Amlexanox (ALX) is a small molecule drug for the treatment of inflammatory, autoimmune, metabolic and tumor diseases. At present, there are no studies on whether ALX has a therapeutic effect on inflammatory bowel disease (IBD). In this study, we used a mouse model of dextran sulfate sodium (DSS)-induced colitis to investigate the effect of ALX targeted inhibition of TBK1 on colitis. We found that the severity of colitis in mice was correlated with TBK1 expression. Notably, although ALX inhibited the activation of the TBK1-NF-κB/TBK1-IRF3 pro-inflammatory signaling pathway, it exacerbated colitis and reduced survival in mice. The results of drug safety experiments ruled out a relationship between this exacerbating effect and drug toxicity. In addition, ELISA results showed that ALX promoted the secretion of IL-1β and IFN-α, and inhibited the production of cytokines IL-6, TNF-α, IL-10, TGF-β and secretory IgA. Flow cytometry results further showed that ALX promoted T cell proliferation, activation and differentiation, and thus played a pro-inflammatory role; Also, ALX inhibited the generation of dendritic cells and the polarization of macrophages to M1 type, thus exerting anti-inflammatory effect. These data suggest that the regulation of ALX on the function of different immune cells is different, so the effect on the inflammatory response is bidirectional. In conclusion, our study demonstrates that simply inhibiting TBK1 in all immune cells is not effective for the treatment of colitis. Further investigation the anti-inflammatory mechanism of ALX on dendritic cells and macrophages may provide a new strategy for the treatment of IBD.
{"title":"Amlexanox targeted inhibition of TBK1 regulates immune cell function to exacerbate DSS-induced inflammatory bowel disease.","authors":"Lu Hui, Meng-Ke Huang, Qing-Kai Dai, Cheng-Lin Miao, Yun-Long Yang, Chen-Xi Liu, Ting Liu, Yong-Mei Jiang","doi":"10.1093/cei/uxae082","DOIUrl":"https://doi.org/10.1093/cei/uxae082","url":null,"abstract":"<p><p>Amlexanox (ALX) is a small molecule drug for the treatment of inflammatory, autoimmune, metabolic and tumor diseases. At present, there are no studies on whether ALX has a therapeutic effect on inflammatory bowel disease (IBD). In this study, we used a mouse model of dextran sulfate sodium (DSS)-induced colitis to investigate the effect of ALX targeted inhibition of TBK1 on colitis. We found that the severity of colitis in mice was correlated with TBK1 expression. Notably, although ALX inhibited the activation of the TBK1-NF-κB/TBK1-IRF3 pro-inflammatory signaling pathway, it exacerbated colitis and reduced survival in mice. The results of drug safety experiments ruled out a relationship between this exacerbating effect and drug toxicity. In addition, ELISA results showed that ALX promoted the secretion of IL-1β and IFN-α, and inhibited the production of cytokines IL-6, TNF-α, IL-10, TGF-β and secretory IgA. Flow cytometry results further showed that ALX promoted T cell proliferation, activation and differentiation, and thus played a pro-inflammatory role; Also, ALX inhibited the generation of dendritic cells and the polarization of macrophages to M1 type, thus exerting anti-inflammatory effect. These data suggest that the regulation of ALX on the function of different immune cells is different, so the effect on the inflammatory response is bidirectional. In conclusion, our study demonstrates that simply inhibiting TBK1 in all immune cells is not effective for the treatment of colitis. Further investigation the anti-inflammatory mechanism of ALX on dendritic cells and macrophages may provide a new strategy for the treatment of IBD.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153267","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}
Clinical manifestations, as distinct from thrombotic and obstetric morbidity, were recently included in the update of classification criteria of the antiphospholipid syndrome (APS). However, the existence of several patients with clinical manifestations suggestive of APS, but negative for criteria antiphospholipid antibodies (aPLs) [anti-cardiolipin antibodies (aCL), anti-β2-glycoprotein I antibodies (aβ2-GPI) and lupus anticoagulant] may suggest an update of diagnostic criteria. In this study, we analyzed the prevalence of six non-criteria aPLs in a large monocentric cohort of patients with seronegative APS (SN-APS), to investigate their possible diagnostic role. aCL IgA, aβ2-GPI IgA and aβ2-GPI Domain 1 antibodies were detected by chemiluminescence, anti-phosphatidylserine/prothrombin (aPS/PT) IgG, anti-vimentin/cardiolipin (aVim/CL) IgG and anti-carbamylated-β2-glycoprotein I (aCarb-β2-GPI) IgG by ELISA in sera from 144 SN-APS patients. In SN-APS patients, aCL IgA were detected in 4/144 (2.77%), aβ2-GPI IgA in 2/144 (1.39%), aβ2-GPI-Domain 1 in 1/144 (0.69%), aPS/PT in 16/144 (11.11%), aVim/CL in 37/144 (25.69%) and aCarb-β2-GPI in 43/144 patients (29.86%). Patients negative for all non-criteria aPL assays were 77/144 (53.47%). Notably, the Venn diagram showed that aCarb-β2-GPI together with aVim/CL represented the prevalent combination of positive antibodies. In SN-APS patients, aCL IgA were associated with recurrent thrombosis (OR11.48; p=0.03); in obstetric SN-APS patients, aPS/PT were significantly associated with foetal deaths (OR4.84; p=0.01), aVim/CL with spontaneous abortions (OR2.71; p=0.016). This study indicates that aPS/PT, aVim/CL and aCarb-β2-GPI antibodies may represent useful tools to identify "seronegative" APS patients, who are negative for criteria aPLs, supporting the need to make testing for non-criteria aPLs more accessible in patients with SN-APS.
{"title":"Antibody profiles in the mosaic of \"seronegative\" APS syndrome.","authors":"Simona Truglia, Gloria Riitano, Silvia Mancuso, Serena Recalchi, Luca Rapino, Cristina Garufi, Valeria Manganelli, Tina Garofalo, Roberta Misasi, Cristiano Alessandri, Maurizio Sorice, Agostina Longo, Fabrizio Conti, Antonella Capozzi","doi":"10.1093/cei/uxae079","DOIUrl":"https://doi.org/10.1093/cei/uxae079","url":null,"abstract":"<p><p>Clinical manifestations, as distinct from thrombotic and obstetric morbidity, were recently included in the update of classification criteria of the antiphospholipid syndrome (APS). However, the existence of several patients with clinical manifestations suggestive of APS, but negative for criteria antiphospholipid antibodies (aPLs) [anti-cardiolipin antibodies (aCL), anti-β2-glycoprotein I antibodies (aβ2-GPI) and lupus anticoagulant] may suggest an update of diagnostic criteria. In this study, we analyzed the prevalence of six non-criteria aPLs in a large monocentric cohort of patients with seronegative APS (SN-APS), to investigate their possible diagnostic role. aCL IgA, aβ2-GPI IgA and aβ2-GPI Domain 1 antibodies were detected by chemiluminescence, anti-phosphatidylserine/prothrombin (aPS/PT) IgG, anti-vimentin/cardiolipin (aVim/CL) IgG and anti-carbamylated-β2-glycoprotein I (aCarb-β2-GPI) IgG by ELISA in sera from 144 SN-APS patients. In SN-APS patients, aCL IgA were detected in 4/144 (2.77%), aβ2-GPI IgA in 2/144 (1.39%), aβ2-GPI-Domain 1 in 1/144 (0.69%), aPS/PT in 16/144 (11.11%), aVim/CL in 37/144 (25.69%) and aCarb-β2-GPI in 43/144 patients (29.86%). Patients negative for all non-criteria aPL assays were 77/144 (53.47%). Notably, the Venn diagram showed that aCarb-β2-GPI together with aVim/CL represented the prevalent combination of positive antibodies. In SN-APS patients, aCL IgA were associated with recurrent thrombosis (OR11.48; p=0.03); in obstetric SN-APS patients, aPS/PT were significantly associated with foetal deaths (OR4.84; p=0.01), aVim/CL with spontaneous abortions (OR2.71; p=0.016). This study indicates that aPS/PT, aVim/CL and aCarb-β2-GPI antibodies may represent useful tools to identify \"seronegative\" APS patients, who are negative for criteria aPLs, supporting the need to make testing for non-criteria aPLs more accessible in patients with SN-APS.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142079413","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}
Asthma exacerbation is a common clinical occurrence. The causal factors are not fully understood yet. Environmental pollution is linked to asthma exacerbation. The objective of this study is to elucidate the role of 3-methyl-4-nitrophenol (MNP), an environmental pollutant, in asthma exacerbation. In this study, an airway allergy mouse model was established with ovalbumin as a specific antigen with or without the presence of MNP. The results showed that, in a mouse model, the intensity of airway allergy was significantly increased by exposure to MNP. RNAseq results showed an increase in ER stress-associated molecules and the Osm expression in airway epithelial cells of mice with airway allergy. Exposure of epithelial cells to MNP in culture induced the expression of OSM and ER stress associated molecules. The OSM receptor was expressed by macrophages. OSM could drive macrophages to produce TNF-α. Inhibition of PERK, one of the key molecules of ER stress, or depletion of OSM receptor in macrophages, could effectively attenuate the MNP/OVA protocol induced airway allergy. To sum up, by promoting ER stress, environmental pollutant MNP can cause airway epithelial cells to produce OSM. The latter induces macrophages to produce TNF-α, which can exacerbate airway allergy.
哮喘加重是一种常见的临床现象。其致病因素尚不完全清楚。环境污染与哮喘恶化有关。本研究旨在阐明环境污染物 3-甲基-4-硝基苯酚(MNP)在哮喘恶化中的作用。本研究以卵清蛋白为特异性抗原,在有或没有 MNP 的情况下建立了气道过敏小鼠模型。结果显示,在小鼠模型中,暴露于 MNP 会显著增加气道过敏的强度。RNAseq 结果显示,气道过敏小鼠气道上皮细胞中的 ER 应激相关分子和 Osm 表达量增加。将上皮细胞暴露于 MNP 培养液中可诱导 OSM 和 ER 应激相关分子的表达。巨噬细胞表达 OSM 受体。OSM 可驱动巨噬细胞产生 TNF-α。抑制ER应激的关键分子之一PERK或消耗巨噬细胞中的OSM受体,可有效减轻MNP/OVA方案诱导的气道过敏。综上所述,环境污染物MNP可通过促进ER应激,促使气道上皮细胞产生OSM。后者诱导巨噬细胞产生 TNF-α,从而加剧气道过敏。
{"title":"Environmental pollutant 3-methyl-4-nitrophenol promotes the expression of oncostatin M to exacerbate airway allergic inflammation.","authors":"Lihua Mo, Xinxin Wang, Yun Liao, Yu Liu, Aifa Tang, Jing Li, Pingchang Yang","doi":"10.1093/cei/uxae078","DOIUrl":"https://doi.org/10.1093/cei/uxae078","url":null,"abstract":"<p><p>Asthma exacerbation is a common clinical occurrence. The causal factors are not fully understood yet. Environmental pollution is linked to asthma exacerbation. The objective of this study is to elucidate the role of 3-methyl-4-nitrophenol (MNP), an environmental pollutant, in asthma exacerbation. In this study, an airway allergy mouse model was established with ovalbumin as a specific antigen with or without the presence of MNP. The results showed that, in a mouse model, the intensity of airway allergy was significantly increased by exposure to MNP. RNAseq results showed an increase in ER stress-associated molecules and the Osm expression in airway epithelial cells of mice with airway allergy. Exposure of epithelial cells to MNP in culture induced the expression of OSM and ER stress associated molecules. The OSM receptor was expressed by macrophages. OSM could drive macrophages to produce TNF-α. Inhibition of PERK, one of the key molecules of ER stress, or depletion of OSM receptor in macrophages, could effectively attenuate the MNP/OVA protocol induced airway allergy. To sum up, by promoting ER stress, environmental pollutant MNP can cause airway epithelial cells to produce OSM. The latter induces macrophages to produce TNF-α, which can exacerbate airway allergy.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142079414","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}
Yang Zhang, Weifeng Hong, Danxue Zheng, Zongjuan Li, Yong Hu, Yixing Chen, Ping Yang, Zhaochong Zeng, Shisuo Du
Pre-clinical data suggest that type I interferon (IFN) responsiveness is essential for the antitumor effects of radiotherapy (RT). However, its clinical value remains unclear. This study aimed to explore this from a clinical perspective. In cohort 1, data from 152 hepatocellular carcinoma (HCC) patients who received RT were analyzed. Blood samples were taken 1 day before and 2 weeks after RT. RT was found to increase serum levels of IFN-β (a subtype of IFN-I) in HCC patients (3.42 ± 1.57 to 5.51 ± 2.11 pg/mL, p < 0.01), particularly in those with favorable responses. Higher post-RT serum IFN-β levels (≥ 4.77 pg/mL) were associated with better progression-free survival (HR = 0.58, p < 0.01). Cohort 2 included 46 HCC patients, including 23 who underwent preoperative RT and 23 matched control HCC who received surgical resection without RT. Formalin-fixed paraffin-embedded samples were obtained. Neoadjuvant RT significantly increased IFN-β expression in tumor tissues compared to direct surgery (8.13% ± 5.19% to 15.10% ± 5.89%, p < 0.01). Higher post-RT IFN-β (> median) indicated better disease-free survival (p = 0.049). Additionally, increased CD11c+MHCII+CD141+ antigen presenting cell subsets and CD103+CD39+CD8+ tumor-infiltrating lymphocytes were found in the higher IFN-β group (p = 0.02, p = 0.03), which may contribute to the favorable prognosis in higher IFN-β group. Collectively, these findings suggest that IFN-β response activated by radiation may serve as a prognostic biomarker for HCC patients undergoing RT.
{"title":"Increased IFN-β Indicates Better Survival in Hepatocellular Carcinoma Treated with Radiotherapy.","authors":"Yang Zhang, Weifeng Hong, Danxue Zheng, Zongjuan Li, Yong Hu, Yixing Chen, Ping Yang, Zhaochong Zeng, Shisuo Du","doi":"10.1093/cei/uxae075","DOIUrl":"https://doi.org/10.1093/cei/uxae075","url":null,"abstract":"<p><p>Pre-clinical data suggest that type I interferon (IFN) responsiveness is essential for the antitumor effects of radiotherapy (RT). However, its clinical value remains unclear. This study aimed to explore this from a clinical perspective. In cohort 1, data from 152 hepatocellular carcinoma (HCC) patients who received RT were analyzed. Blood samples were taken 1 day before and 2 weeks after RT. RT was found to increase serum levels of IFN-β (a subtype of IFN-I) in HCC patients (3.42 ± 1.57 to 5.51 ± 2.11 pg/mL, p < 0.01), particularly in those with favorable responses. Higher post-RT serum IFN-β levels (≥ 4.77 pg/mL) were associated with better progression-free survival (HR = 0.58, p < 0.01). Cohort 2 included 46 HCC patients, including 23 who underwent preoperative RT and 23 matched control HCC who received surgical resection without RT. Formalin-fixed paraffin-embedded samples were obtained. Neoadjuvant RT significantly increased IFN-β expression in tumor tissues compared to direct surgery (8.13% ± 5.19% to 15.10% ± 5.89%, p < 0.01). Higher post-RT IFN-β (> median) indicated better disease-free survival (p = 0.049). Additionally, increased CD11c+MHCII+CD141+ antigen presenting cell subsets and CD103+CD39+CD8+ tumor-infiltrating lymphocytes were found in the higher IFN-β group (p = 0.02, p = 0.03), which may contribute to the favorable prognosis in higher IFN-β group. Collectively, these findings suggest that IFN-β response activated by radiation may serve as a prognostic biomarker for HCC patients undergoing RT.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055114","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}
Acquired Aplastic Anaemia (AA) often results from immune destruction of hematopoietic stem and progenitor cells. However, only 60-70% of patients with AA respond to immunosuppressive therapy (IST). There is lack of strong predictive marker for response to IST which can help therapy. Our study sought to pinpoint unique immune markers in AA patients and validate established predictors for response to IST. We enrolled 51 severe AA patients and analyzed 57 immunological parameters via flow cytometry. Additionally, we measured paroxysmal nocturnal hemoglobinuria (PNH) clone, telomere length, and thrombopoietin (TPO) levels prior to IST. After a 6-months follow-up, response was observed. Patients with AA had a distinct immunological signature characterized by absolute lymphopenia, skewed CD4/CD8 ratio with expansion of CD8 T cells with activated and senescent phenotype. Treg counts were reduced, while proportion of Treg A and B was comparable to controls. Treatment response was correlated with elevated Absolute Neutrophil Count (ANC), Absolute Reticulocyte Count (ARC), and reduced CD57+ CD8+ naive cells and B cell % before therapy. However, predictors like TPO, telomere length, and PNH did not emerge as indicators of treatment response. Identifying predictors for treatment response in AA is challenging due to abnormal haematopoiesis, genetic mutations, and treatment variables.
获得性再生障碍性贫血(AA)通常是造血干细胞和祖细胞遭到免疫破坏所致。然而,只有60-70%的再生障碍性贫血患者对免疫抑制疗法(IST)有反应。目前还缺乏有助于治疗的强效免疫抑制疗法反应预测标志物。我们的研究旨在确定 AA 患者的独特免疫标记物,并验证已建立的 IST 反应预测指标。我们招募了 51 名重症 AA 患者,并通过流式细胞术分析了 57 项免疫学参数。此外,我们还测量了 IST 前阵发性夜间血红蛋白尿(PNH)克隆、端粒长度和血小板生成素(TPO)水平。经过 6 个月的随访,观察到了反应。AA患者具有独特的免疫学特征,表现为绝对淋巴细胞减少、CD4/CD8比例失调、具有活化和衰老表型的CD8 T细胞扩增。Treg数量减少,而Treg A和B的比例与对照组相当。治疗反应与治疗前绝对中性粒细胞计数(ANC)和绝对网织红细胞计数(ARC)升高、CD57+ CD8+ 幼稚细胞和 B 细胞比例降低有关。然而,TPO、端粒长度和 PNH 等预测指标并未成为治疗反应的指标。由于造血异常、基因突变和治疗变量,确定 AA 治疗反应的预测指标具有挑战性。
{"title":"Unveiling Immunological Signatures and Predictors of Response to Immunosuppressive Therapy in Acquired Aplastic Anaemia\".","authors":"Maya Gupta, Chandrakala S, Baburao Vundinti, Amrutha Jose, Shashank Tiwari, Amiya Bhowmick, Manisha Madkaikar","doi":"10.1093/cei/uxae076","DOIUrl":"https://doi.org/10.1093/cei/uxae076","url":null,"abstract":"<p><p>Acquired Aplastic Anaemia (AA) often results from immune destruction of hematopoietic stem and progenitor cells. However, only 60-70% of patients with AA respond to immunosuppressive therapy (IST). There is lack of strong predictive marker for response to IST which can help therapy. Our study sought to pinpoint unique immune markers in AA patients and validate established predictors for response to IST. We enrolled 51 severe AA patients and analyzed 57 immunological parameters via flow cytometry. Additionally, we measured paroxysmal nocturnal hemoglobinuria (PNH) clone, telomere length, and thrombopoietin (TPO) levels prior to IST. After a 6-months follow-up, response was observed. Patients with AA had a distinct immunological signature characterized by absolute lymphopenia, skewed CD4/CD8 ratio with expansion of CD8 T cells with activated and senescent phenotype. Treg counts were reduced, while proportion of Treg A and B was comparable to controls. Treatment response was correlated with elevated Absolute Neutrophil Count (ANC), Absolute Reticulocyte Count (ARC), and reduced CD57+ CD8+ naive cells and B cell % before therapy. However, predictors like TPO, telomere length, and PNH did not emerge as indicators of treatment response. Identifying predictors for treatment response in AA is challenging due to abnormal haematopoiesis, genetic mutations, and treatment variables.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970765","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}
Anti-SSA antibodies are non-organ-specific autoantibodies highly prevalent in various autoimmune diseases. This study primarily investigated the prevalence of anti-SSA antibodies in the health screening population. Additionally, we explored the clinical features of the anti-SSA antibody-positive population and evaluated the development of connective tissue diseases (CTD) over the years in individuals with anti-SSA antibodies for whom follow-up was available. 64045 individuals without a history of CTD from 2013 to 2022 who visited Peking Union Medical College Hospital for health screening were screened for autoimmune antibodies. 1.7% (1091/64045) of the Chinese health screening population were positive for anti-SSA antibodies, with a prevalence of 0.9% (290/33829) in men and 2.7% (801/30216) in women. Compared with matched autoantibody-negative controls, anti-SSA antibody-positive individuals had higher levels of serological abnormalities including erythrocyte sedimentation rate (ESR) [10 (6-15) mm/h vs. 7 (4-12) mm/h, p<0.0001], rheumatoid factor (RF) [7.15 (4.30-16.90) IU/ml vs. 5.00 (3.20-7.90) IU/ml, p<0.0001], and Immunoglobulin G [13.09 (11.20-15.45) g/L vs. 11.34 (9.85-13.18) g/L, p<0.0001], and lower levels of white blood cells (WBC) (5.49 ± 1.50 *109/L vs. 5.82 ± 1.49 *109/L, p<0.0001). Additionally, they had a higher proportion of coexisting thyroid autoantibodies, including anti-thyroid peroxidase antibodies (TPO-Ab) (17.1% vs. 11.3%, p<0.0001) and anti-thyroglobulin antibodies (Tg-Ab) (17.8% vs. 11.0%, p<0.0001). Among the 381 subjects who were anti-SSA positive and followed up for a median of 4.6 years, 146 (38.3%) individuals developed CTD, including 68 (17.8%) cases of primary Sjögren syndrome (pSS), 10 (2.6%) cases of rheumatoid arthritis (RA), 5 cases (1.3%) of systemic lupus erythematosus (SLE), and 59 (15.5%) cases of undifferentiated connective tissue disease (UCTD). 235 (61.7%) individuals did not develop CTD over a median time of 5.9 (2.9-8.1) years after the earliest autoantibody detection. Elevated ESR (>20 mm/h), RF positivity (>20 IU/ml), and female gender were identified as independent risk factors for CTD among the anti-SSAantibody-positive individuals. Anti-SSA antibodies were found in 17 among approximately 1000 individuals without a history of autoimmune diseases. Anti-SSA antibody-positive individuals are advised to periodically monitor thyroid function. Elevated ESR (>20 mm/h), female gender, and rheumatoid factor positivity may delineate a high-risk cohort for CTDs.
{"title":"Prevalence and clinical significance of anti-SSA antibody in the Chinese health screening population.","authors":"Yimeng Jia, Shuqi Luan, Sicheng Huang, Wen Zhang, Mengtao Li, Tengda Xu, Yunyun Fei","doi":"10.1093/cei/uxae073","DOIUrl":"https://doi.org/10.1093/cei/uxae073","url":null,"abstract":"<p><p>Anti-SSA antibodies are non-organ-specific autoantibodies highly prevalent in various autoimmune diseases. This study primarily investigated the prevalence of anti-SSA antibodies in the health screening population. Additionally, we explored the clinical features of the anti-SSA antibody-positive population and evaluated the development of connective tissue diseases (CTD) over the years in individuals with anti-SSA antibodies for whom follow-up was available. 64045 individuals without a history of CTD from 2013 to 2022 who visited Peking Union Medical College Hospital for health screening were screened for autoimmune antibodies. 1.7% (1091/64045) of the Chinese health screening population were positive for anti-SSA antibodies, with a prevalence of 0.9% (290/33829) in men and 2.7% (801/30216) in women. Compared with matched autoantibody-negative controls, anti-SSA antibody-positive individuals had higher levels of serological abnormalities including erythrocyte sedimentation rate (ESR) [10 (6-15) mm/h vs. 7 (4-12) mm/h, p<0.0001], rheumatoid factor (RF) [7.15 (4.30-16.90) IU/ml vs. 5.00 (3.20-7.90) IU/ml, p<0.0001], and Immunoglobulin G [13.09 (11.20-15.45) g/L vs. 11.34 (9.85-13.18) g/L, p<0.0001], and lower levels of white blood cells (WBC) (5.49 ± 1.50 *109/L vs. 5.82 ± 1.49 *109/L, p<0.0001). Additionally, they had a higher proportion of coexisting thyroid autoantibodies, including anti-thyroid peroxidase antibodies (TPO-Ab) (17.1% vs. 11.3%, p<0.0001) and anti-thyroglobulin antibodies (Tg-Ab) (17.8% vs. 11.0%, p<0.0001). Among the 381 subjects who were anti-SSA positive and followed up for a median of 4.6 years, 146 (38.3%) individuals developed CTD, including 68 (17.8%) cases of primary Sjögren syndrome (pSS), 10 (2.6%) cases of rheumatoid arthritis (RA), 5 cases (1.3%) of systemic lupus erythematosus (SLE), and 59 (15.5%) cases of undifferentiated connective tissue disease (UCTD). 235 (61.7%) individuals did not develop CTD over a median time of 5.9 (2.9-8.1) years after the earliest autoantibody detection. Elevated ESR (>20 mm/h), RF positivity (>20 IU/ml), and female gender were identified as independent risk factors for CTD among the anti-SSAantibody-positive individuals. Anti-SSA antibodies were found in 17 among approximately 1000 individuals without a history of autoimmune diseases. Anti-SSA antibody-positive individuals are advised to periodically monitor thyroid function. Elevated ESR (>20 mm/h), female gender, and rheumatoid factor positivity may delineate a high-risk cohort for CTDs.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970764","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}
Our ability to understand the cellular complexity of tissues has been revolutionised in recent years with significant advances in proteogenomic technologies including those enabling spatial analyses. This has led to numerous consortium efforts, such as the human cell atlas (HCA) initiative which aims to profile all cells in the human body in healthy and diseased contexts. The availability of such information will subsequently lead to the identification of novel biomarkers of disease and of course therapeutic avenues. However, before such an atlas of any given healthy or diseased tissue can be generated, several factors should be considered including which specific techniques are optimal for the biological question at hand. In this review, we aim to highlight some of the considerations we believe to be important in the experimental design and analysis process, with the goal of helping to navigate the rapidly changing landscape of technologies available.
{"title":"Implementing distinct spatial proteogenomic technologies; opportunities, challenges, and key considerations.","authors":"Bram Verstappe, Charlotte L Scott","doi":"10.1093/cei/uxae077","DOIUrl":"https://doi.org/10.1093/cei/uxae077","url":null,"abstract":"<p><p>Our ability to understand the cellular complexity of tissues has been revolutionised in recent years with significant advances in proteogenomic technologies including those enabling spatial analyses. This has led to numerous consortium efforts, such as the human cell atlas (HCA) initiative which aims to profile all cells in the human body in healthy and diseased contexts. The availability of such information will subsequently lead to the identification of novel biomarkers of disease and of course therapeutic avenues. However, before such an atlas of any given healthy or diseased tissue can be generated, several factors should be considered including which specific techniques are optimal for the biological question at hand. In this review, we aim to highlight some of the considerations we believe to be important in the experimental design and analysis process, with the goal of helping to navigate the rapidly changing landscape of technologies available.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916226","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}
Mathilde A M Chayé, Oscar R J van Hengel, Astrid L Voskamp, Arifa Ozir-Fazalalikhan, Marion H König, Koen A Stam, Mikhael D Manurung, Yoanne D Mouwenda, Yvonne A Aryeetey, Agnes Kurniawan, Yvonne C M Kruize, Erliyani Sartono, Anne-Marie Buisman, Maria Yazdanbakhsh, Tamar Tak, Hermelijn H Smits
B-cells play a critical role in the formation of immune responses against pathogens by acting as antigen-presenting cells, by modulating immune responses and by generating immune memory and antibody responses. Here, we studied B-cell subset distributions between regions with higher and lower microbial exposure, i.e. by comparing peripheral blood B-cells from people living in Indonesia or Ghana to those from healthy Dutch residents using a 36-marker mass cytometry panel. By applying an unbiased multidimensional approach, we observed differences in the balance between the naïve and memory compartments, with higher CD11c+ and double negative (DN-IgDnegCD27neg) memory (M)B-cells in individuals from rural tropical areas, and conversely lower naïve B-cells compared to residents from an area with less pathogen exposure. Furthermore, characterization of total B-cell populations, CD11c+, DN and Breg cells showed the emergence of specific memory clusters in individuals living in rural tropical areas. Some of these differences were more pronounced in children compared to adults and suggest that a higher microbial exposure accelerates memory B cell formation, which 'normalizes' with age.
B 细胞通过充当抗原递呈细胞、调节免疫反应以及产生免疫记忆和抗体反应,在形成针对病原体的免疫反应中发挥着至关重要的作用。在这里,我们研究了微生物暴露程度较高和较低的地区之间的 B 细胞亚群分布情况,即使用 36 标记的质控细胞仪面板,将印度尼西亚或加纳居民的外周血 B 细胞与健康荷兰居民的外周血 B 细胞进行比较。通过采用一种无偏多维方法,我们观察到幼稚细胞和记忆细胞之间的平衡存在差异,来自热带农村地区的人体内CD11c+和双阴性(DN-IgDnegCD27neg)记忆(M)B细胞较高,相反,与来自病原体接触较少地区的居民相比,幼稚B细胞较低。此外,对总 B 细胞群、CD11c+、DN 和 Breg 细胞的特征分析表明,热带农村地区的居民出现了特定的记忆集群。其中一些差异在儿童身上比在成人身上更为明显,这表明较高的微生物暴露会加速记忆 B 细胞的形成,而这种形成会随着年龄的增长而 "正常化"。
{"title":"Multi-dimensional analysis of B cells reveals the expansion of memory and regulatory B cell clusters in humans living in rural tropical areas.","authors":"Mathilde A M Chayé, Oscar R J van Hengel, Astrid L Voskamp, Arifa Ozir-Fazalalikhan, Marion H König, Koen A Stam, Mikhael D Manurung, Yoanne D Mouwenda, Yvonne A Aryeetey, Agnes Kurniawan, Yvonne C M Kruize, Erliyani Sartono, Anne-Marie Buisman, Maria Yazdanbakhsh, Tamar Tak, Hermelijn H Smits","doi":"10.1093/cei/uxae074","DOIUrl":"https://doi.org/10.1093/cei/uxae074","url":null,"abstract":"<p><p>B-cells play a critical role in the formation of immune responses against pathogens by acting as antigen-presenting cells, by modulating immune responses and by generating immune memory and antibody responses. Here, we studied B-cell subset distributions between regions with higher and lower microbial exposure, i.e. by comparing peripheral blood B-cells from people living in Indonesia or Ghana to those from healthy Dutch residents using a 36-marker mass cytometry panel. By applying an unbiased multidimensional approach, we observed differences in the balance between the naïve and memory compartments, with higher CD11c+ and double negative (DN-IgDnegCD27neg) memory (M)B-cells in individuals from rural tropical areas, and conversely lower naïve B-cells compared to residents from an area with less pathogen exposure. Furthermore, characterization of total B-cell populations, CD11c+, DN and Breg cells showed the emergence of specific memory clusters in individuals living in rural tropical areas. Some of these differences were more pronounced in children compared to adults and suggest that a higher microbial exposure accelerates memory B cell formation, which 'normalizes' with age.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916227","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}
Leonardo Oliveira Mendonça, Vinicius N C Leal, Mariela V Roa, Samar Freschi Barros, Jorge Kalil, Alessandra Pontillo
The aim of this study is to investigate the inflammasome dysregulation in peripheral blood leukocytes of VEXAS patients. The constitutive and in vitro triggered activation of inflammasome in PBMC and neutrophils was analysed in two Brazilian patients with typical UBA1 mutations, and compared with heathy donors. Our findings highlight the constitutive activation of caspase-1 in VEXAS leukocytes, accompanied by increased plasma levels of IL-18. Furthermore, upon stimulation of isolated peripheral blood mononuclear cells (PBMC) and neutrophils, we observed not only the exhaustion of NLRP3 and NLRP1/CARD8 pathways in VEXAS PBMC but also a significant increase in NLRP3-mediated NETs release in VEXAS neutrophils. These findings support previous studies on the contribution of the inflammasome to VEXAS pathogenesis, identifying at least two profoundly affected pathways (NLRP3 and NLRP1/CARD8) in VEXAS peripheral blood.
{"title":"Unexplained fever with consumptive syndrome in the elderly: two cases of VEXAS syndrome with inflammasome dysregulation.","authors":"Leonardo Oliveira Mendonça, Vinicius N C Leal, Mariela V Roa, Samar Freschi Barros, Jorge Kalil, Alessandra Pontillo","doi":"10.1093/cei/uxae069","DOIUrl":"https://doi.org/10.1093/cei/uxae069","url":null,"abstract":"<p><p>The aim of this study is to investigate the inflammasome dysregulation in peripheral blood leukocytes of VEXAS patients. The constitutive and in vitro triggered activation of inflammasome in PBMC and neutrophils was analysed in two Brazilian patients with typical UBA1 mutations, and compared with heathy donors. Our findings highlight the constitutive activation of caspase-1 in VEXAS leukocytes, accompanied by increased plasma levels of IL-18. Furthermore, upon stimulation of isolated peripheral blood mononuclear cells (PBMC) and neutrophils, we observed not only the exhaustion of NLRP3 and NLRP1/CARD8 pathways in VEXAS PBMC but also a significant increase in NLRP3-mediated NETs release in VEXAS neutrophils. These findings support previous studies on the contribution of the inflammasome to VEXAS pathogenesis, identifying at least two profoundly affected pathways (NLRP3 and NLRP1/CARD8) in VEXAS peripheral blood.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141906030","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}