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Female-specific enhancement of eosinophil recruitment and activation in a type 2 innate inflammation model in the lung. 在肺部 2 型先天性炎症模型中,嗜酸性粒细胞招募和活化的女性特异性增强。
IF 3.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2024-03-12 DOI: 10.1093/cei/uxad100
Rami Karkout, Véronique Gaudreault, Lydia Labrie, Haya Aldossary, Noelia Azalde Garcia, Jichuan Shan, Elizabeth D Fixman

A sex disparity in asthma prevalence and severity exists in humans. Multiple studies have highlighted the role of innate cells in shaping the adaptive immune system in chronic asthma. To explore the sex bias in the eosinophilic response, we delivered IL-33 to the lungs of mice and delineated the kinetics by which the inflammatory response was induced. Our data demonstrate that females recruited more eosinophils capable of responding to IL-33. Eosinophil activation occurred selectively in the lung tissue and was enhanced in females at all time points. This increase was associated with increased ex vivo type 2 cytokine and chemokine production and female-specific expansion of group 2 innate lymphoid cells lacking expression of the killer-cell lectin-like receptor G1. Our findings suggest that the enhanced eosinophilic response in females is due, firstly, to a greater proportion of eosinophils recruited to the lungs in females that can respond to IL-33; and secondly, to an enhanced production of type 2 cytokines in females. Our data provide insight into the mechanisms that guide the female-specific enhancement of eosinophil activation in the mouse and form the basis to characterize these responses in human asthmatics.

人类在哮喘发病率和严重程度方面存在性别差异。多项研究强调了先天性细胞在塑造慢性哮喘适应性免疫系统中的作用。为了探索嗜酸性粒细胞反应中的性别差异,我们向小鼠肺部注射了 IL-33,并研究了诱导炎症反应的动力学过程。我们的数据表明,雌性小鼠招募的嗜酸性粒细胞对 IL-33 的反应能力更强。嗜酸性粒细胞的活化选择性地发生在肺组织中,并且在所有时间点上雌性嗜酸性粒细胞的活化都有所增强。这种增加与体内外 2 型细胞因子和趋化因子产生的增加以及缺乏杀伤细胞凝集素样受体 G1 表达的 2 组先天性淋巴细胞的女性特异性扩增有关。我们的研究结果表明,女性嗜酸性粒细胞反应增强的原因首先是女性肺部招募的嗜酸性粒细胞对 IL-33 有反应的比例更高;其次是女性 2 型细胞因子的产生增强。我们的数据让人们深入了解了小鼠嗜酸性粒细胞活化的雌性特异性增强机制,并为描述人类哮喘患者的这些反应奠定了基础。
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引用次数: 0
The CXCL10-CXCR3 axis plays an important role in Kawasaki disease. CXCL10-CXCR3轴在川崎病中起重要作用。
IF 3.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2024-03-12 DOI: 10.1093/cei/uxad125
Sho Hosaka, Kazuo Imagawa, Yusuke Yano, Lisheng Lin, Junko Shiono, Miho Takahashi-Igari, Hideki Hara, Daisuke Hayashi, Hironori Imai, Atsushi Morita, Hiroko Fukushima, Hidetoshi Takada

The precise pathogenesis of Kawasaki disease remains unknown. In an attempt to elucidate the pathogenesis of KD through the analysis of acquired immunity, we comprehensively examined the immunophenotypic changes in immune cells such as lymphocytes and monocytes along with various cytokines, focusing on differences between pre- and post- treatment samples. We found high levels of CXCL9 and CXCL10 chemokines that decreased with treatment, which coincided with a post-treatment expansion of Th1 cells expressing CXCR3. Our results show that the CXCL10-CXCR3 axis plays an important role in the pathogenesis of KD.

川崎病的确切发病机制尚不清楚。为了通过获得性免疫分析来阐明KD的发病机制,我们全面检查了免疫细胞如淋巴细胞和单核细胞以及各种细胞因子的免疫表型变化,重点研究了治疗前和治疗后样本的差异。我们发现高水平的CXCL9和CXCL10趋化因子随着治疗而降低,这与治疗后表达CXCR3的Th1细胞扩增相一致。我们的研究结果表明,CXCL10-CXCR3轴在KD的发病机制中起重要作用。
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引用次数: 0
FGL1 in plasma extracellular vesicles is correlated with clinical stage of lung adenocarcinoma and anti-PD-L1 response. 血浆细胞外囊泡中的FGL1与肺腺癌的临床分期和抗PD-L1反应相关。
IF 4.6 3区 医学 Q3 IMMUNOLOGY Pub Date : 2024-03-12 DOI: 10.1093/cei/uxad137
Yuchen Zhang, Kunpeng Zhang, Haoyu Wen, Di Ge, Jie Gu, Chunyi Zhang

Fibrinogen-like protein-1 (FGL1) is confirmed a major ligand of lymphocyte activation gene-3 which could inhibit antigen-mediated T-cell response and evade immune supervision. Although hepatocytes secrete large amounts of FGL1, its high expression also be detected in solid tumors such as lung cancer, leading to a poor efficacy of immune checkpoint inhibitors therapy. Here we reported that FGL1 was overexpressed in lung adenocarcinoma (LUAD) but not in lung squamous cell carcinoma. However, FGL1 in tissue and plasma can only distinguish LUAD patients from healthy donors and cannot correlate with clinical Tumor Node Metastasis (TNM) stage. Using lung cancer cell lines, we confirmed that FGL1 can be detected on extracellular vesicles (EVs) and we established a method using flow cytometry to detect FGL1 on the surface of EVs, which revealed that FGL1 could be secreted via EVs. Both animal model and clinical samples proved that plasma FGL1 in EVs would increase when the tumor was loaded. The level of FGL1 in plasma EVs was correlated with clinical TNM stage and tumor size, and a higher level indicated non-responsiveness to anti-programmed cell death ligand 1 (anti-PD-L1) immunotherapy. Its effect on tumor progression and immune evasion may be achieved by impairing the killing and proliferating capacities of CD8+ T cells. Our result demonstrates that FGL1 levels in plasma EVs, but not total plasma FGL1, could be a promising biomarker that plays an important role in predicting anti-PD-L1 immune therapy in LUAD and suggests a new strategy in LUAD immunotherapy.

纤维蛋白原样蛋白-1(FGL1)被证实是淋巴细胞活化基因-3(LAG3)的主要配体,可抑制抗原介导的T细胞反应,逃避免疫监视。虽然肝细胞会分泌大量的 FGL1,但在肺癌等实体瘤中也能检测到其高表达,导致免疫检查点抑制剂治疗效果不佳。我们在此报告了 FGL1 在肺腺癌(LUAD)中的高表达,但在肺鳞癌(LUSC)中却没有发现。然而,组织和血浆中的 FGL1 仅能区分 LUAD 患者和健康供体,不能与临床 TNM 分期相关联。利用肺癌细胞系,我们证实了FGL1可在细胞外囊泡(EVs)上检测到,并建立了一种利用流式细胞术检测EVs表面FGL1的方法,从而揭示了FGL1可通过EVs分泌。动物模型和临床样本均证明,肿瘤负荷时,EVs 中血浆 FGL1 的含量会增加。血浆EV中FGL1的水平与临床TNM分期和肿瘤大小相关,较高的水平表示对抗PD-L1免疫疗法无反应。它对肿瘤进展和免疫逃避的影响可能是通过损害CD8+ T细胞的杀伤和增殖能力来实现的。我们的研究结果表明,血浆EVs中的FGL1水平(而非血浆总FGL1水平)可能是一种有前途的生物标志物,在预测LUAD的抗PD-L1免疫治疗中发挥着重要作用,并为LUAD免疫治疗提出了一种新策略。
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引用次数: 0
Enhanced efficacy of the novel recombinant clone VasSF in a mouse model of antineutrophil cytoplasmic antibody-associated vasculitis. 新型重组克隆 VasSF 在抗中性粒细胞胞浆抗体相关性血管炎小鼠模型中的疗效增强。
IF 4.6 3区 医学 Q3 IMMUNOLOGY Pub Date : 2024-03-12 DOI: 10.1093/cei/uxad140
Minako Koura, Yosuke Kameoka, Fukuko Kishi, Yoshio Yamakawa, Fuyu Ito, Ryuichi Sugamata, Yuko Doi, Kazuko Uno, Toshinori Nakayama, Takashi Miki, Hiroshi Nakajima, Kazuo Suzuki, Osamu Suzuki

Based on the efficacy of intravenous immunoglobulin (IVIg) for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), we developed a recombinant single-chain-fragment variable clone, VasSF, therapeutic against AAV in a mouse model (SCG/Kj mice). VasSF is thought to bind to vasculitis-associated apolipoprotein A-II (APOA2) as a target molecule. VasSF is a promising new drug against AAV, but difficulties in the yield and purification of VasSF remain unresolved. We produced monomers of new VasSF molecules by modifying the plasmid structure for VasSF expression and simplifying the purification method using high-performance liquid chromatography. We compared the therapeutic effects between 5-day continuous administration of the monomers, as in IVIg treatment, and single shots of 5-day-equivalent doses. We also evaluated the life-prolonging effect of the single-shot treatment. Two-dimensional western blots were used to examine the binding of VasSF to APOA2. Our improved manufacturing method resulted in a 100-fold higher yield of VasSF than in our previous study. Monomerization of VasSF stabilized its efficacy. Single shots of a small amount (1/80 000 of IVIg) produced sufficient therapeutic effects, including decreased glomerular crescent formation, a decreasing trend of serum ANCA against myeloperoxidase (MPO-ANCA), decreases in multiple proinflammatory cytokines, and a trend toward prolonged survival. Two-dimensional western blots confirmed the binding of VasSF to APOA2. The newly produced pure VasSF monomers are stable and therapeutic for AAV with a single low-dose injection, possibly by removing vasculitis-associated APOA2. Thus, the new VasSF described herein is a promising drug against AAV.

基于静脉注射免疫球蛋白(IVIg)治疗抗中性粒细胞胞浆抗体(ANCA)相关性脉管炎(AAV)的疗效,我们在小鼠模型(SCG/Kj 小鼠)中开发了一种针对 AAV 的重组单链片段可变克隆 VasSF。VasSF 被认为能与脉管炎相关载脂蛋白 A-II (APOA2) 结合,成为一种靶分子。VasSF 是一种很有前途的抗 AAV 新药,但 VasSF 的产量和纯化方面的困难仍未解决。我们通过修改表达 VasSF 的质粒结构和使用高效液相色谱法简化纯化方法,制备了新的 VasSF 分子单体。我们比较了连续 5 天给予单体(如 IVIg 治疗)和单次注射 5 天同等剂量的治疗效果。我们还评估了单次注射治疗对延长生命的作用。我们使用二维 Western 印迹检查了 VasSF 与 APOA2 的结合情况。我们改进了生产方法,使 VasSF 的产量比以前的研究高出 100 倍。VasSF 的单体化使其药效更加稳定。单次注射少量(1/80000 IVIg)就能产生足够的治疗效果,包括肾小球新月体形成减少、血清 ANCA 抗髓过氧化物酶(MPO-ANCA)呈下降趋势、多种促炎细胞因子减少以及存活时间延长的趋势。二维 Western 印迹证实了 VasSF 与 APOA2 的结合。新生产的纯 VasSF 单体是稳定的,只需一次低剂量注射就能治疗 AAV,这可能是通过去除脉管炎相关 APOA2 实现的。因此,本文所述的新型 VasSF 是一种很有前景的抗 AAV 药物。
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引用次数: 0
Sicilian semi- and supercentenarians: age-related Tγδ cell immunophenotype contributes to longevity trait definition. 西西里半百岁老人和超百岁老人:与年龄相关的 Tγδ 细胞免疫表型有助于界定长寿特征。
IF 4.6 3区 医学 Q3 IMMUNOLOGY Pub Date : 2024-03-12 DOI: 10.1093/cei/uxad132
Mattia Emanuela Ligotti, Giulia Accardi, Anna Aiello, Anna Calabrò, Calogero Caruso, Anna Maria Corsale, Francesco Dieli, Marta Di Simone, Serena Meraviglia, Giuseppina Candore

The immune system of semi- (from ≥105 to <110 years old) and supercentenarians (≥110 years old), i.e. oldest centenarians, is thought to have characteristics that allow them to reach extreme longevity in relatively healthy status. Thus, we investigated variations of the two principal subsets of Tγδ, Vδ1, and Vδ2, and their functional subsets using the markers defining Tαβ cells, i.e. CD27, CD45RA, in a cohort of 28 women and 26 men (age range 19-110 years), including 11 long-living individuals (from >90 years old to<105 years old), and eight oldest centenarians (≥105 years old), all of them were previously analysed for Tαβ and NK cell immunophenotypes on the same blood sample collected on recruitment day. Naïve Vδ1 and Vδ2 cells showed an inverse relationship with age, particularly significant for Vδ1 cells. Terminally differentiated T subsets (TEMRA) were significantly increased in Vδ1 but not in Vδ2, with higher values observed in the oldest centenarians, although a great heterogeneity was observed. Both naïve and TEMRA Vδ1 and CD8+ Tαβ cell values from our previous study correlated highly significantly, which was not the case for CD4+ and Vδ2. Our findings on γδ TEMRA suggest that these changes are not unfavourable for centenarians, including the oldest ones, supporting the hypothesis that immune ageing should be considered as a differential adaptation rather than a general immune alteration. The increase in TEMRA Vδ1 and CD8+, as well as in NK, would represent immune mechanisms by which the oldest centenarians successfully adapt to a history of insults and achieve longevity.

半(从≥105 岁到 90 岁到
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引用次数: 0
Gene expression analysis revealed downregulation of complement receptor 1 in clonal B cells in cold agglutinin disease. 基因表达分析显示,冷凝集素病的克隆 B 细胞中补体受体 1 下调。
IF 4.6 3区 医学 Q3 IMMUNOLOGY Pub Date : 2024-03-12 DOI: 10.1093/cei/uxad135
Agnieszka Małecka, Ingunn Østlie, Gunhild Trøen, Jędrzej Małecki, Jan Delabie, Anne Tierens, Ludvig A Munthe, Sigbjørn Berentsen, Geir E Tjønnfjord

Cold agglutinin disease (CAD) is a rare B-cell lymphoproliferative disorder of the bone marrow, manifested by autoimmune hemolytic anemia caused by binding of monoclonal IgM autoantibodies to the I antigen. Underlying genetic changes have previously been reported, but their impact on gene expression profile has been unknown. Here, we define differentially expressed genes in CAD B cells. To unravel downstream alteration in cellular pathways, gene expression by RNA sequencing was undertaken. Clonal B-cell samples from 12 CAD patients and IgM-expressing memory B cells from 4 healthy individuals were analyzed. Differential expression analysis and filtering resulted in 93 genes with significant differential expression. Top upregulated genes included SLC4A1, SPTA1, YBX3, TESC, HBD, AHSP, TRAF1, HBA2, RHAG, CA1, SPTB, IL10, UBASH3B, ALAS2, HBA1, CRYM, RGCC, KANK2, and IGHV4-34. They were upregulated at least 8-fold, while complement receptor 1 (CR1/CD35) was downregulated 11-fold in clonal CAD B cells compared to control B cells. Flow cytometry analyses further confirmed reduced CR1 (CD35) protein expression by clonal CAD IgM+ B cells compared to IgM+ memory B cells in controls. CR1 (CD35) is an important negative regulator of B-cell activation and differentiation. Therefore, reduced CR1 (CD35) expression may increase activation, proliferation, and antibody production in CAD-associated clonal B cells.

冷凝集素病(Cold Agglutinin Disease,CAD)是一种罕见的骨髓 B 细胞淋巴细胞增生性疾病,表现为单克隆 IgM 自身抗体与 I 抗原结合引起的自身免疫性溶血性贫血。此前已有相关基因变化的报道,但其对基因表达谱的影响尚不清楚。在这里,我们确定了 CAD B 细胞中表达不同的基因。为了揭示细胞通路的下游变化,我们通过 RNA 测序进行了基因表达分析。我们分析了 12 例 CAD 患者的克隆 B 细胞样本和 4 例健康人的 IgM 表达记忆 B 细胞。通过差异表达分析和筛选,得出了 93 个具有显著差异表达的基因。上调最多的基因包括 SLC4A1、SPTA1、YBX3、TESC、HBD、AHSP、TRAF1、HBA2、RHAG、CA1、SPTB、IL10、UBASH3B、ALAS2、HBA1、CRYM、RGCC、KANK2 和 IGHV4-34。与对照组 B 细胞相比,它们在克隆 CAD B 细胞中上调了至少 8 倍,而补体受体 1(CR1/CD35)则下调了 11 倍。流式细胞术分析进一步证实,与对照组的 IgM+ 记忆 B 细胞相比,克隆 CAD IgM+ B 细胞的 CR1(CD35)蛋白表达减少。CR1 (CD35) 是 B 细胞活化和分化的重要负调控因子。因此,CR1(CD35)表达的减少可能会增加 CAD 相关克隆 B 细胞的活化、增殖和抗体产生。
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引用次数: 0
Shift in the B cell subsets between children with type 1 diabetes and/or celiac disease. 1 型糖尿病和/或乳糜泻患儿 B 细胞亚群的变化。
IF 4.6 3区 医学 Q3 IMMUNOLOGY Pub Date : 2024-03-12 DOI: 10.1093/cei/uxad136
Andrea Tompa, Maria Faresjö

Our purpose was to characterize the pattern of B cell subsets in children with a combined diagnosis of type 1 diabetes (T1D) and celiac disease (C) since children with single or double diagnosis of these autoimmune diseases may differ in peripheral B cell subset phenotype patterns. B cells were analyzed with flow cytometry for the expression of differentiation/maturation markers to identify transitional, naive, and memory B cells. Transitional (CD24hiCD38hiCD19+) and memory Bregs (mBregs; CD24hiCD27+CD19+, CD1d+CD27+CD19+, and CD5+CD1d+CD19+) were classified as B cells with regulatory capacity. Children with a combined diagnosis of T1D and C showed a pattern of diminished peripheral B cell subsets. The B cells compartment in children with combined diagnosis had higher percentages of memory B subsets and Bregs, including activated subsets, compared to children with either T1D or C. Children with combined diagnosis had a lower percentage of naive B cells (CD27-CD19+; IgD+CD19+) and an increased percentage of memory B cells (CD27+CD19+; IgD-CD19+). A similar alteration was seen among the CD39+ expressing naive and memory B cells. Memory Bregs (CD1d+CD27+CD19+) were more frequent, contrary to the lower percentage of CD5+ transitional Bregs in children with a combined diagnosis. In children with either T1D or C, the peripheral B cell compartment was dominated by naive cells. Differences in the pattern of heterogeneous peripheral B cell repertoire subsets reflect a shifting in the B cell compartment between children with T1D and/or C. This is an immunological challenge of impact on the pathophysiology of these autoimmune diseases.

我们的目的是描述合并诊断为1型糖尿病(T1D)和乳糜泻(C)的儿童的B细胞亚群模式,因为单一或双重诊断为这些自身免疫性疾病的儿童的外周B细胞亚群表型模式可能有所不同。用流式细胞术分析 B 细胞的分化/成熟标记表达,以确定过渡型、幼稚型和记忆型 B 细胞。过渡性 B 细胞(CD24hiCD38hiCD19+)和记忆性 B 细胞(CD24hiCD27+CD19+、CD1d+CD27+CD19+、CD5+CD1d+CD19+)被归类为具有调节能力的 B 细胞。合并诊断为 T1D 和 C 的儿童表现出外周 B 细胞亚群减少的模式。与 T1D 或 C 合并诊断的儿童相比,合并诊断的儿童的 B 细胞分区中记忆 B 亚群和 Bregs(包括活化亚群)的比例更高。在表达 CD39+ 的幼稚 B 细胞和记忆 B 细胞中也出现了类似的变化。记忆B细胞(CD1d+CD27+CD19+)更常见,而在合并诊断的儿童中,CD5+过渡B细胞的比例较低。在患有 T1D 或 C 的儿童中,外周 B 细胞区系以幼稚细胞为主。外周B细胞异源汇集亚群模式的差异反映了T1D和/或C患儿B细胞区系的变化。
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引用次数: 0
Defining the cross-reactivity between peanut allergens Ara h 2 and Ara h 6 using monoclonal antibodies. 使用单克隆抗体确定花生过敏原 Ara h 2 和 Ara h 6 之间的交叉反应。
IF 3.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2024-03-12 DOI: 10.1093/cei/uxae005
Orlee Marini-Rapoport, Monica L Fernández-Quintero, Tarun Keswani, Guangning Zong, Jane Shim, Lars C Pedersen, Geoffrey A Mueller, Sarita U Patil

In peanut allergy, Arachis hypogaea 2 (Ara h 2) and Arachis hypogaea 6 (Ara h 6) are two clinically relevant peanut allergens with known structural and sequence homology and demonstrated cross-reactivity. We have previously utilized X-ray crystallography and epitope binning to define the epitopes on Ara h 2. We aimed to quantitatively characterize the cross-reactivity between Ara h 2 and Ara h 6 on a molecular level using human monoclonal antibodies (mAbs) and structural characterization of allergenic epitopes. We utilized mAbs cloned from Ara h 2 positive single B cells isolated from peanut-allergic, oral immunotherapy-treated patients to quantitatively analyze cross-reactivity between recombinant Ara h 2 (rAra h 2) and Ara h 6 (rAra h 6) proteins using biolayer interferometry and indirect inhibitory ELISA. Molecular dynamics simulations assessed time-dependent motions and interactions in the antibody-antigen complexes. Three epitopes-conformational epitopes 1.1 and 3, and the sequential epitope KRELRNL/KRELMNL-are conserved between Ara h 2 and Ara h 6, while two more conformational and three sequential epitopes are not. Overall, mAb affinity was significantly lower to rAra h 6 than it was to rAra h 2. This difference in affinity was primarily due to increased dissociation of the antibodies from rAra h 6, a phenomenon explained by the higher conformational flexibility of the Ara h 6-antibody complexes in comparison to Ara h 2-antibody complexes. Our results further elucidate the cross-reactivity of peanut 2S albumins on a molecular level and support the clinical immunodominance of Ara h 2.

在花生过敏中,Arachis hypogaea 2(Ara h 2)和Arachis hypogaea 6(Ara h 6)是两种与临床相关的花生过敏原,它们在结构上和序列上具有已知的同源性,并显示出交叉反应性。我们以前曾利用 X 射线晶体学和表位分选来确定 Ara h 2 上的表位。我们的目标是利用人类单克隆抗体(mAbs)和过敏原表位的结构特征,在分子水平上定量描述 Ara h 2 和 Ara h 6 之间的交叉反应。我们利用从花生过敏、口服免疫疗法患者体内分离出的 Ara h 2 阳性单 B 细胞克隆出的 mAbs,使用生物层干涉测量法和间接抑制性 ELISA 定量分析了重组 Ara h 2(rAra h 2)和 Ara h 6(rAra h 6)蛋白之间的交叉反应。分子动力学模拟评估了抗体-抗原复合物中随时间变化的运动和相互作用。三个表位--构象表位 1.1 和 3 以及序列表位 KRELRNL/KRELMNL 在 Ara h 2 和 Ara h 6 之间是保守的,而另外两个构象表位和三个序列表位则不保守。总体而言,mAb 与 rAra h 6 的亲和力明显低于与 rAra h 2 的亲和力。这种亲和力上的差异主要是由于抗体与 rAra h 6 的解离度增加所致,与 Ara h 2-抗体复合物相比,Ara h 6-抗体复合物具有更高的构象灵活性。我们的研究结果进一步阐明了花生 2S 蛋白在分子水平上的交叉反应性,并支持 Ara h 2 的临床免疫优势。
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引用次数: 0
Clinical & Experimental Immunology: Highlights of 2023. 临床与实验免疫学:2023 年亮点。
IF 4.6 3区 医学 Q3 IMMUNOLOGY Pub Date : 2024-02-27 DOI: 10.1093/cei/uxae017
Leonie S Taams, Sevda Dogan
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引用次数: 0
IAPs and RIPK1 mediate LPS-induced cytokine production in healthy subjects and Crohn's disease. IAPs 和 RIPK1 在健康人和克罗恩病患者中介导 LPS 诱导的细胞因子产生。
IF 3.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2024-02-19 DOI: 10.1093/cei/uxad092
Jakob Benedict Seidelin, Simone Jensen, Morten Hansen, Mariana Rodrigues de Carvalho Bronze, Delphine Cuchet-Lourenҫo, Sergey Nejentsev, Eric Charles LaCasse, Ole Haagen Nielsen

Innate immune activity fuels intestinal inflammation in Crohn's disease (CD), an inflammatory bowel disease. Identification and targeting of new molecular regulators of the innate activity are warranted to control the disease. Inhibitor of apoptosis proteins (IAPs) regulate both cell survival and inflammatory signaling. We investigated the effects of IAP inhibition by second mitochondria-derived activator of caspases (SMAC) mimetics (SMs) on innate responses and cell death to pathogen-associated molecular patterns in peripheral blood mononuclear cells (PBMCs) and monocytes. IAPs inhibited lipopolysaccharide (LPS)-induced expression of proinflammatory interleukin (IL)-1β, IL-6. Likewise, LPS (but not muramyl dipeptide or Escherichia coli) induced TNF-α was inhibited in CD and control PBMCs. The SM effect was partially reversed by inhibition of receptor-interacting serine/threonine-protein kinase 1 (RIPK1). The effect was mainly cell death independent. Thus, IAP inhibition by SMs leads to reduced production of proinflammatory cytokines and may be considered in the efforts to develop new therapeutic strategies to control CD.

在克罗恩病(CD)这种炎症性肠病中,先天性免疫活动助长了肠道炎症。为了控制这种疾病,有必要确定和瞄准先天性免疫活动的新分子调控因子。细胞凋亡抑制蛋白(IAPs)同时调节细胞存活和炎症信号转导。我们研究了线粒体衍生的第二种活化酶(SMAC)模拟物(SMs)抑制 IAP 对外周血单核细胞(PBMCs)和单核细胞对病原体相关分子模式的先天性反应和细胞死亡的影响。IAPs 可抑制脂多糖(LPS)诱导的促炎性白细胞介素(IL)-1β、IL-6 的表达。同样,CD 和对照组 PBMCs 也能抑制 LPS(但不能抑制氨酰二肽或大肠杆菌)诱导的 TNF-α。抑制受体丝氨酸/苏氨酸蛋白激酶 1(RIPK1)可部分逆转 SM 的效应。这种效应主要与细胞死亡无关。因此,SM抑制IAP可减少促炎细胞因子的产生,在开发控制CD的新治疗策略时可加以考虑。
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引用次数: 0
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Clinical and experimental immunology
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