Molecular immunology最新文献

{"title":"Estradiol conjugation to estrogen receptorα upregulates Brms1 expression mediating M2 polarization of alveolar macrophages and exacerbating airway inflammation in asthmatic mice","authors":"Shu Dong ,&nbsp;Yingzi Chen ,&nbsp;Ya Li ,&nbsp;Xingyue Liu ,&nbsp;Jiaqi Yan ,&nbsp;Minyu Xie ,&nbsp;Fan Wu ,&nbsp;Minzhu Niu ,&nbsp;Feifei Shang ,&nbsp;Han Huang ,&nbsp;Wenwen Wu ,&nbsp;Shujun Guo ,&nbsp;Yulin Du ,&nbsp;Mengqing Hua ,&nbsp;Chuanwang Song","doi":"10.1016/j.molimm.2025.03.002","DOIUrl":"10.1016/j.molimm.2025.03.002","url":null,"abstract":"<div><div>Asthma is a common condition involving chronic airway inflammation that primarily affects women and boys. Estrogen levels correlate with the observed differences in the prevalence of asthma between the sexes, but the exact mechanism is unclear. This study established a castration mice (OVX) model through bilateral ovariectomy surgery, and subcutaneously injected estradiol (E2) into OVX asthmatic mice to analyze the effect of E2 on the onset of asthma. Then, airway inflammation was evaluated in the mice using airway resistance measurements, lung tissue hematoxylin and eosin staining, and eosinophil counts. Furthermore, the proportion of CD206-positive cells and the expression of M2 polarization markers, such as Arg1 and YM1, were detected in alveolar macrophages (AMs). The effects of different concentrations of E2 on M2 polarization of AMs were examined <em>in vitro</em>, and the types of estrogen receptors (ERs) involved were investigated. Transcriptome analysis combined with volcano plots and heatmaps were used to compare the differentially expressed genes to investigate the mechanism by which E2 affects M2 polarization of AMs. The results showed that female asthmatic mice had more severe airway inflammation and higher airway responsiveness than male asthmatic mice. E2 increased airway inflammation and airway resistance in asthmatic mice. E2 not only promoted M2 polarization of AMs in asthmatic mice <em>in vivo</em>, but also increased the expression of M2 markers, such as Arg1 and YM1, by AMs <em>in vitro</em>. The use of ERα antagonist AZD9496 reduced the effect of E2 on the promotion of M2 polarization in AMs. Analysis of transcriptome differences indicated that E2 upregulated expression of M2 breast cancer metastasis suppressor gene 1 (<em>Brms1</em>) in AMs. Notably, antagonism of ERα inhibited this upregulation of <em>Brms1</em> gene expression. Interference with <em>Brms1</em> mRNA production reduced the gene expression of <em>Arg1</em> and <em>YM1</em> in AMs undergoing M2 polarization after E2 stimulation. In summary, E2 exacerbates airway inflammation in asthmatic mice and binds to ERα, upregulating <em>Brms1</em> expression and mediating M2 polarization of AMs.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"181 ","pages":"Pages 84-92"},"PeriodicalIF":3.2,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143643999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A retrospective study on the correlation between antibody levels and endothelial function in SLE patients: An analysis based on ultrasound and serum biomarkers","authors":"Huan Xia,&nbsp;Zaixing Pan,&nbsp;Yun Hong,&nbsp;Qingzhu Zhao,&nbsp;Weili Fan","doi":"10.1016/j.molimm.2025.02.018","DOIUrl":"10.1016/j.molimm.2025.02.018","url":null,"abstract":"<div><h3>Background</h3><div>Systemic lupus erythematosus (SLE) was a complex autoimmune disease characterized by a spectrum of clinical and immunological manifestations, with cardiovascular disease (CVD) being a leading cause of morbidity and mortality. Endothelial dysfunction was critical in the pathogenesis of atherosclerosis and other cardiovascular complications in SLE. This study aimed to investigate the correlation between autoantibody levels and endothelial function in SLE patients using ultrasound and serum biomarkers.</div></div><div><h3>Methods</h3><div>A retrospective case-control study was conducted with 317 SLE patients treated from December 2021 to December 2023. Patients were categorized based on Flow-Mediated Dilation (FMD) values into an abnormal endothelial function group (n = 191) and a normal function group (n = 126). Serum biomarkers, including soluble thrombomodulin (sTM), von Willebrand factor (vWF), and soluble vascular cell adhesion molecule-1 (sVCAM-1), were assessed. Autoantibody levels were measured using enzyme-linked immunosorbent assays for anti-double stranded DNA (anti-dsDNA), anti-Smith, and anticardiolipin antibodies levels. Statistical analyses, including correlation and logistic regression, were performed to determine associations between antibody levels and endothelial function.</div></div><div><h3>Results</h3><div>Higher levels of Anti-Smith were significantly associated with poorer endothelial function, while higher Anti-dsDNA levels were positive correlated with endothelial function (Anti-Smith: coefficient = −0.168, Std_Error = 0.027, t_value = −6.228, P &lt; 0.001; Anti-dsDNA: coefficient = 0.140, Std_Error = 0.022, t_value = 6.345, P &lt; 0.001). These results underscore the importance of antibody levels in assessing endothelial health.</div></div><div><h3>Conclusion</h3><div>This study highlights the intricate relationship between specific autoantibodies and endothelial dysfunction in SLE patients. Elevated sVCAM-1 and Anti-Smith levels were associated with a higher risk of endothelial impairment, whereas Anti-dsDNA antibodies showed a positively correlated better endothelial function.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"181 ","pages":"Pages 66-74"},"PeriodicalIF":3.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143601379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Caveolin-1 protects against liver injury and lipid accumulation in alcoholic fatty liver via ferroptosis resistance","authors":"Weiju Xue ,&nbsp;Ning Guo ,&nbsp;Liang Shan ,&nbsp;Zhengsheng Zhang ,&nbsp;Yuquan Sun ,&nbsp;Yong Wang ,&nbsp;Xing Fang ,&nbsp;Xiuzhen Liu ,&nbsp;Jianjun Liu ,&nbsp;Chengmu Hu","doi":"10.1016/j.molimm.2025.02.012","DOIUrl":"10.1016/j.molimm.2025.02.012","url":null,"abstract":"<div><div>Alcoholic fatty liver (AFL) is one of the most common chronic liver diseases globally with complex and controversial pathogenesis. Recent evidence suggests that iron overload and lipid peroxidation are risk factors for AFL. Caveolin-1 (CAV1) is an important signal platform that can maintain lipid homeostasis during the development of non-alcoholic fatty liver. Here, we studied the effect of CAV1 on ferroptosis in AFL. The AFL mouse model was established by chronic-plus-binge alcohol feeding. In vitro, AML-12 cells were incubated with ethanol and oleic acid for 48 h. We found alcohol-induced AFL triggered ferroptosis and decreased CAV1 expression. Overexpression of CAV1 by CAV1 scaffolding domain peptides (CSD) attenuated liver injury and hepatic steatosis, as well as inhibited ferroptosis in AFL mice. Additionally, the effects of CAV1 on ferroptosis-related protein levels (such as SLC7A11, GPX4, and ACSL4) and lipid accumulation were reversed by its small interfering RNA administration. Ferroptosis agonist (Erastin) treatment abrogated CAV1 plasmid-mediated ferroptosis resistance and steatosis alleviation. Collectively, the results revealed a crucial role of CAV1 in preventing hepatic steatosis and ferroptosis in alcohol-induced liver injury, which may identify potential targets for the treatment of AFL.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"181 ","pages":"Pages 53-65"},"PeriodicalIF":3.2,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143592460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BATF participates in airway inflammation of neutrophilic asthma via regulating Th17 cells activation","authors":"Chunming Liu ,&nbsp;Xue Yang ,&nbsp;Yiling Tan ,&nbsp;Yuxin Wang ,&nbsp;Jian Lan ,&nbsp;Pu Yang ,&nbsp;Dongchi Zhao","doi":"10.1016/j.molimm.2025.03.001","DOIUrl":"10.1016/j.molimm.2025.03.001","url":null,"abstract":"<div><div>Neutrophilic asthma (NA) is a common subtype of non-eosinophilic asthma, characterized by the infiltration of neutrophils. Basic leucine zipper transcription factor ATF-like (BATF) is the nuclear transcription factor that initiates lymphocyte differentiation. The mechanism by which BATF affects T cell differentiation leading to neutrophil accumulation in NA lung tissue remains unclear. In this study, we established murine models of NA through sensitization with ovalbumin (OVA) /complete Freund's adjuvant and subsequent challenge with OVA/lipopolysaccharide. Using these models, we systematically investigated pathological alterations, inflammatory cell infiltration patterns, and cytokine expression profiles in murine lung tissues. The impact of glucocorticoid intervention on the pathology of airway inflammation in NA mice was assessed, and the markers associated with lymphocyte differentiation RORγt and FoxP3 were detected. Furthermore, on the basis of BATF knockdown, the distribution of lymphocyte subtypes and the effect on neutrophil activity in the lung tissues of NA mice were observed. Our results revealed that both BATF and IL-17A showed high expression in NA lung tissue, and neutrophils were predominant in bronchoalveolar lavage fluid (BALF). Glucocorticoid treatment failed to alleviate lung histopathological lesion and exacerbated neutrophil accumulation in NA. Inhibiting BATF could significantly reduce neutrophil accumulation, as well as downregulate IL-17A expression, thus alleviating lung histopathological injury in NA. BATF was involved in mainly regulating naïve lymphocyte differentiation to T helper cell 17 (Th17) rather than regulatory T cells (Tregs). Our results demonstrate that BATF plays an important proinflammatory role in neutrophil asthma, and the inhibition of BATF could reduce lung inflammation by reducing IL-17A, acting as a potential therapeutic target.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"181 ","pages":"Pages 40-52"},"PeriodicalIF":3.2,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143592461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutrophil-derived exosomal S100A8 aggravates lung injury in sepsis by inducing pyroptosis","authors":"Xinxin Li ,&nbsp;Wei Zhou ,&nbsp;Liangliang Zhou,&nbsp;Yingbin Li,&nbsp;Xufeng Wu,&nbsp;Jianjun Chen","doi":"10.1016/j.molimm.2025.03.003","DOIUrl":"10.1016/j.molimm.2025.03.003","url":null,"abstract":"<div><div>Acute lung injury (ALI) is a common and life-threatening complication in patients with sepsis, with pro-inflammatory cell pyroptosis playing a crucial role in the associated organ damage. In this study, we aimed to identify potential therapeutic targets. Utilizing the GEO database (GSE232753), we analyzed the differentially expressed genes in the peripheral blood of healthy individuals and sepsis patients, identifying the significantly upregulated gene S100A8. Subsequently, we constructed a septic ALI model using lipopolysaccharide (LPS). Notably, S100A8 was highly expressed not only in serum and bronchoalveolar lavage fluid (BALF) but also in neutrophil exosomes. We then co-incubated BEAS-2B cells with neutrophil exosomes that were either treated or untreated with LPS. Cell proliferation activity was assessed using the CCK-8 assay, cell death was evaluated through propidium iodide (PI) staining, and the changes in pyroptosis indicators were detected via Western blot and ELISA. To further validate that LPS-induced neutrophil exosomes promote BEAS-2B cell pyroptosis through the delivery of S100A8, we conducted additional experiments involving the addition of S100A8 protein alone or S100A8 antibody in conjunction with neutrophil exosome treatment, followed by relevant assessments. Moreover, <em>in vivo</em> validation was also performed. Mechanistically, we revealed that S100A8 induces pyroptosis in BEAS-2B cells through the TLR4 signaling pathway. In conclusion, our findings provide new promising targets for the treatment of septic ALI.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"181 ","pages":"Pages 29-39"},"PeriodicalIF":3.2,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143577194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fructus arctii mitigates diabetic nephropathy via the Apoh/PPAR-γ pathway","authors":"Na Zhang ,&nbsp;Anhui Chen ,&nbsp;Yuwei Dong ,&nbsp;Deqiang Dou","doi":"10.1016/j.molimm.2025.02.017","DOIUrl":"10.1016/j.molimm.2025.02.017","url":null,"abstract":"<div><h3>Background</h3><div>Diabetic nephropathy (DN) is characterized by renal fibrosis and functional decline. Apolipoprotein H (Apoh) and Fructus arctii, a traditional medicinal plant, have demonstrated potential in treating metabolic and fibrotic disorders. This study Focused on revealing the roles of Apoh and Fructus arctii in mitigating DN.</div></div><div><h3>Methods</h3><div>Db/db mice served as an <em>in vivo</em> DN model, and mouse glomerular mesangial cells (mMCs) and renal tubular epithelial cells (mTECs) were treated with high glucose (HG) to simulate DN in vitro. Apoh silencing and overexpression were performed using shRNA and pcDNA3.1 vectors. Fructus arctii was administered to both cellular and animal models to assess its therapeutic potential. Cellular proliferation was measured using CCK-8 and EdU assays, while fibrosis markers were analyzed by Western blot, IHC and RT-qPCR. PPAR-γ pathway involvement was confirmed through treatment with the antagonist GW9662. Renal structural changes were evaluated with histological staining including H&amp;E, PAS, Masson’s trichrome, and picrosirius red staining.</div></div><div><h3>Results</h3><div>Apoh expression was markedly reduced in HG-treated cells and the kidneys of db/db mice. Overexpression of Apoh suppressed HG-induced proliferation in mMCs and mTECs by downregulating cyclin D1 and PCNA. Additionally, Apoh overexpression alleviated fibrosis by reducing Fibronectin, Collagen I, and α-SMA levels, effects mediated through the PPAR-γ pathway. Treatment with the PPAR-γ antagonist GW9662 reversed these protective effects. In db/db mice, Fructus arctii administration improved renal function by reducing blood glucose, proteinuria, and renal collagen deposition. It also alleviated fibrosis and enhanced Apoh and PPAR-γ expression. Silencing Apoh nullified the protective effects of Fructus arctii on cell proliferation and fibrosis, confirming its reliance on the Apoh/PPAR-γ pathway.</div></div><div><h3>Conclusion</h3><div>Fructus arctii alleviated DN progression by modulating cell proliferation and renal fibrosis via the Apoh/PPAR-γ pathway.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"181 ","pages":"Pages 18-28"},"PeriodicalIF":3.2,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143563443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cigarette smoke-exposed microparticles released from T lymphocytes contribute to autophagy and apoptosis dysfunction in pulmonary microvascular endothelial cells","authors":"Gang Chen ,&nbsp;Zhaoji Meng ,&nbsp;Pei Wang","doi":"10.1016/j.molimm.2025.02.020","DOIUrl":"10.1016/j.molimm.2025.02.020","url":null,"abstract":"<div><div>Cigarette smoke can cause dysfunction of the vascular endothelium; however, the underlying mechanisms have not been fully elucidated. We hypothesized that T lymphocyte-derived microparticles (TLMPs) are involved in cigarette-related diseases, especially those involving the vascular endothelium. The effect of cigarette smoke on the release of microparticles from human lymphocytes was investigated. The contributions of TLMPs induced by cigarette smoke to endothelial proliferation/apoptosis, autophagy and cytokine levels were also measured. Notably, the potential mechanism of autophagy and apoptosis dysfunction in endothelial cells was further examined. Cigarette smoke promoted the release of microparticles from T lymphocytes. TLMPs attenuated endothelial proliferation but promoted endothelial apoptosis/autophagy and the expression of proinflammatory cytokines, especially when T lymphocytes were preexposed to cigarette smoke. The potential mechanism may involve disorders of oxidative stress and STAT3 phosphorylation. In conclusion, cigarette smoke-exposed microparticles released from T lymphocytes contribute to autophagy and apoptosis dysfunction in pulmonary microvascular endothelial cells.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"181 ","pages":"Pages 9-17"},"PeriodicalIF":3.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143549964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The superantigen SEA binds to human γδ T cell receptor and activates γδ T cells with moderate MHC class II dependence","authors":"Sibel Uzunçayır ,&nbsp;Ganna Petruk ,&nbsp;Manuel Mata Forsberg ,&nbsp;Claudia Arasa ,&nbsp;Eva Sverremark-Ekström ,&nbsp;Karin Lindkvist-Petersson","doi":"10.1016/j.molimm.2025.02.019","DOIUrl":"10.1016/j.molimm.2025.02.019","url":null,"abstract":"<div><div>Bacterial toxins, called superantigens, are produced by <em>Staphylococcus aureus</em> and are known to activate γδ T cells. γδ T cells contribute to long-lasting immunity against bacterial skin infections caused by <em>S. aureus</em>. γδ T cells are a distinct subgroup of T cells containing the T cell receptor (TCR) γ and δ chains. The γδ TCR harbouring the variable chains TRGV9/TRDV2 is the most common TCR in human peripheral blood and is known to be activated by superantigens and are also promising candidates for tumor immunotherapy. However, detailed analyses of antigen binding to γδ TCR have been severely hampered by difficulties in producing large amounts of γδ TCR. In this study, we report a protocol to produce recombinant γδ TCR (TRGV9/TRDV2) by fusing the variable domains γδ TCR with the constant domains of αβ TCR. Subsequently, binding analyses were executed applying microscale thermophoresis showing a clear binding between superantigen and the γδ TCR in the micro molar range. In addition, the superantigen SEA was shown to induce cytokine expression in γδ T cells with moderate MHC dependence, suggesting that other receptors can act as antigen presenting molecules upon γδ T cell activation. These results pave the way towards a better understanding of superantigen recognition by the γδ T cells and facilitates the future use of γδ TCR in cellular tumor immunotherapy.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"181 ","pages":"Pages 1-8"},"PeriodicalIF":3.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143549963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"circSTIL mediates pirarubicin inhibiting the malignant phenotype of triple-negative breast cancer and acts as a biomarker in plasma exosomes","authors":"Jiahua Ji ,&nbsp;Min Li ,&nbsp;Kaixu Yan ,&nbsp;Jiulong Ma ,&nbsp;Dexian Wei ,&nbsp;Fan Zhang ,&nbsp;Sennan Qiao ,&nbsp;Peng Huang ,&nbsp;Wenqing Zhang ,&nbsp;Lu Li ,&nbsp;Wentao Zheng ,&nbsp;Liqun Ren","doi":"10.1016/j.molimm.2025.02.014","DOIUrl":"10.1016/j.molimm.2025.02.014","url":null,"abstract":"<div><div>In clinical practice, pirarubicin (THP) is a widely used triple-negative breast cancer (TNBC) agent. It has been found that circular RNAs (circRNAs) are involved in cancer treatment and progression. However, the biological function of circRNAs in TNBC and the relationship between THP and circRNAs remain poorly studied. circSTIL (hsa_circ_0000069) was screened and validated by bioinformatics analysis, demonstrating that it was highly expressed in TNBC cell lines and plasma exosomes, and correlated with a poor prognosis of patients. The expression level of circSTIL in patients’ plasma exosomes has potential diagnostic value in distinguishing TNBC from non-TNBC. In vitro studies confirmed that overexpression of circSTIL promotes the proliferation, migration, and invasion of MDA-MB-231 cells whereas silicification of circSTIL shows the reverse effect. Also, circSTIL mediates THP inhibiting the malignant phenotype of MDA-MB-231 cells. The above results suggested that circSTIL is a possible biomarker for the diagnosis, treatment, and prognosis of TNBC.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"180 ","pages":"Pages 86-95"},"PeriodicalIF":3.2,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143520212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel mechanistic insights into the comorbidity of anemia and rheumatoid arthritis: Identification of therapeutic targets","authors":"Cun Li ,&nbsp;Xiongzhi Shi,&nbsp;Shou Chen ,&nbsp;Xiaoming Peng ,&nbsp;Shaohui Zong","doi":"10.1016/j.molimm.2025.02.011","DOIUrl":"10.1016/j.molimm.2025.02.011","url":null,"abstract":"<div><h3>Objectives</h3><div>To investigate the mechanisms underlying the comorbidity of anemia and rheumatoid arthritis (RA) and identify promising therapeutic targets.</div></div><div><h3>Methods</h3><div>We assessed the phenotypic linkage between anemia and RA. Using the largest genome-wide association studies (GWAS) summary statistics of European populations, we scrutinized the causal association and shared genetic architecture between the two conditions using multiple complementary approaches.</div></div><div><h3>Results</h3><div>Logistic regression analysis confirmed a strong clinical association between anemia and RA. Using GWAS data, we identified a significant causal effect of RA on anemia and positive global genetic correlations between the two conditions (r_g (genotype) = 0.28, P = 9.6 × 10⁻⁷; r_g (gene expression) = 0.45, P = 2 × 10⁻³). After dividing the genome into 2495 independent regions, we identified 15 significant regions associated with both conditions, with 14 showing concordant effects. Fine-mapping at the SNP level revealed 72 % of RA-associated SNPs overlapped with anemia, most with concordant effects. Stratified Q-Q plots visualized the shared genetic enrichment, showing a 12-fold enrichment for RA conditional on anemia and 100-fold enrichment for anemia conditional on RA. Further analysis using conjFDR method pinpointed 14 pleiotropic loci, including several novel loci. Gene mapping identified 33 shared genes, with BLK and FAM167A further prioritized as the top two genes by SMR analysis. Enrichment analysis highlighted pathways related to inflammation, immune response, and iron metabolism. Blood and T cells showed significant tissue- and cell-type-specific enrichment.</div></div><div><h3>Conclusions</h3><div>This study provides novel insights into anemia-RA comorbidity mechanisms and identifies new drug targets for RA.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"180 ","pages":"Pages 74-85"},"PeriodicalIF":3.2,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143508221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}