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IntroductionRecently, a novel type of metabolic-regulated cell demise titled disulfidptosis has been discovered. Studies have demonstrated its importance in immune responses against cancer and its impact on the proliferation of cancer cells. Nonetheless, the precise mechanism and roles of disulfidptosis are not fully understood, particularly regarding the prognosis for individuals with uterine corpus endometrial carcinoma (UCEC).MethodsIn this research, a distinctive disulfidptosis pattern was developed in UCEC, and by utilizing Non-negative Matrix Factorization (NMF) on 23 disulfidptosis related genes within the TCGA database, 3 distinct subgroups were distinguished. To collect data, we acquired gene expression profiles, somatic mutation information, copy number variation data, and corresponding clinical data from the TCGA and GEO database, specifically from UCEC patients. Cell line experiments and immunohistochemical (IHC) staining were conducted to validate the role of the LRPPRC in proliferation, migration and invasion.ResultsThe genetic features and immune microenvironment of these subgroups were examined. It is worth mentioning that these subgroups offer important insights into comprehending the tumor microenvironment (TME) and the response of patients to immunotherapy and chemotherapy. Moreover, a disulfidptosis model was developed and validated, demonstrating a high level of accuracy in predicting the prognosis and outcomes of immunotherapy in UCEC patients. Additionally, a novel biomarker, LRPPRC, was identified, which can server as a promising predictor for forecasting prognosis in UCEC patients, with validation through tissue microarray staining and cell line experiments.DiscussionThis study has designed a classification system and a disulfidptosis model for UCEC, in addition to identifying a new biomarker, LRPPRC, for UCEC. These advancements serve as reliable and positive indicators for predicting outcomes and the efficacy of immunotherapy for each UCEC patient.

Botulinum neurotoxin (BoNT), produced by Clostridium botulinum, is the most toxic protein known, capable of causing severe paralysis and posing a significant bioterrorism threat due to its extreme lethality even in minute quantities. Despite this, there are currently no FDA-approved vaccines for widespread public use. To address this urgent need, we have developed an innovative vaccine platform by fusing the neuronal binding domain of BoNT/E (Hc/E) with core-streptavidin (CS), resulting in a stable CS-Hc/E vaccine. Mice vaccinated with CS-Hc/E exhibited superior antibody titers compared to those receiving Hc/E alone. To develop a trivalent vaccine against BoNT/A, BoNT/B, and BoNT/E— key contributors to the vast majority of human botulism—we conjugated CS-Hc/E with a biotinylated atoxic chimeric protein incorporating neutralizing epitopes from BoNT/A and BoNT/B. This chimeric protein includes the binding domain of BoNT/A, along with the protease-inactive light chain and translocation domains of BoNT/B. The interaction between CS and biotin formed a stable tetrameric antigen, EBA. Vaccination with EBA in mice elicited robust antibody responses and provided complete protection against lethal doses of BoNT/A, BoNT/B, and BoNT/E. Our findings highlight EBA’s potential as a stable and effective broad-spectrum vaccine against BoNT. Moreover, our technology offers a versatile platform for developing multivalent, stable vaccines targeting various biological threats by substituting the BoNT domain(s) with neutralizing epitopes from other life-threatening pathogens, thereby enhancing public health preparedness and biodefense strategies.

The aryl hydrocarbon receptor (AhR) is a transcription factor that is activated by various ligands, including pollutants, microorganisms, and metabolic substances. It is expressed extensively in pulmonary and intestinal epithelial cells, where it contributes to barrier defense. The expression of AhR is pivotal in regulating the inflammatory response to microorganisms. However, dysregulated AhR expression can result in endocrine disorders, leading to immunotoxicity and potentially promoting the development of carcinoma. This review focuses on the crucial role of the AhR in facilitating and limiting the proliferation of pathogens, specifically in relation to the host cell type and the species of etiological agents involved in microbial pathogen infections. The activation of AhR is enhanced through the IDO1-AhR-IDO1 positive feedback loop, which is manipulated by viruses. AhR primarily promotes the infection of SARS-CoV-2 by inducing the expression of angiotensin-converting enzyme 2 (ACE2) and the secretion of pro-inflammatory cytokines. AhR also plays a significant role in regulating various types of T-cells, including CD4+ T cells and CD8+ T cells, in the context of pulmonary infections. The AhR pathway plays a crucial role in regulating immune responses within the respiratory and intestinal barriers when they are invaded by viruses, bacteria, parasites, and fungi. Additionally, we propose that targeting the agonist and antagonist of AhR signaling pathways could serve as a promising therapeutic approach for combating pathogen infections, especially in light of the growing prevalence of drug resistance to multiple antibiotics.

Persistent inflammation and associated pain significantly impact individuals’ quality of life, posing substantial healthcare challenges. Proinflammatory cytokines, released by activated macrophages, play crucial roles in the development of chronic inflammatory conditions such as rheumatoid arthritis. To identify and evaluate potential therapeutic interventions targeting this process for mitigating inflammation and pain, we created myeloid cell-specific knockout of Vamp3 (vesicle-associated membrane protein 3) mice (Vamp3Δmyel) by crossing LysM-Cre mice with newly engineered Vamp3flox/flox mice. Bone marrow-derived macrophages and peritoneal resident macrophages from Vamp3Δmyel mice exhibited a significant reduction in TNF-α and IL-6 release compared to control mice. Moreover, Vamp3 deficiency led to decreased paw edema and ankle joint swelling induced by intraplantar injection of complete Freund’s adjuvant (CFA). Furthermore, Vamp3 depletion also mitigated CFA-induced mechanical allodynia and thermal hyperalgesia. Mechanistically, Vamp3 loss ameliorated the infiltration of macrophages in peripheral sites of the hind paw and resulted in reduced levels of TNF-α and IL-6 in the CFA-injected paw and serum. RT-qPCR analysis demonstrated downregulation of various inflammation-associated genes, including TNF-α, IL-6, IL-1β, CXCL11, TIMP-1, COX-2, CD68, and CD54 in the injected paw at the test day 14 following CFA administration. These findings highlight the novel role of Vamp3 in regulating inflammatory responses and suggest it as a potential therapeutic target for the development of novel Vamp-inactivating therapeutics, with potential applications in the management of inflammatory diseases.

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a treatable autoimmune disorder affecting the central nervous system. Despite extensive research, the exact etiology and pathogenesis of this condition remain unclear. In recent years, autoimmune encephalitis (AE) after viral encephalitis (VE) has gathered significant attention. Here, we present a case report of autoimmune GFAP astrocytopathy after VE in a 43-year-old Asian male with a history of oral and labial herpes. The patient presented with high-grade fever, headache, urinary retention, unresponsiveness, and apathy. Elevated levels of protein and GFAP-IgG were observed in the cerebrospinal fluid (CSF), and enhanced brain magnetic resonance imaging (MRI) revealed linear enhancement oriented radially to the ventricles. Treatment with intravenous immunoglobulin (IVIG) resulted in symptom relief, reduced lesion enhancement, and decreased protein levels. This case report highlights bimodal encephalitis with no discernible interval between VE and autoimmune GFAP astrocytopathy, which poses diagnostic challenges. Notably, autoimmune GFAP astrocytopathy is a novel form of autoimmune encephalitis, and its treatment lacks sufficient clinical experience. Intriguingly, our patient demonstrated sensitivity to IVIG, a treatment that differed from past reports. Therefore, further exploration of treatment strategies for this condition is warranted.

The important role of MHC in the pathogenesis of vitiligo and SLE has been confirmed in various populations. To map the most significant MHC variants associated with the risk of vitiligo and SLE, we conducted fine mapping analysis using 1117 vitiligo cases, 1046 SLE cases and 1693 healthy control subjects in the Han-MHC reference panel and 1000 Genomes Project phase 3. rs113465897 (P=1.03×10-13, OR=1.64, 95%CI =1.44–1.87) and rs3129898 (P=4.21×10-17, OR=1.93, 95%CI=1.66–2.25) were identified as being most strongly associated with vitiligo and SLE, respectively. Stepwise conditional analysis revealed additional independent signals at rs3130969(p=1.48×10-7, OR=0.69, 95%CI=0.60–0.79), HLA-DPB1*03:01 (p=1.07×10-6, OR=1.94, 95%CI=1.49–2.53) being linked to vitiligo and HLA-DQB1*0301 (P=4.53×10-7, OR=0.62, 95%CI=0.52-0.75) to SLE. Considering that epidemiological studies have confirmed comorbidities of vitiligo and SLE, we used the GCTA tool to analyse the genetic correlation between these two diseases in the HLA region, the correlation coefficient was 0.79 (P=5.99×10-10, SE=0.07), confirming their similar genetic backgrounds. Our findings highlight the value of the MHC region in vitiligo and SLE and provide a new perspective for comorbidities among autoimmune diseases.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Recently was been found that pyroptosis is a unique form of proinflammatory programmed death, that is different from apoptosis. A growing number of studies have investigated pyroptosis and its relationship with sepsis, including the mechanisms, role, and relevant targets of pyroptosis in sepsis. While moderate pyroptosis in sepsis can control pathogen infection, excessive pyroptosis can lead to a dysregulated host immune response and even organ dysfunction. This review provides an overview of the mechanisms and potential therapeutic targets underlying pyroptosis in sepsis identified in recent decades, looking forward to the future direction of treatment for sepsis.

Autoreactive T cells play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). TGF-β type I receptor (TGFβRI) is pivotal in determining T cell activation. Here, we showed that TGFβRI expression in naïve CD4+ T cells was decreased in SLE patients, especially in those with high disease activity. Moreover, IL-6 was found to downregulate TGFβRI expression through JAK/STAT3 pathway in SLE patients. In vitro, the JAK inhibitor tofacitinib inhibited SLE T cell activating by upregulating TGFβRI expression in a dose-dependent manner. In MRL/lpr mice, tofacitinib treatment ameliorated the clinical indicators and lupus nephritis, as evidenced by reduced plasma anti-dsDNA antibody levels, decreased proteinuria, and lower renal histopathological score. Consistently, tofacitinib enhanced TGFβRI expression and inhibited T cell activation in vivo. TGFβRI inhibitor SB431542 reversed the effects of tofacitinib on T cell activation. Thus, our results have indicated that tofacitinib can suppress T cell activation by upregulating TGFβRI expression, which provides a possible molecular mechanism underlying clinical efficacy of tofacitinib in treating SLE patients.

Atopic dermatitis (AD) is a multifaceted, chronic relapsing inflammatory skin disease that affects people of all ages. It is characterized by chronic eczema, constant pruritus, and severe discomfort. AD often progresses from mild annoyance to intractable pruritic inflammatory lesions associated with exacerbated skin sensitivity. The T helper-2 (Th2) response is mainly linked to the acute and subacute phase, whereas Th1 response has been associated in addition with the chronic phase. IL-17, IL-22, TSLP, and IL-31 also play a role in AD. Transient receptor potential (TRP) cation channels play a significant role in neuroinflammation, itch and pain, indicating neuroimmune circuits in AD. However, the Th2-driven cutaneous sensitization of TRP channels is underappreciated. Emerging findings suggest that critical Th2-related cytokines cause potentiation of TRP channels, thereby exaggerating inflammation and itch sensation. Evidence involves the following: (i) IL-13 enhances TRPV1 and TRPA1 transcription levels; (ii) IL-31 sensitizes TRPV1 via transcriptional and channel modulation, and indirectly modulates TRPV3 in keratinocytes; (iii) The Th2-cytokine TSLP increases TRPA1 synthesis in sensory neurons. These changes could be further enhanced by other Th2 cytokines, including IL-4, IL-25, and IL-33, which are inducers for IL-13, IL-31, or TSLP in skin. Taken together, this review highlights that Th2 cytokines potentiate TRP channels through diverse mechanisms under different inflammatory and pruritic conditions, and link this effect to distinct signaling cascades in AD. This review strengthens the notion that interrupting Th2-driven modulation of TRP channels will inhibit transition from acute to chronic AD, thereby aiding the development of effective therapeutics and treatment optimization.

BackgroundStudies have revealed important roles for IL-17A in the development of acute lung injury (ALI) following sepsis. However, the mechanism underlying the regulation of lung IL-17A remains to be fully addressed. Recent studies suggested the effect of neuromedin U (NMU) on immune cell activation and the role of group 2 innate lymphoid cells (ILC2s) in the modulation of IL-17A production. We aimed to gain in-depth insight into the mechanism underlying sepsis-induced lung IL-17A production, particularly, the role of NMU in mediating neuronal regulation of ILC2s and IL-17A-producing γδ T cells activation in sepsis.MethodsWild type mice were subjected to cecal ligation and puncture (CLP) to induce sepsis with or without intraperitoneal injection of NMU. The levels of ILC2s, γδ T cells, IL-17A, NMU and NMU receptor 1 (NMUR1) in the lung were then measured. In order to determine the role of NMU signaling in ILC2 activation and the role of ILC2-released IL-9 in ILC2-γδ T cell interaction, ILC2s were sorted, and the genes of nmur1 and il9 in the ILC2s were knocked down using CRISPR/Cas9. The genetically manipulated ILC2s were then co-cultured with lung γδ T cells, and the levels of IL-17A from co-culture systems were measured.ResultsIn septic mice, the levels of NMU, IL-17A, ILC2s, and IL-17A-producing γδ T cells in the lung are significantly increased, and the expression of NMUR1 in ILC2s is increased as well. Exogenous NMU further augments these increases. The main source of IL-17A in response to CLP is γδ T cells, and lung nmur1 is specifically expressed in ILC2s. In vitro co-culture of ILC2s and γδ T cells leads to increased number of γδ T cells and higher production of IL-17A from γδ T cells, and these alterations are further augmented by septic treatment and exogenous NMU. Genetic knockdown of nmur1 or il9 in ILC2s attenuated the upregulation of γδ T cells and IL-17A production.ConclusionIn sepsis, NMU acting through NMUR1 in lung ILC2s initiates the ILC2 activation, which, in turn, promote IL-17A-producing γδ T cell expansion and secretion of IL-17A. ILC2-derived IL-9 plays an important role in mediating γδ T cell expansion and IL-17A production. This study explores a new mechanism underlying neuronal regulation of innate immunity in sepsis.

Emerging evidence supports the involvement of nervous system in the regulation of immune responses. Group 2 innate lymphoid cells (ILC2), which function as a crucial bridge between innate and adaptive immunity, are present in large numbers in barrier tissues. Neuropeptides and neurotransmitters have been found to participate in the regulation of ILC2, adding a new dimension to neuroimmunity. However, a comprehensive and detailed overview of the mechanisms of neural regulation of ILC2, associated with previous findings and prospects for future research, is still lacking. In this review, we compile existing information that supports neurons as yet poorly understood regulators of ILC2 in the field of lung innate and adaptive immunity, focusing on neural regulation of the interaction between ILC2 and pulmonary immune cells.

Interleukin 27 (IL-27) plays diverse immune regulatory roles in autoimmune disorders and promotes the generation of IL-10–producing CD4+ T cells characterized by producing the immunosuppressive cytokine IL-10. However, whether IL-27 participates in pathological progress of Sjögren syndrome (SS) through regulating CD4+IL-10+ T cells remains unknown. Here we aimed to explore the potential role of IL-27 and CD4+IL-10+ T cells in the pathogenesis of SS. The IL-27 gene knockout non-obese diabetic (Il-27−/−NOD) mice were generated and injected with exogenous IL-27. Exogenous injection of IL-27 and neutralization of IL-27 with anti–IL-27 antibody in NOD mice were performed. The histopathologic changes in submandibular glands, lacrimal glands and lung, salivary flow rate, and percentages of CD4+IL-10+ T cells were determined. And, ovalbumin-immunized C57L/B6 mice were injected with IL-27 to detect the percentage of CD4+IL-10+ T cells. In vitro, splenic naive T cells from C57L/B6 mice were cultured with IL-27 for 4 days to induce the differentiation of CD4+IL-10+ T cells. In addition, IL-27, IL-10, and CD4+IL-10+ T cells were determined in health control and SS patients. The results showed that Il-27−/−NOD mice had more severe disease and lower level of CD4+IL-10+ T cells than control mice. And IL-27 promoted the generation and differentiation of CD4+IL-10+ T cells in vivo and in vitro significantly. In agreement with the findings in the SS-like mice, patients with SS showed lower levels of IL-27, IL-10, and CD4+IL-10+ T cells. Our findings indicated that IL-27 deficiency aggravated SS by regulating CD4+IL-10+ T cells. Targeting IL-27 and CD4+IL-10+ T cells may be a novel therapy for patients with SS.