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Substance P and neurokinin 1 receptor boost the pathogenicity of granulocyte-macrophage colony-stimulating factor-producing T helper cells in dry eye disease. P物质和神经激肽1受体增强粒细胞-巨噬细胞集落刺激因子生成T辅助细胞在干眼病中的致病性
IF 4.1 4区 医学 Q2 IMMUNOLOGY Pub Date : 2025-01-01 DOI: 10.1111/sji.13434
Hua Rong, Hai Yang, Qingqing Liu, Hui Zhang, Shaolin Wang

Dry eye disease (DED) is an inflammatory disorder in which CD4+ T cells play a significant role in its pathogenesis. A CD4+ T cell subset termed granulocyte-macrophage colony-stimulating factor-producing T helper (ThGM) cells would contribute to DED pathogenesis. However, the mechanisms by which the activity of ThGM cells is modulated are not thoroughly understood. In this research, we characterized the effects of neurokinin 1 receptor (NK1R) and neurokinin 2 receptor (NK2R) on ThGM cells and T helper 1 (Th1) cells in a murine DED model. We found that ThGM cells expressed NK1R and NK2R, whereas Th1 cells predominantly expressed NK1R. Furthermore, substance P and neurokinin A (NKA), the ligands of NK1R and NK2R, were upregulated in post-DED LNs and conjunctivae. Substance P significantly promoted granulocyte-macrophage colony-stimulating factor (GM-CSF) expression while mildly upregulating the expression of interferon-gamma (IFN-γ) and interleukin 2 (IL-2) in ThGM cells. By contrast, NKA did not change GM-CSF expression but significantly increased IFN-γ expression in ThGM cells. Importantly, the adoptive transfer of NK1R-expressing ThGM cells significantly exacerbated DED, whereas the transfer of NK1R-knockdown ThGM cells weakly aggravated DED. NK2R knockdown in ThGM cells did not affect DED progression. In conclusion, this study identifies the substance P-NK1R axis as a novel mechanism that reinforces the pathogenicity of ThGM cells in DED.

干眼病(Dry eye disease, DED)是一种炎症性疾病,CD4+ T细胞在其发病机制中起重要作用。CD4+ T细胞亚群称为粒细胞-巨噬细胞集落刺激因子产生T辅助细胞(ThGM)可能有助于DED的发病。然而,调控ThGM细胞活性的机制尚不完全清楚。在本研究中,我们在小鼠DED模型中表征了神经激肽1受体(NK1R)和神经激肽2受体(NK2R)对ThGM细胞和T辅助1 (Th1)细胞的影响。我们发现ThGM细胞表达NK1R和NK2R,而Th1细胞主要表达NK1R。此外,NK1R和NK2R的配体P物质和神经激肽A (NKA)在ded后的LNs和结膜中表达上调。P物质显著促进ThGM细胞中粒细胞-巨噬细胞集落刺激因子(GM-CSF)的表达,同时轻度上调干扰素-γ (IFN-γ)和白细胞介素2 (IL-2)的表达。相比之下,NKA没有改变ThGM细胞中GM-CSF的表达,但显著增加了IFN-γ的表达。重要的是,表达nk1r的ThGM细胞的过继性转移显著加重了DED,而nk1r敲低的ThGM细胞的过继性转移则轻度加重了DED。ThGM细胞中NK2R敲低不影响DED的进展。总之,本研究确定了P-NK1R轴物质是增强ThGM细胞在DED中的致病性的新机制。
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引用次数: 0
Expression of STAT- and T-cell-related genes in women with first-line treatment of relapsing-remitting multiple sclerosis. 接受一线治疗的女性复发性多发性硬化症患者中 STAT 和 T 细胞相关基因的表达。
IF 4.1 4区 医学 Q2 IMMUNOLOGY Pub Date : 2025-01-01 Epub Date: 2024-11-15 DOI: 10.1111/sji.13424
Ludmiła Szewczak, Maja Machcińska, Magdalena Kierasińska, Urszula Zawadzka-Więch, Marta Maruszewska-Cheruiyot, Paweł Majewski, Anna Karlińska, Rafał Rola, Katarzyna Donskow-Łysoniewska

Relapsing-remitting multiple sclerosis is associated with changes in Jak/STAT pathways in immune cells, but the influence of disease-modifying drugs on these pathways is poorly understood. The aim of this study was to evaluate the impact of first-line disease-modifying drugs used in treatment of RRMS on expression of the STAT pathway and T-cell-related genes in the blood and on serum concentrations of sgp130 and TGF-β1 in women, as well as on the level of phosphorylated STAT3 and STAT5 proteins in T cells of untreated patients and heathy controls. Expression of STAT1, STAT3, STAT5A, STAT5B, SOCS1, SOCS3, FOXP3, IKZF2, RORC and ICOS genes in the blood of untreated RRMS patients, in the blood of patients treated with interferon-β, glatiramer acetate, dimethyl fumarate or teriflunomide and in the blood of healthy controls was evaluated using droplet digital PCR. Serum concentrations of sgp130 and TGF-β1 were evaluated by ELISA. Phosphorylated STAT3 and STAT5 protein levels in T cells were evaluated by flow cytometry. STAT3 gene expression was significantly higher in untreated patients than in healthy control, but the level of phosphorylated STAT3 in T cells was significantly lower. Patients treated with interferon-β or dimethyl fumarate had significantly lower STAT3 gene expression. Patients treated with teriflunomide had higher STAT1 gene expression, than untreated patients. Patients treated with dimethyl fumarate also had significantly lower RORC gene expression than untreated patients. The study shows the impact of drugs used in first-line treatment of relapsing-remitting multiple sclerosis on expression of STAT and T-cell-related genes.

复发性多发性硬化症与免疫细胞中Jak/STAT通路的变化有关,但人们对疾病调节药物对这些通路的影响知之甚少。本研究的目的是评估用于治疗 RRMS 的一线疾病调节药物对血液中 STAT 通路和 T 细胞相关基因的表达、女性血清中 sgp130 和 TGF-β1 浓度的影响,以及对未经治疗的患者和健康对照组 T 细胞中磷酸化 STAT3 和 STAT5 蛋白水平的影响。使用液滴数字 PCR 评估了未经治疗的 RRMS 患者血液中、接受干扰素-β、醋酸格拉替雷、富马酸二甲酯或特氟隆胺治疗的患者血液中以及健康对照组血液中 STAT1、STAT3、STAT5A、STAT5B、SOCS1、SOCS3、FOXP3、IKZF2、RORC 和 ICOS 基因的表达情况。血清中 sgp130 和 TGF-β1 的浓度通过 ELISA 进行评估。流式细胞术评估了 T 细胞中磷酸化 STAT3 和 STAT5 蛋白水平。未经治疗的患者 STAT3 基因表达明显高于健康对照组,但 T 细胞中磷酸化 STAT3 的水平明显低于健康对照组。接受干扰素-β或富马酸二甲酯治疗的患者的STAT3基因表达量明显较低。与未接受治疗的患者相比,接受特立氟胺治疗的患者 STAT1 基因表达较高。接受富马酸二甲酯治疗的患者的 RORC 基因表达也明显低于未接受治疗的患者。这项研究显示了用于复发性多发性硬化症一线治疗的药物对 STAT 和 T 细胞相关基因表达的影响。
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引用次数: 0
Adjuvant alum regulates the eIF2a-GATA3 axis in CD4+ T cells to influence allergen immunotherapy. 明矾佐剂可调节 CD4+ T 细胞中的 eIF2a-GATA3 轴,从而影响过敏原免疫疗法。
IF 4.1 4区 医学 Q2 IMMUNOLOGY Pub Date : 2025-01-01 Epub Date: 2024-11-19 DOI: 10.1111/sji.13419
Yan Feng, Zhishou Zhang, Hui Huangfu, Haiyang Han, Bailing Xie, Shuo Song, Tao Liu, Yunfang An, Pingchang Yang

Allergen-specific immunotherapy (AIT) is an aetiology-targeting therapy for allergic diseases. The therapeutic mechanism of AIT is not fully understood yet. Endoplasmic reticulum stress is associated with the pathogenesis of allergic disorders. This study aims to elucidate the effects of AIT on suppressing allergic response through regulating endoplasmic reticulum stress. In this study, patients with perennial allergic rhinitis were recruited. AIT was conducted for the patients. An allergic rhinitis (AR) mouse model was established with mite extracts as allergens. We found that AIT modulated the endoplasmic reticulum stress status in peripheral CD4+ T cells in patients with allergic rhinitis. The intensity of endoplasmic reticulum stress associated the PERK (protein kinase RNA-like endoplasmic reticulum kinase)-eIF2a (eukaryotic translation initiation factor 2a) axis in CD4+ T cells was upregulated by AIT, which was closely associated with the improvement in allergic rhinitis response after AIT. eIF2a interacted with GATA3 to downregulate the IL4 gene transcription in CD4+ T cells. High doses of aluminium hydroxide (alum) in AIT vaccines enhanced the activity of XBP1 to suppress eIF2a in CD4+ T cells. AIT containing a low dose of alum effectively mitigated the experimental allergic rhinitis, while the AIT without alum or a high dose of alum exacerbated the experimental allergic rhinitis. In conclusion, the alum adjuvant in allergen vaccines can regulate the activity of eIF2a to regulate the expression of Th2 cytokines in CD4+ T cells. Manipulating the alum dose in AIT vaccines has the potential to enhance the therapeutic effects of AIT.

过敏原特异性免疫疗法(AIT)是一种针对过敏性疾病的病原学疗法。过敏原特异性免疫疗法的治疗机制尚未完全明了。内质网应激与过敏性疾病的发病机制有关。本研究旨在阐明 AIT 通过调节内质网应激抑制过敏反应的作用。本研究招募了常年过敏性鼻炎患者。对患者进行了 AIT 治疗。以螨虫提取物为过敏原,建立了过敏性鼻炎(AR)小鼠模型。我们发现,AIT 可调节过敏性鼻炎患者外周 CD4+ T 细胞的内质网应激状态。AIT 上调了 CD4+ T 细胞中与 PERK(蛋白激酶 RNA 样内质网激酶)-eIF2a(真核翻译起始因子 2a)轴相关的内质网应激强度,这与 AIT 后过敏性鼻炎反应的改善密切相关。AIT 疫苗中的高剂量氢氧化铝(明矾)增强了 XBP1 抑制 CD4+ T 细胞中 eIF2a 的活性。含有低剂量明矾的 AIT 能有效缓解实验性过敏性鼻炎,而不含明矾或高剂量明矾的 AIT 则会加重实验性过敏性鼻炎。总之,过敏原疫苗中的明矾佐剂可以调节 eIF2a 的活性,从而调节 CD4+ T 细胞中 Th2 细胞因子的表达。调节过敏原疫苗中明矾的剂量有可能增强过敏原疫苗的治疗效果。
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引用次数: 0
Production of novel peptide-targeting antibodies for anti-Müllerian hormone receptor 2 and induction of cytotoxicity in ovarian cancer cells. 生产新型抗缪勒氏管激素受体 2 多肽靶向抗体并诱导卵巢癌细胞产生细胞毒性。
IF 4.1 4区 医学 Q2 IMMUNOLOGY Pub Date : 2025-01-01 Epub Date: 2024-11-25 DOI: 10.1111/sji.13426
Çağrı Şakalar, Büşra Kurt, Sedat Sezen, Savaş Kaya

Ovarian cancer is generally diagnosed at late stages. Monoclonal antibodies (MAbs) targeting antigens in ovarian cancer are used in the clinic. Anti-Müllerian hormone receptor type 2 (AMHR2) is a receptor highly expressed in ovarian cancer and it is a potential target antigen for immunotherapy. Extracellular domain of AMHR2 was analysed in terms of 3D structure and physicochemical properties, and 3 peptide sequences (Peptides 1, 7 and 11) were determined as targets. MAb production protocol was performed, and 6 MAb clones showing high affinity for peptides were obtained. P3B1, P10A10, P10B6 and P2A6 clones were for peptide 11 (P11), P2C9 was for P7, and P6C5 was for P1. Antibody isotype of P2A6 was IgG2a and the others were of IgG1 isotype. MAb binding to the native recombinant protein (AMHR2-Fc) was analysed by enzyme-linked immunosorbent assay (ELISA) and MAb binding to AMHR2 expressed by SKOV-3 ovarian cancer cells was analysed by western blot and immunofluorescent staining. P3B1 showed strong, P10A10, P10B6 and P2C9 showed medium affinity for the native protein (AMHR2-Fc). P3B1 and P2C9 showed strong binding in western blot analysis. Clones showed moderate binding in immunoflorescent staining. A complement dependent cytotoxicity (CDC) experiment was conducted using MAbs and transfected SKOV-3 cells. P3B1 induced a significant CDC. Variable regions of P3B1 MAb were sequenced. In conclusion, MAbs for three different regions of AMHR2 were produced. One clone was shown to induce cytotoxicity in ovarian cancer cells and its sequence was determined for future use as a humanised therapeutic MAb.

卵巢癌通常在晚期才被诊断出来。针对卵巢癌抗原的单克隆抗体(MAbs)已用于临床。抗缪勒氏管激素受体2型(AMHR2)是一种在卵巢癌中高度表达的受体,也是一种潜在的免疫疗法靶抗原。研究人员对 AMHR2 的胞外结构域进行了三维结构和理化性质分析,并确定了 3 个肽序列(肽 1、肽 7 和肽 11)作为靶标。进行了 MAb 生产规程,获得了 6 个对肽具有高亲和力的 MAb 克隆。P3B1、P10A10、P10B6 和 P2A6 克隆针对肽 11(P11),P2C9 针对 P7,P6C5 针对 P1。P2A6 的抗体同种型为 IgG2a,其他抗体同种型为 IgG1。酶联免疫吸附试验(ELISA)分析了 MAb 与原生重组蛋白(AMHR2-Fc)的结合情况,Western 印迹和免疫荧光染色分析了 MAb 与 SKOV-3 卵巢癌细胞表达的 AMHR2 的结合情况。P3B1 与原生蛋白(AMHR2-Fc)的亲和力较强,P10A10、P10B6 和 P2C9 与原生蛋白(AMHR2-Fc)的亲和力中等。P3B1 和 P2C9 在 Western 印迹分析中显示出很强的结合力。克隆在免疫荧光染色中显示出中等程度的结合力。使用 MAbs 和转染的 SKOV-3 细胞进行了补体依赖性细胞毒性(CDC)实验。P3B1 诱导了明显的 CDC。对 P3B1 MAb 的可变区进行了测序。总之,针对 AMHR2 的三个不同区域制备了 MAb。其中一个克隆可诱导卵巢癌细胞产生细胞毒性,其序列已被确定,将来可用作人源化治疗 MAb。
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引用次数: 0
Association between peripheral activated naive and double negative 2 B-cell subsets and clinical parameters in lupus nephritis patients. 狼疮性肾炎患者外周活化的天真和双阴性 2 型 B 细胞亚群与临床指标之间的关系。
IF 4.1 4区 医学 Q2 IMMUNOLOGY Pub Date : 2025-01-01 Epub Date: 2024-11-26 DOI: 10.1111/sji.13427
Kittikorn Wangriatisak, Charlotte de Vries, Ravi Kumar Sharma, Wenqi Huang, Caroline Grönwall, Prapaporn Pisitkun, Iva Gunnarsson, Vivianne Malmström, Patchanee Chootong, Francesca Faustini

Altered composition of B-cell compartments is a known feature in patients with systemic lupus erythematosus (SLE). However, deep characterisation of B-cell subsets and their relation to clinical manifestations and disease activity in patients is limited. In this study, we analysed peripheral B-cell subsets phenotype in SLE (n = 35) and healthy controls (HCs, n = 15) by spectral flow cytometry. Disease activity was stratified as inactive (SLEDAI-2 K score 0, n = 2), mild (SLEDAI-2 K score 1-5, n = 12), moderate (SLEDAI-2 K score 6-10, n = 6) or high (SLEDAI-2 K > 10, n = 15). An elevated proportion of activated naive (aNAV), double negative 2 (DN2) and plasmablasts (PB) was observed in patients with high disease activity, compared to other groups of patients and HCs. An upregulation of BTLA was found on both aNAV and DN2 and shifted to lower levels with increasing disease activity. In lupus nephritis (LN) patients (n = 21), aNAV B-cells were especially expanded and positively correlated with DN2 (r = 0.5, p = 0.019) and PB (r = 0.43, p = 0.048). Also, correlation was observed between DN2 and PB (r = 0.6, p = 0.003). Moreover, aNAV frequencies positively correlated with SLEDAI-2 K score, and negatively with the complement fractions C3 and C4. Further, aNAV, DN2 and PB were more expanded in association with positive anti-dsDNA antibodies, rather than other antibody specificities (anti-Sm). These data suggest roles of extrafollicular B cells as key players in disease development of LN. Their association with presence of anti-dsDNA antibodies may indicate their value as candidate biomarkers of kidney involvement in SLE.

B细胞组成的改变是系统性红斑狼疮(SLE)患者的一个已知特征。然而,对B细胞亚群及其与患者临床表现和疾病活动的关系的深入研究还很有限。在这项研究中,我们通过光谱流式细胞术分析了系统性红斑狼疮患者(35 人)和健康对照组(15 人)的外周 B 细胞亚群表型。疾病活动度分为非活动(SLEDAI-2 K 评分 0,n = 2)、轻度(SLEDAI-2 K 评分 1-5,n = 12)、中度(SLEDAI-2 K 评分 6-10,n = 6)或高度(SLEDAI-2 K > 10,n = 15)。与其他组患者和 HCs 相比,在疾病活动度高的患者中观察到活化的幼稚细胞(aNAV)、双阴性 2 型细胞(DN2)和浆细胞(PB)比例升高。在 aNAV 和 DN2 上都发现了 BTLA 的上调,并随着疾病活动性的增加而转为较低水平。在狼疮性肾炎(LN)患者(n = 21)中,aNAV B 细胞尤其增大,并与 DN2(r = 0.5,p = 0.019)和 PB(r = 0.43,p = 0.048)呈正相关。DN2 和 PB 之间也存在相关性(r = 0.6,p = 0.003)。此外,aNAV 频率与 SLEDAI-2 K 评分呈正相关,与补体分数 C3 和 C4 呈负相关。此外,aNAV、DN2 和 PB 与抗dsDNA 抗体阳性相关,而不是与其他抗体特异性(抗-Sm)相关。这些数据表明,滤泡外 B 细胞是 LN 疾病发展的关键因素。它们与抗dsDNA抗体的存在有关,这可能表明它们是系统性红斑狼疮肾脏受累的候选生物标志物。
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引用次数: 0
Tetraspanin32 (TSPAN32) is downregulated in rheumatoid arthritis: Evidence from animal models and patients. Tetraspanin32 (TSPAN32) 在类风湿性关节炎中被下调:来自动物模型和患者的证据
IF 4.1 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-12-01 Epub Date: 2024-09-27 DOI: 10.1111/sji.13410
Katia Mangano, Jose' Francisco Munoz-Valle, Claudia Azucena Palafox-Sánchez, Maria Cristina Petralia, Gian Marco Leone, Paolo Fagone, Ferdinando Nicoletti

This study aimed to investigate the role of TSPAN32, a member of the tetraspanin family, in rheumatoid arthritis (RA). The objective was to assess the expression levels of TSPAN32 in experimental RA models and in RA patient immune cells, exploring its potential as a regulatory factor in RA pathogenesis. The study employed adjuvant-induced arthritis in rats and collagen-induced arthritis (CIA) in mice as experimental models. Ex vivo analyses included evaluating TSPAN32 expression in immune cells at different stages of the disease. In silico data analysis involved examining transcriptomic datasets from drug-naïve and treated RA patients to correlate TSPAN32 expression with clinical parameters. TSPAN32 overexpression experiments in splenocytes from CIA mice aimed to demonstrate its functional impact on antigen-specific immune responses. The animal models revealed a significant downregulation of TSPAN32, particularly in synovial-infiltrating T cells. Also, TSPAN32 overexpression inhibited pro-inflammatory cytokine production in splenocytes. In RA patients, TSPAN32 was consistently downregulated in circulating and synovial-infiltrating T cells, as well as in CD8+ T cells, B cells and NK cells. Drug treatment did not significantly alter TSPAN32 levels. Negative correlations were observed between TSPAN32 expression and inflammatory markers (CRP, ESR) and clinical scores (SDAI) in RA patients. This study suggests that reduced TSPAN32 expression characterizes pathogenic T-cell populations in RA, highlighting its potential as biomarker for inflammation and disease activity. TSPAN32 may play a crucial role in shaping adaptive immune responses in RA, opening avenues for novel therapeutic strategies targeting this tetraspanin family member.

本研究旨在探讨四泛蛋白家族成员 TSPAN32 在类风湿性关节炎(RA)中的作用。目的是评估TSPAN32在实验性RA模型和RA患者免疫细胞中的表达水平,探索其作为RA发病机制调控因子的潜力。研究采用佐剂诱导的大鼠关节炎和胶原诱导的小鼠关节炎(CIA)作为实验模型。体内外分析包括评估疾病不同阶段免疫细胞中 TSPAN32 的表达。硅学数据分析包括检查未接受过药物治疗和接受过药物治疗的 RA 患者的转录组数据集,以将 TSPAN32 的表达与临床参数联系起来。TSPAN32在CIA小鼠脾细胞中的过表达实验旨在证明其对抗原特异性免疫反应的功能影响。动物模型显示 TSPAN32 的表达明显下调,尤其是在滑膜浸润 T 细胞中。此外,TSPAN32 的过表达抑制了脾细胞中促炎细胞因子的产生。在 RA 患者中,TSPAN32 在循环和滑膜浸润 T 细胞以及 CD8+ T 细胞、B 细胞和 NK 细胞中持续下调。药物治疗并未明显改变 TSPAN32 的水平。在 RA 患者中,TSPAN32 的表达与炎症指标(CRP、ESR)和临床评分(SDAI)之间呈负相关。这项研究表明,TSPAN32表达的减少是RA致病性T细胞群的特征,突出了其作为炎症和疾病活动生物标志物的潜力。TSPAN32可能在形成RA的适应性免疫反应中起着至关重要的作用,为针对这种四泛蛋白家族成员的新型治疗策略开辟了道路。
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引用次数: 0
Immunomodulatory effect of mesenchymal stem cells-derived extracellular vesicles to modulate the regulatory T cells and Th1/Th2 imbalance in peripheral blood mononuclear cells of patients with allergic rhinitis. 间充质干细胞衍生的细胞外囊泡对调节过敏性鼻炎患者外周血单核细胞中调节性T细胞和Th1/Th2失衡的免疫调节作用。
IF 4.1 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-12-01 Epub Date: 2024-10-29 DOI: 10.1111/sji.13416
Zhao Wang, Khawar Ali Shahzad, Xuran Li, Boyu Cai, Maoxiang Xu, Jiaojiao Li, Fei Tan

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have shown promising immunomodulatory capabilities for a variety of clinical conditions. However, the potential regulatory mechanisms of MSC-EVs in allergic rhinitis (AR) remain unexplored. The present study was designed to investigate the immunomodulatory effect of MSC-EVs in patients with AR. Peripheral blood mononuclear cells (PBMCs) were isolated from AR patients. The number of peripheral CD4+Foxp3+IL-17+, CD4+Foxp3+IL-17- and CD4+Foxp3-IL-17+ T cells in healthy controls and AR patients were evaluated using flow cytometry. Therapeutic effect of MSC-EVs was determined by detecting IFN-γ, IL-4, IL-17 and IL-10 cytokines in supernatant by ELISA and flow cytometry. The mean fluorescence intensity (MFI) was calculated in PBMCs for IL-10, IL-17 and TGF-β on T cells after MSC-EVs treatment. Bioinformatic analysis of microRNA was performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. CD4+Foxp3+IL-17+ T cells expression in PBMCs was higher in the AR group and the balance of Treg/Th17 was tilted towards Th17 cells. Supernatant from AR patients revealed that MSC-EVs treatment upregulated IL-10 and IFN-γ, and downregulated IL-4 and IL-17. EVs treatment effectively re-established Th1(CD4+IFN-γ+cells)/Th2(CD4+IL-4+cells) balance, reduced CD4+IL-17+ and increased CD4+IL-10+ and CD4+TGF-β+ cells. The MFI of IL-10 and TGF-β in CD4+CD25+CD127- T cells were higher, whereas lower levels of IL-17 were observed. Bioinformatic analysis revealed that the TGF-β, Wnt signalling pathways and STAT5 transcription factor might mechanistically support the immunomodulatory effect of MSC-EVs. This study presents the immunomodulatory effect of MSC-EVs in PBMCs from AR patients. The results provide a new therapeutic strategy for AR.

间充质干细胞衍生的细胞外囊泡(MSC-EVs)已在多种临床疾病中显示出良好的免疫调节能力。然而,间充质干细胞-细胞外小泡在过敏性鼻炎(AR)中的潜在调节机制仍有待探索。本研究旨在探讨间充质干细胞-EVs对过敏性鼻炎患者的免疫调节作用。研究人员从 AR 患者体内分离出外周血单核细胞(PBMCs)。使用流式细胞术评估了健康对照组和 AR 患者外周 CD4+Foxp3+IL-17+、CD4+Foxp3+IL-17- 和 CD4+Foxp3-IL-17+ T 细胞的数量。通过 ELISA 和流式细胞术检测上清液中的 IFN-γ、IL-4、IL-17 和 IL-10 细胞因子,确定间充质干细胞-EVs 的治疗效果。计算了间充质干细胞-EVs 处理后 T 细胞上 IL-10、IL-17 和 TGF-β 在 PBMCs 中的平均荧光强度(MFI)。通过基因本体(GO)和京都基因组百科全书(KEGG)分析对 microRNA 进行生物信息学分析。AR 组 PBMCs 中 CD4+Foxp3+IL-17+ T 细胞的表达量更高,Treg/Th17 的平衡向 Th17 细胞倾斜。AR患者的上清液显示,间充质干细胞-EVs治疗可上调IL-10和IFN-γ,下调IL-4和IL-17。EVs处理能有效重建Th1(CD4+IFN-γ+细胞)/Th2(CD4+IL-4+细胞)平衡,减少CD4+IL-17+,增加CD4+IL-10+和CD4+TGF-β+细胞。CD4+CD25+CD127- T细胞中IL-10和TGF-β的MFI较高,而IL-17的水平较低。生物信息学分析表明,TGF-β、Wnt 信号通路和 STAT5 转录因子可能从机理上支持间充质干细胞-EVs 的免疫调节作用。本研究揭示了间充质干细胞-EVs 对 AR 患者 PBMCs 的免疫调节作用。研究结果为AR提供了一种新的治疗策略。
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引用次数: 0
A sex-dependent algorithm including kappa free light chain for multiple sclerosis diagnosis. 用于诊断多发性硬化症的包括卡帕游离轻链在内的性别依赖算法。
IF 4.1 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-12-01 Epub Date: 2024-11-06 DOI: 10.1111/sji.13421
Julia Maroto-García, Minerva Mañez, Ana Martínez-Escribano, Ahlam Hachmaoui-Ridaoui, Carmen Ortiz, Carmen Ábalos-García, Inmaculada Gónzález, Ángela García de la Torre, Maximiliano Ruiz-Galdón

Multiple sclerosis (MS) diagnosis includes the presence of restricted oligoclonal bands (OCB) in cerebrospinal fluid (CSF), but it has several limitations, as it is an observer-dependent time-consuming technique and offers a dichotomous result. Thus kappa free light chains (KFLC) have emerged as a quantitative alternative. However, the cut-off values for KFLC have not been well established yet and it is not clear if differences between sexes exist. We aim to evaluate these and to compare the diagnostic accuracy of KFLC concentrations and their related indexes versus OCB. For that purpose, paired CSF and serum samples were collected and immediately processed for albumin, total protein, immunoglobulins and OCB, then frozen at -20°C. KFLC was measured in a BN II (Siemens Healthineers, Germany). KFLC-derived indexes were calculated. Diagnostic accuracy was evaluated by the area under the curve (AUC), Youden's index and odds ratio. From the 193 patients included, 56 were classified as MS according to the 2017 McDonald criteria. K-index, Q KFLC and Reiber's diagram showed good accuracy in MS diagnosis when studied distinguishing between sexes, similar to OCB. Cut-offs for K-index and Q KFLC change substantially between sex having the highest AUC similar than OCB. A sex-dependent algorithm combining the use of K-index, Q KFLC and OCB yields the highest diagnostic accuracy. In conclusion, CSF KFLC measurement is a rapid, quantitative and easy-to-standardize tool that used through the proposed sex-dependent algorithm may reduce the number of manual OCB tests performed.

多发性硬化症(MS)的诊断包括脑脊液(CSF)中是否存在局限性寡克隆带(OCB),但这种诊断方法存在一些局限性,因为它是一种依赖于观察者的耗时技术,而且只能得出二分法的结果。因此,卡帕游离轻链(KFLC)成为一种定量替代方法。然而,KFLC 的临界值尚未得到很好的确定,性别之间是否存在差异也不清楚。我们旨在评估这些差异,并比较 KFLC 浓度及其相关指标与 OCB 的诊断准确性。为此,我们采集了配对的 CSF 和血清样本,并立即进行了白蛋白、总蛋白、免疫球蛋白和 OCB 的检测,然后冷冻于 -20°C。KFLC 由 BN II(德国西门子医疗集团)测量。计算KFLC衍生指数。诊断准确性通过曲线下面积(AUC)、尤登指数和几率比进行评估。在纳入的 193 名患者中,有 56 人根据 2017 年麦克唐纳标准被归类为多发性硬化症。在对性别进行区分时,K指数、Q KFLC和Reiber图显示了MS诊断的良好准确性,与OCB相似。K-index 和 Q KFLC 的临界值在不同性别之间变化很大,其最高 AUC 与 OCB 相似。结合使用 K-指数、Q KFLC 和 OCB 的性别相关算法可获得最高的诊断准确性。总之,CSF KFLC 测量是一种快速、定量和易于标准化的工具,通过所建议的性别依赖性算法使用该工具可减少人工 OCB 检测的次数。
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引用次数: 0
Whole exome sequencing in patients with childhood-onset systemic lupus erythematosus: Results from a Croatian national study. 儿童期系统性红斑狼疮患者的全外显子组测序:克罗地亚全国性研究的结果。
IF 4.1 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-12-01 Epub Date: 2024-10-08 DOI: 10.1111/sji.13411
Mario Sestan, Todor Arsov, Nastasia Kifer, Marijan Frkovic, Danica Grguric, Julia Ellyard, Matthew Cook, Carola G Vinuesa, Marija Jelusic

The purpose of this study was to identify new and low-frequency gene variants using whole exome sequencing (WES) in patients with childhood-onset systemic lupus erythematosus (cSLE), that may be involved in the pathogenesis of SLE. We performed WES on selected 17 trios (in some cases including other informative family members) in which the proband presented with severe, atypical clinical features, resistance to conventional therapy, a family pattern of occurrence and/or syndromic characteristics. After performing WES and analysis of gene variants, 17 novel and/or low-frequency variants were identified in 7 patients. One variant was classified as pathogenic (KMT2D, NM_003482.3:c.8626delC, predicted to truncate the protein p.(Gln2876Serfs*34)) and two as likely pathogenic according to the American College of Medical Genetics and Genomics classification guidelines (ADAR, NM_001111.3:c.2815A>G, predicted to encode p.(Ile939Val); BLK, NM_001715.2:c.211G>A, predicted to encode p.(Ala71Thr)). The other variants remain of uncertain significance at this point of time. WES is an important diagnostic and research instrument, producing a growing list of likely genes and gene variants that may be of relevance in the pathogenesis of cSLE and potentially point to novel therapeutic targets.

本研究的目的是利用全外显子组测序(WES)在儿童期发病的系统性红斑狼疮(cSLE)患者中鉴定可能与系统性红斑狼疮发病机制有关的新的低频基因变异。我们对筛选出的 17 个三联体(在某些情况下包括其他有信息的家庭成员)进行了 WES 测序,这些三联体的原型具有严重的非典型临床特征、对常规治疗有抵抗力、家族发病模式和/或综合征特征。经过 WES 和基因变异分析,在 7 名患者中发现了 17 个新型和/或低频变异。根据美国医学遗传学和基因组学学院(American College of Medical Genetics and Genomics)的分类指南,其中一个变异被归类为致病变异(KMT2D,NM_003482.3:c.8626delC,预测为截短蛋白 p.(Gln2876Serfs*34)),两个变异被归类为可能致病变异(ADAR,NM_001111.3:c.2815A>G,预测为编码蛋白 p.(Gln2876Serfs*34))。A>G,预测编码 p.(Ile939Val);BLK,NM_001715.2:c.211G>A,预测编码 p.(Ala71Thr))。其他变异的意义目前仍不确定。WES 是一种重要的诊断和研究工具,它能发现越来越多可能与系统性红斑狼疮发病机制有关的基因和基因变异,并有可能找到新的治疗靶点。
{"title":"Whole exome sequencing in patients with childhood-onset systemic lupus erythematosus: Results from a Croatian national study.","authors":"Mario Sestan, Todor Arsov, Nastasia Kifer, Marijan Frkovic, Danica Grguric, Julia Ellyard, Matthew Cook, Carola G Vinuesa, Marija Jelusic","doi":"10.1111/sji.13411","DOIUrl":"10.1111/sji.13411","url":null,"abstract":"<p><p>The purpose of this study was to identify new and low-frequency gene variants using whole exome sequencing (WES) in patients with childhood-onset systemic lupus erythematosus (cSLE), that may be involved in the pathogenesis of SLE. We performed WES on selected 17 trios (in some cases including other informative family members) in which the proband presented with severe, atypical clinical features, resistance to conventional therapy, a family pattern of occurrence and/or syndromic characteristics. After performing WES and analysis of gene variants, 17 novel and/or low-frequency variants were identified in 7 patients. One variant was classified as pathogenic (KMT2D, NM_003482.3:c.8626delC, predicted to truncate the protein p.(Gln2876Serfs*34)) and two as likely pathogenic according to the American College of Medical Genetics and Genomics classification guidelines (ADAR, NM_001111.3:c.2815A>G, predicted to encode p.(Ile939Val); BLK, NM_001715.2:c.211G>A, predicted to encode p.(Ala71Thr)). The other variants remain of uncertain significance at this point of time. WES is an important diagnostic and research instrument, producing a growing list of likely genes and gene variants that may be of relevance in the pathogenesis of cSLE and potentially point to novel therapeutic targets.</p>","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":" ","pages":"e13411"},"PeriodicalIF":4.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
F-Box and WD repeat domain containing 7 induces infectious osteomyelitis by regulating MYB stability and ubiquitination. 含 F-Box 和 WD 重复域的 7 通过调节 MYB 的稳定性和泛素化诱导传染性骨髓炎。
IF 4.1 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-12-01 Epub Date: 2024-11-01 DOI: 10.1111/sji.13414
Yongbo Wan, Gehan Jiang, Haojie Shan, Yiwei Lin, Wenyang Xia, Fuli Yin, Chaolai Jiang, Zhongmin Shi

Osteomyelitis is a bone inflammation initiated by invading pathogens. Macrophages and inflammation play essential roles in osteomyelitis. F-Box and WD repeat domain containing 7 (Fbxw7) is a tumour suppressor and E3 ubiquitin ligase. In the present study, the potential roles of Fbxw7 in osteomyelitis were explored. The mRNA level of Fbxw7 was measured in bone marrow cells from patients with osteomyelitis and Staphylococcus aureus (S. aureus)-infected macrophages. The conditional knockout mice with Fbxw7 deficiency in myeloid cells were generated. The expression of interleukin (IL)-6, IL-23a and nitric oxide synthase 2 (Nos2) was measured in S. aureus-infected Fbxw7-deficient bone marrow-derived macrophages (BMDMs). The body weight loss, bacterial burden, bone loss and formation and serum level of IL-6, IL-23 and TNF-α were measured in S. aureus-infected Fbxw7 conditional KO mice. The interacting partners of Fbxw7 were predicted using STRING and the interaction were tested. Elevated expression of Fbxw7 was observed in bone marrow cells from patients with osteomyelitis and in S. aureus-infected macrophages. The expression of IL-6, IL-23a and Nos2 was remarkably suppressed in S. aureus-infected Fbxw7-deficient BMDMs. Fbxw7 conditional knockout mice had less body weight loss, higher bacterial burden, less bone loss and formation and decreased serum level of cytokines. Fbxw7 interacted with MYB. S. aureus-infected Fbxw7-deficient BMDMs had higher level of MYB and less ubiquitination of MYB. Fbxw7 promotes osteomyelitis symptoms by regulating ubiquitination and stability of MYB.

骨髓炎是由入侵病原体引发的骨炎。巨噬细胞和炎症在骨髓炎中起着至关重要的作用。F-Box and WD repeat domain containing 7 (Fbxw7) 是一种肿瘤抑制因子和 E3 泛素连接酶。本研究探讨了 Fbxw7 在骨髓炎中的潜在作用。研究人员检测了骨髓炎患者骨髓细胞和金黄色葡萄球菌(S. aureus)感染的巨噬细胞中 Fbxw7 的 mRNA 水平。在骨髓细胞中产生了缺乏 Fbxw7 的条件性基因敲除小鼠。测量了金黄色葡萄球菌感染的骨髓巨噬细胞(BMDMs)中白细胞介素(IL)-6、IL-23a和一氧化氮合酶2(Nos2)的表达。测定了金黄色葡萄球菌感染的 Fbxw7 条件性 KO 小鼠的体重减轻、细菌负荷、骨质流失和形成以及血清中 IL-6、IL-23 和 TNF-α 的水平。利用 STRING 预测了 Fbxw7 的相互作用伙伴,并对其相互作用进行了测试。在骨髓炎患者的骨髓细胞和金黄色葡萄球菌感染的巨噬细胞中观察到 Fbxw7 的高表达。在被金黄色葡萄球菌感染的 Fbxw7 基因缺陷的 BMDMs 中,IL-6、IL-23a 和 Nos2 的表达明显受到抑制。Fbxw7条件性基因敲除小鼠体重减轻,细菌负荷增加,骨质流失和形成减少,血清细胞因子水平降低。Fbxw7 与 MYB 相互作用。金黄色葡萄球菌感染的Fbxw7缺陷BMDMs的MYB水平较高,MYB泛素化程度较低。Fbxw7通过调节MYB的泛素化和稳定性促进骨髓炎症状的出现。
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引用次数: 0
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Scandinavian Journal of Immunology
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