AIM:To investigate the association between anti-DFS70 antibody positivity and ocular parameters,specifically,the choroidal vascularity index(CVI)and other optical coherence tomography(OCT)metrics,in a healthy populati...AIM:To investigate the association between anti-DFS70 antibody positivity and ocular parameters,specifically,the choroidal vascularity index(CVI)and other optical coherence tomography(OCT)metrics,in a healthy population.METHODS:This age-and sex-matched case-control study enrolled 84 healthy individuals with positive anti-DFS70 antibody findings and 84 healthy negative controls.All participants underwent detailed ophthalmological examinations,including biometry and OCT imaging.Anti-DFS70 positivity was determined by indirect immunofluorescence and scored semi-quantitatively(1+to 3+).CVI was calculated from OCT images using a standardized protocol with Image J software.Statistical analyses,including Student’s t-test,Mann-Whitney U test,Spearman correlation,and logistic regression,were used to compare groups and identify predictive factors.RESULTS:The individuals who tested positive and negative for anti-DFS70 included in the study were matched for age(median age=47y)and sex(F:M=7:1).CVI was significantly lower in the anti-DFS70-positive group compared to the negative group.A higher anti-DFS70 antibody titer was significantly associated with decreased subfoveal and nasal choroidal thickness(P=0.016 and P=0.014,respectively).In univariate regression analysis,CVI was the only significant predictor of anti-DFS70 positivity[odds ratio(OR)=0.02,P=0.025].Multivariate analysis revealed a positive correlation between macular thinning outside the subfoveal area and anti-DFS70 status(P<0.05).CONCLUSION:Our study demonstrates a novel association between anti-DFS70 antibody positivity and reduced choroidal vascularity in healthy individuals.These findings suggest that anti-DFS70 antibodies may be associated with subtle choroidal vascular changes detectable by OCT,even in asymptomatic individuals.Further longitudinal research is warranted to clarify the underlying mechanisms and long-term clinical significance of these ocular changes.展开更多
Small intestinal villi are essential for nutrient absorption,and their impairment can lead to malabsorption.Small intestinal villous atrophy(VA)encompasses a heterogeneous group of disorders,including immune-mediated ...Small intestinal villi are essential for nutrient absorption,and their impairment can lead to malabsorption.Small intestinal villous atrophy(VA)encompasses a heterogeneous group of disorders,including immune-mediated conditions(e.g.,celiac disease,autoimmune enteropathy,inborn errors of immunity),lymphoproliferative disorders(e.g.,enteropathy-associated T-cell lymphoma),infectious causes(e.g.,tropical sprue,Whipple’s disease),iatrogenic factors(e.g.,Olmesartanassociated enteropathy,graft-vs-host disease),as well as inflammatory and idiopathic types.These disorders are often rare and challenging to distinguish due to overlapping clinical,serological,endoscopic,and histopathological features.Through a systematic literature search using keywords such as small intestinal VA,malabsorption,and specific enteropathies,this review provides a comprehensive overview of diagnostic clues for VA and malabsorption.We systematically summarize the pathological characteristics of each condition to assist pathologists and clinicians in accurately identifying the underlying etiologies.Current studies still have many limitations and lack broader and deeper investigations into these diseases.Therefore,future research should focus on the development of novel diagnostic tools,predictive models,therapeutic targets,and mechanistic molecular studies to refine both diagnosis and management strategies.展开更多
The interleukin-17 family is the key group of cytokines and displays a broad spectrum of biological functions,including regulating the inflammatory cascade in various autoimmune and inflammatory diseases,such as multi...The interleukin-17 family is the key group of cytokines and displays a broad spectrum of biological functions,including regulating the inflammatory cascade in various autoimmune and inflammatory diseases,such as multiple sclerosis,neuromyelitis optica spectrum disorder,myasthenia gravis,Guillain–Barre syndrome,acute disseminated encephalomyelitis,diabetes,inflammatory skin diseases,joint inflammation,and cancer.Although the function of the interleukin-17 family has attracted increasing research attention over many years,the expression,function,and regulation mechanisms of different interleukin-17 members are complicated and still only partially understood.Currently,the interleukin-17A pathway is considered a critical therapeutic target for numerous immune and chronic inflammatory diseases,with several monoclonal antibodies against interleukin-17A having been successfully used in clinical practice.Whether other interleukin-17 members have the potential to be targeted in other diseases is still debated.This review first summarizes the recent advancements in understanding the physicochemical properties,physiological functions,cellular origins,and downstream signaling pathways of different members and corresponding receptors of the interleukin-17 family.Subsequently,the function of interleukin-17 in various immune diseases is discussed,and the important role of interleukin-17 in the pathological process of immune diseases is demonstrated from multiple perspectives.Then,the current status of targeted interleukin-17 therapy is summarized,and the effectiveness and safety of targeted interleukin-17 therapy are analyzed.Finally,the clinical application prospects of targeting the interleukin-17 pathway are discussed.展开更多
Parkinson's disease is a neurodegenerative disorder marked by the degeneration of dopaminergic neurons and clinical symptoms such as tremors,rigidity,and slowed movements.A key feature of Parkinson's disease i...Parkinson's disease is a neurodegenerative disorder marked by the degeneration of dopaminergic neurons and clinical symptoms such as tremors,rigidity,and slowed movements.A key feature of Parkinson's disease is the accumulation of misfoldedα-synuclein,forming insoluble Lewy bodies in the substantia nigra pars compacta,which contributes to neurodegeneration.Theseα-synuclein aggregates may act as autoantigens,leading to T-cell-mediated neuroinflammation and contributing to dopaminergic cell death.Our perspective explores the hypothesis that Parkinson's disease may have an autoimmune component,highlighting research that connects peripheral immune responses with neurodegeneration.T cells derived from Parkinson's disease patients appear to have the potential to initiate an autoimmune response againstα-synuclein and its modified peptides,possibly leading to the formation of neo-epitopes.Recent evidence associates Parkinson's disease with abnormal immune responses,as indicated by increased levels of immune cells,such as CD4^(+)and CD8^(+)T cells,observed in both patients and mouse models.The convergence of T cells filtration increasing major histocompatibility complex molecules,and the susceptibility of dopaminergic neurons supports the hypothesis that Parkinson's disease may exhibit autoimmune characteristics.Understanding the immune mechanisms involved in Parkinson's disease will be crucial for developing therapeutic strategies that target the autoimmune aspects of the disease.Novel approaches,including precision medicine based on major histocompatibility complex/human leukocyte antigen typing and early biomarker identification,could pave the way for immune-based treatments aimed at slowing or halting disease progression.This perspective explores the relationship between autoimmunity and Parkinson's disease,suggesting that further research could deepen understanding and offer new therapeutic avenues.In this paper,it is organized to provide a comprehensive perspective on the autoimmune aspects of Parkinson's disease.It investigates critical areas such as the autoimmune response observed in Parkinson's disease patients and the role of autoimmune mechanisms targetingα-synuclein in Parkinson's disease.The paper also examines the impact of CD4~+T cells,specifically Th1 and Th17,on neurons through in vitro and ex vivo studies.Additionally,it explores howα-synuclein influences glia-induced neuroinflammation in Parkinson's disease.The discussion extends to the clinical implications and therapeutic landscape,offering insights into potential treatments.Consequently,we aim to provide a comprehensive perspective on the autoimmune aspects of Parkinson's disease,incorporating both supportive and opposing views on its classification as an autoimmune disorder and exploring implications for clinical applications.展开更多
Multiple sclerosis is a severe autoimmune disorder that is mainly mediated by pathogenic cluster of CD4^(+)T cell subsets.Despite advancements in the management of multiple sclerosis,there is a critical need for more ...Multiple sclerosis is a severe autoimmune disorder that is mainly mediated by pathogenic cluster of CD4^(+)T cell subsets.Despite advancements in the management of multiple sclerosis,there is a critical need for more effective and safer treatments.In the present study,we administered Lycium barbarum glycopeptide to a mouse model of experimental autoimmune encephalomyelitis-an animal model of multiple sclerosis-and evaluated its effects on pathogenic CD4^(+)T cell activation both in vivo and in vitro.Lycium barbarum glycopeptide significantly mitigated the clinical severity of experimental autoimmune encephalomyelitis,as demonstrated by reduced demyelination and neuroinflammation.Moreover,Lycium barbarum glycopeptide treatment decreased the infiltration of peripheral leukocytes into the central nervous system and suppressed pro-inflammatory cytokine expression.Lycium barbarum glycopeptide also modulated pathogenic CD4^(+)T cell activation by inhibiting T helper 1/T helper 17 cell differentiation while promoting regulatory T cell expansion.Notably,no side effects were observed,suggesting the long-term safety and tolerability of Lycium barbarum glycopeptide.Furthermore,RNA sequencing data indicated that Lycium barbarum glycopeptide inhibits activator protein-1,an essential regulator of T cell activation and differentiation.This finding was supported by the reversal of T helper/T helper 17 cell response suppression upon AP-1 blockade.Collectively,these results highlight the potential of Lycium barbarum glycopeptide as an innovative therapeutic agent for CD4^(+)T cell-associated autoimmune or inflammatory diseases,such as multiple sclerosis.展开更多
BACKGROUND Autoimmune hepatitis(AIH)is typically treated with immunomodulators and steroids.However,some patients are refractory to these treatments,necessitating alternative approaches.Biological therapies have recen...BACKGROUND Autoimmune hepatitis(AIH)is typically treated with immunomodulators and steroids.However,some patients are refractory to these treatments,necessitating alternative approaches.Biological therapies have recently been explored for these difficult cases.AIM To assess the efficacy and safety of biologics in AIH,focusing on patients unresponsive to standard treatments and evaluating outcomes such as serological markers and histological remission.METHODS A case-based systematic review was performed following the PRISMA protocol to evaluate the efficacy and safety of biological therapies in AIH.The primary focus was on serological improvement and histological remission.The secondary focus was on assessing therapy safety and additional outcomes.A standardized search command was applied to MEDLINE,EMBASE,and Cochrane Library databases to identify relevant studies.Inclusion criteria encompassed adult AIH patients treated with biologics.Data were analyzed based on demographics,prior treatments,and therapy-related outcomes.A narrative synthesis was employed to address biases and provide a comprehensive overview of the evidence.RESULTS A total of 352 studies were reviewed,with 30 selected for detailed analysis.Key findings revealed that Belimumab led to a favourable response in five out of eight AIH patients across two studies.Rituximab demonstrated high efficacy,with 41 out of 45 patients showing significant improvement across six studies.Basiliximab was assessed in a single study,where the sole patient treated experienced a beneficial outcome.Additionally,a notable number of AIH cases were induced by anti-tumor necrosis factor(TNF)medications,including 16 cases associated with infliximab and four cases with adalimumab.All these cases showed improvement upon withdrawal of the biologic agent.CONCLUSION Belimumab and Rituximab show promise as effective alternatives for managing refractory AIH,demonstrating significant improvements in clinical outcomes and liver function.However,the variability in patient responses to different therapies highlights the need for personalized treatment strategies.The risk of AIH induced by anti-TNF therapies underscores the need for vigilant monitoring and prompt symptom recognition.These findings support the incorporation of biologic agents into AIH treatment protocols,particularly for patients who do not respond to conventional therapies.展开更多
Chloroquine(CQ)and hydroxychloroquine(HCQ),originally developed as anti-malarial drugs,have found a new purpose in treating various autoimmune dis-eases due to their immunomodulatory properties.These drugs work throug...Chloroquine(CQ)and hydroxychloroquine(HCQ),originally developed as anti-malarial drugs,have found a new purpose in treating various autoimmune dis-eases due to their immunomodulatory properties.These drugs work through mu-ltiple mechanisms,including inhibiting Toll-like receptor signaling,suppressing antigen presentation,and modulating autophagy.This review article provides a comprehensive analysis of the immunomodulatory effects of CQ and HCQ in several autoimmune diseases such as systemic lupus erythematosus,rheumatoid arthritis,systemic sclerosis,and others.We delve into the intricate mechanisms of action,highlighting the key immune cells involved and discussing the clinical implications of these drugs in managing autoimmune conditions.Our review covers the latest research and clinical trials,offering a comprehensive under-standing of the therapeutic potential of CQ and HCQ in autoimmune diseases.We also discuss the challenges and controversies surrounding the use of these drugs,such as their long-term side effects and the need for personalized treatment approaches.By synthesizing current knowledge and identifying areas for future research,this review aims to provide a valuable resource for healthcare profes-sionals and researchers involved in the management of autoimmune diseases.展开更多
Autoimmune enteropathy(AIE)is a rare immune mediated disorder primarily affecting children,characterized by chronic diarrhea,malabsorption,vomiting,weight loss and villous atrophy.It has also been observed in adults p...Autoimmune enteropathy(AIE)is a rare immune mediated disorder primarily affecting children,characterized by chronic diarrhea,malabsorption,vomiting,weight loss and villous atrophy.It has also been observed in adults presenting diagnostic and treatment challenges due to its overlap with other gastrointestinal disorders such as celiac disease.Initial diagnostic criteria for AIE include small bowel villous atrophy,lack of response to dietary restrictions,presence of anti-enterocyte antibodies,and predisposition to autoimmunity without severe immu-nodeficiency.Refined criteria emphasize characteristic histological findings and exclusion of other causes of villous atrophy.AIE is associated with various autoimmune disorders and can present with overlapping features with Celiac disease,including villous atrophy but without significant intraepithelial lympho-cytosis.Treatment primarily involves immunosuppression using corticosteroids,calcineurin inhibitors,and anti-tumor necrosis factor therapy,alongside nutri-tional support.Despite the challenges,understanding AIE’s diverse manifest-ations and improving diagnostic criteria are essential for effective management and improved patient outcome.Further research is needed to elucidate the pathogenesis,disease progression and long-term outcomes of AIE.展开更多
Background:Previous studies have highlighted the frequent occurrence of sarcopenia in patients with pancreatic diseases,including chronic pancreatitis.We aimed to clarify the prevalence of skeletal muscle(SM)loss and ...Background:Previous studies have highlighted the frequent occurrence of sarcopenia in patients with pancreatic diseases,including chronic pancreatitis.We aimed to clarify the prevalence of skeletal muscle(SM)loss and sarcopenia,and their associations with clinical characteristics,bone mineral density,and pancreatic imaging findings in patients with autoimmune pancreatitis(AIP).Methods:This study included 114 patients with AIP treated at Tohoku University Hospital.The SM index was assessed using a bioelectrical impedance analysis device,grip strength was measured using a hand dynamometer,and bone mineral density was evaluated using dual-energy X-ray absorptiometry.Univari-ate and multivariate logistic regression analyses were used to analyze factors associated with SM loss and sarcopenia.Results:Among 114 patients,57(50.0%)had SM loss,31(27.2%)had reduced grip strength,and 27(23.7%)had both.Patients with SM loss were older and had a lower body mass index,weaker grip strength,higher Controlling Nutritional Status scores,and lower serum lipase and albumin levels compared to those without SM loss.Computed tomography scans revealed a higher prevalence of pancreatic parenchy-mal atrophy in patients with SM loss.Similar differences were observed between patients with sarcopenia and those without.Osteopathy was observed in 35.6%of patients with SM loss and 38.1%of those with sarcopenia,whereas only 4.1%of patients without SM loss had osteopathy.Low BMI(<21.0 kg/m^(2))was also found to be an independent risk factor for SM loss in multivariate analysis.Age>72 years,low BMI(<20.0 kg/m^(2)),and low serum lipase levels(<13 U/L)were independent risk factors for sarcopenia in multivariate analysis.Conclusions:SM loss and sarcopenia are prevalent in patients with AIP and are associated with aging,poor nutritional status,low serum lipase levels,and pancreatic parenchymal atrophy.In addition to the high risk of osteopathy,careful attention should be paid to maintain muscle health in AIP patients.展开更多
Rheumatoid arthritis(RA)is an autoimmune disease characterized by inflammation and abnormal osteoclast activation,leading to bone destruction.We previously demonstrated that the large extracellular loop(LEL)of Tm4sf19...Rheumatoid arthritis(RA)is an autoimmune disease characterized by inflammation and abnormal osteoclast activation,leading to bone destruction.We previously demonstrated that the large extracellular loop(LEL)of Tm4sf19 is important for its function in osteoclast differentiation,and LEL-Fc,a competitive inhibitor of Tm4sf19,effectively suppresses osteoclast multinucleation and prevent bone loss associated with osteoporosis.This study aimed to investigate the role of Tm4sf19 in RA,an inflammatory and abnormal osteoclast disease,using a mouse model of collagen-induced arthritis(CIA).Tm4sf19 expression was observed in macrophages and osteoclasts within the inflamed synovium,and Tm4sf19 expression was increased together with inflammatory genes in the joint bones of CIA-induced mice compared with the sham control group.Inhibition of Tm4sf19 by LEL-Fc demonstrated both preventive and therapeutic effects in a CIA mouse model,reducing the CIA score,swelling,inflammation,cartilage damage,and bone damage.Knockout of Tm4sf19 gene or inhibition of Tm4sf19 activity by LEL-Fc suppressed LPS/IFN-γ-induced TLR4-mediated inflammatory signaling in macrophages.LEL-Fc disrupted not only the interaction between Tm4sf19 and TLR4/MD2,but also the interaction between TLR4 and MD2.μCT analysis showed that LEL-Fc treatment significantly reduced joint bone destruction and bone loss caused by hyperactivated osteoclasts in CIA mice.Taken together,these findings suggest that LELFc may be a potential treatment for RA and RA-induced osteoporosis by simultaneously targeting joint inflammation and bone destruction caused by abnormal osteoclast activation.展开更多
Rheumatoid arthritis(RA)is a systemic autoimmune disease in which synovial fibroblasts(SFs)maintain chronic inflammation by secreting proinflammatory mediators,leading to joint destruction.While the role of proinflamm...Rheumatoid arthritis(RA)is a systemic autoimmune disease in which synovial fibroblasts(SFs)maintain chronic inflammation by secreting proinflammatory mediators,leading to joint destruction.While the role of proinflammatory mediators in this process is well-established,the contribution of non-inflammatory regulators in SFs to joint pathology remains poorly understood.In this study,we investigated the non-inflammatory role of SFs in RA using a co-culture model,and found that SFs from RA patients promote apoptosis of human chondrocytes.Mechanistic investigations reveal that SFs can secrete small extracellular vesicles(sEVs),which are taken up by chondrocytes and induce chondrocyte apoptosis in both normal chondrocytes and chondrocytes from patients with RA.sEV-derived miRNA 15-29148 are identified as key signaling molecules mediating the apoptosis effects of chondrocytes.Further studies reveal that SF-derived miRNA 15-29148 targeting CIAPIN1 results in increased chondrocyte apoptosis.We further demonstrate that SF-derived miRNA 15-29148 is transferred to chondrocytes,exacerbating cartilage damage in vivo.Moreover,chondrocyte-specific aptamer-modified polyamidoamine nanoparticles not only ameliorated RA but also prevented its onset.This study suggests that,in RA,the secretion of specific sEV-miRNAs from SFs plays a crucial role in promoting chondrocyte apoptosis,potentially through non-inflammatory regulation,and that sEV-miRNA inhibition in SFs may represent an early preventive treatment strategy for cartilage degradation in RA.展开更多
Monogenic diabetes is a heterogeneous disorder characterized by hyperglycemia arising from defects in a single gene.Maturity-onset diabetes of the young(MODY)is the most common type with 14 subtypes,each linked to spe...Monogenic diabetes is a heterogeneous disorder characterized by hyperglycemia arising from defects in a single gene.Maturity-onset diabetes of the young(MODY)is the most common type with 14 subtypes,each linked to specific mutations affecting insulin synthesis,secretion and glucose regulation.Common traits across MODY subtypes include early-onset diabetes,a family history of autosomal dominant diabetes,lack of features of insulin resistance,and absent islet cell autoimmunity.Many cases are misdiagnosed as type 1 and type 2 diabetes mellitus.Biomarkers and scoring systems can help identify candidates for genetic testing.GCK-MODY,a common subtype,manifests as mild hyperglycemia and doesn’t require treatment except during pregnancy.In contrast,mutations in HNF4A,HNF1A,and HNF1B genes lead to progressive beta-cell failure and similar risks of complications as type 2 diabetes mellitus.Neonatal diabetes mellitus(NDM)is a rare form of monogenic diabetes that usually presents within the first six months.Half of the cases are lifelong,while others experience transient remission.Permanent NDM is most commonly due to activating mutations in genes encoding the adenosine triphosphate-sensitive potassium channel(KCNJ11 or ABCC8)and can be transitioned to sulfonylurea after confirmation of diagnosis.Thus,in many cases,monogenic diabetes offers an opportunity to provide precision treatment.The scope has broadened with next-generation sequencing(NGS)technologies,replacing older methods like Sanger sequencing.NGS can be for targeted gene panels,whole-exome sequencing(WES),or whole-genome sequencing.Targeted gene panels offer specific information efficiently,while WES provides comprehensive data but comes with bioinformatic challenges.The surge in testing has also led to an increase in variants of unknown significance(VUS).Deciding whether VUS is disease-causing or benign can be challenging.Computational models,functional studies,and clinical knowledge help to determine pathogenicity.Advances in genetic testing technologies offer hope for improved diagnosis and personalized treatment but also raise concerns about interpretation and ethics.展开更多
Foot reflexology(FR)is a Chinese-originated and non-invasive complementary therapy increasingly used by functional,alternative and para-medical professionals.Enhance attempts are made to study FR in non-functional org...Foot reflexology(FR)is a Chinese-originated and non-invasive complementary therapy increasingly used by functional,alternative and para-medical professionals.Enhance attempts are made to study FR in non-functional organic conditions.The present invited Editorial discusses the application of FR in autoimmune diseases(AD),highlighting a few successful studies demonstrating symptomatic relief and objective improvements.Despite promising results,the FR domain remains under-investigated and an urgent need to confirm and understand the effect of FR in chronic diseases,including AD,is highly recommended.展开更多
BACKGROUND The relationship between autoimmune gastritis(AIG)and gastric polyps(GPs)is not well understood.AIM To explore the clinical characteristics and risk factors of AIG with GPs in patients.METHODS This double c...BACKGROUND The relationship between autoimmune gastritis(AIG)and gastric polyps(GPs)is not well understood.AIM To explore the clinical characteristics and risk factors of AIG with GPs in patients.METHODS This double center retrospective study included 530 patients diagnosed with AIG from July 2019 to July 2023.We collected clinical,biochemical,serological,and demographic data were of each patient.Logistic regression analyses,both multivariate and univariate,were conducted to pinpoint independent risk factors for GPs in patients with AIG patients.Receiver operating characteristic curves were utilized to establish the optimal cutoff values,sensitivity,and specificity of these risk factors for predicting GPs in patients with AIG.RESULTS Patients with GPs had a higher median age than those without GPs[61(52.25-69)years vs 58(47-66)years,P=0.006].The gastrin-17 levels were significantly elevated in patients with GPs compared with those without GPs[91.9(34.2-138.9)pmol/mL vs 60.9(12.6-98.4)pmol/mL,P<0.001].Additionally,the positive rate of parietal cell antibody(PCA)antibody was higher in these patients than in those without GPs(88.6%vs 73.6%,P<0.001).Multivariate and univariate analyses revealed that PCA positivity[odds ratio(OR)=2.003,P=0.017],pepsinogen II(OR=1.053,P=0.015),and enterochromaffin like cells hyperplasia(OR=3.116,P<0.001)were significant risk factors for GPs,while pepsinogen I was identified as a protective factor.CONCLUSION PCA positivity and enterochromaffin like cells hyperplasia are significant risk factor for the development of GPs in patients with AIG.Elevated gastrin-17 levels may also play a role in this process.These findings suggest potential targets for further research and therapeutic intervention in managing GPs in patients with AIG.展开更多
BACKGROUND Bullous pemphigoid(BP)is an autoimmune blistering skin disorder.It is associated with other autoimmune disorders and the use of certain drugs.We describe a case of BP in a patient with ulcerative colitis(UC...BACKGROUND Bullous pemphigoid(BP)is an autoimmune blistering skin disorder.It is associated with other autoimmune disorders and the use of certain drugs.We describe a case of BP in a patient with ulcerative colitis(UC)treated with mesalamine.CASE SUMMARY A 38-year-old male patient with UC and a history of multiple flares was maintained on mesalamine with good clinical response.One year after starting mesalamine,he sought medical care following the onset of a severe itchy rash of several weeks’duration with a recent appearance of skin bullae.A biopsy of the skin revealed subepidermal blistering dermatitis with focal eosinophilic spongiosis.Direct immunofluorescence studies revealed linear IgG and C3 immune reactant deposits at the dermoepidermal junction,consistent with the diagnosis of BP.Prednisone therapy alleviated his symptoms.However,tapering prednisone led to re-eruption of the bullae.CONCLUSION BP should be considered when patients with UC develop skin manifestations.Although BP is not one of the extraintestinal manifestations of UC,there may be an association between these two conditions.Whether treatment with mesalamine or other therapeutic agents plays a role in the development of BP remains unclear.展开更多
Tear fluid,also referred to as tears or tear film,is an important biological fluid that plays a key role in maintaining ocular surface health and immune homeostasis.Recent studies have found that tear fluid not only p...Tear fluid,also referred to as tears or tear film,is an important biological fluid that plays a key role in maintaining ocular surface health and immune homeostasis.Recent studies have found that tear fluid not only participates in the occurrence and development of ocular diseases,but also exerts profound effects in the immune pathological mechanisms of systemic diseases,breaking through the inherent understanding previously held by the scientific community.Immune cells in tear fluid(such as T cells,neutrophils,natural killer cells,macrophages),cytokines,and immunoglobulins can specifically participate in autoimmune diseases(such as Sjögren’s syndrome,rheumatoid arthritis,systemic lupus erythematosus,multiple sclerosis,Graves’ophthalmopathy)and systemic diseases(such as Alzheimer’s disease,diabetes mellitus,graft-versus-host disease).The dynamic changes in tear fluid components can reflect systemic immune homeostasis imbalance.Tear fluid biomarkers,such as exosomal microRNA(miR)-204,miR-200b-5p,and the protein markerβ2-microglobulin,have shown great potential in early disease screening,diagnostic stratification,and therapeutic target discovery.Tear fluid immune component analysis may provide innovative diagnostic tools and therapeutic targets for systemic diseases.Future research should focus on promoting the standardization and clinical transformation of tear fluid testing technologies and their clinical application.展开更多
Regulatory T cells(Treg cells)are a specialized subset of CD4+T cells defined by expression of the lineage-specifying transcription factor FOXP3 and a potent capacity to maintain peripheral immune tolerance.The modern...Regulatory T cells(Treg cells)are a specialized subset of CD4+T cells defined by expression of the lineage-specifying transcription factor FOXP3 and a potent capacity to maintain peripheral immune tolerance.The modern concept of Tregs was catalyzed by Shimon Sakaguchi's identification of CD4+CD25+suppressive T cells and subsequent work establishing FOXP3 as a central determinant of Treg cell development and function;together with landmark FOXP3 genetic discoveries by Mary E.Brunkow and Fred Ramsdell,these advances transformed understanding of immune homeostasis and were recognized by the 2025 Nobel Prize in Physiology or Medicine.Under normal physiological conditions,FOXP3+Treg cells restrain autoreactive lymphocytes,prevent excessive inflammation,and shape antigen-presenting cell activity through contact-dependent pathways and suppressive cytokines,thereby protecting tissues from immune-mediated damage.Disruption of Treg abundance,stability,or suppressive capacity can therefore lead to immune dysregulation and disease.Over the past two decades,Treg cells have become a major focus of immunology because their roles are highly context-dependent.In autoimmune and chronic inflammatory diseases,impaired Treg cell function or insufficient Treg activity contributes to loss of tolerance and persistent tissue injury,supporting therapeutic approaches designed to enhance Treg cell number,stability,and suppressive potency.In contrast,many cancers exploit Treg cells by promoting their expansion,activation,and recruitment into the tumor microenvironment(TME),where they blunt antitumor immunity by suppressing cytotoxic T-cell priming and effector function,limiting dendritic cell activation,and fostering immune escape.In both settings,immune checkpoint pathways critically influence Treg cell biology.Beyond PD-1/PD-L1 and CTLA-4,emerging checkpoints and costimulatory receptors,including TIGIT,TIM-3,LAG-3,and OX40,modulate Treg cell generation,stability,and suppressive functions,thereby shaping the balance between tolerance and immunity.Meanwhile,immunometabolic adaptations further tune Treg cell fitness and function in inflamed tissues and tumors;lipid utilization and mitochondrial programs,among other metabolic axes,enable Treg cells to persist in nutrient-and oxygen-restricted microenvironments,while microenvironmental stress can drive functional remodeling or fragility in a subset-dependent manner.In this review,we summarize the discovery and defining biological features of Treg cells,highlight core suppressive mechanisms and regulatory circuits,and synthesize evidence for the dual roles of Treg cells in preventing autoimmunity yet enabling tumor immune evasion.We further outline current and emerging therapeutic strategies aimed at augmenting Treg cell activity to restore tolerance in autoimmune disease,or selectively depleting,functionally inhibiting,and reprogramming tumor-resident Treg cells to enhance cancer immunotherapy.Overall we discuss how deeper insight into Treg heterogeneity,checkpoint control,and immunometabolic regulation may enable more precise Treg celldirected interventions and inform next-generation immunotherapeutic combinations across immune-mediated and malignant diseases.展开更多
Autoimmune hepatitis(AIH)is a rare cause of chronic liver disease.The exact pa-thophysiology of AIH is unknown.Breakdown of self-tolerance against hepatic antigens and molecular mimicry are often implicated in the pat...Autoimmune hepatitis(AIH)is a rare cause of chronic liver disease.The exact pa-thophysiology of AIH is unknown.Breakdown of self-tolerance against hepatic antigens and molecular mimicry are often implicated in the pathogenesis of AIH.Immunosuppressive therapy is the mainstay of treatment;however,10%–25%of patients with AIH may not respond to primary therapy.Those patients are often salvaged with second-and third-line immunosuppressive therapy.Workup for other concomitant diseases should be done for patients who fail to respond to primary immunosuppressive therapy.Concurrent metabolic dysfunction-asso-ciated steatotic liver disease,alcohol-related liver disease,overlap syndrome(AIH with primary biliary cholangitis or sclerosing cholangitis),chronic hepatitis B virus,hepatitis C virus,and human immunodeficiency virus infection should be ruled out in such cases.Targeting the concomitant etiology may lead to resolution of the clinical symptoms and induce biochemical and histological remission.Isolated AIH without other etiologies for liver injury should be managed with a higher dose of steroids,azathioprine,or other immunosuppressive agents.Second-and third-line immunosuppressive agents include mycophenolate mofetil,cyclosporine,tacrolimus,infliximab,and rituximab.Patients with AIH may present with acute severe AIH(AS-AIH)and AIH-related acute on chronic liver failure,and they often require liver transplantation.The terms refractory or difficult-to-treat AIH have been used interchangeably and have no distinct definition.Difficult-to-treat AIH includes patients with intolerable side effects,fulminant disease(AIH with acute on chronic liver failure and AS-AIH),AIH in pregnancy,and HIV infection.Patients who fail to respond to standard first-line immunosuppressive therapy should be classified as refractory AIH.This review addresses the issues in the management of difficult-to-treat AIH with recent advances in pharmacological management.展开更多
Recently,Jayabalan et al published an important study.The authors defined the liver outcome score as a novel biomarker for predicting liver-related mortality in patients with autoimmune hepatitis-primary biliary chola...Recently,Jayabalan et al published an important study.The authors defined the liver outcome score as a novel biomarker for predicting liver-related mortality in patients with autoimmune hepatitis-primary biliary cholangitis overlap syndrome.After thoroughly reviewing their work,we offer insights that primarily relate to their study design to enhance the medical community’s understanding of this complex disease.展开更多
BACKGROUND Autoimmune autonomic ganglionopathy(AAG),formerly known as acute pandysautonomia,is a rare,acquired,antibody-mediated,potentially curable autonomic disorder that presents with diffuse autonomic failure.High...BACKGROUND Autoimmune autonomic ganglionopathy(AAG),formerly known as acute pandysautonomia,is a rare,acquired,antibody-mediated,potentially curable autonomic disorder that presents with diffuse autonomic failure.High levels of anti-ganglionic nicotinic acetylcholine receptor(gAChR)serum antibodies are detected in approximately 50%of AAG cases,confirming the diagnosis.CASE SUMMARY We present the case of a 68-year-old man who developed autonomic failure gradually over a 2-year period.Recently,the patient was unable to stand upright for more than a few seconds before fainting.Additionally,he presented with decreased sweating,dry mouth,urinary retention,early satiety,weight loss,bloating,constipation,and erectile dysfunction.Neurological examination revealed dilated pupils that were unresponsive to light.Deep tendon reflexes were absent or diminished.Serologic evaluation revealed the presence of gAChR autoantibodies.An orthostatic hypotension test yielded a positive result.The patient did not respond to symptomatic therapy,including midodrine,fludrocortisone and atomoxetine.Second-line therapy with immunoadsorption produced a noticeable clinical improvement;however,orthostatic hypotension persisted.Sequential rituximab infusion therapy successfully led to a significant improvement in symptoms.CONCLUSION Our case report supports the benefit of combined immunomodulatory therapy for refractory AAG cases that are unresponsive to single-agent treatment.展开更多
文摘AIM:To investigate the association between anti-DFS70 antibody positivity and ocular parameters,specifically,the choroidal vascularity index(CVI)and other optical coherence tomography(OCT)metrics,in a healthy population.METHODS:This age-and sex-matched case-control study enrolled 84 healthy individuals with positive anti-DFS70 antibody findings and 84 healthy negative controls.All participants underwent detailed ophthalmological examinations,including biometry and OCT imaging.Anti-DFS70 positivity was determined by indirect immunofluorescence and scored semi-quantitatively(1+to 3+).CVI was calculated from OCT images using a standardized protocol with Image J software.Statistical analyses,including Student’s t-test,Mann-Whitney U test,Spearman correlation,and logistic regression,were used to compare groups and identify predictive factors.RESULTS:The individuals who tested positive and negative for anti-DFS70 included in the study were matched for age(median age=47y)and sex(F:M=7:1).CVI was significantly lower in the anti-DFS70-positive group compared to the negative group.A higher anti-DFS70 antibody titer was significantly associated with decreased subfoveal and nasal choroidal thickness(P=0.016 and P=0.014,respectively).In univariate regression analysis,CVI was the only significant predictor of anti-DFS70 positivity[odds ratio(OR)=0.02,P=0.025].Multivariate analysis revealed a positive correlation between macular thinning outside the subfoveal area and anti-DFS70 status(P<0.05).CONCLUSION:Our study demonstrates a novel association between anti-DFS70 antibody positivity and reduced choroidal vascularity in healthy individuals.These findings suggest that anti-DFS70 antibodies may be associated with subtle choroidal vascular changes detectable by OCT,even in asymptomatic individuals.Further longitudinal research is warranted to clarify the underlying mechanisms and long-term clinical significance of these ocular changes.
基金Supported by National High-Level Hospital Clinical Research Funding,No.2022-PUMCH-B-022,and No.2022-PUMCH-D-002CAMS Innovation Fund for Medical Sciences,No.CIFMS 2021-1-I2M-003Undergraduate Innovation Program,No.2024dcxm025.
文摘Small intestinal villi are essential for nutrient absorption,and their impairment can lead to malabsorption.Small intestinal villous atrophy(VA)encompasses a heterogeneous group of disorders,including immune-mediated conditions(e.g.,celiac disease,autoimmune enteropathy,inborn errors of immunity),lymphoproliferative disorders(e.g.,enteropathy-associated T-cell lymphoma),infectious causes(e.g.,tropical sprue,Whipple’s disease),iatrogenic factors(e.g.,Olmesartanassociated enteropathy,graft-vs-host disease),as well as inflammatory and idiopathic types.These disorders are often rare and challenging to distinguish due to overlapping clinical,serological,endoscopic,and histopathological features.Through a systematic literature search using keywords such as small intestinal VA,malabsorption,and specific enteropathies,this review provides a comprehensive overview of diagnostic clues for VA and malabsorption.We systematically summarize the pathological characteristics of each condition to assist pathologists and clinicians in accurately identifying the underlying etiologies.Current studies still have many limitations and lack broader and deeper investigations into these diseases.Therefore,future research should focus on the development of novel diagnostic tools,predictive models,therapeutic targets,and mechanistic molecular studies to refine both diagnosis and management strategies.
基金supported by the National Natural Science Foundational of China(Key Program),No.U24A20692(to CJZ)the National Natural Science Foundational of China,Nos.82101414(to MLJ),82371355(to CJZ)+4 种基金the National Natural Science Foundational of China for Excellent Young Scholars,No.82022019(to CJZ)Sichuan Special Fund for Distinguished Young Scholars,No.24NSFJQ0052(to CJZ)The Innovation and Entrepreneurial Team of Sichuan Tianfu Emei Program,No.CZ2024018(to CJZ)Funding for Distinguished Young Scholars of Sichuan Provincial People’s Hospital,No.30420230005(to CJZ)Funding for Distinguished Young Scholars of University of Electronic Science and Technology of China,No.A1098531023601381(to CJZ)。
文摘The interleukin-17 family is the key group of cytokines and displays a broad spectrum of biological functions,including regulating the inflammatory cascade in various autoimmune and inflammatory diseases,such as multiple sclerosis,neuromyelitis optica spectrum disorder,myasthenia gravis,Guillain–Barre syndrome,acute disseminated encephalomyelitis,diabetes,inflammatory skin diseases,joint inflammation,and cancer.Although the function of the interleukin-17 family has attracted increasing research attention over many years,the expression,function,and regulation mechanisms of different interleukin-17 members are complicated and still only partially understood.Currently,the interleukin-17A pathway is considered a critical therapeutic target for numerous immune and chronic inflammatory diseases,with several monoclonal antibodies against interleukin-17A having been successfully used in clinical practice.Whether other interleukin-17 members have the potential to be targeted in other diseases is still debated.This review first summarizes the recent advancements in understanding the physicochemical properties,physiological functions,cellular origins,and downstream signaling pathways of different members and corresponding receptors of the interleukin-17 family.Subsequently,the function of interleukin-17 in various immune diseases is discussed,and the important role of interleukin-17 in the pathological process of immune diseases is demonstrated from multiple perspectives.Then,the current status of targeted interleukin-17 therapy is summarized,and the effectiveness and safety of targeted interleukin-17 therapy are analyzed.Finally,the clinical application prospects of targeting the interleukin-17 pathway are discussed.
基金supported by the National Research Foundation of South Korea(2023R1A2C2004516,RS-2023-00219399 to SPY,and 2022R1I1A1A01063513 to MGJ)。
文摘Parkinson's disease is a neurodegenerative disorder marked by the degeneration of dopaminergic neurons and clinical symptoms such as tremors,rigidity,and slowed movements.A key feature of Parkinson's disease is the accumulation of misfoldedα-synuclein,forming insoluble Lewy bodies in the substantia nigra pars compacta,which contributes to neurodegeneration.Theseα-synuclein aggregates may act as autoantigens,leading to T-cell-mediated neuroinflammation and contributing to dopaminergic cell death.Our perspective explores the hypothesis that Parkinson's disease may have an autoimmune component,highlighting research that connects peripheral immune responses with neurodegeneration.T cells derived from Parkinson's disease patients appear to have the potential to initiate an autoimmune response againstα-synuclein and its modified peptides,possibly leading to the formation of neo-epitopes.Recent evidence associates Parkinson's disease with abnormal immune responses,as indicated by increased levels of immune cells,such as CD4^(+)and CD8^(+)T cells,observed in both patients and mouse models.The convergence of T cells filtration increasing major histocompatibility complex molecules,and the susceptibility of dopaminergic neurons supports the hypothesis that Parkinson's disease may exhibit autoimmune characteristics.Understanding the immune mechanisms involved in Parkinson's disease will be crucial for developing therapeutic strategies that target the autoimmune aspects of the disease.Novel approaches,including precision medicine based on major histocompatibility complex/human leukocyte antigen typing and early biomarker identification,could pave the way for immune-based treatments aimed at slowing or halting disease progression.This perspective explores the relationship between autoimmunity and Parkinson's disease,suggesting that further research could deepen understanding and offer new therapeutic avenues.In this paper,it is organized to provide a comprehensive perspective on the autoimmune aspects of Parkinson's disease.It investigates critical areas such as the autoimmune response observed in Parkinson's disease patients and the role of autoimmune mechanisms targetingα-synuclein in Parkinson's disease.The paper also examines the impact of CD4~+T cells,specifically Th1 and Th17,on neurons through in vitro and ex vivo studies.Additionally,it explores howα-synuclein influences glia-induced neuroinflammation in Parkinson's disease.The discussion extends to the clinical implications and therapeutic landscape,offering insights into potential treatments.Consequently,we aim to provide a comprehensive perspective on the autoimmune aspects of Parkinson's disease,incorporating both supportive and opposing views on its classification as an autoimmune disorder and exploring implications for clinical applications.
基金supported by the National Natural Science Foundational of China,Nos.U24A20692(to CJZ),82371355(to CJZ),and 82101414(to MH)National NaturalScience Foundational of China for Excellent Young Scholars,No.82022019(to CJZ)+5 种基金Sichuan Special Fund for Distinguished Young Scholars,No.24NSFJQ0052(to CJZ)The Innovationand Entrepreneurial Team of Sichuan Tianfu Emei Program,No.CZ2024018(to CJZ)Funding for Distinguished Young Scholars of Sichuan Provincial People’sHospital,No.30420230005Funding for Distinguished Young Scholars of University of Electronic Science and Technology of China,No.A1098531023601381(toCJZ)Sichuan Science and Technology Support Project,No.2023YFS0212(to BH)Project of Sichuan Provincial Health Commission,No.19PJ265(to LD).
文摘Multiple sclerosis is a severe autoimmune disorder that is mainly mediated by pathogenic cluster of CD4^(+)T cell subsets.Despite advancements in the management of multiple sclerosis,there is a critical need for more effective and safer treatments.In the present study,we administered Lycium barbarum glycopeptide to a mouse model of experimental autoimmune encephalomyelitis-an animal model of multiple sclerosis-and evaluated its effects on pathogenic CD4^(+)T cell activation both in vivo and in vitro.Lycium barbarum glycopeptide significantly mitigated the clinical severity of experimental autoimmune encephalomyelitis,as demonstrated by reduced demyelination and neuroinflammation.Moreover,Lycium barbarum glycopeptide treatment decreased the infiltration of peripheral leukocytes into the central nervous system and suppressed pro-inflammatory cytokine expression.Lycium barbarum glycopeptide also modulated pathogenic CD4^(+)T cell activation by inhibiting T helper 1/T helper 17 cell differentiation while promoting regulatory T cell expansion.Notably,no side effects were observed,suggesting the long-term safety and tolerability of Lycium barbarum glycopeptide.Furthermore,RNA sequencing data indicated that Lycium barbarum glycopeptide inhibits activator protein-1,an essential regulator of T cell activation and differentiation.This finding was supported by the reversal of T helper/T helper 17 cell response suppression upon AP-1 blockade.Collectively,these results highlight the potential of Lycium barbarum glycopeptide as an innovative therapeutic agent for CD4^(+)T cell-associated autoimmune or inflammatory diseases,such as multiple sclerosis.
文摘BACKGROUND Autoimmune hepatitis(AIH)is typically treated with immunomodulators and steroids.However,some patients are refractory to these treatments,necessitating alternative approaches.Biological therapies have recently been explored for these difficult cases.AIM To assess the efficacy and safety of biologics in AIH,focusing on patients unresponsive to standard treatments and evaluating outcomes such as serological markers and histological remission.METHODS A case-based systematic review was performed following the PRISMA protocol to evaluate the efficacy and safety of biological therapies in AIH.The primary focus was on serological improvement and histological remission.The secondary focus was on assessing therapy safety and additional outcomes.A standardized search command was applied to MEDLINE,EMBASE,and Cochrane Library databases to identify relevant studies.Inclusion criteria encompassed adult AIH patients treated with biologics.Data were analyzed based on demographics,prior treatments,and therapy-related outcomes.A narrative synthesis was employed to address biases and provide a comprehensive overview of the evidence.RESULTS A total of 352 studies were reviewed,with 30 selected for detailed analysis.Key findings revealed that Belimumab led to a favourable response in five out of eight AIH patients across two studies.Rituximab demonstrated high efficacy,with 41 out of 45 patients showing significant improvement across six studies.Basiliximab was assessed in a single study,where the sole patient treated experienced a beneficial outcome.Additionally,a notable number of AIH cases were induced by anti-tumor necrosis factor(TNF)medications,including 16 cases associated with infliximab and four cases with adalimumab.All these cases showed improvement upon withdrawal of the biologic agent.CONCLUSION Belimumab and Rituximab show promise as effective alternatives for managing refractory AIH,demonstrating significant improvements in clinical outcomes and liver function.However,the variability in patient responses to different therapies highlights the need for personalized treatment strategies.The risk of AIH induced by anti-TNF therapies underscores the need for vigilant monitoring and prompt symptom recognition.These findings support the incorporation of biologic agents into AIH treatment protocols,particularly for patients who do not respond to conventional therapies.
基金Supported by the Oman Ministry of Higher Education,Research,and Innovation,No.BFP/RGP/HSS/24/015.
文摘Chloroquine(CQ)and hydroxychloroquine(HCQ),originally developed as anti-malarial drugs,have found a new purpose in treating various autoimmune dis-eases due to their immunomodulatory properties.These drugs work through mu-ltiple mechanisms,including inhibiting Toll-like receptor signaling,suppressing antigen presentation,and modulating autophagy.This review article provides a comprehensive analysis of the immunomodulatory effects of CQ and HCQ in several autoimmune diseases such as systemic lupus erythematosus,rheumatoid arthritis,systemic sclerosis,and others.We delve into the intricate mechanisms of action,highlighting the key immune cells involved and discussing the clinical implications of these drugs in managing autoimmune conditions.Our review covers the latest research and clinical trials,offering a comprehensive under-standing of the therapeutic potential of CQ and HCQ in autoimmune diseases.We also discuss the challenges and controversies surrounding the use of these drugs,such as their long-term side effects and the need for personalized treatment approaches.By synthesizing current knowledge and identifying areas for future research,this review aims to provide a valuable resource for healthcare profes-sionals and researchers involved in the management of autoimmune diseases.
文摘Autoimmune enteropathy(AIE)is a rare immune mediated disorder primarily affecting children,characterized by chronic diarrhea,malabsorption,vomiting,weight loss and villous atrophy.It has also been observed in adults presenting diagnostic and treatment challenges due to its overlap with other gastrointestinal disorders such as celiac disease.Initial diagnostic criteria for AIE include small bowel villous atrophy,lack of response to dietary restrictions,presence of anti-enterocyte antibodies,and predisposition to autoimmunity without severe immu-nodeficiency.Refined criteria emphasize characteristic histological findings and exclusion of other causes of villous atrophy.AIE is associated with various autoimmune disorders and can present with overlapping features with Celiac disease,including villous atrophy but without significant intraepithelial lympho-cytosis.Treatment primarily involves immunosuppression using corticosteroids,calcineurin inhibitors,and anti-tumor necrosis factor therapy,alongside nutri-tional support.Despite the challenges,understanding AIE’s diverse manifest-ations and improving diagnostic criteria are essential for effective management and improved patient outcome.Further research is needed to elucidate the pathogenesis,disease progression and long-term outcomes of AIE.
基金supported in part by the Japan Pancreas Soci-ety and the MHLW Research Program on Rare and Intractable Dis-eases(Grant Number 23FC1015,Principal investigator:Mitsuhiro Kawano).
文摘Background:Previous studies have highlighted the frequent occurrence of sarcopenia in patients with pancreatic diseases,including chronic pancreatitis.We aimed to clarify the prevalence of skeletal muscle(SM)loss and sarcopenia,and their associations with clinical characteristics,bone mineral density,and pancreatic imaging findings in patients with autoimmune pancreatitis(AIP).Methods:This study included 114 patients with AIP treated at Tohoku University Hospital.The SM index was assessed using a bioelectrical impedance analysis device,grip strength was measured using a hand dynamometer,and bone mineral density was evaluated using dual-energy X-ray absorptiometry.Univari-ate and multivariate logistic regression analyses were used to analyze factors associated with SM loss and sarcopenia.Results:Among 114 patients,57(50.0%)had SM loss,31(27.2%)had reduced grip strength,and 27(23.7%)had both.Patients with SM loss were older and had a lower body mass index,weaker grip strength,higher Controlling Nutritional Status scores,and lower serum lipase and albumin levels compared to those without SM loss.Computed tomography scans revealed a higher prevalence of pancreatic parenchy-mal atrophy in patients with SM loss.Similar differences were observed between patients with sarcopenia and those without.Osteopathy was observed in 35.6%of patients with SM loss and 38.1%of those with sarcopenia,whereas only 4.1%of patients without SM loss had osteopathy.Low BMI(<21.0 kg/m^(2))was also found to be an independent risk factor for SM loss in multivariate analysis.Age>72 years,low BMI(<20.0 kg/m^(2)),and low serum lipase levels(<13 U/L)were independent risk factors for sarcopenia in multivariate analysis.Conclusions:SM loss and sarcopenia are prevalent in patients with AIP and are associated with aging,poor nutritional status,low serum lipase levels,and pancreatic parenchymal atrophy.In addition to the high risk of osteopathy,careful attention should be paid to maintain muscle health in AIP patients.
基金supported by GILO Foundation.This research is in part supported by Korea Drug Development Fund funded by Ministry of Science and ICT,Ministry of Trade,Industry,and Energy,and Ministry of Health and Welfare(RS-2023-00282595,Republic of Korea).
文摘Rheumatoid arthritis(RA)is an autoimmune disease characterized by inflammation and abnormal osteoclast activation,leading to bone destruction.We previously demonstrated that the large extracellular loop(LEL)of Tm4sf19 is important for its function in osteoclast differentiation,and LEL-Fc,a competitive inhibitor of Tm4sf19,effectively suppresses osteoclast multinucleation and prevent bone loss associated with osteoporosis.This study aimed to investigate the role of Tm4sf19 in RA,an inflammatory and abnormal osteoclast disease,using a mouse model of collagen-induced arthritis(CIA).Tm4sf19 expression was observed in macrophages and osteoclasts within the inflamed synovium,and Tm4sf19 expression was increased together with inflammatory genes in the joint bones of CIA-induced mice compared with the sham control group.Inhibition of Tm4sf19 by LEL-Fc demonstrated both preventive and therapeutic effects in a CIA mouse model,reducing the CIA score,swelling,inflammation,cartilage damage,and bone damage.Knockout of Tm4sf19 gene or inhibition of Tm4sf19 activity by LEL-Fc suppressed LPS/IFN-γ-induced TLR4-mediated inflammatory signaling in macrophages.LEL-Fc disrupted not only the interaction between Tm4sf19 and TLR4/MD2,but also the interaction between TLR4 and MD2.μCT analysis showed that LEL-Fc treatment significantly reduced joint bone destruction and bone loss caused by hyperactivated osteoclasts in CIA mice.Taken together,these findings suggest that LELFc may be a potential treatment for RA and RA-induced osteoporosis by simultaneously targeting joint inflammation and bone destruction caused by abnormal osteoclast activation.
基金the National Natural Science Foundation of China(82372412)the Social Development Project of Jiangsu Province(BE2022701)+4 种基金the Top Talent Support Program for Young and Middle-aged People of the Wuxi Health Committee(BJ2020044,BJ2020057,HB2020043)the Fundamental Research Funds of the Health and Family Planning Commission of Wuxi(M202024)the Special Program for Translational Medicine Research of the Wuxi Translational Medicine Center(2020DHYB07,2020DHYB03)the Key Special Project of Precision Medicine of the Wuxi Health Commission(J202101)peking union medical college hospital talent cultivation program(UHB50192).
文摘Rheumatoid arthritis(RA)is a systemic autoimmune disease in which synovial fibroblasts(SFs)maintain chronic inflammation by secreting proinflammatory mediators,leading to joint destruction.While the role of proinflammatory mediators in this process is well-established,the contribution of non-inflammatory regulators in SFs to joint pathology remains poorly understood.In this study,we investigated the non-inflammatory role of SFs in RA using a co-culture model,and found that SFs from RA patients promote apoptosis of human chondrocytes.Mechanistic investigations reveal that SFs can secrete small extracellular vesicles(sEVs),which are taken up by chondrocytes and induce chondrocyte apoptosis in both normal chondrocytes and chondrocytes from patients with RA.sEV-derived miRNA 15-29148 are identified as key signaling molecules mediating the apoptosis effects of chondrocytes.Further studies reveal that SF-derived miRNA 15-29148 targeting CIAPIN1 results in increased chondrocyte apoptosis.We further demonstrate that SF-derived miRNA 15-29148 is transferred to chondrocytes,exacerbating cartilage damage in vivo.Moreover,chondrocyte-specific aptamer-modified polyamidoamine nanoparticles not only ameliorated RA but also prevented its onset.This study suggests that,in RA,the secretion of specific sEV-miRNAs from SFs plays a crucial role in promoting chondrocyte apoptosis,potentially through non-inflammatory regulation,and that sEV-miRNA inhibition in SFs may represent an early preventive treatment strategy for cartilage degradation in RA.
文摘Monogenic diabetes is a heterogeneous disorder characterized by hyperglycemia arising from defects in a single gene.Maturity-onset diabetes of the young(MODY)is the most common type with 14 subtypes,each linked to specific mutations affecting insulin synthesis,secretion and glucose regulation.Common traits across MODY subtypes include early-onset diabetes,a family history of autosomal dominant diabetes,lack of features of insulin resistance,and absent islet cell autoimmunity.Many cases are misdiagnosed as type 1 and type 2 diabetes mellitus.Biomarkers and scoring systems can help identify candidates for genetic testing.GCK-MODY,a common subtype,manifests as mild hyperglycemia and doesn’t require treatment except during pregnancy.In contrast,mutations in HNF4A,HNF1A,and HNF1B genes lead to progressive beta-cell failure and similar risks of complications as type 2 diabetes mellitus.Neonatal diabetes mellitus(NDM)is a rare form of monogenic diabetes that usually presents within the first six months.Half of the cases are lifelong,while others experience transient remission.Permanent NDM is most commonly due to activating mutations in genes encoding the adenosine triphosphate-sensitive potassium channel(KCNJ11 or ABCC8)and can be transitioned to sulfonylurea after confirmation of diagnosis.Thus,in many cases,monogenic diabetes offers an opportunity to provide precision treatment.The scope has broadened with next-generation sequencing(NGS)technologies,replacing older methods like Sanger sequencing.NGS can be for targeted gene panels,whole-exome sequencing(WES),or whole-genome sequencing.Targeted gene panels offer specific information efficiently,while WES provides comprehensive data but comes with bioinformatic challenges.The surge in testing has also led to an increase in variants of unknown significance(VUS).Deciding whether VUS is disease-causing or benign can be challenging.Computational models,functional studies,and clinical knowledge help to determine pathogenicity.Advances in genetic testing technologies offer hope for improved diagnosis and personalized treatment but also raise concerns about interpretation and ethics.
文摘Foot reflexology(FR)is a Chinese-originated and non-invasive complementary therapy increasingly used by functional,alternative and para-medical professionals.Enhance attempts are made to study FR in non-functional organic conditions.The present invited Editorial discusses the application of FR in autoimmune diseases(AD),highlighting a few successful studies demonstrating symptomatic relief and objective improvements.Despite promising results,the FR domain remains under-investigated and an urgent need to confirm and understand the effect of FR in chronic diseases,including AD,is highly recommended.
基金Supported by the Health Technology Project of Pudong New District Health Commission,No.PW2020D-12.
文摘BACKGROUND The relationship between autoimmune gastritis(AIG)and gastric polyps(GPs)is not well understood.AIM To explore the clinical characteristics and risk factors of AIG with GPs in patients.METHODS This double center retrospective study included 530 patients diagnosed with AIG from July 2019 to July 2023.We collected clinical,biochemical,serological,and demographic data were of each patient.Logistic regression analyses,both multivariate and univariate,were conducted to pinpoint independent risk factors for GPs in patients with AIG patients.Receiver operating characteristic curves were utilized to establish the optimal cutoff values,sensitivity,and specificity of these risk factors for predicting GPs in patients with AIG.RESULTS Patients with GPs had a higher median age than those without GPs[61(52.25-69)years vs 58(47-66)years,P=0.006].The gastrin-17 levels were significantly elevated in patients with GPs compared with those without GPs[91.9(34.2-138.9)pmol/mL vs 60.9(12.6-98.4)pmol/mL,P<0.001].Additionally,the positive rate of parietal cell antibody(PCA)antibody was higher in these patients than in those without GPs(88.6%vs 73.6%,P<0.001).Multivariate and univariate analyses revealed that PCA positivity[odds ratio(OR)=2.003,P=0.017],pepsinogen II(OR=1.053,P=0.015),and enterochromaffin like cells hyperplasia(OR=3.116,P<0.001)were significant risk factors for GPs,while pepsinogen I was identified as a protective factor.CONCLUSION PCA positivity and enterochromaffin like cells hyperplasia are significant risk factor for the development of GPs in patients with AIG.Elevated gastrin-17 levels may also play a role in this process.These findings suggest potential targets for further research and therapeutic intervention in managing GPs in patients with AIG.
文摘BACKGROUND Bullous pemphigoid(BP)is an autoimmune blistering skin disorder.It is associated with other autoimmune disorders and the use of certain drugs.We describe a case of BP in a patient with ulcerative colitis(UC)treated with mesalamine.CASE SUMMARY A 38-year-old male patient with UC and a history of multiple flares was maintained on mesalamine with good clinical response.One year after starting mesalamine,he sought medical care following the onset of a severe itchy rash of several weeks’duration with a recent appearance of skin bullae.A biopsy of the skin revealed subepidermal blistering dermatitis with focal eosinophilic spongiosis.Direct immunofluorescence studies revealed linear IgG and C3 immune reactant deposits at the dermoepidermal junction,consistent with the diagnosis of BP.Prednisone therapy alleviated his symptoms.However,tapering prednisone led to re-eruption of the bullae.CONCLUSION BP should be considered when patients with UC develop skin manifestations.Although BP is not one of the extraintestinal manifestations of UC,there may be an association between these two conditions.Whether treatment with mesalamine or other therapeutic agents plays a role in the development of BP remains unclear.
基金supported by the Medical Scientific Research Foundation of Guangdong Province,China(A2023423)。
文摘Tear fluid,also referred to as tears or tear film,is an important biological fluid that plays a key role in maintaining ocular surface health and immune homeostasis.Recent studies have found that tear fluid not only participates in the occurrence and development of ocular diseases,but also exerts profound effects in the immune pathological mechanisms of systemic diseases,breaking through the inherent understanding previously held by the scientific community.Immune cells in tear fluid(such as T cells,neutrophils,natural killer cells,macrophages),cytokines,and immunoglobulins can specifically participate in autoimmune diseases(such as Sjögren’s syndrome,rheumatoid arthritis,systemic lupus erythematosus,multiple sclerosis,Graves’ophthalmopathy)and systemic diseases(such as Alzheimer’s disease,diabetes mellitus,graft-versus-host disease).The dynamic changes in tear fluid components can reflect systemic immune homeostasis imbalance.Tear fluid biomarkers,such as exosomal microRNA(miR)-204,miR-200b-5p,and the protein markerβ2-microglobulin,have shown great potential in early disease screening,diagnostic stratification,and therapeutic target discovery.Tear fluid immune component analysis may provide innovative diagnostic tools and therapeutic targets for systemic diseases.Future research should focus on promoting the standardization and clinical transformation of tear fluid testing technologies and their clinical application.
文摘Regulatory T cells(Treg cells)are a specialized subset of CD4+T cells defined by expression of the lineage-specifying transcription factor FOXP3 and a potent capacity to maintain peripheral immune tolerance.The modern concept of Tregs was catalyzed by Shimon Sakaguchi's identification of CD4+CD25+suppressive T cells and subsequent work establishing FOXP3 as a central determinant of Treg cell development and function;together with landmark FOXP3 genetic discoveries by Mary E.Brunkow and Fred Ramsdell,these advances transformed understanding of immune homeostasis and were recognized by the 2025 Nobel Prize in Physiology or Medicine.Under normal physiological conditions,FOXP3+Treg cells restrain autoreactive lymphocytes,prevent excessive inflammation,and shape antigen-presenting cell activity through contact-dependent pathways and suppressive cytokines,thereby protecting tissues from immune-mediated damage.Disruption of Treg abundance,stability,or suppressive capacity can therefore lead to immune dysregulation and disease.Over the past two decades,Treg cells have become a major focus of immunology because their roles are highly context-dependent.In autoimmune and chronic inflammatory diseases,impaired Treg cell function or insufficient Treg activity contributes to loss of tolerance and persistent tissue injury,supporting therapeutic approaches designed to enhance Treg cell number,stability,and suppressive potency.In contrast,many cancers exploit Treg cells by promoting their expansion,activation,and recruitment into the tumor microenvironment(TME),where they blunt antitumor immunity by suppressing cytotoxic T-cell priming and effector function,limiting dendritic cell activation,and fostering immune escape.In both settings,immune checkpoint pathways critically influence Treg cell biology.Beyond PD-1/PD-L1 and CTLA-4,emerging checkpoints and costimulatory receptors,including TIGIT,TIM-3,LAG-3,and OX40,modulate Treg cell generation,stability,and suppressive functions,thereby shaping the balance between tolerance and immunity.Meanwhile,immunometabolic adaptations further tune Treg cell fitness and function in inflamed tissues and tumors;lipid utilization and mitochondrial programs,among other metabolic axes,enable Treg cells to persist in nutrient-and oxygen-restricted microenvironments,while microenvironmental stress can drive functional remodeling or fragility in a subset-dependent manner.In this review,we summarize the discovery and defining biological features of Treg cells,highlight core suppressive mechanisms and regulatory circuits,and synthesize evidence for the dual roles of Treg cells in preventing autoimmunity yet enabling tumor immune evasion.We further outline current and emerging therapeutic strategies aimed at augmenting Treg cell activity to restore tolerance in autoimmune disease,or selectively depleting,functionally inhibiting,and reprogramming tumor-resident Treg cells to enhance cancer immunotherapy.Overall we discuss how deeper insight into Treg heterogeneity,checkpoint control,and immunometabolic regulation may enable more precise Treg celldirected interventions and inform next-generation immunotherapeutic combinations across immune-mediated and malignant diseases.
文摘Autoimmune hepatitis(AIH)is a rare cause of chronic liver disease.The exact pa-thophysiology of AIH is unknown.Breakdown of self-tolerance against hepatic antigens and molecular mimicry are often implicated in the pathogenesis of AIH.Immunosuppressive therapy is the mainstay of treatment;however,10%–25%of patients with AIH may not respond to primary therapy.Those patients are often salvaged with second-and third-line immunosuppressive therapy.Workup for other concomitant diseases should be done for patients who fail to respond to primary immunosuppressive therapy.Concurrent metabolic dysfunction-asso-ciated steatotic liver disease,alcohol-related liver disease,overlap syndrome(AIH with primary biliary cholangitis or sclerosing cholangitis),chronic hepatitis B virus,hepatitis C virus,and human immunodeficiency virus infection should be ruled out in such cases.Targeting the concomitant etiology may lead to resolution of the clinical symptoms and induce biochemical and histological remission.Isolated AIH without other etiologies for liver injury should be managed with a higher dose of steroids,azathioprine,or other immunosuppressive agents.Second-and third-line immunosuppressive agents include mycophenolate mofetil,cyclosporine,tacrolimus,infliximab,and rituximab.Patients with AIH may present with acute severe AIH(AS-AIH)and AIH-related acute on chronic liver failure,and they often require liver transplantation.The terms refractory or difficult-to-treat AIH have been used interchangeably and have no distinct definition.Difficult-to-treat AIH includes patients with intolerable side effects,fulminant disease(AIH with acute on chronic liver failure and AS-AIH),AIH in pregnancy,and HIV infection.Patients who fail to respond to standard first-line immunosuppressive therapy should be classified as refractory AIH.This review addresses the issues in the management of difficult-to-treat AIH with recent advances in pharmacological management.
基金Supported by The Key Research and Development Project of the Science and Technology Department of Sichuan Province,China,No.2023YFS0280The High-Level Research Initiation Fund of The First Affiliated Hospital of Chengdu Medical College,China,No.CYFY-GQ43.
文摘Recently,Jayabalan et al published an important study.The authors defined the liver outcome score as a novel biomarker for predicting liver-related mortality in patients with autoimmune hepatitis-primary biliary cholangitis overlap syndrome.After thoroughly reviewing their work,we offer insights that primarily relate to their study design to enhance the medical community’s understanding of this complex disease.
文摘BACKGROUND Autoimmune autonomic ganglionopathy(AAG),formerly known as acute pandysautonomia,is a rare,acquired,antibody-mediated,potentially curable autonomic disorder that presents with diffuse autonomic failure.High levels of anti-ganglionic nicotinic acetylcholine receptor(gAChR)serum antibodies are detected in approximately 50%of AAG cases,confirming the diagnosis.CASE SUMMARY We present the case of a 68-year-old man who developed autonomic failure gradually over a 2-year period.Recently,the patient was unable to stand upright for more than a few seconds before fainting.Additionally,he presented with decreased sweating,dry mouth,urinary retention,early satiety,weight loss,bloating,constipation,and erectile dysfunction.Neurological examination revealed dilated pupils that were unresponsive to light.Deep tendon reflexes were absent or diminished.Serologic evaluation revealed the presence of gAChR autoantibodies.An orthostatic hypotension test yielded a positive result.The patient did not respond to symptomatic therapy,including midodrine,fludrocortisone and atomoxetine.Second-line therapy with immunoadsorption produced a noticeable clinical improvement;however,orthostatic hypotension persisted.Sequential rituximab infusion therapy successfully led to a significant improvement in symptoms.CONCLUSION Our case report supports the benefit of combined immunomodulatory therapy for refractory AAG cases that are unresponsive to single-agent treatment.
