Interleukin-17 receptor A (IL17RA) and IL17RC form a receptor complex critical for initiating IL-17A-mediated immune responses, a hallmark of T helper 17 (Th17) cells. In this study, il17ra and il17rc were identified in miiuy croaker (Miichthys miiuy) and bioinformatics analysis revealed their evolutionary and structural conservation, underscoring their roles in immunity. However, there has been little research on the IL-17 receptor family from the perspective of N6-methyladenosine (m6A) modifications. Using methylated RNA immunoprecipitation sequencing (MeRIP-seq), we identified strong m6A modifications on the last exons of il17ra and il17rc, validated by MeRIP-PCR. Poly(I:C) stimulation significantly upregulated il17ra and il17rc expression, while reducing their m6A modification levels, implicating these changes in antiviral immunity. Interestingly, cycloleucine (CL), a well-known methylation inhibitor, did not alter the expression of il17ra and il17rc but promoted the nuclear-to-cytoplasmic transport of il17ra mRNA, potentially influencing its translation process. These findings provide valuable insights into the regulatory roles of m6A modifications in il17ra and il17rc function and highlight their importance in the antiviral immune response.

Th17 lymphocytes are a distinct subpopulation of T cells that are characterized by the production of interleukins IL-17, IL-21, IL-22, and IL-26, and high expression of RORγt. These cells play an important role in inflammation and autoimmune diseases. Recent studies using rodent and human models have also highlighted their promising properties as agents in cellular immunotherapy for cancer. However, much less is known about the properties of canine Th17 lymphocytes, despite the domestic dog being an important model used in comparative medicine. In this study, we developed methods of activation and differentiation of canine CD4+ T lymphocytes towards the Th17 phenotype. Additionally, we targeted the Wnt/β-catenin signaling pathway to modulate the efficiency of Th17 cells differentiation. CD4+ T cells were successfully activated with magnetic EpoxyBeads, and in combination with the appropriate programming medium, they acquired the Th17 phenotype. Furthermore, indomethacin, an inhibitor of the Wnt/β-catenin pathway, significantly increased the efficiency of differentiation, causing elevated production of IL-17 and changed T cell metabolism by promoting oxidative phosphorylation. The protocol elaborated in our study provides an efficient method of canine Th17 lymphocyte differentiation. Our findings also suggested that the modification of the Wnt/β-catenin signaling pathway could be a valuable strategy for optimizing canine Th17 cell differentiation and advancing cell-based immunotherapy.

Chikungunya virus (CHIKV) is a mosquito-borne virus that can cause chronic chikungunya virus disease (CHIKVD), which is characterized by persistent incapacitating arthralgia. Despite recurring CHIKV outbreaks and recent approval of a vaccine, the breadth and target of T cell responses in CHIKVD remain largely understudied. Here, we tested peripheral blood mononuclear cells (PBMCs) collected from CHIKV-infected individuals against overlapping peptide pools sequentially spanning the entire CHIKV proteome. We detected robust CHIKV-specific CD4+, but not CD8+, T cell responses in infected individuals. Individuals with chronic arthralgia displayed significantly higher CD4+ T cell responses against nsP1, nsP2, and E2 proteins and exhibited a significantly lower Th1 CD4+ T cell population, compared to individuals who had recovered. Additionally, CD4+ T cells in chronic individuals were marked by a predominant production of tumor necrosis factor alpha (TNF-α). Overall, our work comprehensively characterizes T cell responses in CHIKVD in humans and provides insights into the role of T cells in CHIKVD.

Recombinant adeno-associated virus (rAAV) is considered the most promising vector for gene therapy. However, the transgene- induced immune response hinders treatment efficacy. Current strategies to suppress immune responses include tissue-specific promoters and miRNA-binding sites; however, neither approach alone completely inhibits transgene-induced immune response. This study innovatively combines the C5-12 promoter and miRNA148a-3p binding sequences (miRNA148BS) in rAAV vectors express full-length ovalbumin (OVA) as a model antigen. We evaluated their effects on antigen presentation, cellular immunity, and humoral immunity. Results demonstrate that the combination of miRNA148BS and C5-12 promoter preserves expression of OVA in C2C12 cells while completely suppressing the expression in antigen-presenting cells (APC). Antigen presentation assays confirmed near-undetectable levels of the SIINFEKL peptide-MHC complex. Notably, the dual-modification strategy enabled higher and more stable transgene expression in mouse muscle compared to individual modifications. Furthermore, the combination significantly inhibited cytotoxic CTL activation and suppressed Th17 responses in vivo. This synergistic approach provides a foundation for development safe and more effective rAAV-based gene therapy.

Group B Streptococcus is a significant cause of early-onset disease in term newborns, with a global incidence of 0.41/1000 live births. Intrapartum antibiotic prophylaxis (IAP) has reduced EOD incidence by over 80%, but concerns exist about its impact on the neonatal gut microbiome and potential long-term health effects.

This single center study examines the effects of IAP on the fecal infant microbiome in the first year of age and on the T cell phenotype in the first days after birth among 22 infants receiving IAP with penicillin due to maternal GBS colonization and 26 infants not exposed to IAP. The fecal microbiome was analyzed at birth, one month and one year of age through 16S rRNA gene sequencing. Additionally, a T cell phenotyping of peripheral blood was performed between the second and fifth day of age.

At one month, IAP exposed infants had a significantly lower relative abundance of Bifidobacterium longum in fecal samples, an effect which was sustained at one year. In IAP exposed infants we found a proinflammatory T-helper cell profile, characterized by higher IL-17A, RORgt, and TGF-b expression.

This study proposes a sustained impact of IAP on the neonatal microbiome and T cell repertoire.

Autoimmune and inflammatory diseases are characterized by aberrant immune responses. The immunoproteasome was proposed as a target for such Th cell-mediated diseases due to its role in the activation, differentiation and function of T cells. Even though many studies demonstrated reductions in Th17 cells upon immunoproteasome inhibition, it is still unclear if the differentiation or survival of these cells is affected. Therefore, this study used DSS-induced colitis and house dust mite airway inflammation mouse models to investigate the effect of immunoproteasome inhibition on Th17 cells and Tregs at different time points. Th17 cells were almost abolished when immunoproteasome inhibition was applied continuously in DSS-induced colitis. In contrast, immunoproteasome inhibition did not decrease levels of already differentiated Th17 cells and did not enhance Treg induction. Dendritic cells were barely affected by immunoproteasome inhibition. Moreover, immunoproteasome inhibition reduced T cell activation in vitro and in vivo, suggesting impaired activation as the underlying mechanism for reduced Th17 differentiation. In conclusion, immunoproteasome inhibition reduces Th17 differentiation by impairing the activation of naïve T cells, but it does not affect the survival of already-differentiated Th17 cells and Tregs.

Th17 cells can perform either regulatory or inflammatory functions depending on the cytokine microenvironment. These plastic cells can transdifferentiate into Tregs during inflammation resolution, in allogenic heart transplantation models, or in cancer through mechanisms that remain poorly understood. Here, we demonstrated that NLRP3 expression in Th17 cells is essential for maintaining their immunosuppressive functions through an inflammasome-independent mechanism. In the absence of NLRP3, Th17 cells produce more inflammatory cytokines (IFNγ, Granzyme B, TNFα) and exhibit reduced immunosuppressive activity toward CD8+ cells. Moreover, the capacity of NLRP3-deficient Th17 cells to transdifferentiate into Treg-like cells is lost. Mechanistically, NLRP3 in Th17 cells interacts with the TGF-β receptor, enabling SMAD3 phosphorylation and thereby facilitating the acquisition of immunosuppressive functions. Consequently, the absence of NLRP3 expression in Th17 cells from tumor-bearing mice enhances CD8 + T-cell effectiveness, ultimately inhibiting tumor growth.

The onset of multiple sclerosis (MS) in older individuals correlates with a higher risk of developing primary progressive MS, faster progression to secondary progressive MS, and increased disability accumulation. This phenomenon can be related to age-related changes in the immune system: with age, the immune system undergoes a process called immunosenescence, characterized by a decline in the function of both the innate and adaptive immune responses. This decline can lead to a decreased ability to control inflammation and repair damaged tissue. Additionally, older individuals often experience a shift toward a more pro-inflammatory state, known as inflammaging, which can exacerbate the progression of neurodegenerative diseases like MS. Therefore, age-related alterations in the immune system could be responsible for the difference in the phenotype of MS observed in older and younger patients. In this study, we investigated the effects of age on the immunopathogenesis of experimental autoimmune encephalomyelitis (EAE). Our findings indicate that EAE is more severe in aged mice due to a more inflammatory and neurodegenerative environment in the central nervous system. Age-related changes predominantly affect adaptive immunity, characterized by altered T cell ratios, a pro-inflammatory Th1 response, increased regulatory T cells, exhaustion of T cells, altered B cell antigen presentation, and reduced NK cell maturation and cytotoxicity. Transcriptomic analysis reveals that fewer pathways and transcription factors are activated with age in EAE. These findings allow us to identify potential therapeutic targets specific to elderly MS patients and work on their development in the future.

This study aimed to investigate the potential reduction on the sensitization of sesame protein Ses i 3 through ultrasound-assisted glycation. Ses i 3 was extracted and purified using an immunoaffinity column, and the allergenicity changes of Ses i 3 were assessed by a comprehensive strategy, and T cell polarization was also assessed in vivo. Results showed ultrasound-assisted glycation treated Ses i 3 was more easily digestible; and the cell degranulation model showed the histamine, tryptase, and β-hexosaminidase induced by ultrasound-assisted glycation treatment were significantly decreased; besides, the serological results demonstrated that a notable decrease in the binding ability of immunoglobulin E (IgE) and IgG; finally, a BALB/c mice model demonstrated an alleviation of allergic responses induced by ultrasonic-assisted glycation treatment. Meanwhile, the results in vivo also found that ultrasonic-assisted glycation treated Ses i 3 induced enhanced Helper T cell (TH) 1 cell differentiation while weakening TH2 cell differentiation, promoting TH1/TH2 balance polarization. Additionally, it induced stronger regulatory T (Treg) cell differentiation, and suppressed TH17 cell differentiation, promoting Treg/TH17 balance. This study demonstrated that the sensitization of Ses i 3 was reduced after ultrasonic-assisted glycation treatment, and this effect was associated with the modulation of T cell differentiation.

Effective treatment of chronic posterior ocular diseases such as uveitis, diabetic retinopathy, and age-related macular degeneration requires improvements in targeted drug delivery strategies. This study introduces a novel injectable drug delivery system co-assembled with a peptide-based hydrogel and secukinumab (SEK), an IL-17A neutralising monoclonal antibody, targeting retinal pigmented epithelium (RPE) cells. Compared to a SEK solution, the SEK loaded hydrogel significantly enhanced the protein uptake (3.7 times higher) by RPE cells in an inflammatory state after 24 hours of treatment and increased the drug concentration in retinal tissues during 20 days of treatment. A single intravitreal injection of the SEK loaded hydrogel effectively suppressed inflammation in a uveitis model. It also reduced the immunoreactivity of microglia and T helper 17 cells, preserved the integrity of the blood-retina barrier, mitigated retinal cell apoptosis, and facilitated the recovery of the retinal function. This delivery system comprising an antibody-drug co-assembled with a peptide-based hydrogel shows promising potential for targeting the retina and treating complex chronic posterior ocular diseases.

Leishmania spp. infections pose a significant global health challenge, affecting approximately 1 billion people across more than 88 endemic countries. This unicellular, obligate intracellular parasite causes a spectrum of diseases, ranging from localized cutaneous lesions to systemic visceral infections. Despite advancements in modern medicine and increased understanding of the parasite's etiology and associated diseases, treatment options remain limited to pentavalent antimonials, liposomal amphotericin B, and miltefosine. A deeper understanding of the interactions between immune and non-immune cells involved in the clearance of Leishmania spp. infections could uncover novel therapeutic strategies for this debilitating disease. This review highlights recent progress in elucidating how various cell types contribute to the regulation and resolution of Leishmania spp. infections.

Psoriasis is a global chronic, immune-mediated, inflammatory skin disease. Bai-Jie-Jing-Xie (BJJX) ointment has been widely used in the clinic practice for its notable efficacy and is an empirical prescription for psoriasis treatment in hospitals. Nevertheless, its precise mechanism of action on psoriasis remains unclear.

To study the mechanism of action of the hospital empirical prescription BJJX in the treatment of psoriasis.

Imiquimod (IMQ) was used to induce the psoriasis model in BALB/c mice and UPLC-MS/MS analysis was used for quality control. Subsequently, a combination of network pharmacology (NP) and Transcriptomic (RNA-Seq) methodology was used to assess the potential targets and mechanisms of action of BJJX on psoriasis. Finally, further validation was performed using flow cytometry, RT-qPCR, and western blotting.

BJJX significantly ameliorated IMQ-induced skin damage in psoriatic mice, reduced keratinocyte proliferation, and inhibited the levels of inflammatory factors (IL-23, IL-22, IL-17A, IL-6, IL-1β, and IL-8). NP predicts that BJJX may exert its therapeutic effects on psoriasis by modulating the IL-17 signaling pathway and Th17 cell differentiation. RNA-Seq analysis showed that BJJX regulated the expression of IL-17 pathway-related genes. Further experimental results demonstrated that BJJX treatment significantly reduced the mRNA expression of inflammatory factors CXCL2, CXCL3, MMP13, IL-1β, IL-23, IL-22, and IL-17A, as well as the proportion of Th17 cells. In addition, BJJX significantly inhibited the protein expression of JAK2 and STAT3.

BJJX attenuated IMQ-induced skin lesions in psoriasis mice by decreasing the expression of cytokines and chemokines mediated by the Th17/IL-17 axis. This study revealed, for the first time, the mechanism used by BJJX to treat psoriasis, providing a new paradigm for its pharmacological role in the clinical treatment of psoriasis.

This study aimed to investigate the evidence for presence of Th17 cells and their biomarkers, and to assess their impact on the immune-inflammatory response in periodontitis.

An electronic search was performed in MEDLINE (PubMed), SCOPUS, EBSCOhost, and Google Scholar databases from their earliest records to April 2023. Additionally, the reference lists of included articles and grey literature were hand-searched. Study selection and quality assessment of the included articles was performed using the Newcastle-Ottawa scale.

This systematic review included case-control, cross-sectional, and cohort studies published in English, specifically those evaluating the presence and influence of Th17 or its related biomarkers in the progression of periodontal disease. Of the 26,797 articles screened, 47 studies met the eligibility criteria and were included. The studies varied in design, molecular methods, and sample types.

This systematic review confirms the presence of Th17 cells and related biomarkers in periodontal tissues, highlighting their role in the immune-inflammatory response and pathogenesis of periodontitis. The review underscores the need for more comprehensive research to overcome current limitations and effectively translate these findings into clinical practice.

Neuroinflammation is an inflammatory response occurring within the central nervous system (CNS). The process is marked by the production of pro-inflammatory cytokines, chemokines, small-molecule messengers, and reactive oxygen species. Microglia and astrocytes are primarily involved in this process, while endothelial cells and infiltrating blood cells contribute to neuroinflammation when the blood-brain barrier (BBB) is damaged. Neuroinflammation is increasingly recognized as a pathological hallmark of several neurological diseases, including amyotrophic lateral sclerosis (ALS), and is closely linked to neurodegeneration, another key feature of ALS. In fact, neurodegeneration is a pathological trigger for inflammation, and neuroinflammation, in turn, contributes to motor neuron (MN) degeneration through the induction of synaptic dysfunction, neuronal death, and inhibition of neurogenesis. Importantly, resolution of acute inflammation is crucial for avoiding chronic inflammation and tissue destruction. Inflammatory processes are mediated by soluble factors known as cytokines, which are involved in both promoting and inhibiting inflammation. Cytokines with anti-inflammatory properties may exert protective roles in neuroinflammatory diseases, including ALS. In particular, interleukin (IL)-10, transforming growth factor (TGF)-β, IL-4, IL-13, and IL-9 have been shown to exert an anti-inflammatory role in the CNS. Other recently emerging immune regulatory cytokines in the CNS include IL-35, IL-25, IL-37, and IL-27. This review describes the current understanding of neuroinflammation in ALS and highlights recent advances in the role of anti-inflammatory cytokines within CNS with a particular focus on their potential therapeutic applications in ALS. Furthermore, we discuss current therapeutic strategies aimed at enhancing the anti-inflammatory response to modulate neuroinflammation in this disease.

Thyroid hormone homeostasis during pregnancy is crucial for proper neurodevelopment and cognitive capacity during adulthood. Accumulating evidence reveals that gestational hypothyroxinemia (HTX) modulates the immune response of the adult offspring.

In the present study, adult mice gestated in HTX and their euthyroid counterparts were induced with a mild form of experimental autoimmune encephalomyelitis (EAE), a widespread model of multiple sclerosis, and analyzed at baseline and 7 days after EAE induction.

Levels of circulating IL-17 were significantly lower in mice gestated in HTX at both timepoints, while circulating IFN-γ was significantly higher only in mice gestated in HTX, 7 days after EAE induction. A significant increase in type 1 innate lymphoid cells (ILC1) was found only in mice gestated in HTX 7 days after EAE induction, while type 3 innate lymphoid cells (ILC3) populations showed no variation. Interestingly, a significant increase of Th17 CD4+ cells was found only in mice of euthyroid gestation, 7 days after EAE induction.

These results highlight the repercussions of thyroid hormone impairment in utero at adult ages while dissecting on the pathogenesis of EAE in terms of Th1/Th17 balance from an innate immune perspective. These findings contribute to the advancement of our comprehension of the presymptomatic stage of EAE, unveiling new paths for basic and translational research in the field of neuroinflammation.

Cytotoxic T-lymphocyte-associated antigen -4 (CTLA-4) is a co-inhibitory receptor that restricts T cell activation. CTLA-4 exists as membrane (mCTLA-4) and soluble (sCTLA-4) forms, but the key producers, kinetics, and functions of sCTLA-4 are unclear. Here, we investigated the roles of sCTLA-4 in immune regulation under non-inflammatory and inflammatory conditions. Effector regulatory T (Treg) cells were the most active sCTLA-4 producers in basal and inflammatory states, with distinct kinetics upon T cell receptor (TCR) stimulation. We generated mice specifically deficient in sCTLA-4 production, which exhibited spontaneous activation of type 1 immune cells and heightened autoantibody/immunoglobulin E (IgE) production. Conversely, mCTLA-4-deficient mice developed severe type 2-skewed autoimmunity. sCTLA-4 blockade of CD80/86 on antigen-presenting cells inhibited T helper (Th)1, but not Th2, differentiation in vitro. In vivo, Treg-produced sCTLA-4, suppressed Th1-mediated experimental colitis, and enhanced wound healing but hampered tumor immunity. Thus, sCTLA-4 is essential for immune homeostasis and controlling type 1 immunity while allowing type 2 immunity to facilitate resolution in inflammatory conditions.

Obsessive-compulsive disorder (OCD) is a psychiatric disease with a prevalence of 2%-3%. Despite the effectiveness of antidepressants, such as serotonin reuptake inhibitors, for treating OCD, its pathogenesis remains unclear. Recent research has implicated immunological mechanisms, particularly in OCD patients with comorbid neurodevelopmental disorders (NDD), such as autism spectrum disorder, attention deficit/hyperactive disorder, and Tourette's disorder. To examine these mechanisms, we investigated immunological factors involved in OCD patients with any NDD comorbidity (OCD + NDD group), compared with those without comorbid NDD (OCD group).

Twenty-eight OCD patients treated at Hyogo Medical University Hospital were recruited for this study. Of them, 14 patients with NDD comorbidity (OCD + NDD) were compared with 14 patients without comorbid NDD (OCD). RNA was extracted from blood samples and analyzed using RNA sequencing and Ingenuity Pathway Analysis (IPA). Plasma levels of IL11 and IL17A were measured with ELISA.

RNA sequencing identified 716 significantly differentially expressed genes, with 47 related to immune functions, in the OCD + NDD group compared with the OCD group. IL11 and IL17A were central, with IL11 linked to neutrophil production and IL17A to T cell migration and cytokine secretion. Pathway analysis indicated complex interactions among these genes.

This study highlights significant immunological changes in OCD patients with any NDD. Decreased anti-inflammatory IL11 and increased proinflammatory IL17A suggest a shift towards inflammation, which may contribute to neurodevelopmental issues.

Immunological dysregulation in OCD with comorbid NDD may offer potential therapeutic targets. Immune gene interactions should be further investigated in effort to improve treatment strategies for treatment-refractory OCD patients, especially those with neurodevelopmental comorbidities.

T helper (Th) cell subsets play pivotal roles in regulating immune responses within the tumor microenvironment, influencing both tumor progression and anti-tumor immunity. Among these subsets, Th1 cells promote cytotoxic responses through the production of IFN-γ, while Th2 cells and regulatory T cells (Tregs) exert immunosuppressive effects that support tumor growth. Th9 and Th17 cells have context-dependent roles, contributing to both pro-inflammatory and regulatory processes in tumor immunity. Tumor antigen-specific T cells within the tumor microenvironment often exhibit a dysfunctional phenotype due to increased expression of inhibitory receptors such as CTLA-4 and PD-1, leading to reduced antitumor activity. Monoclonal antibodies that block these inhibitory signals-collectively known as immune checkpoint inhibitors (ICIs)-can reactivate these T cells, enhancing their ability to target and destroy cancer cells. Recent advancements have highlighted the critical role of T helper subsets in modulating responses to ICIs, with their interactions remaining a focus of ongoing research. Both positive and negative effects of ICIs have been reported in relation to Th cell subsets, with some effects depending on the type of tumor microenvironment. This review summarizes the crucial roles of different T helper cell subsets in tumor immunity and their complex relationship with immune checkpoint inhibitor therapy.

Reactive oxygen species (ROS) at elevated levels trigger oxidative DNA damage, which is a significant factor in psoriasis exacerbation. However, normal ROS levels are essential for cell signaling, cell growth regulation, differentiation, and immune responses. To address this, we developed ROS control strategies inspired by compensatory effects. DNA nanostructures with the advantage of being more stable than linear nucleic acid molecules in physiological environments were exquisitely fabricated and incorporated into microneedles (MN). These nanostructures regulate ROS levels and facilitate the delivery of IL-17A siRNA to psoriatic lesions. Our findings demonstrate that this transdermal drug delivery system effectively manages ROS levels in the psoriatic microenvironment, inhibiting pyroptosis and abnormal immune activation. Moreover, modulating ROS levels enhances the therapeutic impact of IL-17A siRNA, offering a promising in situ treatment approach for psoriasis.

Recent research has shown a strong link between Th17 cells and their cytokine IL-17, and various cardiovascular diseases such as atherosclerosis, myocardial infarction, myocarditis, and arrhythmia. Moreover, Th17 cell signalling is likely to be a key factor in cardiovascular disease. Here, we summarize recent advances in the source, function, regulation, and the effects of Th17 signaling in cardiovascular disease. Research on Th17 will suggest more specific strategies to manipulate these functions. Thus, effective treatment of cardiovascular disease and future clinical treatment will be possible.

Psoriasis is a chronic inflammatory skin autoimmune disease. Th17 cells, when pathologically activated, significantly contribute to the progression of psoriasis. The symptoms of this skin condition could be notably alleviated by targeting and suppressing the activity of these cells. Retinoic acid receptor-associated orphan nuclear hormone receptor γ-t (RORγt), a critical transcription factor in Th17 cells, emerges as a promising therapeutic target for autoimmune conditions which are mediated by the dysregulation of these cells. In this study, we designed and synthesised a series of artemisinin analogues based on the chemical structure of artemisinin, and screened 3 compounds, QHS-1, QHS-2, and QHS-3, with better inhibition efficiency of RORγt activity. We found that each of the three artemisinin analogues were demonstrated efficacy in curbing IMQ-induced skin inflammation and the abnormal proliferation of keratinocytes within the BALB/c mouse model of psoriasis. Our findings indicate that the three artemisinin analogues not only effectively mitigated skin inflammation and the abnormal proliferation of keratinocytes in the IMQ-induced psoriasis model of BALB/c mice but also curtailed the infiltration of immune cells and the production of pro-inflammatory cytokines in the dermis. Furthermore, these compounds modulated the cytokine expression profiles within Th17 cells. They exerted a suppressive effect on the activity of Th17 cells by targeting RORγt, thereby dampening the inflammatory response in the dorsal skin of the mice. This inhibition led to a reduction in the pathological proliferation of keratinocytes. In conclusion, our research underscores the promising therapeutic potential of artemisinin analogues in the treatment of psoriasis, offering a slate of candidate compounds which could pave the way for novel drug development in this field.

The chemokine receptor CCR6 guides pathogenic T17 cells, implicated in autoimmune diseases including psoriasis, to sites of inflammation via the chemokine CCL20. Therefor, pharmacological inhibition of CCR6+ immune cell migration provides a novel therapeutic approach. Translatability of such an intervention has not yet been assessed in detail. We evaluated the translatability of the Aldara® mouse model induced skin inflammation to psoriasis, with particular focus on immune cell trafficking and assessed the efficacy of IDOR-1117-2520, a highly selective, potent and orally available CCR6 small inhibitor.

Effects of IDOR-1117-2520 were investigated in the Aldara® and IL23 mouse models of skin inflammation using flow cytometry, RNA sequencing and transcriptome-based cell type deconvolution approaches to characterise immune cell migration patterns. These results were compared to human psoriasis transcriptomics data.

IDOR-1117-2520 dose dependently reduced infiltration of CCR6+ immune cells into inflamed skin, and was equally efficacious as IL-17 and IL-23 inhibition in models of skin inflammation. Pathway analysis showed molecular similarities in the immune response between human psoriasis and the Aldara® mouse model. IL-17/IL-23 pathway genes were expressed in both human psoriasis and the mouse model. CCR6 inhibition modulated multiple pathways associated with inflammation beyond the proximal IL-17/IL-23 pathway. A chemokine-chemokine receptor interaction map implicated CCL20-CCR6 as the dominant axis in recruiting pathogenic T17 cells in both the model and in human psoriasis.

IDOR-1117-2520 could provide a promising novel targeted approach to treating psoriasis and, potentially, other autoimmune diseases involving the CCR6/CCL20 axis and the IL-17/IL-23 pathway. IDOR-1117-2520 is currently being evaluated in a clinical phase 1 trial (ISRCTN28892128).

Microbial, especially fungal, sensitization has been associated with the development and exacerbation of treatment-refractory neutrophilic asthma. Among the airway-inhabiting fungi, Aspergillus fumigatus and Candida albicans are the dominant species that elicit protective T helper (Th) 17 and other T cell responses, contributing to airway neutrophilia and steroid resistance. However, it is not fully understood how fungal airway colonization impacts the immunopathogenesis of asthma. Here, we used a neutrophilic asthma model induced by C. albicans to study the immune regulation of this disease. We found that intranasal administration of C. albicans induced platelet infiltration into the lung. Platelet-expressed latent TGF-β could be activated specifically by Th17 cells and drive the commitment, maintenance, and expansion of Th17 cells. In Candida-induced asthma, an adoptive transfer of platelets enhanced Th17 responses, increasing airway neutrophil influx. Thus, managing airway mycobiota and reducing platelet intrapulmonary infiltration may serve as a promising interventional approach.

With the widespread use of type 2 immune response inhibitors (IRIs), there is growing concern about their association with the occurrence of vitiligo. This study aimed to comprehensively search for cases of vitiligo associated with type 2 IRIs in the US Food and Drug Administration Adverse Event Reporting System (FAERS). We retrieved the clinical characteristics of cases from January 2004 to September 2024 from the FAERS database. Disproportionality and Bayesian analyses were conducted to detect signals for vitiligo associated with type 2 IRIs. A total of 86 cases of vitiligo were identified in association with these inhibitors. The mean onset time was 326 days. Vitiligo associated with dupilumab was the most common (81.4%), with the highest reporting odds ratio (2.67, 95% confidence interval  2.11-3.4), proportional reporting ratio (2.67, χ2 = 70.59), information component (1.38, [IC025 = 1.09), and empirical Bayes geometric mean (2.61, EBGM05 = 2.14). The link between vitiligo and type 2 IRIs underscores the need for continued pharmacovigilance to better understand these drugs and the incidence of related conditions.

Psoriasis is a chronic inflammatory skin disease characterized by periods of remission and relapse. In this pathology, keratinocytes, dendritic cells, and different subpopulations of T cells are critical to developing psoriatic lesions. Although current treatments can reduce symptoms, they reappear in previously injured areas months after stopping treatment. Evidence has pointed out that besides T-helper 17 cells, other T-cell subsets may be involved in relapses. This review focuses on the leading evidence linking resident memory T cells and P2X7 receptor to psoriasis' pathogenesis and their role in this pathology. Finally, we discuss some of the most widely used experimental murine models and novel strategies to investigate further the role of resident memory T cells in psoriasis.

Severe steroid hyporesponsive asthma is a heterogeneous group of chronic inflammatory diseases characterized by irreversible airflow limitation, hyperresponsiveness, inflammation, and remodelling of the airways. Severe asthmatics account for more than 60% of asthma-related healthcare cost worldwide given they are hyporesponsive to corticosteroids and due to the absence of targeted treatment specifically for the T helper-17 (Th-17) high endotype. Hence, there is a clear unmet need to investigate other treatment options to control patients' symptoms. The role of the NLRP3 inflammasome pathway has been highlighted in the literature to contribute to disease pathogenesis and severity. Interestingly, vitamin D3 is an important regulator of the NLRP3 inflammasome pathway.

Using house dust mite (HDM) and lipopolysaccharide (LPS), we induced a neutrophilic steroid hyporesponsive asthma mouse model to investigate the effect of vitamin D3 on downregulating the NLRP3 inflammasome pathway and enhancing steroid sensitivity.

We showed that calcitriol, the active form of vitamin D3, could downregulate the NLRP3 inflammasome pathway. This was associated with a significant reduction in airway hyperresponsiveness, IL-17 release, neutrophil infiltration, and mucus secretion. Further, calcitriol enhanced steroid sensitivity by inhibiting the expression of GR-β. Mechanistically, calcitriol targeted the NLRP3 inflammasome to ubiquitination.

Our research highlights the potential use of calcitriol as a low cost and accessible supplement to ameliorate airway inflammation during severe steroid hyporesponsive asthma.

Primary sclerosing cholangitis (PSC) is a rare immune-mediated hepatobiliary disease, characterised by progressive biliary fibrosis, cirrhosis, and end-stage liver disease. As yet, no licensed pharmacological therapy exists. While significant advancements have been made in our understanding of the pathophysiology, the exact aetiology remains poorly defined. Compelling evidence from basic science and translational studies implicates the role of T helper 17 cells (Th17) and the interleukin 17 (IL-17) pro-inflammatory signalling pathway in the pathogenesis of PSC. However, exploration of the safety and efficacy of inhibiting the IL-17 pathway in PSC is lacking.

This is a phase 2a, open-label, multicentre pilot study, testing the safety of brodalumab, a recombinant human monoclonal antibody that binds with high affinity to interleukin-17RA, in adults with PSC. This study will enrol 20 PSC patients across five large National Health Service tertiary centres in the UK. The primary outcome of the study relates to determining the safety and feasibility of administering brodalumab in early, non-cirrhotic PSC patients. Secondary efficacy outcomes include non-invasive assessment of liver fibrosis, changes in alkaline phosphatase values and other liver biochemical readouts, assessment of biliary metrics through quantitative MR cholangiography+, and quality of life evaluation on completion of follow-up (using the 5D-itch tool, the PSC-patient-reported outcome and PSC-specific Chronic Liver Disease Questionnaire).

Ethical approval for this study has been obtained from the London Bridge Research Ethics Committee (REC23/LO/0718). Written informed consent will be obtained from all trial participants prior to undertaking any trial-specific examinations or investigations. On completion of the study, results will be submitted for publication in peer-reviewed journals and presented at national and international hepatology meetings. A summary of the findings will also be shared with participants and PSC communities.

ISRCTN15271834.

Maternal vaccination is essential for safeguarding both mother and foetus from infectious diseases. This study investigated the immunogenicity and efficacy of a maternal ORF-B2L genetic vaccine in a pregnant rat model, focusing on maternal-neonatal immune modulation, placental and neonatal spleen transcriptomics and the underlying mechanisms contributing to neonatal immune development. Female rats received intramuscular injections of either a gene vaccine (GV) containing 200 μg of recombinant ORF-B2L DNA and 50 μg of a subunit protein or an empty plasmid as a control. Results showed significantly higher levels of specific anti-B2L antibodies and Th1 and Th2 cytokine levels in both maternal and neonatal sera from the GV group compared to the control group (p < 0.05). Transcriptome analysis identified 1295 differentially expressed genes (DEGs) in the placenta and 998 DEGs in the neonatal spleen, with upregulated pathways associated with immune cell recruitment, cytokine signalling and hormone regulation in the GV group. Notably, upregulated DEGs such as TLR4, ESR1 and various cytokine/chemokine-related genes in the placenta suggest enhanced immune regulation and foetal protection. In the neonatal spleen, increased expression of IL-1β, IL-6, IL-10 and CD69 indicates enhanced T and B cell development and pathogen defence. The upregulation of IL-1β suggests a Th1 response, while elevated IL-10 indicates a potential Th2-biased immunity, reflecting a balanced Th1/Th2 response that is crucial for effective adaptive immunity. Overall, maternal ORF-B2L genetic vaccination induces a robust immune response, enhancing maternal-foetal protection and shaping neonatal immune responses, offering valuable insights for optimizing maternal vaccination strategies.

Acute pancreatitis (AP) and chronic pancreatitis (CP) are considered to be two separate pancreatic diseases in most studies, but some clinical retrospective analyses in recent years have found some degree of correlation between the two in actual treatment, however, the exact association is not clear. In this study, bioinformatics analysis was utilized to examine microarray sequencing data in mice, with the aim of elucidating the critical signaling pathways and genes involved in the progression from AP to CP. Differential gene expression analyses on murine transcriptomes were conducted using the R programming language and the R/Bioconductor package. Additionally, gene network analysis was performed using the STRING database to predict correlations among genes in the context of pancreatic diseases. Functional enrichment and gene ontology pathways common to both diseases were identified using Metascape. The hub genes were screened in the cytoscape algorithm, and the mRNA levels of the hub genes were verified in mice pancreatic tissues of AP and CP. Then the drugs corresponding to the hub genes were obtained in the drug-gene relationship. A set of hub genes, including Jun, Cd44, Epcam, Spp1, Anxa2, Hsp90aa1, and Cd9, were identified through analysis, demonstrating their pivotal roles in the progression from AP to CP. Notably, these genes were found to be enriched in the Helper T-cell factor (Th17) signaling pathway. Up-regulation of these genes in both AP and CP mouse models was validated through quantitative real-time polymerase chain reaction (qRT-PCR) results. The significance of the Th17 signaling pathway in the transition from AP to CP was underscored by our findings. Specifically, the essential genes driving this progression were identified as Jun, Cd44, Epcam, Spp1, Anxa2, Hsp90aa1, and Cd9. Crucial insights into the molecular mechanisms underlying pancreatitis progression were provided by this research, offering promising avenues for the development of targeted therapeutic interventions.

Asthma is a common chronic inflammatory disease of the airways. A substantial number of patients present with severe and therapy-resistant asthma, for which the underlying biological mechanisms remain poorly understood. In most asthma patients, airway inflammation is characterized by chronic activation of type 2 immunity. CD4+ T helper 2 (Th2) cells are the canonical producers of the cytokines that fuel type 2 inflammation: interleukin (IL)-4, IL-5, IL-9, and IL-13. However, more recent findings have shown that other lymphocyte subsets, in particular group 2 innate lymphoid cells (ILC2s) and type 2 CD8+ cytotoxic T (Tc2) cells, can also produce large amounts of type 2 cytokines. Importantly, a substantial number of severe therapy-resistant asthma patients present with chronic type 2 inflammation, despite the high sensitivity of Th2 cells for suppression by corticosteroids-the mainstay drugs for asthma. Emerging evidence indicates that ILC2s and Tc2 cells are more abundant in severe asthma patients and can adopt corticosteroid-resistance states. Moreover, many severe asthma patients do not present with overt type 2 airway inflammation, implicating non-type 2 immunity as a driver of disease. In this review, we will discuss asthma pathophysiology and focus on the roles played by ILC2s, Tc2 cells, and non-type 2 lymphocytes, placing special emphasis on severe disease forms.

Immune thrombocytopenia (ITP) is an autoimmune disease, characterized by increased bleeding due to a reduced platelet count. The pathogenesis of ITP is very complex and involves autoantibody production and T-cell-mediated immune abnormalities. An imbalance of effector and regulatory CD4+ T cells and the breach of tolerance primarily cause ITP, leading to the dysfunctional development of autoreactive Th cells (including Th1, Th2, and Th17 cells) and Tregs. The loss of auto-platelet antigen tolerance in ITP results in autoantibody- and cytotoxic T-cell-mediated platelet clearance. T-cell-related genetic risk factors significantly influence the development and progression of this disease. New therapies targeting T cells have emerged as potentially effective cures for this disease. This review summarizes the role of T cells in ITP.

The HECT E3 ubiquitin ligase Nedd4 has been shown to positively regulate T cell responses, but its role in T helper (Th) cell differentiation and autoimmunity is unknown. Th17 cells are believed to play a pivotal role in the development and pathogenesis of autoimmune diseases. Nevertheless, the regulation of RORγt activation during Th17 cell differentiation by TCR signaling is yet to be elucidated. These uncharted aspects inspire us to explore the potential role of Nedd4 in Th17-mediated autoimmunity.

We evaluated the impact of Nedd4 deficiency on mouse T cell development and differentiation using flow cytometry and siRNA transfection, and subsequently validated these findings in T cells from patients with multiple sclerosis (MS). Furthermore, we investigated the influence of Nedd4 deficiency on Th17-mediated autoimmunity through experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Subsequently, we elucidated the molecular mechanism underlying the interaction between Nedd4 and RORgt through immunoprecipitation, mass spectrometry analysis, and lentiviral transduction. Additionally, we identified Nedd4 as an E3 ubiquitin ligase for RORγt. Moreover, we characterized the tyrosine residue sites and polyubiquitination patterns involved in RORγt ubiquitination.

In this study, we report that loss of Nedd4 in T cells specifically impairs pathogenic and non-pathogenic Th17 responses, and Th17-mediated EAE development. At the molecular level, Nedd4 binds to the PPLY motif within the ligand binding domain of RORγt, and targets RORγt at K112 for K27-linked polyubiquitination, thus augmenting its activity.

Nedd4 is a crucial E3 ubiquitin ligase for RORγt in the regulating Th17 cell development and offers potential therapeutic benefits for treating Th17-mediated autoimmune diseases.

Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disorder of the central nervous system (CNS) targeting myelinated axons. Pathogenesis of MS entails an intricate genetic, environmental, and immunological interaction. Dysregulation of immune response i.e. autoreactive T & B-Cells and macrophage infiltration into the CNS leads to inflammation, demyelination, and neurodegeneration. Disease progression of MS varies among individuals transitioning from one form of relapsing-remitting to secondary progressive MS (SPMS). Research advances have unfolded various molecular targets involved in MS from oxidative stress to blood-brain barrier (BBB) disruption. Different pathways are being targeted so far such as inflammatory and cytokine signaling pathways to overcome disease progression. Therapeutic innovations have significantly transformed the management of MS, especially the use of disease-modifying therapies (DMTs) to reduce relapse rates and control disease progression. Advancements in research, neuroprotective strategies, and remyelination strategies hold promising results in reversing CNS damage. Various mice models are being adopted for testing new entities in MS research.

Zhushao Granules (ZSG) had exhibited beneficial effects in the treatment of ulcerative colitis (UC) as an effective herbal prescription in Traditional Chinese Medicine. However, the underlying anti-inflammatory mechanism of ZSG remains unclear. This study aimed to decipher the mechanism of ZSG against UC combining network pharmacology and animal-based experiments.

Network pharmacology was employed to identify active components and therapeutic targets of ZSG against UC. The protein-protein interaction (PPI) network was constructed among the therapeutic targets using the STRING database, and GO and pathway analyses were carried out using DAVID. Then, the "herb-component-target-pathway" network based on therapeutic targets was established and the topological parameters were subsequently calculated to identify hub active components, targets and pathways by Cytoscape. Finally, the therapeutic function and the special pathway of ZSG against UC were validated using a TNBS-induced UC model in BABL/c mice.

Ninety-four active components of ZSG and 460 potential targets were acquired from the Encyclopedia of Traditional Chinese Medicine and Tradition Chinese Medicine Systems Pharmacology Database and Analysis Platform. 884 potential targets of UC were obtained from OMIM and HINT. Sixty-two overlapping potential targets were identified as therapeutic targets of ZSG against UC. PPI network filtered out 61 therapeutic targets. GO and pathway analyses extracted 48, 25, and 98 terms corresponding to biological processes, molecular functions and Reactome pathways, respectively. Enrichment analysis suggested that the therapeutic targets were mainly involved in immune regulation, especially RIP-mediated NF-κB activation via ZBP1. Topological analysis of the "herb-component-target-pathway" network recognized 9 hub components, 20 hub targets and 18 hub pathways. The animal-based experiments revealed that ZSG ameliorated symptoms and histological changes in TNBS-induced colitis by significantly inhibiting the ZBP1/RIP/NF-κB pathway.

ZSG might alleviate the mucosal damage and ameliorate colitis via targeting ZBP1/RIP/NF-κB pathway, which laid the theoretical foundation for the clinical application and further study of ZSG and provided new insights into UC treatment.