Chronic liver fluke infections represent a major global health burden, driving liver fibrosis and elevating cancer risk, yet the immunological mechanisms linking persistent infection to tissue damage remain poorly defined. Using Clonorchis sinensis, a carcinogenic liver fluke infecting millions worldwide, as a representative model, we map immune responses during chronic infection in mice. We show that intrahepatic CD8⁺ tissue-resident memory T cells (TRM) progressively accumulate and drive pathology by producing chemokines that promote immune recruitment and fibroblast activation. Depletion of CD8⁺ T cells during defined disease phases markedly alleviates liver inflammation and fibrosis, demonstrating their causal role. Strikingly, C-C motif chemokine ligand 4, predominantly secreted by CD8⁺ TRM cells, correlates with fibrosis severity in both experimental models and patient cohorts, establishing it as a circulating biomarker for noninvasive disease monitoring. These findings define a pathogenic CD8⁺ TRM-chemokine axis underlying helminth-induced liver injury and highlight TRM-derived chemokines as biomarkers and therapeutic targets for fibrosis across chronic parasitic infections.

BackgroundThe role of sebaceous glands (SGs) in the early pathogenesis of hidradenitis suppurativa (HS) remains undefined, with an unclear causal relationship to inflammatory sequelae. The aim of this study is to determine whether SG aberrations constitute a primary pathogenic driver in early HS and elucidate the underlying mechanisms.MethodsWe employed histology, single-cell RNA sequencing, and in-vitro functional assays. Clinical specimens included non-lesional skin (NLS, n = 6), early lesional skin (LS, Hurley I, n = 12) from HS patients, and healthy controls (HC, n = 8). Human SZ95 sebocytes were used for mechanistic studies, including gene knockdown, bulk RNA sequencing, and lipidomic analysis.ResultsSG size was significantly reduced in both NLS (47.26% of HC area, p = 0.04) and LS (30.74%, p = 0.006). Single-cell RNA sequencing analysis revealed aberrant stem cell commitment in the hair follicle junctional zone and a significant downregulation of tight junction signaling (e.g., CLDN1, TJP1, OCLN) in HS SGs, associated with compromised barrier integrity and early immune cell (CD45+) infiltration. CLDN1 knockdown in SZ95 sebocytes recapitulated these findings, inducing a robust pro-inflammatory response (upregulation of IL-1β, TNF-α, IL-6, S100A7/A8, and CXCL8), suppression of the sebocyte lineage regulator c-Myc, and a shift toward keratinocyte-like differentiation. This was accompanied by metabolic reprogramming, specifically overproduction of lysophosphatidylcholine (LPC). Exogenous LPC directly promoted proliferation and inflammatory cytokine secretion in HaCaT keratinocytes.ConclusionsSG dysfunction, initiated by tight junction disruption and CLDN1 deficiency, is a primary event in early HS. This leads to aberrant sebocyte differentiation, inflammatory amplification, and sebum metabolite LPC-mediated crosstalk with keratinocytes. Our findings position SG-derived LPC as a potential novel biomarker and therapeutic target in HS pathogenesis.

Mast cells play a central role in allergic reactions, acting as key effector cells that initiate and amplify the inflammatory response. In this study, we demonstrate that phosphatase of regenerating liver 2 (PRL2) functions as a negative regulator of FcεRI-mediated mast cell activation. In PRL2-deficient myeloid cells, PRL2 conditional knockout mice developed more severe passive systemic anaphylaxis (PSA). Although PRL2 deficiency does not impact mast cell development, in the absence of PRL2 FcεRI-mediated mast cell activation is enhanced. In the presence of IgE the expression of mast cell PRL2 is downregulated, leading to modulation of the cellular response. In PRL2-deficient mast cells, the PI3K signaling pathway is upregulated, resulting in increased calcium influx. This, in turn, enhances mast cell degranulation and the production of inflammatory mediators. Moreover, hydroxychloroquine (an inhibitor of PRL2 degradation) reduces the severity of PSA in wild-type mice. Our findings suggest that PRL2 acts as a negative regulator of FcεRI-mediated mast cell activation. Therefore, therapeutic strategies aimed at enhancing PRL2 activity in mast cells may offer a promising approach for the treatment of allergic disorders.

The apocrine glands (AGs) are not considered to be primarily involved in hidradenitis suppurativa (HS). This study investigated the potential role of AGs in HS pathogenesis using immunohistochemistry and single-cell sequencing of nonlesional skin and early lesional skin (LS) from patients with HS (n = 12) and healthy controls (n = 8). AG cell destruction was more frequent, and AG size was significantly reduced in the nonlesional skin and LS. Barrier-related genes (eg, CLDN1 and CDH1) were downregulated in the AGs of the nonlesional skin and LS. Damaged AGs in the LS primarily recruited and activated neutrophils through the CXCL-CXCR and SAA1-FPR2 pathways. Elevated levels of specific keratins (keratin 18 and keratin 19) released from damaged AGs were observed on the skin surface of patients and were associated with disease severity. Keratin 19 was also detected in the dermis of the nonlesional skin and LS and was surrounded by neutrophils and macrophages. Moreover, serum keratin 19 levels in patients (N = 20) were significantly negatively correlated with the age at HS onset. Collectively, our findings provide previously unreported evidence that the AGs are damaged and release specific keratins in early HS lesions, indicating a crucial role of the AGs in HS pathogenesis.

Mast cells are phenotypically and functionally heterogeneous, and their state is possibly controlled by local microenvironment. Therefore, specific analyses are needed to understand whether mast cells function as powerful participants or dispensable bystanders in specific diseases. Here, we show that degranulation of mast cells in inflammatory synovial tissues of patients with rheumatoid arthritis (RA) is induced via MAS-related G protein-coupled receptor X2 (MRGPRX2), and the expression of MHC class II and costimulatory molecules on mast cells are upregulated. Collagen-induced arthritis mice treated with a combination of anti-IL-17A and cromolyn sodium, a mast cell membrane stabilizer, show significantly reduced clinical severity and decreased bone erosion. The findings of the present study suggest that synovial microenvironment-influenced mast cells contribute to disease progression and may provide a further mast cell-targeting therapy for RA.

Golimumab and etanercept both exhibit good efficacy in treating rheumatic diseases, while the patient self-reported measurement of treatment improvement and injection experience lacks sufficient evidence. Hence, this study aimed to compare the satisfaction with disease improvement and injection experience and the level of injection site reactions (ISRs) between golimumab-treated and etanercept-treated patients with rheumatic diseases. A total of 312 patients with rheumatic diseases were serially enrolled. Among them, 158 patients received golimumab (golimumab group); the other 154 patients were treated with etanercept (etanercept group) according to the actual disease status, physician advice, and patient willingness. Satisfaction with disease improvement was assessed using the 7-point Likert scale; satisfaction with injection experience and level of ISRs were both determined by the 5-point Likert scale. Satisfaction degrees with global injection experience (P = .025), injection device (P = .008), injection frequency (P = .010), and injection convenience (P = .003) were superior in the golimumab group to the etanercept group, while satisfaction degrees with global disease improvement, symptom relief, and speed of action did not vary (all P > .050) between the 2 groups. Discomfort (P = .005), swelling (P < .001), pain (P = .028), and burning (P = .035) levels were lower in the golimumab group than in the etanercept group. In addition, among 56 patients with a history of tumor necrosis factor inhibitor treatment before golimumab, 40 (71.4%) patients preferred golimumab to other tumor necrosis factor inhibitor. After switching to golimumab treatment, the level of ISRs in most patients was reduced or comparable. Golimumab achieves a satisfying injection experience and relieves the level of ISRs over etanercept in patients with rheumatic diseases.

Excessive host immune responses contribute to severe malaria with high mortality. Here, we show that PRL2 in innate immune cells is highly related to experimental malaria disease progression, especially the development of murine severe malaria. In the absence of PRL2 in myeloid cells, Plasmodium berghei infection results in augmented lung injury, leading to significantly increased mortality. Intravital imaging revealed greater neutrophilic inflammation and NET formation in the lungs of PRL2 myeloid conditional knockout mice. Depletion of neutrophils prior to the onset of severe disease protected mice from NETs associated lung injury, and eliminated the difference between WT and PRL2 CKO mice. PRL2 regulates neutrophil activation and NET accumulation via the Rac-ROS pathway, thus contributing to NETs associated ALI. Hydroxychloroquine, an inhibitor of PRL2 degradation alleviates NETs associated tissue damage in vivo. Our findings suggest that PRL2 serves as an indicator of progression to severe malaria and ALI. In addition, our study indicated the importance of PRL2 in NET formation and tissue injury. It might open a promising path for adjunctive treatment of NET-associated disease.

Abstract Objectives The ‘Host Defense and Immunology’ course is compulsory for undergraduate students majoring in clinical medicine at Shanghai Jiao Tong University School of Medicine. In order to promote students’ self-directed and active learning, we innovated teaching activities around ‘seamless learning’ which is emphasising learner-centredness. Methods Guided by the concept of seamless learning, we integrated teaching content, constructed course resources, innovated course-teaching modes, and reformed assessment and evaluation. Then two survey questionnaires were provided to students to get feedback on the course achievement. One set of survey questionnaire with written descriptions was designed to collect feedback on the overall evaluation of the course. Another survey questionnaire was presented in the form of multiple-choice questions to get feedback on more specific questions. Results 294 questionnaires were distributed to eight-year clinical medicine students in years 2021–2022, and 234 were valid. Overall student feedback revealed that the students mastered the immunological basic theories, research techniques and have acquired integrated systematic thinking. The students also deepened their application ability, pursued clinical rigor and logic, and shaped their clinical thinking patterns. The survey questionnaire revealed that the comprehensive immunological mind map was highly beneficial for analysing clinical immunological problems, understanding immunological principles, grasping interrelationships between knowledge points, and fostering self-learning abilities. Case-based learning (CBL), micro-lecture videos, and learning about scientists’ and doctors’ stories also had positive effects on students’ active learning, understanding, logical thinking, innovation, and humanistic literacy, with over 79 % of students reporting benefits. Conclusions Based on seamless learning, students acquired integrated systematic thinking through the course, shaped clinical thinking patterns, developed communication and collaboration skills, and enhanced their ability to analyse and solve clinical problems. The exploration and practice of the ‘Host Defense and Immunology’ course provides a good example for the integration of seamless learning concepts into teaching.

Introduction:Clonorchis sinensis infection results in various complications in the liver and biliary systems and is a neglected tropical disease in Eastern Asia. In this study, we report that C. sinensis calcium-binding protein Cs16 activates host immune cells and induces immunopathology in liver.Methods:Immunohistochemistry was used to detect the localization of Cs16 in C. sinensis adult worms. ELISA was used to detect the serum levels of anti-Cs16 IgG antibody in infected humans and mice. Bile duct injection model was used to figure out the role of Cs16 in vivo. RT-qPCR and ELISA were used to detect the cytokine production from Cs16-treated BMMs in vitro. Seahorse assay was used to detect the metabolic pathway of Cs16-treated BMMs in vitro.Result:Cs16 localizes in the tegument and gut of C. sinensis. Humans and mice with C. sinensis infection exhibited increased levels of anti-Cs16-specific antibody. Using the bile duct injection technique, we found that Cs16 induced obvious inflammation and hepatic necrosis in vivo. Cs16 treatment caused the upregulation of inflammatory cytokines in innate immune cells. Moreover, Cs16-treated monocytes relied more on the glycolytic metabolic pathway.Discussion:Our findings suggest that Cs16 is a potential pathogenic factor derived from C. sinensis adult worm. By reprogramming the metabolic pathway of innate immune cells, Cs16 triggers pro-inflammatory responses in the liver, and therefore, Cs16 is a potential target for the prevention and treatment of clonorchiasis.

银屑病关节炎(psoriatic arthritis,PsA)的特征是外周关节和中轴骨骼的慢性炎症,其临床表现除有特征性银屑病皮疹外,还有外周关节炎、指趾炎、肌腱附着点炎、骶髂关节炎以及指甲病变.由于PsA致残率很高,早期诊断及治疗尤为重要.而目前早期诊断PsA比较困难,生物标志物的出现为其提供了可能.风湿病中的生物标志物可分为与遗传、可溶性、细胞、滑膜和影像学特征相关的生物标志物.在PsA中,也有生物标志物可能与诊断、疾病活动度、治疗反应和共病有关.为了更好地讨论生物标志物在PsA中的意义,我们把与PsA相关生物标志物的研究进展进行了系统综述.

类风湿关节炎(rheumatoid arthritis,RA)是以侵蚀性关节炎为主要特征的自身免疫性疾病,发病机制复杂,免疫细胞、滑膜细胞和破骨细胞均参与其发生、发展.Notch信号通路是一条存在于所有多细胞生物中高度保守的细胞内信号转导通路,在RA患者细胞中存在异常激活,与RA的发生发展密切相关.该文主要分析Notch信号通路在免疫细胞、滑膜细胞及破骨细胞增殖、分化、生存及效应过程中的作用,介绍Notch信号通路介导RA的可能途径,有利于从Notch信号通路角度认识RA的发病机制,为该病的临床治疗提供新的思路.

Psoriatic arthritis (PsA) is a disease that transformed from psoriasis (PsO), and its underlying mechanisms are still not fully understood. Overactivation of the immune system is a key factor driving inflammatory diseases. Our goal is to define the unbalanced subsets of peripheral blood CD4 +T cells between PsO and PsA patients. Blood samples from 43 patients (23 PsA and 20 PsO) and 36 healthy donors (HD) were studied. Peripheral blood mononuclear cells (PBMC) were separated from blood and underwent fluorescent staining to assess CD4+T cell subsets by flow cytometry. We found that frequencies of various CD4+T cells including Th1, Th2, Th17, and Tfh were higher in the patients with PsO or PsA than those of healthy donors, indicating the general expansion of CD4+T cells in inflammatory conditions. More importantly, we observed the significant imbalance of Th1/Th2 between patients with PsO and PsA. Pearson correlation analysis showed that Th1/Th2 ratio was positively correlated with disease activity in psoriatic arthritis (DAPSA), Tfh/Tfr ratio was positively correlated with DAPSA score and visual analogue scale (VAS) score in PsA patients. Together, our results highlight the CD4+T cell changes in the transition from PsO to PsA, may contribute to early assessment and intervention.

Fibroblast-like synoviocytes (FLS) mediate many pathological processes in rheumatoid arthritis (RA), including pannus formation, bone erosion, and inflammation. RA FLS have unique aggressive phenotypes and exhibit several tumor cell-like characteristics, including hyperproliferation, excessive migration and invasion. Casein kinase 2 (CK2) is reportedly overexpressed in numerous tumor types, and targeted inhibition of CK2 has ther-apeutic benefits for tumors. However, the expression level of CK2 and its functions in RA FLS remain unclear. Herein, we aimed to elucidate whether CK2 is responsible for the aggressive phenotypes of RA FLS and whether targeted therapy can alleviate the severity of RA. We found that CK2 subunits were elevated in RA FLS compared with osteoarthritis FLS, and the activity of CK2 also markedly increased in RA FLS. Targeted inhibition of CK2 using CX-4945 suppressed RA FLS proliferation through cell cycle arrest. Cell migration and invasion were also inhibited by CX-4945 treatment. Moreover, CX-4945 reduced Interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2) and Matrix metalloproteinase-3 (MMP-3) secretion in RA FLS. Further proteomic investigation revealed that p53 signaling pathway significantly changes after CX-4945 treatment in RA FLS. The siRNA-mediated p53 knockdown partly abolished the anti-proliferation and reduced IL-6, MMP-3 secretion effects of CX-4945. Furthermore, CX-4945 administration alleviates arthritis severity in CIA mice. Collectively, our results demon-strated the abnormal elevation of CK2 and its positive association with abnormal phenotypes in RA FLS. Our novel findings suggest the possible therapeutic potential of CX-4945 for RA.

"Host Defense and Immunity" is an integrated course for medical undergraduates in Medical School of Shanghai JiaoTong University, which trains students "excellent medical innovative talents with soul" from aspects of knowledge, ability and quality. Host Defense and Immunity has won honor of the first batch of national first-class undergraduate offline courses. This paper introduces construction and practical experience of this course in ideological and political aspects, adds corresponding ideological and political objectives, condense value shaping point, organizes and compiles corresponding ideological and political cases and shoots a series of micro-videos, and practices combination of ideological and political courses and majors in teaching, discussion and usual assessment, so as to achieve educational purpose of "Building morality and cultivating people".

The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is an essential component of the human innate immune system, and is closely associated with adaptive immunity. In most cases, the activation of the NLRP3 inflammasome requires priming and activating, which are influenced by various ion flux signals and regulated by various enzymes. Aberrant functions of intracellular NLRP3 inflammasomes promote the occurrence and development of autoimmune diseases, with the majority of studies currently focused on rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis. In recent years, a number of bioactive substances have shown new potentiality for regulating the NLRP3 inflammasome in autoimmune diseases. This review provides a concise overview of the composition, functions, and regulation of the NLRP3 inflammasome. Additionally, we focus on the newly discovered bioactive substances for regulating the NLRP3 inflammasome in autoimmune diseases in the past three years.

Neobavaisoflavone (NBIF), a monomolecular compound extracted from Psoralea corylifolia (Leguminosae), is commonly used in traditional Chinese medicine for multiple purposes. NBIF is known to exert anti-fungal and anti-tumor effects, and promote bone formation. Whether NBIF exhibits anti-allergic effects by regulating mast cell activation remains unclear. Therefore, we designed this study to investigate the anti-allergic effects of NBIF on IgE/Ag-induced mouse bone marrow-derived mast cells and ovalbumin-induced asthma, and the passive systemic anaphylaxis (PSA) reaction in mice. Our results showed that NBIF suppresses the production of leukotriene C4, prostaglandin D2 and inflammatory cytokines, and decreases the degranulation of BMMCs stimulated by IgE/Ag. A thorough investigation ascertained that NBIF suppresses the phosphorylation of mitogen-activated protein kinases, and represses the nuclear factor-κB-related signaling pathway. In addition, the oral administration of NBIF in mice inhibited the IgE-induced PSA reaction in a dose-dependent manner. Overall, we provide new insights into how NBIF regulates the IgE/Ag-mediated signaling pathways. Moreover, our investigation promotes the potential use of NBIF in treating allergy and asthma.

Infection with helminths can modulate the host immune response, which ultimately shape morbidity and mortality of the associated diseases. We studied key cytokines for essential immune response in sera from 229 southeastern China individuals infected with Clonorchis sinensis and 60 individuals without C. sinensis infection, and measured serum specific IgG and IgE against worms in these people. Individuals infected with C. sinensis had significantly higher antigen-specific IgG and IgE levels, which were positively correlated with egg counts in feces. However, less enhancement of IgE antibody was observed in females when compared to males with similar infection levels. C. sinensis infection caused diminished Th1 cytokines (IL-1β, IL-2, IL-12p70, IFN-γ and TNF-α), Th2 cytokine (IL-4), as well as Th17 cytokine (IL-17A) in sera, which showed decreasing trend by infection intensity. Notably, these phenotypes were more significant in females than those in males. Although C. sinensis infection is associated with the development of hepatobiliary diseases, there was no significant correlation between the dampened cytokine profiles and the hepatobiliary morbidities. Our study indicates C. sinensis infection is strongly related to the immune suppression in human. Sex differences shape the immune milieus of clonorchiasis. This study provides a better understanding of how worms affect immune responses and cause a long-term immune alternation in humans with C. sinensis infection.

目的:明确clascoterone对雄激素作用下人皮脂腺细胞增殖、脂质合成和炎症因子表达的影响,探索其抗痤疮机制.方法:体外培养SZ95人皮脂腺细胞,分为双氢睾酮(DHT)组、clascoterone组,clascoterone+DHT组,CCK8法检测细胞增殖,尼罗红染色检测细胞内中性脂质,蛋白免疫印迹检测脂质合成相关基因表达.酶联免疫吸附检测细胞培养上清液中炎症因子蛋白,RT-qPCR检测细胞因子转录水平.结果:与DHT组相比,clascoterone和DHT共培养24h后细胞数量出现显著下降(P<0.01);在亚油酸(LA)作用下,clascoterone+DHT组细胞内中性脂质低于DHT组(P<0.0001);此外,clascoterone+DHT组PPARγ、PLIN2、FASN、SCD1等脂质合成相关基因的表达、炎症因子IL-1α、IL-1β、IL-6、IL-8及相应蛋白水平低于DHT组(均P<0.05).结论:clascoterone体外对人皮脂腺细胞增殖、脂质合成相关基因和炎症因子具有调节作用,可能是其抗痤疮治疗机制之一.

γ-Tocotrienol (GT3), a member of the vitamin E family, is well known for its medicinal value in clinical treatments. However, the role of GT3 in T helper 17 (Th17)/regulatory T cell (Treg) differentiation and function is not fully understood. Here, we demonstrated that GT3 suppressed Th17 differentiation in vitro by inhibiting signal transducer and activator of transcription 3 (STAT3) phosphorylation in the interleukin 6 (IL-6)/Janus kinase (JAK)/STAT3 signaling pathway. GT3 also inhibited HIF1A expression in Th17 metabolism. Additionally, we showed that GT3 treatment inhibited disease aggravation in an imiquimod (IMQ)-induced psoriasis-like mouse model by reducing the percentage of Th17 cells in the spleen in vivo. The findings of this study demonstrated the effects of GT3 on Th17 cells through the STAT3 signaling pathway.

Inflammation leads to systemic osteoporosis or local bone destruction, however, the underlying molecular mechanisms are still poorly understood. In this study, we report that PRL2 is a negative regulator of osteoclastogenesis and bone absorption. Mice with PRL2 deficiency exhibit a decrease in bone volume and an increase in osteoclast numbers. PRL2 negatively regulates RANKL-induced reactive oxygen species production through the activation of RAC1, thus PRL2 deficient osteoclast precursors have both increased osteoclast differentiation ability and bone resorptive capacity. During inflammation, oxidized PRL2 is a selected substrate of HSC70 and conditions of oxidative stress trigger rapid degradation of PRL2 by HSC70 mediated endosomal microautophagy and chaperone-mediated autophagy. Ablation of PRL2 in mouse models of inflammatory bone disease leads to an increase in the number of osteoclasts and exacerbation of bone damage. Moreover, reduced PRL2 protein levels in peripheral myeloid cells are highly correlated with bone destruction in a mouse arthritis model and in human rheumatoid arthritis, while the autophagy inhibitor hydroxychloroquine blocked inflammation-induced PRL2 degradation and bone destruction in vivo. Therefore, our findings identify PRL2 as a new regulator in osteoimmunity, providing a link between inflammation and osteoporosis. As such, PRL2 is a potential therapeutic target for inflammatory bone disease and inhibition of HSC70 mediated autophagic degradation of PRL2 may offer new therapeutic tools for the treatment of inflammatory bone disease.