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Single-cell transcriptomic analysis uncovers heterogeneity in the labial gland microenvironment of primary Sjögren's syndrome 单细胞转录组分析揭示原发性斯约格伦综合征唇腺微环境的异质性
IF 4.7 Q2 IMMUNOLOGY Pub Date : 2024-07-16 DOI: 10.1016/j.jtauto.2024.100248

Objective

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disorder with an unclear pathogenetic mechanism in the labial gland. This study aims to investigate the cellular and molecular mechanisms contributing to the development of this disease.

Methods

Single-cell RNA sequencing (scRNA-seq) was performed on 32,337 cells of labial glands from three pSS patients and three healthy individuals. We analyzed all cell subsets implicated in pSS pathogenesis.

Results

Our research revealed diminished differentiation among epithelial cells, concomitant with an enhancement of interferons (IFNs)-mediated signaling pathways. This indicates a cellular functional shift in reaction to inflammatory triggers. Moreover, we observed an augmentation in the population of myofibroblasts and endothelial cells, likely due to the intensified IFNs signaling, suggesting a possible reconfiguration of tissue structure and vascular networks in the impacted regions. Within the immune landscape, there was an apparent increase in immunosuppressive macrophages and dendritic cells (DCs), pointing to an adaptive immune mechanism aimed at modulating inflammation and averting excessive tissue harm. Elevated activation levels of CD4+T cells, along with a rise in regulatory T (Treg) cells, were noted, indicating a nuanced immune interplay designed to manage the inflammatory response. In the CD8+T cell subsests, we detected a notable increase in cells expressing granzyme K (GZMK), signaling an intensified cytotoxic activity. Additionally, the escalated presence of T cells with high levels of heat shock proteins (HSPs) suggests a cellular stress condition, possibly associated with persistent low-grade inflammation, mirroring the chronic aspect of the condition.

Conclusions

Our research identified distinct stromal and immune cell populations linked to pSS, revealing new potential targets for its management. The activation of myeloid, B, and T cells could contribute to pSS pathogenesis, providing important guidance for therapeutic approaches.

目的原发性斯约格伦综合征(pSS)是一种全身性自身免疫性疾病,唇腺的发病机制尚不清楚。本研究旨在探讨导致这种疾病发生的细胞和分子机制。方法对来自三名 pSS 患者和三名健康人的 32,337 个唇腺细胞进行了单细胞 RNA 测序(scRNA-seq)。我们分析了与 pSS 发病机制有关的所有细胞亚群。结果我们的研究发现,上皮细胞分化减弱,同时干扰素(IFNs)介导的信号通路增强。这表明细胞对炎症诱因的反应发生了功能性转变。此外,我们还观察到肌成纤维细胞和内皮细胞的数量增加,这可能是由于 IFNs 信号的增强,表明受影响区域的组织结构和血管网络可能发生了重组。在免疫环境中,免疫抑制巨噬细胞和树突状细胞(DCs)明显增加,这表明适应性免疫机制旨在调节炎症和避免对组织造成过度伤害。CD4+T细胞活化水平升高,调节性T细胞(Treg)增加,这表明免疫系统之间存在着微妙的相互作用,旨在控制炎症反应。在 CD8+T 细胞亚群中,我们检测到表达颗粒酶 K (GZMK) 的细胞明显增加,这表明细胞毒性活性增强。此外,热休克蛋白(HSPs)水平较高的 T 细胞的增加表明细胞处于应激状态,可能与持续的低度炎症有关,反映了病情的慢性方面。结论我们的研究发现了与 pSS 相关的不同基质和免疫细胞群,揭示了治疗 pSS 的新潜在靶点。髓系细胞、B 细胞和 T 细胞的活化可能有助于 pSS 的发病机制,为治疗方法提供了重要指导。
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引用次数: 0
To switch or to swap? Evidence from a meta-analysis for the best treatment approach in childhood chronic uveitis resistant to the I anti-TNF 换药还是换药?荟萃分析为对I型抗肿瘤坏死因子耐药的儿童慢性葡萄膜炎最佳治疗方法提供证据
IF 4.7 Q2 IMMUNOLOGY Pub Date : 2024-06-22 DOI: 10.1016/j.jtauto.2024.100247
Ilaria Maccora , Sara Soldovieri , Teodoro Oliverio , Salvatore de Masi , Edoardo Marrani , Ilaria Pagnini , Maria Vincenza Mastrolia , Gabriele Simonini

Objective

Since adalimumab approval in childhood chronic non-infectious uveitis (cNIU), the prognosis has been dramatically changed, but the 25 % failed to achieve inactivity. There is not accordance if it is better to switch to another anti-TNF or to swap to another category of biologic. Thus, we aim to summarize evidence regarding the best treatment of cNIU refractory to the first anti-TNF.

Methods

A systematic literature review and meta-analysis, according to PRISMA Guidelines, was performed(Jan2000-Aug2023). Studies investigating the efficacy of treatment in cNIU refractory to the first anti-TNF were considered for inclusion. The primary outcome was the improvement of intraocular inflammation according to SUN. A combined estimation of the proportion of children responding to switch or swap and for each drug was performed.

Results

23 articles were eligible, reporting 150 children of whom 109 switched anti-TNF (45 adalimumab, 49 infliximab, 9 golimumab) and 41 swapped to another biologics (31 abatacept, 8 tocilizumab and 1 rituximab). The proportion of responding children was 46 %(95 % CI 23-70) for switch and 38 %(95 % CI 8-73) for swap (χ20.02, p = 0.86). Instead analysing for each drug, the proportion of responding children was the 24 %(95 % CI 2-55) for adalimumab, 43 %(95 % CI 2-80) for abatacept, 79 %(95 % CI 61-93) for infliximab, 56 %(95 % CI 14-95) for golimumab and 96 %(95 % CI 58-100) for tocilizumab. We evaluated a superiority of tocilizumab and infliximab compared to the other drugs(χ2 27.5 p < 0.0001).

Conclusion

Although non-conclusive, this meta-analysis suggests that, after the first anti-TNF failure, tocilizumab and infliximab are the best available treatment for the management of cNIU.

目的自从阿达木单抗被批准用于儿童慢性非感染性葡萄膜炎(cNIU)以来,预后发生了巨大变化,但仍有25%的患者未能达到无效状态。目前尚不清楚是改用另一种抗肿瘤坏死因子(anti-TNF)更好,还是改用另一类生物制剂更好。因此,我们旨在总结有关对第一种抗肿瘤坏死因子(anti-TNF)治疗无效的 cNIU 的最佳治疗方法的证据。纳入考虑的研究对象是对首次抗肿瘤坏死因子治疗无效的 cNIU 进行疗效调查的研究。主要结果是眼内炎症的改善程度(根据 SUN 标准)。结果23篇文章符合条件,共报告了150名患儿,其中109名患儿换用了抗肿瘤坏死因子(45名阿达木单抗、49名英夫利昔单抗、9名戈利木单抗),41名患儿换用了其他生物制剂(31名阿帕他赛、8名托珠单抗和1名利妥昔单抗)。换药儿童的应答比例为 46%(95 % CI 23-70),换药儿童的应答比例为 38%(95 % CI 8-73)(χ20.02,P = 0.86)。如果对每种药物进行分析,阿达木单抗的应答儿童比例为 24%(95 % CI 2-55),阿帕他赛的应答儿童比例为 43%(95 % CI 2-80),英夫利西单抗的应答儿童比例为 79%(95 % CI 61-93),戈利木单抗的应答儿童比例为 56%(95 % CI 14-95),托珠单抗的应答儿童比例为 96%(95 % CI 58-100)。我们评估了托西珠单抗和英夫利昔单抗与其他药物相比的优越性(χ2 27.5 p < 0.0001)。结论尽管尚无定论,但这项荟萃分析表明,在首次抗肿瘤坏死因子治疗失败后,托西珠单抗和英夫利昔单抗是治疗 cNIU 的最佳药物。
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引用次数: 0
Urinary soluble CD163 is useful as “liquid biopsy” marker in lupus nephritis at both diagnosis and follow-up to predict impending flares 尿液可溶性 CD163 可作为狼疮肾炎的 "液体活检 "标记物,在诊断和随访时预测即将复发的病情
IF 4.7 Q2 Medicine Pub Date : 2024-06-20 DOI: 10.1016/j.jtauto.2024.100244
Yves Renaudineau , Dominique Chauveau , Stanislas Faguer , Antoine Huart , David Ribes , Gregory Pugnet , Laurent Sailler , Thibaut Jamme , Emmanuel Treiner , Françoise Fortenfant , Chloé Bost , Caroline Carlé , Julie Belliere

Lupus nephritis (LN) diagnosis and follow-up requires noninvasive biomarkers. Therefore, the added value of coupling the urinary soluble (s)CD163/creatinuria ratio with serological markers was evaluated in a real-world clinical practice. To this end, a monocentric and retrospective study was conducted in 139 SLE patients with biopsy-proven nephritis having an active LN (LN-A, n = 63 with a positive SLEDAI-renal score) or inactive (n = 76), as well as 98 non-renal SLE patients. The urinary sCD163/creatinuria ratio outperformed serological markers for predicting LN-A (AUC>0.972; p < 10−4 with a 100 % specificity threshold fixed at 320 ng/mmol), and for monitoring renal activity allowing prediction of impending flares and remissions in follow-up (AUC = 0.789, p < 10−4). LN-A patients with an elevated spot proteinuria/creatinuria ratio (p = 8 × 10−6) and sCD163/creatinuria ratio (p = 10−3) were at risk for developing end-stage kidney disease but sCD163/creatinuria ratio cannot substitute kidney biopsy to discriminate LN-A from other glomerulonephritis. Among serological markers (n = 14), anti-dsDNA and anti-C1q antibodies (Abs) (AUC>0.750 versus non-LN patients, and AUC>0.640 versus LN-IR patients) best predicted LN-A, and higher levels were retrieved in class III/IV proliferative LN-A. In multivariate logistic regression analysis, the urinary sCD163/creatinuria ratio remained the only statistically significant biomarker to predict LN-A (p < 0.001). In conclusion, and as compared to classical serological markers, the urinary sCD163/creatinuria ratio provides an additional parameter for monitoring LN patients.

狼疮性肾炎(LN)的诊断和随访需要无创生物标志物。因此,我们在实际临床实践中评估了尿可溶性(s)CD163/肌酐尿比值与血清学标志物相结合的附加值。为此,我们对 139 名经活检证实患有活动性 LN(LN-A,n = 63,SLEDAI-肾脏评分为阳性)或非活动性(n = 76)肾炎的系统性红斑狼疮患者,以及 98 名非肾脏病系统性红斑狼疮患者进行了单中心回顾性研究。在预测LN-A(AUC>0.972; p <10-4,100%特异性阈值固定为320纳克/毫摩尔)和监测肾脏活动方面,尿液sCD163/肌酐尿量比值优于血清学标记物(AUC = 0.789, p <10-4)。斑点蛋白尿/肌酐尿比值升高(p = 8 × 10-6)和 sCD163/肌酐尿比值升高(p = 10-3)的 LN-A 患者有发展为终末期肾病的风险,但 sCD163/肌酐尿比值不能替代肾活检来区分 LN-A 和其他肾小球肾炎。在血清学标记物(n = 14)中,抗dsDNA和抗C1q抗体(Abs)(与非LN患者相比,AUC>0.750;与LN-IR患者相比,AUC>0.640)最能预测LN-A,在III/IV级增生性LN-A中,Abs水平更高。在多变量逻辑回归分析中,尿 sCD163/肌酐尿比值仍是预测 LN-A 的唯一具有统计学意义的生物标志物(p <0.001)。总之,与传统的血清学标志物相比,尿液中的 sCD163/肌酐比值为监测 LN 患者提供了一个额外的参数。
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引用次数: 0
Association of autoantibodies with the IFN signature and NETosis in patients with systemic lupus erythematosus 自身抗体与系统性红斑狼疮患者 IFN 特征和 NETosis 的关系
IF 4.7 Q2 Medicine Pub Date : 2024-06-20 DOI: 10.1016/j.jtauto.2024.100246
Ellen D. Kaan , Tammo E. Brunekreef , Julia Drylewicz , Lucas L. van den Hoogen , Maarten van der Linden , Helen L. Leavis , Jacob M. van Laar , Michiel van der Vlist , Henny G. Otten , Maarten Limper

Objective

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a variety of disease symptoms and an unpredictable clinical course. To improve treatment outcome, stratification based on immunological manifestations commonly seen in patients with SLE such as autoantibodies, type I interferon (IFN) signature and neutrophil extracellular trap (NET) release may help. It is assumed that there is an association between these immunological phenomena, since NET release induces IFN production and IFN induces autoantibody formation via B-cell activation. Here we studied the association between autoantibodies, the IFN signature, NET release, and clinical manifestations in patients with SLE.

Methods

We performed principal component analysis (PCA) and hierarchical clustering of 57 SLE-related autoantibodies in 25 patients with SLE. We correlated each autoantibody to the IFN signature and NET inducing capacity.

Results

We observed two distinct clusters: one cluster contained mostly patients with a high IFN signature. Patients in this cluster often present with cutaneous lupus, and have higher anti-dsDNA concentrations. Another cluster contained a mix of patients with a high and low IFN signature. Patients with high and low NET inducing capacity were equally distributed between the clusters. Variance between the clusters is mainly driven by antibodies against histones, RibP2, RibP0, EphB2, RibP1, PCNA, dsDNA, and nucleosome. In addition, we found a trend towards increased concentrations of autoantibodies against EphB2, RibP1, and RNP70 in patients with an IFN signature. We found a negative correlation of NET inducing capacity with anti-FcER (r = −0.530; p = 0.007) and anti-PmScl100 (r = −0.445; p = 0.03).

Conclusion

We identified a subgroup of patients with an IFN signature that express increased concentrations of antibodies against DNA and RNA-binding proteins, which can be useful for further patient stratification and a more targeted therapy. We did not find positive associations between autoantibodies and NET inducing capacity. Our study further strengthens the evidence of a correlation between RNA-binding autoantibodies and the IFN signature.

目的系统性红斑狼疮(SLE)是一种自身免疫性疾病,其特点是疾病症状多样,临床病程难以预测。为了改善治疗效果,根据系统性红斑狼疮患者常见的免疫学表现(如自身抗体、I型干扰素(IFN)特征和中性粒细胞胞外捕获物(NET)释放)进行分层可能会有所帮助。据推测,这些免疫现象之间存在关联,因为NET的释放会诱导IFN的产生,而IFN会通过B细胞活化诱导自身抗体的形成。我们对 25 名系统性红斑狼疮患者的 57 种系统性红斑狼疮相关自身抗体进行了主成分分析(PCA)和分层聚类。我们将每种自身抗体与 IFN 标志和 NET 诱导能力相关联。结果我们观察到两个不同的群组:一个群组主要包含具有高 IFN 标志的患者。这个群组的患者通常伴有皮肤狼疮,抗dsDNA浓度较高。另一个群组则混合了高IFN和低IFN特征的患者。具有高和低NET诱导能力的患者在两个群组之间分布相当。群组间的差异主要由针对组蛋白、RibP2、RibP0、EphB2、RibP1、PCNA、dsDNA和核小体的抗体驱动。此外,我们还发现在有IFN特征的患者中,针对EphB2、RibP1和RNP70的自身抗体浓度呈上升趋势。我们发现NET诱导能力与抗FcER(r = -0.530;p = 0.007)和抗PmScl100(r = -0.445;p = 0.03)呈负相关。我们没有发现自身抗体与NET诱导能力之间存在正相关。我们的研究进一步加强了RNA结合自身抗体与IFN特征之间相关性的证据。
{"title":"Association of autoantibodies with the IFN signature and NETosis in patients with systemic lupus erythematosus","authors":"Ellen D. Kaan ,&nbsp;Tammo E. Brunekreef ,&nbsp;Julia Drylewicz ,&nbsp;Lucas L. van den Hoogen ,&nbsp;Maarten van der Linden ,&nbsp;Helen L. Leavis ,&nbsp;Jacob M. van Laar ,&nbsp;Michiel van der Vlist ,&nbsp;Henny G. Otten ,&nbsp;Maarten Limper","doi":"10.1016/j.jtauto.2024.100246","DOIUrl":"https://doi.org/10.1016/j.jtauto.2024.100246","url":null,"abstract":"<div><h3>Objective</h3><p>Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a variety of disease symptoms and an unpredictable clinical course. To improve treatment outcome, stratification based on immunological manifestations commonly seen in patients with SLE such as autoantibodies, type I interferon (IFN) signature and neutrophil extracellular trap (NET) release may help. It is assumed that there is an association between these immunological phenomena, since NET release induces IFN production and IFN induces autoantibody formation via B-cell activation. Here we studied the association between autoantibodies, the IFN signature, NET release, and clinical manifestations in patients with SLE.</p></div><div><h3>Methods</h3><p>We performed principal component analysis (PCA) and hierarchical clustering of 57 SLE-related autoantibodies in 25 patients with SLE. We correlated each autoantibody to the IFN signature and NET inducing capacity.</p></div><div><h3>Results</h3><p>We observed two distinct clusters: one cluster contained mostly patients with a high IFN signature. Patients in this cluster often present with cutaneous lupus, and have higher anti-dsDNA concentrations. Another cluster contained a mix of patients with a high and low IFN signature. Patients with high and low NET inducing capacity were equally distributed between the clusters. Variance between the clusters is mainly driven by antibodies against histones, RibP2, RibP0, EphB2, RibP1, PCNA, dsDNA, and nucleosome. In addition, we found a trend towards increased concentrations of autoantibodies against EphB2, RibP1, and RNP70 in patients with an IFN signature. We found a negative correlation of NET inducing capacity with anti-FcER (r = −0.530; p = 0.007) and anti-PmScl100 (r = −0.445; p = 0.03).</p></div><div><h3>Conclusion</h3><p>We identified a subgroup of patients with an IFN signature that express increased concentrations of antibodies against DNA and RNA-binding proteins, which can be useful for further patient stratification and a more targeted therapy. We did not find positive associations between autoantibodies and NET inducing capacity. Our study further strengthens the evidence of a correlation between RNA-binding autoantibodies and the IFN signature.</p></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589909024000169/pdfft?md5=7ab271c4eddb80612212f613a866cdd3&pid=1-s2.0-S2589909024000169-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141444632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
PNPLA3 I148 M genetic variant in autoimmune hepatitis characterises advanced disease at diagnosis and reduced survival free of cirrhotic events and liver-related mortality 自身免疫性肝炎中的 PNPLA3 I148 M 基因变异是诊断时疾病晚期、无肝硬化事件存活率和肝脏相关死亡率降低的特征
IF 3.9 Q2 Medicine Pub Date : 2024-06-06 DOI: 10.1016/j.jtauto.2024.100243
Kalliopi Azariadis , Nikolaos K. Gatselis , Aggeliki Lyberopoulou , Pinelopi Arvaniti , Kalliopi Zachou , Stella Gabeta , George N. Dalekos

Background

Autoimmune hepatitis (AIH) is a relatively rare autoimmune disease with a strong genetic background. The patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148 M (rs738409 C/G) variant has been associated with hepatic inflammation and fibrosis in chronic hepatic diseases beyond metabolic dysfunction-associated steatotic liver disease (MASLD).

Aim

Our aim was to investigate the significance of PNPLA3 I148 M variant in AIH.

Method

Two hundred AIH patients, followed in our centre, were evaluated while 100 healthy subjects served as controls. Genotyping was performed with allelic discrimination end-point polymerase chain reaction (PCR).

Results

The I148 M variant was present in 95/200 (47.5 %) AIH patients compared to 47/100 (47 %) healthy controls (p = 1.000). Patients with GG/CG genotypes were more likely to present with decompensated cirrhosis at diagnosis (GG/CG 6.3 % vs. CC 1 %, p = 0.039). Comorbidity with cardiometabolic risk factors and concurrence of MASLD was similar across genotypes. Simple steatosis was present in 37/186 (19.9 %) and steatohepatitis in 14/186 (7.5 %) patients with available liver biopsy without correlation with PNPLA3 genotype. Fibrosis stage and grade of inflammation were not correlated with any genotype. Response to treatment was also independent of the presence of the I148 M variant, even though a longer time was needed to achieve complete biochemical response in those carrying the GG/CG genotypes (p = 0.07). On Kaplan Meier analysis homozygosity for the G allele corelated with reduced survival free of decompensation (p = 0.006), cirrhotic events (decompensation, liver transplantation, hepatocellular carcinoma; p = 0.001) and liver-related death or liver transplantation (p = 0.011) in treated patients.

Conclusions

The PNPLA3 I148 M variant in AIH patients is associated with increased risk of advanced disease at diagnosis and reduced survival free of cirrhotic events and liver-related death or liver transplantation, regardless of the presence of MASLD. This signifies a potential role for the PNPLA3 I148 M variant as a new AIH biomarker allowing to identify patients at increased risk of disease progression.

背景自身免疫性肝炎(AIH)是一种相对罕见的自身免疫性疾病,具有很强的遗传背景。我们的目的是研究 PNPLA3 I148 M 变体在 AIH 中的意义。方法评估了本中心随访的 200 名 AIH 患者,并以 100 名健康人作为对照。结果95/200(47.5%)名AIH患者存在I148 M变体,而47/100(47%)名健康对照者存在I148 M变体(P = 1.000)。基因型为 GG/CG 的患者在确诊时更有可能出现失代偿性肝硬化(GG/CG 6.3% vs. CC 1%,p = 0.039)。不同基因型的患者合并心血管代谢风险因素和并发 MASLD 的情况相似。37/186(19.9%)例患者出现单纯性脂肪变性,14/186(7.5%)例患者出现脂肪性肝炎,且肝活检结果与 PNPLA3 基因型无关。纤维化阶段和炎症等级与任何基因型均无相关性。治疗反应也与是否存在 I148 M 变异无关,尽管携带 GG/CG 基因型的患者需要更长的时间才能达到完全生化反应(p = 0.07)。在卡普兰-梅耶尔分析中,G 等位基因的同型性与治疗后患者无失代偿(p = 0.006)、无肝硬化事件(失代偿、肝移植、肝细胞癌;p = 0.001)、肝相关死亡或肝移植(p = 0.011)的生存率降低有关。结论无论是否存在 MASLD,AIH 患者中的 PNPLA3 I148 M 变异与诊断时晚期疾病风险增加、无肝硬化事件、肝相关死亡或肝移植的生存率降低有关。这标志着PNPLA3 I148 M变体作为一种新的AIH生物标记物的潜在作用,可用于识别疾病进展风险增加的患者。
{"title":"PNPLA3 I148 M genetic variant in autoimmune hepatitis characterises advanced disease at diagnosis and reduced survival free of cirrhotic events and liver-related mortality","authors":"Kalliopi Azariadis ,&nbsp;Nikolaos K. Gatselis ,&nbsp;Aggeliki Lyberopoulou ,&nbsp;Pinelopi Arvaniti ,&nbsp;Kalliopi Zachou ,&nbsp;Stella Gabeta ,&nbsp;George N. Dalekos","doi":"10.1016/j.jtauto.2024.100243","DOIUrl":"https://doi.org/10.1016/j.jtauto.2024.100243","url":null,"abstract":"<div><h3>Background</h3><p>Autoimmune hepatitis (AIH) is a relatively rare autoimmune disease with a strong genetic background. The patatin-like phospholipase domain-containing protein 3 (<em>PNPLA3</em>) <em>I148 M</em> (<em>rs7</em>38409 C/G) variant has been associated with hepatic inflammation and fibrosis in chronic hepatic diseases beyond metabolic dysfunction-associated steatotic liver disease (MASLD).</p></div><div><h3>Aim</h3><p>Our aim was to investigate the significance of <em>PNPLA3 I148 M</em> variant in AIH.</p></div><div><h3>Method</h3><p>Two hundred AIH patients, followed in our centre, were evaluated while 100 healthy subjects served as controls. Genotyping was performed with allelic discrimination end-point polymerase chain reaction (PCR).</p></div><div><h3>Results</h3><p>The <em>I148 M</em> variant was present in 95/200 (47.5 %) AIH patients compared to 47/100 (47 %) healthy controls (p = 1.000). Patients with GG/CG genotypes were more likely to present with decompensated cirrhosis at diagnosis (GG/CG 6.3 % vs. CC 1 %, p = 0.039). Comorbidity with cardiometabolic risk factors and concurrence of MASLD was similar across genotypes. Simple steatosis was present in 37/186 (19.9 %) and steatohepatitis in 14/186 (7.5 %) patients with available liver biopsy without correlation with <em>PNPLA3</em> genotype. Fibrosis stage and grade of inflammation were not correlated with any genotype. Response to treatment was also independent of the presence of the <em>I148 M</em> variant, even though a longer time was needed to achieve complete biochemical response in those carrying the GG/CG genotypes (p = 0.07). On Kaplan Meier analysis homozygosity for the G allele corelated with reduced survival free of decompensation (p = 0.006), cirrhotic events (decompensation, liver transplantation, hepatocellular carcinoma; p = 0.001) and liver-related death or liver transplantation (p = 0.011) in treated patients.</p></div><div><h3>Conclusions</h3><p>The <em>PNPLA3 I148 M</em> variant in AIH patients is associated with increased risk of advanced disease at diagnosis and reduced survival free of cirrhotic events and liver-related death or liver transplantation, regardless of the presence of MASLD. This signifies a potential role for the <em>PNPLA3 I148 M</em> variant as a new AIH biomarker allowing to identify patients at increased risk of disease progression.</p></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589909024000133/pdfft?md5=88106cddb30fad94504e751c77e514d0&pid=1-s2.0-S2589909024000133-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141325237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The new era of immune skin diseases: Exploring advances in basic research and clinical translations 免疫性皮肤病的新时代:探索基础研究与临床转化的进展
IF 3.9 Q2 Medicine Pub Date : 2024-06-01 DOI: 10.1016/j.jtauto.2024.100232
Bo Zhang , Xiaole Mei , Ming Zhao , Qianjin Lu
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引用次数: 0
Editorial from the new editor-in-chief 新主编的社论
IF 3.9 Q2 Medicine Pub Date : 2024-06-01 DOI: 10.1016/j.jtauto.2023.100224
Yves Renaudineau
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引用次数: 0
Triptolide regulates neutrophil function through the Hippo signaling pathway to alleviate rheumatoid arthritis disease progression 雷公藤内酯通过 Hippo 信号通路调节中性粒细胞功能,从而缓解类风湿性关节炎的病情进展
IF 3.9 Q2 Medicine Pub Date : 2024-05-03 DOI: 10.1016/j.jtauto.2024.100242
Pengyuan Liu , Huiyang Liu , Yali Sang , Lingyan Zhu , Peiyao Zhang , Chunyan Pang , Yongfu Wang , Li Bai

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammatory changes in the joints, the etiology of which is unclear. It is now well established that regulated cell death (RCD) and migration of neutrophils play an important role in the pathogenesis of RA. Tripterygium wilfordii Hook.f (TwHF) is a total saponin extracted from the root of Tripterygium wilfordii Hook.f, a plant of the family Wesleyanaceae, which has strong anti-inflammatory and immunomodulatory effects and has been used as a basic drug in the clinical treatment of RA. Despite the good efficacy of TwHF treatment, the mechanism of action of TwHF remains unclear. Several studies have demonstrated that the drug tripterygium glycosides, in which TwHF is the main ingredient, has achieved excellent efficacy in the clinical treatment of RA. Investigations have also found that TwHF can affect cellular RCD, cell migration, cell proliferation, and the apoptosis-related Hippo signaling pathway. In this study, we first analyzed the RCD and migration differences of neutrophils in patients with RA through network pharmacology and transcriptome analysis. Subsequently, we used electron microscopy, immunofluorescence, and other methods to identify the RCD phenotype of neutrophils. In collagen-induced arthritis (CIA) model, we demonstrated that Triptolide (the main active ingredient in TwHF) could alleviate the progression of arthritis by reducing the bone destruction and the infiltration of neutrophils. Furthermore, in vitro experiments showed that Triptolide induced neutrophil apoptosis, inhibited the formation of neutrophil extracellular traps (NETs), and impeded the neutrophil migration process in a Hippo pathway-dependent manner. Taken together, these findings indicate that Triptolide has potential for treating RA and provide theoretical support for the clinical application of TwHF, as a traditional Chinese medicine, in RA.

类风湿性关节炎(RA)是一种慢性自身免疫性疾病,以关节炎症性改变为特征,其病因尚不清楚。目前已经确定,调节性细胞死亡(RCD)和中性粒细胞迁移在类风湿性关节炎的发病机制中发挥着重要作用。威斯康辛科植物三尖杉(Tripterygium wilfordii Hook.f)(TwHF)是从其根部提取的一种总皂苷,具有很强的抗炎和免疫调节作用,已被用作临床治疗 RA 的基础药物。尽管TwHF治疗效果良好,但其作用机制仍不清楚。多项研究表明,以TwHF为主要成分的三叶皂苷类药物在临床治疗RA方面取得了很好的疗效。研究还发现,TwHF可影响细胞RCD、细胞迁移、细胞增殖以及与细胞凋亡相关的Hippo信号通路。在本研究中,我们首先通过网络药理学和转录组分析,分析了RA患者中性粒细胞的RCD和迁移差异。随后,我们利用电子显微镜、免疫荧光等方法确定了中性粒细胞的RCD表型。在胶原诱导的关节炎(CIA)模型中,我们证明了特利托利(Triptolide,TwHF 的主要活性成分)可以通过减少骨破坏和中性粒细胞的浸润来缓解关节炎的进展。此外,体外实验表明,曲托列特能诱导中性粒细胞凋亡,抑制中性粒细胞胞外捕获物(NET)的形成,并以依赖 Hippo 通路的方式阻碍中性粒细胞的迁移过程。综上所述,这些研究结果表明,雷公藤内酯具有治疗风湿性关节炎的潜力,并为风湿性关节炎的中药临床应用提供了理论支持。
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引用次数: 0
Stem cell-based therapy for systemic lupus erythematous 干细胞疗法治疗系统性红斑狼疮
IF 3.9 Q2 Medicine Pub Date : 2024-04-26 DOI: 10.1016/j.jtauto.2024.100241
Maryam Zare Moghaddam , Mohammad Javad Mousavi , Somayeh Ghotloo

Systemic lupus erythematosus (SLE), an autoimmune disease, is among the most prevalent rheumatic autoimmune disorders. It affects autologous connective tissues caused by the breakdown of self-tolerance mechanisms. During the last two decades, stem cell therapy has been increasingly considered as a therapeutic option in various diseases, including parkinson's disease, alzheimer, stroke, spinal cord injury, multiple sclerosis, inflammatory bowel disease, liver disease, diabete, heart disease, bone disease, renal disease, respiratory diseases, and hematological abnormalities such as anemia. This is due to the unique properties of stem cells that divide and differentiate to the specialized cells in the damaged tissues. Moreover, they impose immunomodulatory properties affecting the diseases caused by immunological abnormalities such as rheumatic autoimmune disorders.

In the present manuscript, efficacy of stem cell therapy with two main types of stem cells, including mesenchymal stem cell (MSC), and hematopoietic stem cells (HSC) in animal models or human patients of SLE, has been reviewed. Taken together, MSC and HSC therapies improved the disease activity, and severity in kidney, lung, liver, and bone (improvement in the clinical manifestation). In addition, a change in the immunological parameters occurred (improvement in immunological parameters). The level of autoantibodies, including antinuclear antibody (ANA), and anti-double-stranded deoxyribonucleic acid antibodies (dsDNA Abs) reduced. A conversion of Th1/Th2 ratio (in favor of Th2), and Th17/Treg (in favor of Treg) was also detected.

In spite of many advantages of MSC and HSC transplantations, including efficacy, safety, and increased survival rate of SLE patients, some complications, including recurrence of the disease, occurrence of infections, and secondary autoimmune diseases (SAD) were observed after transplantation that should be addressed in the next studies.

系统性红斑狼疮(SLE)是一种自身免疫性疾病,是最常见的风湿性自身免疫疾病之一。它影响自体结缔组织,原因是自身耐受机制遭到破坏。在过去二十年里,干细胞疗法越来越多地被认为是帕金森病、老年痴呆症、中风、脊髓损伤、多发性硬化症、炎症性肠病、肝病、糖尿病、心脏病、骨病、肾病、呼吸系统疾病和血液异常(如贫血)等各种疾病的治疗选择。这是由于干细胞具有独特的特性,能在受损组织中分裂和分化为特化细胞。此外,干细胞还具有免疫调节特性,可影响免疫异常引起的疾病,如风湿性自身免疫性疾病。本手稿综述了干细胞疗法的两种主要类型,包括间充质干细胞(MSC)和造血干细胞(HSC)在系统性红斑狼疮动物模型或人类患者中的疗效。总而言之,间充质干细胞和造血干细胞疗法改善了疾病的活动性,以及肾脏、肺、肝脏和骨骼的严重程度(临床表现得到改善)。此外,免疫学参数也发生了变化(免疫学参数改善)。自身抗体水平降低,包括抗核抗体(ANA)和抗双链脱氧核糖核酸抗体(dsDNA Abs)。尽管间充质干细胞和造血干细胞移植有很多优点,包括疗效好、安全和提高系统性红斑狼疮患者的存活率,但移植后也出现了一些并发症,包括疾病复发、感染和继发性自身免疫性疾病(SAD),这些问题都应在下一步研究中加以解决。
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引用次数: 0
Changes upon the gluten-free diet of HLA-DQ2 and TRAFD1 gene expression in peripheral blood of celiac disease patients 无麸质饮食对乳糜泻患者外周血中 HLA-DQ2 和 TRAFD1 基因表达的影响
IF 3.9 Q2 Medicine Pub Date : 2024-04-09 DOI: 10.1016/j.jtauto.2024.100240
Mariavittoria Laezza , Laura Pisapia , Benedetta Toro , Vincenzo Mercadante , Antonio Rispo , Carmen Gianfrani , Giovanna Del Pozzo

Background

Celiac disease (CD) is a chronic immuno-mediated enteropathy caused by dietary gluten in genetically susceptible individuals carrying HLA (Human Leukocytes Antigen) genes that encode for DQ2.5 and DQ8 molecules. TRAFD1 (TRAF-type zinc finger domain 1) is a gene recently found associated with CD and defined as a master regulator of IFNγ signalling and of MHC class I antigen processing/presentation. There is no specific drug therapy and the only effective treatment is the gluten-free diet (GFD). The great majority of celiac patients when compliant with GFD have a complete remission of symptoms and recovery of gut mucosa architecture and function. Until now, very few studies have investigated molecular differences occurring in CD patients upon the GFD therapy.

Methods

We looked at the expression of both HLA DQ2.5 and TRAFD1 risk genes in adult patients with acute CD at the time of and in treated patients on GFD. Specifically, we measured by qPCR the HLA-DQ2.5 and TRAFD1 mRNAs on peripheral blood mononuclear cells (PBMC) from the two groups of patients.

Results

When we compared the HLA-DQ mRNA expression, we didn't find significant variation between the two groups of patients, thus indicating that GFD patients have the same capability to present gliadin antigens to cognate T cells as patients with active disease. Conversely, TRAFD1 was more expressed in PBMC from treated CD subjects. Notably, TRAFD1 transcripts significantly increased in the patients analyzed longitudinally during the GFD, indicating a role in the downregulation of gluten-induced inflammatory pathways.

Conclusion

Our study demonstrated that HLA-DQ2.5 and TRAFD1 molecules are two important mediators of anti-gluten immune response and inflammatory process.

背景乳糜泻(CD)是一种慢性免疫介导的肠病,由饮食中的麸质引起,易感基因携带编码 DQ2.5 和 DQ8 分子的 HLA(人类白细胞抗原)基因。TRAFD1(TRAF 型锌指结构域 1)是最近发现的一种与 CD 相关的基因,被定义为 IFNγ 信号和 MHC I 类抗原处理/呈递的主调节器。目前尚无特效药物治疗,唯一有效的治疗方法是无麸质饮食(GFD)。绝大多数乳糜泻患者在接受无麸质饮食后,症状会完全缓解,肠道粘膜结构和功能也会恢复。到目前为止,很少有研究调查 CD 患者在接受 GFD 治疗后的分子差异。方法我们观察了急性 CD 成人患者在接受 GFD 治疗时和接受治疗后 HLA DQ2.5 和 TRAFD1 风险基因的表达情况。结果当我们比较 HLA-DQ mRNA 的表达时,我们没有发现两组患者之间有明显的差异,这表明 GFD 患者与活动性疾病患者一样有能力向同源 T 细胞展示麦胶蛋白抗原。相反,TRAFD1 在接受治疗的 CD 患者的 PBMC 中表达较多。值得注意的是,在纵向分析的 GFD 患者中,TRAFD1 转录物显著增加,表明其在下调麸质诱导的炎症通路中发挥作用。
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引用次数: 0
期刊
Journal of Translational Autoimmunity
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