indicating a need for further research. [ABSTRACT FROM AUTHOR]

Background: Epithelial barriers, such as the lungs and skin, face the challenge of providing the tissues' physiological function and maintaining tolerance to the commensal microbiome and innocuous environmental factors while defending the host against infectious microbes. Asthma and allergic diseases can result from maladaptive immune responses, resulting in exaggerated and persistent type 2 immunity and tissue inflammation. Summary: Among the diverse populations of tissue immune cells, CD4+ regulatory T cells (Treg cells) are central to controlling immune responses and inflammation and restoring tissue homeostasis. Humans and mice that are deficient in Treg cells experience extensive inflammation in their mucosal organs and skin. During past decades, major progress has been made toward understanding the immunobiology of Treg cells and the molecular and cellular mechanisms that control their differentiation and function. It is now clear that Treg cells are not a single cell type and that they demonstrate diversity and plasticity depending on their differentiation stages and tissue environment. They could also take on a proinflammatory phenotype in certain conditions. Key Messages: Treg cells perform distinct functions, including the induction of immune tolerance, suppression of inflammation, and promotion of tissue repair. Subsets of Treg cells in mucosal tissues are regulated by their differentiation stage and tissue inflammatory milieu. Treg cell dysfunction likely plays roles in persistent immune responses and tissue inflammation in asthma and allergic diseases. [ABSTRACT FROM AUTHOR]

Tolerogenic vaccines represent a therapeutic approach to induce antigen-specific immune tolerance to disease-relevant antigens. As general immunosuppression comes with significant side effects, including heightened risk of infections and reduced anti-tumor immunity, antigen-specific tolerance by vaccination would be game changing in the treatment of immunological conditions such as autoimmunity, anti-drug antibody responses, transplantation rejection, and hypersensitivity. Tolerogenic vaccines induce antigen-specific tolerance by promoting tolerogenic antigen presenting cells, regulatory T cells, and regulatory B cells, or by suppressing or depleting antigen-specific pathogenic T and B cells. The design of tolerogenic vaccines vary greatly, but they all deliver a disease-relevant antigen with or without a tolerogenic adjuvant. Tolerogenic adjuvants are molecules which mediate anti-inflammatory or immunoregulatory effects and enhance vaccine efficacy by modulating the immune environment to favor a tolerogenic immune response to the vaccine antigen. Tolerogenic adjuvants act through several mechanisms, including immunosuppression, modulation of cytokine signaling, vitamin signaling, and modulation of immunological synapse signaling. This review seeks to provide a comprehensive examination of tolerogenic adjuvants currently utilized in tolerogenic vaccines, describing their mechanism of action and examples of their use in human clinical trials and animal models of disease. [ABSTRACT FROM AUTHOR]

Sialylation is a typical final step of glycosylation, which is a prevalent post-translational modification of proteins. Sialoglycans, the products of sialylation, are located on the outmost of cells and participate in pivotal biological processes. They have been identified as glyco-immune checkpoints and are currently under rigorous investigation in the field of tumor research. It is noteworthy that the exploration of sialoglycans in tumor and pregnancy contexts was both initiated in the 1960s. Mechanisms in these two conditions exhibit similarities. Trophoblast infiltration during pregnancy gets controlled, while tumor invasion is uncontrolled. The maternal-fetal immunotolerance balances acceptance of the semiallogeneic fetus and resistance against "non-self" antigen attack simultaneously. Tumors mask themselves with sialoglycans as "don't eat me" signals to escape immune surveillance. The trophoblastic epithelium is covered with sialoglycans, which have been demonstrated to play an immune regulatory role throughout the entire pregnancy. Immune abnormalities are commonly recognized as an important reason for miscarriages. Therapeutic strategies that desialylation and targeting receptors of sialoglycans have been studied in tumors, while agents that target glyco-immune checkpoints have not been studied in pregnancy. Thus, investigating the roles of sialoglycans in pregnancy and their intersection with tumors may facilitate the development of novel therapies targeting glyco-immune checkpoints for the treatment of pregnancy-related diseases, such as miscarriage and preeclampsia. [ABSTRACT FROM AUTHOR]

Introduction: Allergen immunotherapy (AIT) is the only disease-modifying treatment for patients with IgE-mediated allergic diseases. Successful AIT can induce long-term immune tolerance to the common allergen, which provides clinical benefits for years after discontinuation. The cytokine interleukin (IL)-10, as a key anti-inflammatory mediator with strong immunoregulatory functions, has drawn increasing attention over the past decades. Areas covered: After an extensive search of PubMed, EMBASE, and Web of Science databases, covering articles published from 1989 to 2024, our review aims to emphasize the key common information from previous reviews on the crucial involvement of IL-10 in allergen immunotherapy (AIT) induced immunological tolerance. In this review, we discuss the regulation of IL-10 expression and the molecular pathways associated with IL-10 function. We also further summarize mechanisms of immune tolerance induced by AIT, especially the indispensable role of IL-10 in AIT. Expert opinion: IL-10 plays an indispensable role in immune tolerance induced by AIT. Understanding the importance of the role of IL-10 in AIT would help us comprehend the mechanisms thoroughly and develop targeted therapeutics for allergic diseases. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction Aim Methods Results Conclusion Mortality and morbidity in persons with haemophilia (PWH) have decreased due to improved diagnosis and treatment along with comprehensive population outreach efforts, but the impact is not uniform in different countries.The study aims to assess all‐cause and intracranial haemorrhage (ICH)‐specific mortality of PWH in India.This is a retrospective, observational, multi‐centric cohort study of 1020 haemophilia patients from three centres in India. The mortality data in the family was collected from personal interviews, and subsequently confirmed with the corresponding haemophilia treatment centres (HTCs). The demographic and clinical data, along with other comorbidities, were collected from the medical records.Among 170 reported deaths, 73 (42.9%) were caused by ICH, and 44 (25.9%) resulted from accidents or trauma. Gastrointestinal (GI) bleeding was the third most common cause of death, accounting for 27 cases (15.9%). The average and median ages at death were 27.7 and 26 years, respectively. None of the deceased cases were receiving any prophylactic or immune tolerance induction (ITI) therapy, and all had severe haemophilia. In addition, the prevalence of inhibitors and hypertension was significantly higher in deceased cases compared to that in the general haemophilia population (p < 0.05).Severity of haemophilia, episodic treatment, hypertension and inhibitors showed significant association with mortality. ICH continues to be the leading cause of death among haemophilia patients in the country. This underscores the challenges in managing haemophilia and the need for improved treatment strategies to increase the life expectancy of PWH. [ABSTRACT FROM AUTHOR]

Food allergies are a global health problem that continues to grow annually, with a prevalence of more than 10%. Shrimp allergy is the most common and life-threatening allergy. There is no cure for food allergies, but shrimp allergen extract (SAE) offers promise as a treatment through allergen-specific immunotherapy (AIT). However, whether SAE induces immunological tolerance in seafood allergies remains to be established. This study aimed to determine the effectiveness of SAE in inducing immunological tolerance in a gastro-food allergy mouse model. For the immunotherapy evaluation, mice (n = 24) were intraperitoneally (i.p.) sensitized with 1 mg alum and 100 μg SAE in PBS on days 0, 7, and 14 and randomly divided into four groups of six: a negative control (NC) and high- to low-dose immunotherapy (HI, MI, and LI). The untreated group (n = 6) only received 1 mg alum in PBS (i.p.). All groups were challenged with 400 μg SAE (i.g.) on days 21, 22, 23, 53, and 58. Following the challenge, SAE-sensitized mice from the immunotherapy group were treated (i.p.) with 10 μg SAE for LI, 50 μg SAE for MI, and 100 μg SAE for HI on days 32, 39, and 46. The untreated and NC groups only received PBS (i.p.). All mice were euthanized on day 59. As the results, we found that SAE immunotherapy reduced systemic allergy symptom scores, serum IL-4 levels, IL-4 and FcεR1α mRNA relative expression, and mast cell degranulation in ileum tissue in allergic mice while increasing Foxp3 and IL-10 mRNA relative expression. Notably, we observed an increased ratio of IL-10 to IL-4 mRNA expression, demonstrating the efficacy of SAE immunotherapy in promoting desensitization. Thus, SAE can be developed as an immunotherapeutic agent for food allergies by inducing prolonged allergy tolerance with a wide range of allergen targets. [ABSTRACT FROM AUTHOR]

The establishment of a tolerant space to realize the co‐stimulation of cytokines and contact‐dependent molecules remain challenging in allotransplant. Here, an injectable genetically engineered hydrogel (iGE‐Gel) is reported, which developed with a multivalent network of FOXP3 engineered extracellular vesicles (Foe‐EVs) through the hydrophobic interaction between stearic acid modified hyaluronic acid (HASA) and the membrane phospholipids of extracellular vesicles (EVs). The iGE‐Gel exhibited self‐healing properties, injectability and biocompatibility. It is revealed that iGE‐Gel displayed with abundant regulatory cytokines and coinhibitory contact molecules, promoting the formation of immune tolerance in situ. The multiplex immunohistofluorescence confirmed tolerant niches is dominated by FOXP3+ Tregs and PDL1+ cells in the allograft, which reduced the drainage of alloantigens to subcapsular sinus of lymph nodes, and suppressed the formation of germinal centers. Remarkably, the proportion of alloreactive T cells (IFN‐γ/IL‐2) and B cells (IgG1/IgG2a/IgG3) as well as the serum titers of donor specific antibody (DSA) is decreased by iGE‐Gel. In murine allogeneic transplantation, the injection of iGE‐Gel significantly alleviated immune cell infiltration and complement damage in the graft, preserved the structure and function of renal cells and prolonged recipient survival period from 30.8 to 79.3 days, highlighting the potential of iGE‐Gel as a transformative treatment in allotransplant. [ABSTRACT FROM AUTHOR]

The increased incidence of inflammatory diseases, infectious diseases, autoimmune disorders, and tumors in elderly individuals is closely associated with several well-established features of immunosenescence, including reduced B cell genesis and dampened immune responses. Recent studies have highlighted the critical role of dual receptor lymphocytes in tumors and autoimmune diseases. This study utilized shared data generated through scRNA-seq + scBCR-seq technology to investigate the presence of dual receptor-expressing B cells in the peritoneum of mouse and peripheral blood of healthy volunteers, and whether there are age-related differences in dual receptor B cell populations. In the peritoneum of mice, a high proportion of B cells expressing dual receptors, predominantly dual κ chains, was observed. Notably, there was an increase in dual BCR B cells in elderly mice. Subsequent analysis revealed that the elevated dual BCR B cells in elderly mice primarily originated from B1 cells.Consistent with the results we observed in healthy volunteers of different ages. Furthermore, these cells exhibited differential expressed genes compared to single BCR B cells, including Vim, Ucp2, and Zcwpw1.These findings support a hypothesis that age-related immune changes encompass not only alterations in B cell numbers but also qualitative changes in BCR diversity. Further exploration of the elevated dual BCR B cells in the elderly population can elucidate their function and their association with immune tolerance, revealing their potential role in maintaining immune surveillance and responding to age-related immune challenges. [ABSTRACT FROM AUTHOR]

Introduction: Immunogenicity continues to be a challenge for development and clinical utility of monoclonal antibodies, and there are gaps in our current ability to prevent anti-drug antibody development in a safe and antigen-specific manner. Methods: To mitigate immunogenicity of monoclonal antibodies administered subcutaneously, O-phospho-L-serine (OPLS)—the head group of the tolerance-inducing phospholipid, phosphatidylserine—was investigated as an immunoregulatory adjuvant. Results: Formulations of adalimumab, trastuzumab or rituximab with OPLS showed reduction in relative immunogenicity in mice compared to vehicle formulations, indicated by reduced anti-drug antibody development and significant reductions in CD138+ plasma cell differentiation in bone marrow. Titer development toward recombinant human hyaluronidase, a dispersion enhancer that was co-formulated with monoclonal antibodies, was similarly reduced. Subcutaneous administration of adalimumab with OPLS resulted in a two-fold increase in expression of type 1 regulatory (Tr1) T cell subset in the spleen. This is consistent with in vitro studies where co-culturing of dendritic cells primed with ovalbumin in the presence and absence of OPLS and antigen specific T-cells induced expression of Tr1 phenotype on live CD4+ T cells. Conclusion: This adjuvant does not impact immune competence of non-human primates and mice, and repeated administration of the adjuvant does not show renal or hepatic toxicity. Formulation of monoclonal antibodies with the immunoregulatory adjuvant, OPLS, was found to be safe and effective at mitigating immunogenicity. [ABSTRACT FROM AUTHOR]

BackgroundMethodsResultsConclusionImmune homeostasis plays a crucial role in immunology andis dependent on both central and peripheral tolerance. Centraltolerance and peripheral tolerance occur in the thymus and thesecondary lymphoid tissues, respectively. Tolerance breakdown andimmune regulation defects can lead to autoimmune disorders. In thisreview article, we aimed to describe the role of exosomes inregulating central tolerance and provide a summary of their effectson the pathogenesis, diagnosis, and therapeutic potential inmyasthenia gravis (MG).Articles for this review wereidentified using the PubMed database.As the primarylymphoid organ, the thymus is responsible for building an immunecompetent, yet self-tolerant of T-cell population. Thymic statesinclude thymoma, thymic hyperplasia, and thymic atrophy, which canexert a significant influence on the central immune tolerance andrepresent specific characteristics of MG. Previous studies have foundthat exosomes derived from human thymic epithelial cells carryantigen-presenting molecules and a wide range of tissue restrictedantigens, which may indicate a vital role of thymic exosomes in MG.Besides, exosomal miRNAs and lncRNAs may also play a critical role inthe pathophysiology of MG.This review provides thetherapeutic and diagnostic potential of exosomes in MG patients. [ABSTRACT FROM AUTHOR]

Background: Oral food challenge (OFC) is the gold standard for diagnosing food allergies (FAs) but carries the risk of anaphylactic reaction. Stepwise OFC, starting with a low dose of allergen and progressing to medium and full doses, is effective in determining a tolerable dose. We retrospectively evaluated the results of a stepwise OFC for hen's egg (HE) to demonstrate its safety and efficacy. We discuss whether early low-dose administration of HE induces early immune tolerance in HE allergy. Methods: We included 2,058 children (median, 2.6 years) who underwent HE-OFC between 2017 and 2021 at two institutes in Japan. The target challenge dose of OFC was classified as low (less than 1/8 of a cooked egg), medium (1/8 or more but less than 1/2), or full (1/2 or more). If the low-dose OFC was negative, subjects were allowed to consume the same dose of HE and underwent medium-dose OFC within 12 months. Even if positive, individuals were recommended to consume previously-tolerated amounts of HE and repeat OFC at the same dose within 12 months. We evaluated the correlation between their OFC results and response. Results: A total of 526 (25.6%) children presented positive reactions. There were no cases of anaphylactic shock. Higher serum egg white (EW)- (P < 0.001) and ovomucoid (OVM)- specific IgE (P < 0.001) (sIgE) levels were associated with positive OFC. The low-dose OFC group had more positive reactions (P < 0.001), younger children (P < 0.001), higher EW-sIgE (P < 0.001) and OVM-sIgE (P < 0.001), and more histories of anaphylaxis (P = 0.014). OFC-positive children were younger than OFC-negative children, particularly in low-dose OFC (P = 0.010). OFC results between complete and partial elimination of HE groups across all EW- or OVM-sIgE classes were similar (P > 0.05). Conclusions: Stepwise OFC is safe and effective in diagnosing HE allergy and facilitates the earlier introduction of HE in children. This study suggests the limited potential of early consumption of lower doses of HE to induce earlier immune tolerance, such that other strategies to induce earlier tolerance in infants with HE allergy should be considered. [ABSTRACT FROM AUTHOR]

Type II collagen is a homologous super-helical structure consisting of three identical α1(II) chains. It is a major component of animal cartilage, and is widely used in the food industry. Type II collagen can be extracted by acids, salts, enzymes, and via auxiliary methods and can be further hydrolyzed chemically and enzymatically to produce collagen peptides. Recent studies have shown that type II collagen and its polypeptides have good self-assembly properties and important biological activities, such as maintaining cartilage tissue integrity, inducing immune tolerance, stimulating chondrocyte growth and redifferentiation, and providing antioxidant benefits. This review focuses specifically on type II collagen and describes its structure, extraction, and purification, as well as the preparation of type II collagen peptides. In particular, the self-assembly properties and functional activities of type II collagen and collagen peptides are reviewed. In addition, recent research advances in the application of type II collagen and collagen peptides in functional foods, food additives, food coating materials, edible films, and carriers for the food industry are presented. This paper provides more detailed and comprehensive information on type II collagen and peptide for their application. [ABSTRACT FROM AUTHOR]

Current rheumatoid arthritis (RA) treatments do not restore immune tolerance. Investigating dendritic cell (DC) populations in human synovial tissue (ST) may reveal pathways to reinstate tolerance in RA. Using single-cell and spatial transcriptomics of ST biopsies, as well as co-culture systems, we identified condition- and niche-specific DC clusters with distinct functions. Healthy tissue contained tolerogenic AXL+ DC2s in the lining niche. In active RA, the hyperplasic lining niche was populated with inflammatory DC3s that activated CCL5-positive effector memory T cells, promoting synovitis. Lymphoid niches that emerged in the sublining layer were enriched with CCR7+ DC2s, which interacted with naive T cells, potentially driving the local expansion of new effector T cells. Remission saw the resolution of these pathogenic niches but lacked recovery of tolerogenic DC2s and exhibited activation of blood precursors of ST-DC3 clusters prior to flare-ups. Targeting pathogenic DC3s or restoring tolerogenic DC2s may help restore immune homeostasis in RA joints. [Display omitted] • AXL+ DC2s with a tolerogenic phenotype reside beneath the healthy synovial lining • iDC3s populate the hyperplastic lining in RA, activating Tem and/or Tph cells • CCR7+ DC2s occupy sublining lymphoid niches in RA, interacting with naive T cells • A signature of blood precursors of ST-DC3s predicts RA flare during remission How dendritic cells (DCs) regulate human tissue immunity remains unclear. MacDonald, Elmesmari, Somma, Frew, et al. investigate the role of synovial tissue (ST) myeloid DCs in health and active and remission stages of rheumatoid arthritis. Using a combination of scRNA-seq, spatial transcriptomics, and DC:T cell co-cultures, the authors identify functional features of ST-DCs that reveal their roles in immune tolerance and disease. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives Methods Results Conclusion To report the long‐term safety and efficacy of BAY 81‐8973 in the LEOPOLD Kids extension phase.Patients received BAY 81‐8973 (25–50 IU/kg) at least twice weekly. The primary endpoint was safety, assessed in all patients who entered the extension phase (n = 82). Efficacy endpoints were assessed in patients without high‐titre inhibitors/immune tolerance induction (n = 67).Children (n = 82) received BAY 81‐8973 for a median of 3.1 years per patient and a median of 405 exposure days per patient. Long‐term BAY 81‐8973 treatment was well tolerated, with no cases of de novo inhibitor development in the extension phase. Annualised bleeding rates (ABRs) within 48 h of prophylaxis were low for all bleeds (median [IQR], 0.7 [0–1.9]; mean, 1.4 [SD, 2.1]) and for joint bleeds (median [IQR], 0 [0–0.7]; mean, 0.5 [SD, 1.1]) (n = 67). Twenty‐one of 67 patients (31.3%) had zero bleeds within 48 h of prophylaxis; the treatment response was ‘good’/‘excellent’ in 87.9% of bleeds, and most bleeds resolved with ≤ 2 BAY 81‐8973 infusions (83.5%).Long‐term BAY 81‐8973 treatment is well tolerated and maintains low ABRs for all bleeds and joint bleeds in children with severe haemophilia A.Trial Registration: ClinicalTrials.gov identifier: NCT01311648 [ABSTRACT FROM AUTHOR]

The immune system is endowed with the capacity to distinguish between self and non-self, so-called immune tolerance or "consciousness of the immune system." This type of awareness is designed to achieve host protection by eliminating cells expressing a wide range of non-self antigens including microbial-derived peptides. Such a successful immune response is associated with the secretion of a whole spectrum of soluble mediators, e.g., cytokines and chemokines, which not only contribute to the clearance of infected host cells but also activate T cells that are not specific to the original cognate antigen. This kind of non-specific T-cell activation is called "bystander activation." Although it is well-established that this phenomenon is cytokine-dependent, there is evidence in the literature showing the involvement of peptide/MHC recognition depending on the type of T-cell subset (naive vs. memory). Here, we will summarize our current understanding of the mechanism(s) of bystander T-cell activation as well as its biological significance in a wide range of diseases including microbial infections, cancer, auto- and alloimmunity, and chronic inflammatory diseases such as atherosclerosis. [ABSTRACT FROM AUTHOR]

Regulatory T (Treg) cells are essential for the maintenance of immunological tolerance, yet the molecular components required for their maintenance and effector functions remain incompletely defined. Inactivation of VPS34 in Treg cells led to an early, lethal phenotype, with massive effector T cell activation and inflammation, like mice lacking Treg cells completely. However, VPS34-deficient Treg cells developed normally, populated the peripheral lymphoid organs and effectively supressed conventional T cells in vitro. Our data suggest that VPS34 is required for the maintaining normal numbers of mature Treg. Functionally, we observed that lack of VPS34 activity impairs cargo processing upon transendocytosis, that defective autophagy may contribute to, but is not sufficient to explain this lethal phenotype, and that loss of VPS34 activity induces a state of heightened metabolic activity that may interfere with metabolic networks required for maintenance or suppressive functions of Treg cells. [ABSTRACT FROM AUTHOR]

Introduction: Allergen-specific immunotherapy (AIT) induces long-term immune tolerance to allergens and is effective for treating allergic rhinitis (AR). However, the impact of sublingual immunotherapy (SLIT) on gut microbiota from AR patients and its correlation with treatment efficacy remains unclear. Methods: In the present study, we enrolled 24 AR patients sensitized to Dermatophagoides farinae (Der-f) and 6 healthy donors (HD). All AR patients received SLIT treatment using standardized Der-f drops. Stool samples were collected from AR patients before treatment, and 1- and 3-months post-treatment, as well as from HD, for metagenomic sequencing analysis. Results: AR patients had significantly lower richness and diversity in gut microbiota compared to HD, with notable alterations in composition and function. Besides, three months post-SLIT treatment, significant changes in gut microbiota composition at the genus and species levels were observed in AR patients. Streptococcus parasanguinis_B and Streptococcus parasanguinis , which were significantly lower in AR patients compared to HD, increased notably after three months of treatment. LEfSe analysis identified these species as markers distinguishing HD from AR patients and AR patients pre- from post-SLIT treatment. Furthermore, changes in the relative abundance of S. parasanguinis_B were negatively correlated with changes in VAS scores but positively correlated with changes in RCAT scores, suggesting a positive correlation with effective SLIT treatment. Discussion: SLIT treatment significantly alters the gut microbiota of AR patients, with S. parasanguinis_B potentially linked to its effectiveness. This study offers insights into SLIT mechanisms and suggests that specific strains may serve as biomarkers for predicting SLIT efficacy and as modulators for improving SLIT efficacy. [ABSTRACT FROM AUTHOR]

Achieving sustained activity and tolerance in of allogeneic grafts after post-transplantation remains a substantial challenge. The response of the immune system to "non-self" MHC-antigenic peptides initiates a crucial phase, wherein blocking positive co-stimulatory signals becomes imperative to ensure graft survival and tolerance. MicroRNAs (miRNAs) inhibit mRNA translation or promote mRNA degradation by complementary binding of mRNA seed sequences, which ultimately affects protein synthesis. These miRNAs exhibit substantial promise as diagnostic, prognostic, and therapeutic candidates for within the realm of solid organ transplantations. Current research has highlighted three members of the T cell immunoglobulin and mucin domain (TIM) family as a novel therapeutic avenue in transplantation medicine and alloimmunization. The interplay between miRNAs and TIM proteins has been extensively explored in viral infections, inflammatory responses, and post-transplantation ischemia-reperfusion injuries. This review aims to elucidate the distinct roles of miRNAs and TIM in transplantation immunity and delineate their interdependent relationships in terms of targeted regulation. Specifically, this investigation sought seeks to uncover the potential of miRNA interaction with TIM, aiming to induce immune tolerance and bolster allograft survival after transplantation. This innovative strategy holds substantial promise in for the future of transplantation science and practice. [ABSTRACT FROM AUTHOR]

Immune checkpoints are crucial for regulating immune responses and maintaining self-tolerance, as they play a pivotal role in preventing autoimmunity and facilitating tumor immune evasion. This review concentrates on the immune checkpoint molecules PSGL-1 and VISTA. Both molecules are highly expressed in hematopoietic cells, including T cells and myeloid cells. VISTA functions both as a ligand on myeloid cells, where it regulates cytokine production, chemotaxis, and phagocytosis while promoting their differentiation into a tolerogenic phenotype and as a receptor on T cells, where it contributes to T cell quiescence. PSGL-1, which acts as a binding partner for VISTA, further inhibits T-cell activation and fosters tolerance within the acidic tumor microenvironment. Our review provides a comprehensive analysis of the structure, expression, and biological functions of PSGL-1 and VISTA and emphasizes their therapeutic potential in cancer treatment, autoimmune diseases, and transplantation. The dual role of these checkpoints in immune regulation presents novel opportunities for advancing cancer immunotherapy and developing new strategies for managing autoimmune conditions. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by symmetrical joint inflammation, cartilage degradation, and bone erosion. This review explores the multifaceted aspects of RA pathogenesis, focusing on the dynamic interplay between innate and adaptive immune responses, genetic predisposition, and environmental triggers. The development of RA involves genetic susceptibility and trigger events such as infections, trauma, smoking, obesity, and microbiome alterations, fostering autoimmune reactions and tissue/organ destruction. The innate immune response, including toll-like receptor activation and synovial fibroblasts' roles, contributes to the acceleration of inflammatory processes in joint tissues. Monocytes and macrophages organize and sustain chronic joint inflammation, leading to tissue damage and bone resorption, while highlighting the significance of CD14 and CD16 subsets in RA pathogenesis. In the adaptive immune response, aberrant activation and proliferation of CD4+ T cells and the role of regulatory T cells in maintaining immune tolerance are discussed. Target cytokines like TNF-α, IL-6, IL-1, IL-17, and BAFF, as well as chemokines such as CCL2, CXCL10, CCL5, and CXCL12, have emerged as critical components in managing chronic inflammation and joint damage in RA. This comprehensive overview provides insights into the pathophysiology of RA and potential therapeutic avenues, emphasizing the importance of understanding these complex immunological and genetic mechanisms for developing more effective treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Immunological tolerance is compromised in children with immunological thrombocytopenic purpura (ITP), an autoimmune disease. The purpose of this study was to measure the levels of lymphocyte subsets in children with ITP and to assess how these subsets are related to the patient's chronic illness and responsiveness to treatment. Methods: The pediatric hematology outpatient clinic at Zagazig University Hospitals served as the site of this case-control study. Sixty-four patients (16 with newly diagnosed ITP, 16 with persistent ITP, 16 with chronic ITP, and 16 healthy children as a control group) participated in the study. Using flow cytometry, all of the study's patients and controls had their lymphocyte subsets evaluated. Results: CD3+, CD4+, and CD56+ lymphocytes were significantly lower in patients with ITP compared to controls while CD8+ and CD19+ lymphocytes were significantly higher in patients with ITP compared to controls. Apart from CD8+ lymphocytes which were significantly higher in patients with chronic ITP compared to other patients' groups, there was no significant difference among different patients' groups in relation to different lymphocyte subsets. Patients with newly diagnosed ITP who responded to 1st line therapy had lower CD4+ and higher CD8+ and CD19+ lymphocytes compared to those who did not respond to 1st line therapy. Conclusion: We concluded that lymphocyte subsets play a significant role in the pathogenesis, chronicity, and response to treatment in childhood ITP. [ABSTRACT FROM AUTHOR]

The immune repertoire (IR) is a term that defines the combined unique genetic rearrangements of antigen receptors expressed by B and T lymphocytes. The IR determines the ability of the immune system to identify and respond to foreign antigens while preserving tolerance to host antigens. When immune tolerance is disrupted, development of autoimmune diseases can occur due to the attack of self-antigens. Recent technical advances in immune profiling allowed identification of common patterns and shared antigen-binding sequences unique to diverse array of diseases. However, there is no current literature to date evaluates IR findings in autoimmune and skin inflammatory conditions. In this review, we provide an overview of the past and current research findings of IR in various autoimmune and dermatologic conditions. Enriching our understanding of IRs in these conditions is critical for understanding the pathophysiology behind autoimmune skin disease onset and progression. Furthermore, understanding B-cell and T-cell IR will help devise therapeutic treatments in the hopes of restoring immune tolerance and preventing disease onset and progression. [ABSTRACT FROM AUTHOR]

Infants with congenital heart disease (CHD) often undergo thymectomy during corrective cardiac surgery (CCS). The long‐term immunological effects remain controversial, with concerns regarding increased susceptibility to infections, allergies, autoimmunity due to compromised immune tolerance mechanisms. This study aims to elucidate the long‐term immunological effects of early thymectomy. We enrolled 22 patients who underwent thymectomy in infancy and were followed up in the Pediatric Allergy and Immunology Clinic at Marmara University. We performed demographic characteristics and detailed immunological evaluation, including immunoglobulins, vaccine responses, lymphocyte subset analyses, upregulation, proliferation of T cells and T‐cell receptor excision circles (TRECs). Sixteen patients had a history of infection, including six serious infections, all in the first year. Lymphopenia was observed in 27% of patients, with a significant decrease in naive CD4+ and recent thymic emigrant T cells counts and an increase in the proportion of memory T‐cells, indicating premature immune senescence. Low levels of IgG, IgA and IgM were found in 36%, 40% and 22% of patients respectively. Vaccine responses were positive in 90% of patients. TREC levels were low in all 10 patients analysed. Seven of nine patients had normal proliferation. Twenty‐two percent of patients had allergic disease, and autoimmunity was not observed. Early thymectomy leads to permanent immunological changes that are indicative of early immunosenescence. It is recommended to preserve thymic tissue during surgery and requires long‐term follow‐up in terms of findings such as allergy and autoimmunity as well as infections due to impaired immune tolerance mechanisms. [ABSTRACT FROM AUTHOR]

Breast cancer was considered as a kind of prone breast tumors with the complicated pathological mechanisms and diverse clinical classifications. In the clinical treatments of HER2-positive tumor patients, HER2 monoclonal antibodies, such as Herceptin, have shown well-defined therapeutic effects. Nevertheless, due to the heterogeneity of breast cancers, drug resistance inevitably appeared during the application of Herceptin. In order to fully understand the immune tolerance status of the tumor microenvironment in the population of sensitive and insensitive patients, this study carried out a series of studies through Luminex cytokines assay, clinicopathological analysis, immunofluorescence, and PCR. The results confirmed that in clinical samples sensitive to Herceptin, there were a large number of macrophages, and the protein expression levels and in situ expression of macrophage-related chemokines and inflammatory mediators are significantly higher than drug-resistant tumor samples. Further studies found that T cell function has a low correlation with tumor growth, and there are obvious obstacles in the process of peripheral blood immune cells entering the tumor microenvironment. In summary, this study provided clues for understanding the clinical drug resistance of HER2 monoclonal antibody and the clinical rational use of drugs and combination drugs. [ABSTRACT FROM AUTHOR]

Lactate plays an important role in shaping immune tolerance in tumor microenvironment (TME) and correlates with poor prognosis in various solid tumors. Overcoming the immune resistance in an acidic TME may improve the anti-tumor immunity. Here, this study elucidated that via G-protein-coupled receptor 81 (GPR81), lactate could modulate immune tolerance in TME by recruiting regulatory T cells (Tregs) in vitro and in vivo. A high concentration of lactate was detected in cell supernatant and tissues of gastric cancer (GC), which was modulated by lactic dehydrogenase A (LDHA). GPR81 was the natural receptor of lactate and was overexpressed in different GC cell lines and samples, which correlated with poor outcomes in GC patients. Lactate/GPR81 signaling could promote the infiltration of Tregs into TME by inducing the expression of chemokine CX3CL1. GPR81 deficiency could decrease the infiltration of Tregs into TME, thereby inhibiting GC progression by weakening the inhibition of CD8+T cell function in a humanized mouse model. In conclusion, targeting the lactate/GPR81 signaling may potentially serve as a critical process to overcome immune resistance in highly glycolytic GC. [ABSTRACT FROM AUTHOR]

Background: The complex aetiology of type 1 diabetes (T1D), characterised by a detrimental cross‐talk between the immune system and insulin‐producing beta cells, has hindered the development of effective disease‐modifying therapies. The discovery that the pharmacological activation of LRH‐1/NR5A2 can reverse hyperglycaemia in mouse models of T1D by attenuating the autoimmune attack coupled to beta cell survival/regeneration prompted us to investigate whether immune tolerisation could be translated to individuals with T1D by LRH‐1/NR5A2 activation and improve islet survival. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from individuals with and without T1D and derived into various immune cells, including macrophages and dendritic cells. Cell subpopulations were then treated or not with BL001, a pharmacological agonist of LRH‐1/NR5A2, and processed for: (1) Cell surface marker profiling, (2) cytokine secretome profiling, (3) autologous T‐cell proliferation, (4) RNAseq and (5) proteomic analysis. BL001‐target gene expression levels were confirmed by quantitative PCR. Mitochondrial function was evaluated through the measurement of oxygen consumption rate using a Seahorse XF analyser. Co‐cultures of PBMCs and iPSCs‐derived islet organoids were performed to assess the impact of BL001 on beta cell viability. Results: LRH‐1/NR5A2 activation induced a genetic and immunometabolic reprogramming of T1D immune cells, marked by reduced pro‐inflammatory markers and cytokine secretion, along with enhanced mitohormesis in pro‐inflammatory M1 macrophages and mitochondrial turnover in mature dendritic cells. These changes induced a shift from a pro‐inflammatory to an anti‐inflammatory/tolerogenic state, resulting in the inhibition of CD4+ and CD8+ T‐cell proliferation. BL001 treatment also increased CD4+/CD25+/FoxP3+ regulatory T‐cells and Th2 cells within PBMCs while decreasing CD8+ T‐cell proliferation. Additionally, BL001 alleviated PBMC‐induced apoptosis and maintained insulin expression in human iPSC‐derived islet organoids. Conclusion: These findings demonstrate the potential of LRH‐1/NR5A2 activation to modulate immune responses and support beta cell viability in T1D, suggesting a new therapeutic approach. Key Points: LRH‐1/NR5A2 activation in inflammatory cells of individuals with type 1 diabetes (T1D) reduces pro‐inflammatory cell surface markers and cytokine release.LRH‐1/NR5A2 promotes a mitohormesis‐induced immuno‐resistant phenotype to pro‐inflammatory macrophages.Mature dendritic cells acquire a tolerogenic phenotype via LRH‐1/NR5A2‐stimulated mitochondria turnover.LRH‐1/NR5A2 agonistic activation expands a CD4+/CD25+/FoxP3+ T‐cell subpopulation.Pharmacological activation of LRH‐1/NR5A2 improves the survival iPSC‐islets‐like organoids co‐cultured with PBMCs from individuals with T1D. [ABSTRACT FROM AUTHOR]

Paracoccidioidomycosis (PCM) is a chronic endemic mycosis in Latin America, predominantly caused by Paracoccidioides brasiliensis (Pb18) and Paracoccidioides lutzii (Pl01). Diagnosing PCM is challenging due to species-specific antigenic differences, therefore new biomarkers for accurate and rapid detection are needed. This study explores multiple tolerization subtractive immunization (MTSI) to generate monoclonal antibodies against rare or weakly expressed epitopes of Pb18 and Pl01, potentially improving PCM diagnosis. These strains were cultured to obtain cell-free antigens (CFA). MTSI involved immunizing BALB/c mice with CFA from Pb18 as a tolerogen and Pl01 as an immunogen, using Freund's adjuvant and cyclophosphamide to induce immune tolerance. The immune response was monitored via Enzyme-linked immunosorbent assay (ELISA) and Western blotting. Hybridomas were generated by fusing splenocytes from immunized mice with myeloma cells, after which clonal selection was conducted based on reactivity to Pl01 antigens. The study explores the presence of various proteins, including gp43 and Hsp60, in the protein profile of CFAs. Additionally, polyclonal antibody reactivity to Pb18 antigens was significantly reduced, suggesting that MTSI effectively promoted immunological tolerance. Followig the screening of hybridomas, clones with good reactivity to Pl01 and less reactive to Pb18 were selected. The monoclonal clones C1 and E6 exhibited potential specificity for Pl01 antigens. The effective generation of P. lutzii-specific antibodies by MTSI demonstrates this technology's promise for the development of accurate PCM diagnostic instruments. These antibodies have the potential to enhance patient outcomes and reduce the incidence of false-negative diagnoses, which could lead to better disease management. [ABSTRACT FROM AUTHOR]

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Antibodies are essential to immune homeostasis due to their roles in neutralizing pathogenic agents. However, failures in central and peripheral checkpoints that eliminate autoreactive B cells can undermine self-tolerance and generate autoantibodies that mistakenly target self-antigens, leading to inflammation and autoimmune diseases. While autoantibodies are well-studied in autoimmune and in some communicable diseases, their roles in chronic conditions, such as obesity and aging, are less understood. Obesity and aging share similar aspects of immune dysfunction, such as diminished humoral responses and heightened chronic inflammation, which can disrupt immune tolerance and foster autoantigen production, thus giving rise to autoreactive B cells and autoantibodies. In return, these events may also contribute to the pathophysiology of obesity and aging, to the associated autoimmune disorders linked to these conditions, and to the development of immunosenescence, an age-related decline in immune function that heightens vulnerability to infections, chronic diseases, and loss of self-tolerance. Furthermore, the cumulative exposure to antigens and cellular debris during obesity and aging perpetuates pro-inflammatory pathways, linking immunosenescence with other aging hallmarks, such as proteostasis loss and mitochondrial dysfunction. This review examines the mechanisms driving autoantibody generation during obesity and aging and discusses key putative antigenic targets across these conditions. We also explore the therapeutic potential of emerging approaches, such as CAR-T/CAAR-T therapies, vaccines, and BiTEs, to tackle autoimmune-related conditions in aging and obesity. [ABSTRACT FROM AUTHOR]

As part of our work to develop small-molecule inhibitors (SMIs) of the CD40-CD40L(CD154) costimulatory protein-protein interaction, here, we describe the ability of two of our most promising SMIs, DRI-C21041 and DRI-C21095, to prolong the survival and function of islet allografts in two murine models of islet transplantation (under the kidney capsule and in the anterior chamber of the eye) and to prevent autoimmune type 1 diabetes (T1D) onset in NOD mice. In both transplant models, a significant portion of islet allografts (50%-80%) remained intact and functional long after terminating treatment, suggesting the possibility of inducing operational immune tolerance via inhibition of the CD40-CD40L axis. SMI-treated mice maintained the structural integrity and function of their islet allografts with concomitant reduction in immune cell infiltration as evidenced by direct longitudinal imaging in situ. Furthermore, in female NODs, three-month SMI treatment reduced the incidence of diabetes from 80% to 60% (DRI-C21041) and 25% (DRI-C21095). These results (i) demonstrate the susceptibility of this TNF superfamily protein-protein interaction to small-molecule inhibition, (ii) confirm the in vivo therapeutic potential of these SMIs of a critical immune checkpoint, and (iii) reaffirm the therapeutic promise of CD40-CD40L blockade in islet transplantation and T1D prevention. Thus, CD40L-targeting SMIs could ultimately lead to alternative immunomodulatory therapeutics for transplant recipients and prevention of autoimmune diseases that are safer, less immunogenic, more controllable (shorter half-lives), and more patient-friendly (i.e., suitable for oral administration, which makes them easier to administer) than corresponding antibody-based interventions. [ABSTRACT FROM AUTHOR]

The hypoxic microenvironment, characterized by significantly reduced oxygen levels within tissues, has emerged as a critical factor in the pathogenesis and progression of various autoimmune diseases (AIDs). Central to this process is the hypoxia-inducible factor-1 (HIF-1), which orchestrates a wide array of cellular responses under low oxygen conditions. This review delves into the multifaceted roles of the hypoxic microenvironment in modulating immune cell function, particularly highlighting its impact on immune activation, metabolic reprogramming, and angiogenesis. Specific focus is given to the mechanisms by which hypoxia contributes to the development and exacerbation of diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), and dermatomyositis (DM). In these conditions, the hypoxic microenvironment not only disrupts immune tolerance but also enhances inflammatory responses and promotes tissue damage. The review also discusses emerging therapeutic strategies aimed at targeting the hypoxic pathways, including the application of HIF-1α inhibitors, mTOR inhibitors, and other modulators of the hypoxic response. By providing a comprehensive overview of the interplay between hypoxia and immune dysfunction in AIDs, this review offers new perspectives on the underlying mechanisms of these diseases and highlights potential avenues for therapeutic intervention. [ABSTRACT FROM AUTHOR]

IKKα is a multifunctional serine/threonine kinase that controls various biological processes, either dependent on or independent of its kinase activity. However, the importance of the kinase function of IKKα in human physiology remains unknown since no biallelic variants disrupting its kinase activity have been reported. In this study, we present a homozygous germline missense variant in the kinase domain of IKKα, which is present in three children from two Turkish families. This variant, referred to as IKKαG167R, is in the activation segment of the kinase domain and affects the conserved (DF/LG) motif responsible for coordinating magnesium atoms for ATP binding. As a result, IKKαG167R abolishes the kinase activity of IKKα, leading to impaired activation of the non-canonical NF-κB pathway. Patients carrying IKKαG167R exhibit a range of immune system abnormalities, including the absence of secondary lymphoid organs, hypogammaglobulinemia and limited diversity of T and B cell receptors with evidence of autoreactivity. Overall, our findings indicate that, unlike a nonsense IKKα variant that results in early embryonic lethality in humans, the deficiency of IKKα's kinase activity is compatible with human life. However, it significantly disrupts the homeostasis of the immune system, underscoring the essential and non-redundant kinase function of IKKα in humans. IKKα is an essential regulator of the noncanonical NF-κB signalling, lack of which is incompatible with life. Here authors show that a homozygous missense variant in humans, G167R, disrupting its kinase activity upstream of the non-canonical NF-κB pathway, leads to disrupted innate and adaptive immune functions while largely sparing other major organ systems. [ABSTRACT FROM AUTHOR]

PANoptosis is a newly identified inflammatory programmed cell death (PCD) that involves the interplay of apoptosis, necrosis, and pyroptosis. However, its overall biological effects cannot be attributed to any one type of PCD alone. PANoptosis is regulated by a signaling cascade triggered by the recognition of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) by various sensors. This triggers the assembly of the PANoptosome, which integrates key components from other PCD pathways via adapters and ultimately activates downstream execution molecules, resulting in cell death with necrotic, apoptotic, and pyroptotic features. Autoimmune diseases are characterized by reduced immune tolerance to self-antigens, leading to abnormal immune responses, often accompanied by systemic chronic inflammation. Consequently, PANoptosis, as a unique innate immune-inflammatory PCD pathway, has significant pathophysiological relevance to inflammation and autoimmunity. However, most previous research on PANoptosis has focused on tumors and infectious diseases, leaving its activation and role in autoimmune diseases unclear. This review briefly outlines the characteristics of PANoptosis and summarizes several newly identified PANoptosome complexes, their activation mechanisms, and key components. We also explored the dual role of PANoptosis in diseases and potential therapeutic approaches targeting PANoptosis. Additionally, we review the existing evidence for PANoptosis in several autoimmune diseases and explore the potential regulatory mechanisms involved. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy has revolutionized the treatment landscape by harnessing the power of the immune system to combat malignancies. Two of the most promising players in this field are cluster of differentiation 24 (CD24) and sialic acid‐binding Ig‐like lectin 10 (Siglec‐10), and both of them play pivotal roles in modulating immune responses. CD24, a cell surface glycoprotein, emerges as a convincing fundamental signal transducer for therapeutic intervention, given its significant implication in the processes related to tumour progression and immunogenic evasion. Additionally, the immunomodulatory functions of Siglec‐10, a prominent member within the Siglec family of immune receptors, have recently become a crucial point of interest, particularly in the context of the tumour microenvironment. Hence, the intricate interplay of both CD24 and Siglec‐10 assumes a critical role in fostering tumour growth, facilitating metastasis and also orchestrating immune evasion. Recent studies have found multiple evidences supporting the therapeutic potential of targeting CD24 in cancer treatment. Siglec‐10, on the other hand, exhibits immunosuppressive properties that contribute to immune tolerance within the tumour microenvironment. Therefore, we delve into the complex mechanisms through which Siglec‐10 modulates immune responses and facilitates immune escape in cancer. Siglec‐10 also acts as a viable target for cancer immunotherapy and presents novel avenues for the development of therapeutic interventions. Furthermore, we examine the synergy between CD24 and Siglec‐10 in shaping the immunosuppressive tumour microenvironment and discuss the implications for combination therapies. Therefore, understanding the roles of CD24 and Siglec‐10 in cancer immunotherapy opens exciting possibilities for the development of novel therapeutics. [ABSTRACT FROM AUTHOR]

Allergen specific immunotherapy (AIT) is the only etiological treatment method that alters the course of allergic diseases by inducing allergen-specific immune tolerance. Subcutaneous specific immunotherapy (SCIT), due to its standardized process and high-quality control, has become the most predominant desensitization method in major allergy centers across the country. However, there are limitations in the initial phase of conventional treatment plans, requiring patients to return to the hospital weekly for injections, which involves a high number of needle sticks and a lengthy duration. Consequently, clinical practitioners have been continuously exploring optimized treatment strategies for SCIT. Dust mites are the most common inhalant allergens causing sensitization in children, this article reviews the different optimization strategies and clinical application progress of dust mite allergen SCIT in children, aiming to provide a more comprehensive clinical basis for the implementation of SCIT. After reviewing the literature, it was found that compared with the conventional treatment regimen, the accelerated escalation regimen was helpful to improve treatment compliance. However, at present, the sample size of studies such as rush immunotherapy and single accelerated concentration escalation schemes is generally small, so large-scale studies with larger sample size and more complete research are still needed to provide reliable data support. [ABSTRACT FROM AUTHOR]

Background/Objectives: Dendritic cells (DCs) are master regulators of the adaptive immune response. Inflammatory DCs (inflamDCs) can prime inflammatory T cells in, for instance, cancer and infection. In contrast, tolerogenic DCs (tolDCs) can suppress the immune system through a plethora of regulatory mechanisms in the context of autoimmunity. We successfully generated tolDCs in vitro to durably restore immune tolerance to an islet autoantigen in type 1 diabetes patients in a clinical trial. However, cancers can induce inhibitory DCs in vivo that impair anti-tumor immunity through Siglec signaling. Methods: To connect in vivo and in vitro tolDC properties, we tested whether tolDCs generated in vitro may also employ the Siglec pathway to regulate autoimmunity by comparing the transcriptomes and protein expression of immature and mature inflamDCs and tolDCs, generated from monocytes. Results: Both immature DC types expressed most Siglec genes. The expression of these genes declined significantly in mature inflamDCs compared to mature tolDCs. Surface expression of Siglec proteins by DCs followed the same pattern. The majority of genes involved in the different Siglec pathways were differentially expressed by mature tolDCs, as opposed to inflamDCs, and in inhibitory pathways in particular. Conclusions: Our results show that tolDCs generated in vitro mimic tumor-resident inhibitory DCs in vivo regarding Siglec expression. [ABSTRACT FROM AUTHOR]

The approval of teplizumab to delay the onset of type 1 diabetes is an important inflection point in the decades-long pursuit to treat the cause of the disease rather than its symptoms. The National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop of the Diabetes Mellitus Interagency Coordinating Committee titled "Evolving Concepts in Pathophysiology, Screening, and Prevention of Type 1 Diabetes" to review this accomplishment and identify future goals. Speakers representing Type 1 Diabetes TrialNet (TrialNet) and the Immune Tolerance Network emphasized that the ability to robustly identify individuals destined to develop type 1 diabetes was essential for clinical trials. The presenter from the U.S. Food and Drug Administration described how regulatory approval relied on data from the single clinical trial of TrialNet with testing of teplizumab for delay of clinical diagnosis, along with confirmatory evidence from studies in patients after diagnosis. The workshop reviewed the etiology of type 1 diabetes as a disease involving multiple immune pathways, highlighting the current understanding of prognostic markers and proposing potential strategies to improve the therapeutic response of disease-modifying therapies based on the mechanism of action. While celebrating these achievements funded by the congressionally appropriated Special Diabetes Program, panelists from professional organizations, nonprofit advocacy/funding groups, and industry also identified significant hurdles in translating this research into clinical care. [ABSTRACT FROM AUTHOR]

New approaches to treat autoimmune diseases are needed, and we can be inspired by mechanisms in immune tolerance to guide the design of these approaches. Efferocytosis, the process of phagocyte-mediated apoptotic cell (AC) disposal, represents a potent tolerogenic mechanism that we could draw inspiration from to restore immune tolerance to specific autoantigens. ACs engage multiple avenues of the immune response to redirect aberrant immune responses. Two such avenues are: phosphatidylserine on the outer leaflet of the cell and engaging the aryl hydrocarbon receptor (AhR) pathway. We incorporated these two avenues into one acetalated dextran (Ace-DEX) microparticle (MP) for evaluation in vitro. First phosphatidylserine (PS) was incorporated into Ace-DEX MPs and evaluated for cellular association and mediators of cell tolerance including IL-10 production and M2 associated gene expression when particles were cultured with peritoneal macrophages (PMacs). Further PS Ace-DEX MPs were evaluated as an agent to suppress LPS stimulated PMacs. Then, AhR agonist 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) was incorporated into Ace-DEX MPs and expression of M2 and IL-10 genes was evaluated in PMacs. Further the ITE and PS Ace-DEX MPs (PS/ITE MPs) were evaluated for suppression of T cell priming and Th1 polarization. Our results indicate that the PS/ITE-MPs stimulated anti-inflammatory cytokine expression and suppressed inflammation following LPS stimulation of PMacs. Moreover, PS/ITE MPs induced the anti-inflammatory enzyme IDO1 and suppressed macrophage-mediated T cell priming and Th1 polarization. These findings suggest that PS and ITE-loaded Ace-DEX MPs could be a promising therapeutic tool for suppressing inflammation. [ABSTRACT FROM AUTHOR]

Sublingual immunotherapy (SLIT) has received considerable attention as a method for allergen immunotherapy (AIT). However, the mechanism of SLIT, especially its timing, has not been thoroughly investigated. We evaluated therapeutic and prophylactic SLIT in an allergic airway inflammation model and evaluated their efficacies. Mice were intranasally exposed to Dermatophagoides farinae (Der f) extract and received SLIT before (prophylactic model) and after (therapeutic model) intranasal exposure of Der f. We investigated airway responsiveness, airway inflammation, allergen-specific antibodies, lung histology and single-cell RNA sequencing (scRNA-seq) and T-cell receptor sequencing were also investigated. SLIT in the therapeutic model was effective; however, the effects of SLIT in the prophylactic model were stronger and immune tolerance was maintained for three months. ScRNA-seq of lung CD4+CD25+ T cells revealed that the expansion of induced T regulatory (iTreg) cells was greater in the prophylactic model than that in the therapeutic model. Additionally, the TCR repertoire of iTregs from the prophylactic model was abundant, sharing many clones with the TCR repertoire of effector T cells. These data suggest that the prophylactic model of AIT is extremely effective and persistent, and may respond to allergen diversity, and provide evidence for the clinical recommendation of preventive AIT. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is one of the most common cancers worldwide. Most patients are diagnosed at the progressive stage of GC, and progress in the development of effective anti-GC drugs has been insufficient. The tumor microenvironment (TME) regulates various functions of tumor cells, and interactions between the cellular and molecular components of the TME—e.g., inflammatory cells, fibroblasts, vasculature cells, and innate and adaptive immune cells—promote the aggressiveness of cancer cells and dissemination to distant organs. This review summarizes the roles of various TME cells and molecules in regulating the malignant progression and metastasis of GC. We also address the important roles of signaling pathways in mediating the interaction between cancer cells and the different components of the GC TME. Finally, we discuss the implications of these molecular mechanisms for developing novel and effective therapies targeting molecular and cellular components of the GC TME to control the malignant progression of GC. [ABSTRACT FROM AUTHOR]

Natural autoantibodies (natAAbs) react with evolutionarily conserved antigens but they do not lead to pathological tissue destruction, contrary to pathological autoantibodies (pathAAbs). NatAAbs usually belong to the IgM isotype, and their network, also known as the "immunological homunculus", is thought to play a role in immunological tolerance. NatAAbs are produced by B1 cells found mostly on the serosa surfaces or the spleen. The exact relation between natAAbs and pathAAbs is still not completely understood. The recombinant human proteoglycan (PG) aggrecan G1 domain (rhG1)-induced arthritis (GIA) is an excellent mouse model for rheumatoid arthritis because it represents most of the clinical, immunological and laboratory parameters of the corresponding human pathology. Recently, we studied the role of the spleen in GIA, and found that a splenectomy modified the development of autoimmunity. To further characterize the possible role of the nAAb levels in tolerance and autoimmunity, in the present study, we set out to measure the nat- and pathAAb levels in GIA. We analyzed the natAAb levels in the serum against cartilage PG aggrecan, Hsp60 and Hsp70, and the mitochondrial citrate synthase (CS) antigens in healthy control and arthritic mice. Furthermore, we studied whether the splenectomy influenced the production of nat- and pathAAbs in mice with GIA. Our results show that the natAAb levels against PG aggrecan, Hsp60, Hsp70 and CS showed age-related variations in healthy BALB/c mice. The induction of autoimmune arthritis did not change the levels of the measured natAAbs significantly. Splenectomy, on the other hand, clearly decreased the levels of all the measured natAAbs. Interestingly, the levels of the pathAAbs showed the opposite change: they were higher in the splenectomized group than in the control arthritic mice. Based on these results, we conclude that the spleen plays a role in setting the balance between nat- and pathAAbs in autoimmune arthritis. [ABSTRACT FROM AUTHOR]

Zoonotic viruses originating from reservoir hosts, such as bats and birds, often cause severe illness and outbreaks amongst humans. Upon zoonotic virus transmission, infected cells mount innate immune responses that include the activation of programmed cell death pathways to recruit innate immune cells to the site of infection and eliminate viral replication niches. Different inflammatory and non-inflammatory cell death pathways, such as pyroptosis, apoptosis, necroptosis, and PANoptosis can undergo concurrent activation in humans leading to mortality and morbidity during zoonosis. While controlled activation of PANoptosis is vital for viral clearance during infection and restoring tissue homeostasis, uncontrolled PANoptosis activation results in immunopathology during zoonotic virus infections. Intriguingly, animal reservoirs of zoonotic viruses, such as bats and birds, appear to have a unique immune tolerance adaptation, allowing them to host viruses without succumbing to disease. The mechanisms facilitating high viral tolerance in bats and birds are poorly understood. In this perspective review, we discuss the regulation of PANoptotic pathways in bats and birds and indicate how they co-exist with viruses with mild clinical signs and no immunopathology. Understanding the PANoptotic machinery of bats and birds may thus assist us in devising strategies to contain zoonotic outbreaks amongst humans. [ABSTRACT FROM AUTHOR]

Ovarian cancer remains a formidable challenge in oncology due to its late-stage diagnosis and limited treatment options. Recent research has revealed the intricate interplay between glycan diversity and the immune microenvironment within ovarian tumors, shedding new light on potential therapeutic strategies. This review seeks to investigate the complex role of glycans in ovarian cancer and their impact on the immune response. Glycans, complex sugar molecules decorating cell surfaces and secreted proteins, have emerged as key regulators of immune surveillance in ovarian cancer. Aberrant glycosylation patterns can promote immune evasion by shielding tumor cells from immune recognition, enabling disease progression. Conversely, certain glycan structures can modulate the immune response, leading to either antitumor immunity or immune tolerance. Understanding the intricate relationship between glycan diversity and immune interactions in ovarian cancer holds promise for the development of innovative therapeutic approaches. Immunotherapies that target glycan-mediated immune evasion, such as glycan-based vaccines or checkpoint inhibitors, are under investigation. Additionally, glycan profiling may serve as a diagnostic tool for patient stratification and treatment selection. This review underscores the emerging importance of glycan diversity in ovarian cancer, emphasizing the potential for unraveling immune interplay and advancing tailored therapeutic prospects for this devastating disease. [ABSTRACT FROM AUTHOR]

Islet-antigen-specific tolerization is a key goal of experimental immunotherapies for type 1 diabetes. mRNA-based vaccines have demonstrated the feasibility of RNA delivery in inducing antigen tolerance in autoimmune diseases. In this study, mRNA vaccine, encoded tandem glutamic acid decarboxylase 65 (GAD65) epitopes and cholera toxin B subunit (CTB-GADIII), prepared by an in vitro transcription (IVT) system and encapsulated with lipid nanoparticles (LNP), was intramuscularly administered to non-obese diabetic (NOD) and cyclophosphamide (Cy)-NOD mice respectively. The results showed that the mRNA vaccines significantly reduced the incidence rate of type 1 diabetes, delayed the disease progression, improved glucose tolerance, and protected pancreatic morphology and function compared with the controls. Meanwhile, the vaccines also reduced the levels of autoantibodies to glutamic acid decarboxylase (GADA) and insulin (IAA) in the serum. Furthermore, the proportion of CD4+ T helper cell subsets was modulated in the spleen of mice treated with mRNA vaccines, in correspondence with the increased levels of IL-10 and TGF-β in serum, suggesting the possible mechanism of immune tolerance. This study provides experimental evidence for the application of mRNA vaccines encoding self-antigens in the prevention or treatment of type 1 diabetes. [Display omitted] • LNP-mRNA vaccines based on GAD65 effectively reduce the incidence of T1D in NOD and Cy-NOD mice. • These vaccines can induce immune tolerance by modulating the proportions of CD4+ T helper cell subsets. • This study provides experimental evidence for the application of mRNA vaccines in the prevention or treatment of T1D. [ABSTRACT FROM AUTHOR]

Mammalian orthoreovirus (reovirus) strains type 1 Lang (T1L) and type 3 Dearing-RV (T3D-RV) infect the intestine in mice but differ in the induction of inflammatory responses. T1L infection is associated with the blockade of oral immunological tolerance to newly introduced dietary antigens, whereas T3D-RV is not. T1L infection leads to an increase in infiltrating phagocytes, including macrophages, in gut-associated lymphoid tissues that are not observed in T3D-RV infection. However, the function of macrophages in reovirus intestinal infection is unknown. Using cells sorted from infected intestinal tissue and primary cultures of bone-marrow-derived macrophages (BMDMs), we discovered that T1L infects macrophages more efficiently than T3D-RV. Analysis of T1L × T3D-RV reassortant viruses revealed that the viral S4 gene segment, which encodes outer-capsid protein s3, is responsible for strainspecific differences in infection of BMDMs. Differences in the binding of T1L and T3D-RV to BMDMs also segregated with the s3-encoding S4 gene. Paired immunoglobulin-like receptor B (PirB), which serves as a receptor for reovirus, is expressed on macrophages and engages s3. We found that PirBspecific antibody blocks T1L binding to BMDMs and that T1L binding to PirB-/- BMDMs is significantly diminished. Collectively, our data suggest that reovirus T1L infection of macrophages is dependent on engagement of PirB by viral outer-capsid protein s3. These findings raise the possibility that macrophages function in the innate immune response to reovirus infection that blocks immunological tolerance to new food antigens. IMPORTANCE Mammalian orthoreovirus (reovirus) infects humans throughout their lifespan and has been linked to celiac disease (CeD). CeD is caused by a loss of oral immunological tolerance (LOT) to dietary gluten and leads to intestinal inflammation following gluten ingestion, which worsens with prolonged exposure and can cause malnutrition. There are limited treatment options for CeD. While there are genetic risk factors associated with the illness, triggers for disease onset are not completely understood. Enteric viruses, including reovirus, have been linked to CeD induction. We found that a reovirus strain associated with oral immunological tolerance blockade infects macrophages by virtue of its capacity to bind macrophage receptor PirB. These data contribute to an understanding of the innate immune response elicited by reovirus, which may shed light on how viruses trigger LOT and inform the development of CeD vaccines and therapeutic agents. [ABSTRACT FROM AUTHOR]