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Metformin-induced activation of Ca2+ signaling prevents immune infiltration/pathology in Sjogren’s syndrome-prone mouse models 二甲双胍诱导的Ca2+信号激活可防止干燥综合征易发小鼠模型的免疫浸润/病理
IF 3.9 Q2 IMMUNOLOGY Pub Date : 2023-09-09 DOI: 10.1016/j.jtauto.2023.100210
Viviane Nascimento Da Conceicao , Yuyang Sun , Xiufang Chai , Julian L. Ambrus , Bibhuti B. Mishra , Brij B. Singh

Immune cell infiltration and glandular dysfunction are the hallmarks of autoimmune diseases such as primary Sjogren’s syndrome (pSS), however, the mechanism(s) is unknown. Our data show that metformin-treatment induces Ca2+ signaling that restores saliva secretion and prevents immune cell infiltration in the salivary glands of IL14α-transgenic mice (IL14α), which is a model for pSS. Mechanistically, we show that loss of Ca2+ signaling is a major contributing factor, which is restored by metformin treatment, in IL14α mice. Furthermore, the loss of Ca2+ signaling leads to ER stress in salivary glands. Finally, restoration of metformin-induced Ca2+ signaling inhibited the release of alarmins and prevented the activation of ER stress that was essential for immune cell infiltration. These results suggest that loss of metformin-mediated activation of Ca2+ signaling prevents ER stress, which inhibited the release of alarmins that induces immune cell infiltration leading to salivary gland dysfunction observed in pSS.

免疫细胞浸润和腺体功能障碍是原发性干燥综合征(pSS)等自身免疫性疾病的标志,但其机制尚不清楚。我们的数据表明,二甲双胍处理诱导Ca2+信号,恢复唾液分泌,阻止免疫细胞浸润IL14α-转基因小鼠(IL14α)的唾液腺,这是pSS的模型。在机制上,我们发现Ca2+信号的丢失是一个主要的促成因素,在IL14α小鼠中通过二甲双胍治疗恢复。此外,Ca2+信号的丢失导致唾液腺内质网应激。最后,二甲双胍诱导的Ca2+信号的恢复抑制了警报的释放,并阻止了免疫细胞浸润所必需的内质网应激的激活。这些结果表明,二甲双胍介导的Ca2+信号激活的丧失可以阻止内质网应激,从而抑制诱发免疫细胞浸润的警报器的释放,从而导致pSS中观察到的唾液腺功能障碍。
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引用次数: 0
Paradoxical psoriasis: The flip side of idiopathic psoriasis or an autocephalous reversible drug reaction? 矛盾型牛皮癣:特发性牛皮癣的另一面还是自体可逆药物反应?
IF 3.9 Q2 IMMUNOLOGY Pub Date : 2023-09-06 DOI: 10.1016/j.jtauto.2023.100211
Jiawei Lu, Yan Lu

Psoriasis is a common, chronic skin disease that results mainly from the complex interplay between T cells, dendritic cells, and inflammatory cytokines including TNF-α, IL-17, IL-12, and IL-23. Successful therapy with anti-cytokine antibodies has proved the importance of these key cytokines, especially TNF-α. During the anti-TNF-α treatment of classical idiopathic psoriasis, a small portion of patients develop new psoriasiform lesions. This contradictory phenomenon was named paradoxical psoriasis which resembles idiopathic psoriasis clinically but presents overlapped histological patterns and distinct immunological processes. In this review, we discuss the differences between idiopathic psoriasis and paradoxical psoriasis with an emphasis on their innate immunity, as it is predominant in paradoxical psoriasis which exhibits type I IFN-mediated immunity without the activation of autoreactive T cells and memory T cells. We also put up an instructive algorithm for the management of paradoxical psoriasis. The decision on drug discontinuation or switching of biologics should be made based on the condition of underlying diseases and the severity of lesions.

银屑病是一种常见的慢性皮肤病,主要由T细胞、树突状细胞和炎性细胞因子(包括TNF-α、IL-17、IL-12和IL-23)之间复杂的相互作用引起。抗细胞因子抗体的成功治疗已经证明了这些关键细胞因子,特别是TNF-α的重要性。在经典特发性银屑病的抗tnf -α治疗过程中,一小部分患者出现新的银屑病样病变。这种矛盾的现象被命名为悖论型牛皮癣,它在临床上类似于特发性牛皮癣,但表现出重叠的组织学模式和不同的免疫过程。在这篇综述中,我们讨论了特发性银屑病和悖论型银屑病之间的差异,重点是它们的先天免疫,因为它在悖论型银屑病中占主导地位,表现出I型ifn介导的免疫,而不激活自身反应性T细胞和记忆T细胞。本文还提出了一种具有指导意义的治疗矛盾性牛皮癣的算法。停药或切换生物制剂的决定应根据潜在疾病的情况和病变的严重程度作出。
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引用次数: 0
Evaluation of a machine learning tool for the early identification of patients with undiagnosed psoriatic arthritis – A retrospective population-based study 评估机器学习工具对未确诊银屑病关节炎患者的早期识别-一项基于人群的回顾性研究
IF 3.9 Q2 IMMUNOLOGY Pub Date : 2023-08-02 DOI: 10.1016/j.jtauto.2023.100207
J. Shapiro , B. Getz , S.B. Cohen , Y. Jenudi , D. Underberger , M. Dreyfuss , T.I. Ber , S. Steinberg-Koch , A. Ben-Tov , Y. Shoenfeld , O. Shovman

Background

Psoriatic arthritis (PsA), an immune-mediated chronic inflammatory skin and joint disease, affects approximately 0.27% of the adult population, and 20% of patients with psoriasis. Up to 10% of psoriasis patients are estimated for having undiagnosed PsA. Early diagnosis and treatment can prevent irreversible joint damage, disability and deformity. Questionnaires for screening to identify undiagnosed PsA patients require patient and physician involvement.

Objective

To evaluate a proprietary machine learning tool (PredictAI™) developed for identification of undiagnosed PsA patients 1–4 years prior to the first time that they were suspected of having PsA (reference event).

Methods

This retrospective study analyzed data of the adult population from Maccabi Healthcare Service between 2008 and 2020. We created 2 cohorts: The general adult population (“GP Cohort”) including patients with and without psoriasis and the Psoriasis cohort (“PsO Cohort”) including psoriasis patients only. Each cohort was divided into two non-overlapping train and test sets. The PredictAI™ model was trained and evaluated with 3 years of data predating the reference event by at least one year. Receiver operating characteristic (ROC) analysis was used to investigate the performance of the model, built using gradient boosted trees, at different specificity levels.

Results

Overall, 2096 patients met the criteria for PsA. Undiagnosed PsA patients in the PsO cohort were identified with a specificity of 90% one and four years before the reference event, with a sensitivity of 51% and 38%, and a PPV of 36.1% and 29.6%, respectively. In the GP cohort and with a specificity of 99% and for the same time windows, the model achieved a sensitivity of 43% and 32% and a PPV of 10.6% and 8.1%, respectively.

Conclusions

The presented machine learning tool may aid in the early identification of undiagnosed PsA patients, and thereby promote earlier intervention and improve patient outcomes.

银屑病关节炎(psoriatic arthritis, PsA)是一种免疫介导的慢性炎症性皮肤和关节疾病,约影响0.27%的成年人群和20%的银屑病患者。据估计,高达10%的牛皮癣患者患有未确诊的PsA。早期诊断和治疗可以预防不可逆的关节损伤、残疾和畸形。筛查未确诊PsA患者的问卷需要患者和医生参与。目的评估一种专有的机器学习工具(PredictAI™),该工具用于在首次怀疑患有PsA(参考事件)之前1-4年识别未确诊的PsA患者。方法回顾性分析2008 - 2020年马卡比医疗服务中心的成年人口资料。我们创建了2个队列:普通成年人(GP队列)包括牛皮癣患者和非牛皮癣患者;牛皮癣队列(PsO队列)仅包括牛皮癣患者。每个队列被分为两个不重叠的训练集和测试集。PredictAI模型在参考事件发生至少一年之前的3年数据中进行了训练和评估。使用受试者工作特征(ROC)分析来研究在不同特异性水平下使用梯度增强树构建的模型的性能。结果2096例患者符合PsA诊断标准。PsO队列中未确诊的PsA患者在参考事件发生前1年和4年的特异性分别为90%,敏感性分别为51%和38%,PPV分别为36.1%和29.6%。在GP队列中,该模型的特异性为99%,在相同的时间窗内,该模型的敏感性分别为43%和32%,PPV分别为10.6%和8.1%。结论提出的机器学习工具可以帮助早期识别未确诊的PsA患者,从而促进早期干预并改善患者预后。
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引用次数: 0
Inflammation and immunomodulatory therapies influence the relationship between ATP-binding cassette A1 membrane transporter-mediated cholesterol efflux capacity and coronary atherosclerosis in rheumatoid arthritis 炎症和免疫调节疗法影响atp结合盒A1膜转运体介导的胆固醇外排能力与类风湿关节炎冠状动脉粥样硬化之间的关系
IF 3.9 Q2 IMMUNOLOGY Pub Date : 2023-07-18 DOI: 10.1016/j.jtauto.2023.100209
George A. Karpouzas , Bianca Papotti , Sarah R. Ormseth , Marcella Palumbo , Elizabeth Hernandez , Maria Pia Adorni , Francesca Zimetti , Matthew J. Budoff , Nicoletta Ronda

Objectives

High-density lipoprotein (HDL) removes cholesterol from cells in atherosclerotic lesions, a function known as cholesterol efflux capacity (CEC). ATP-binding-cassette A1 (ABCA1) membrane transporter starts cholesterol transfer from macrophages to HDL particles. In rheumatoid arthritis (RA), methotrexate and biologic disease modifying drugs (bDMARDs) are atheroprotective whereas corticosteroids and C-reactive protein (CRP) are proatherogenic. We evaluated the influence of these factors on the relationship of ABCA1-CEC with atherosclerosis and cardiovascular events.

Methods

Atherosclerosis was evaluated with computed tomography angiography in 140 patients with RA and repeated in 99 after 6.9 ± 0.3 years. Events including acute coronary syndromes, stroke, cardiovascular death, claudication, revascularization, and heart failure were recorded. ABCA1-CEC was quantified in J774A.1 murine macrophages and reported as percentage of effluxed over intracellular cholesterol.

Results

Higher ABCA1-CEC associated with (i) more calcified plaques at baseline only in patients with CRP>7 mg/L (median) (p-interaction = 0.001) and methotrexate nonusers (p-interaction = 0.037), and more partially-calcified plaques only in bDMARD nonusers (p-interaction = 0.029); (ii) fewer new calcified plaques in patients with below-median but not higher time-averaged CRP (p-interaction = 0.028); (iii) fewer new total and calcified plaques in prednisone unexposed but not patients exposed to prednisone during follow-up (p-interaction = 0.034 and 0.004) and (iv) more new plaques in baseline bDMARD nonusers and fewer in bDMARD users (p-interaction 0.001). Also, ABCA1-CEC associated with greater cardiovascular risk only in baseline prednisone users (p-interaction = 0.027).

Conclusion

ABCA1-CEC associated with decreased atherosclerosis in patients with below-median baseline and time-averaged CRP and bDMARD use. Conversely, ABCA1-CEC associated with increased plaque in those with higher CRP, corticosteroid users, methotrexate nonusers, and bDMARD nonusers. While in well-treated and controlled disease ABCA1-CEC appears atheroprotective, in uncontrolled RA its action may be masked or fail to counteract the inflammation-driven proatherogenic state.

目的:高密度脂蛋白(HDL)可清除动脉粥样硬化病变细胞中的胆固醇,这种功能被称为胆固醇外排能力(CEC)。atp结合盒A1 (ABCA1)膜转运蛋白启动胆固醇从巨噬细胞向HDL颗粒的转移。在类风湿性关节炎(RA)中,甲氨蝶呤和生物疾病修饰药物(bDMARDs)具有动脉粥样硬化保护作用,而皮质类固醇和c反应蛋白(CRP)具有动脉粥样硬化促生作用。我们评估了这些因素对ABCA1-CEC与动脉粥样硬化和心血管事件的关系的影响。方法对140例RA患者行ct血管造影检查,99例患者术后6.9±0.3年复查。事件包括急性冠状动脉综合征、中风、心血管死亡、跛行、血运重建术和心力衰竭。在J774A中定量ABCA1-CEC。1小鼠巨噬细胞,以细胞内胆固醇外排百分比报告。结果较高的ABCA1-CEC与(1)基线时较多钙化斑块仅与CRP>7 mg/L(中位数)(p-相互作用= 0.001)和未使用甲氨蝶呤(p-相互作用= 0.037)的患者相关,仅与未使用bDMARD的患者相关(p-相互作用= 0.029);(ii)低于中位数但时间平均CRP不高的患者新发钙化斑块较少(p-相互作用= 0.028);(iii)在随访期间,未暴露于强的松但暴露于强的松的患者中新出现的总斑块和钙化斑块较少(p-相互作用= 0.034和0.004);(iv)基线bDMARD未使用者中新出现的斑块较多,bDMARD使用者中新出现的斑块较少(p-相互作用≤0.001)。此外,ABCA1-CEC仅与基线强的松使用者的心血管风险增加相关(p交互作用= 0.027)。结论:在使用低于中位基线和时间平均CRP和bDMARD的患者中,abca1 - cec与动脉粥样硬化减少相关。相反,在高CRP、皮质类固醇使用者、甲氨蝶呤非使用者和bDMARD非使用者中,ABCA1-CEC与斑块增加相关。虽然在治疗良好和控制的疾病中,ABCA1-CEC表现出动脉粥样硬化保护作用,但在不受控制的RA中,ABCA1-CEC的作用可能被掩盖或无法抵消炎症驱动的促动脉粥样硬化状态。
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引用次数: 0
Ultrastructural skin alterations of healthy subjects with anti-desmoglein 1 antibodies in endemic areas to pemphigus foliaceus: A case series 叶状天疱疮流行区携带抗粘粒蛋白1抗体的健康受试者的皮肤超微结构改变:一个病例系列
IF 3.9 Q2 IMMUNOLOGY Pub Date : 2023-07-13 DOI: 10.1016/j.jtauto.2023.100208
Willy Ramos , Nancy Rojas , Alex G. Ortega-Loayza , Mercedes Tello , Gerardo Jiménez , Nicolás Cuba-Cáceres , Gerardo Ronceros , Jhony A. De La Cruz-Vargas , Víctor Juan Vera-Ponce , Nadia Guerrero , Ericson L. Gutierrez

Background

Endemic pemphigus foliaceus and endemic pemphigus vulgaris are autoimmune dermatologic disorders endemic to the Peruvian Amazon.

Objective

To determine the ultrastructural skin alterations of three healthy subjects with anti DSG-1 antibodies in areas endemic to pemphigus foliaceus and pemphigus vulgaris in the Peruvian Amazon.

Patients and methods

Case series carried out from data of three clinically healthy subjects positive to anti DSG-1 antibodies, from Peru. This study consists of a sub-analysis of data gathered in a previous study.

Results

Ultrastructural results are presented from the skin biopsies of three clinically healthy patients positive to anti-desmoglein 1 (DSG-1) antibodies. High Resolution Optical Microscopy (HROM) showed the absence of acantholysis. Transmission Electron Microscopy (TEM) showed the widening of intercellular space between keratinocytes, the presence of vacuoles in intercellular space with granular material and cytoplasmic vacuolization, loss of desmosome structure, loss of normal distribution among tonofilaments and lateral separation among cells in the stratum basale.

Conclusion

According to our results, healthy subjects that present anti-desmoglein 1 antibodies can develop ultrastructural alterations that are visible through transmission electron microscopy but not through conventional optical microscopy.

背景:流行性叶状天疱疮和地方性寻常型天疱疮是秘鲁亚马逊地区特有的自身免疫性皮肤病。目的观察秘鲁亚马逊地区叶状天疱疮和寻常型天疱疮流行区3名健康人的皮肤超微结构变化。患者与方法对3例秘鲁临床健康患者进行病例系列研究,这些患者抗DSG-1抗体呈阳性。本研究包括对先前研究中收集的数据的子分析。结果3例临床健康患者皮肤活检均显示抗粘粒蛋白1 (DSG-1)抗体阳性。高分辨率光学显微镜(HROM)显示棘皮没有溶解。透射电镜(TEM)显示,角质形成细胞间的细胞间隙变宽,细胞间隙中存在颗粒状物质的空泡,细胞质空泡化,桥粒结构丧失,张力丝间的正态分布丧失,基底层细胞间的侧向分离。根据我们的研究结果,健康受试者的抗粘粒蛋白1抗体可以发生超微结构改变,这种改变在透射电子显微镜下可见,而在常规光学显微镜下却看不见。
{"title":"Ultrastructural skin alterations of healthy subjects with anti-desmoglein 1 antibodies in endemic areas to pemphigus foliaceus: A case series","authors":"Willy Ramos ,&nbsp;Nancy Rojas ,&nbsp;Alex G. Ortega-Loayza ,&nbsp;Mercedes Tello ,&nbsp;Gerardo Jiménez ,&nbsp;Nicolás Cuba-Cáceres ,&nbsp;Gerardo Ronceros ,&nbsp;Jhony A. De La Cruz-Vargas ,&nbsp;Víctor Juan Vera-Ponce ,&nbsp;Nadia Guerrero ,&nbsp;Ericson L. Gutierrez","doi":"10.1016/j.jtauto.2023.100208","DOIUrl":"https://doi.org/10.1016/j.jtauto.2023.100208","url":null,"abstract":"<div><h3>Background</h3><p>Endemic pemphigus foliaceus and endemic pemphigus vulgaris are autoimmune dermatologic disorders endemic to the Peruvian Amazon.</p></div><div><h3>Objective</h3><p>To determine the ultrastructural skin alterations of three healthy subjects with anti DSG-1 antibodies in areas endemic to pemphigus foliaceus and pemphigus vulgaris in the Peruvian Amazon.</p></div><div><h3>Patients and methods</h3><p>Case series carried out from data of three clinically healthy subjects positive to anti DSG-1 antibodies, from Peru. This study consists of a sub-analysis of data gathered in a previous study.</p></div><div><h3>Results</h3><p>Ultrastructural results are presented from the skin biopsies of three clinically healthy patients positive to <em>anti</em>-desmoglein 1 (DSG-1) antibodies. High Resolution Optical Microscopy (HROM) showed the absence of acantholysis. Transmission Electron Microscopy (TEM) showed the widening of intercellular space between keratinocytes, the presence of vacuoles in intercellular space with granular material and cytoplasmic vacuolization, loss of desmosome structure, loss of normal distribution among tonofilaments and lateral separation among cells in the stratum basale.</p></div><div><h3>Conclusion</h3><p>According to our results, healthy subjects that present <em>anti</em>-desmoglein 1 antibodies can develop ultrastructural alterations that are visible through transmission electron microscopy but not through conventional optical microscopy.</p></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"7 ","pages":"Article 100208"},"PeriodicalIF":3.9,"publicationDate":"2023-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49858263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Statins influence the relationship between ATP-binding cassette A1 membrane transporter-mediated cholesterol efflux capacity and coronary atherosclerosis in rheumatoid arthritis 他汀类药物影响atp结合盒A1膜转运体介导的胆固醇外排能力与类风湿关节炎冠状动脉粥样硬化的关系
IF 3.9 Q2 IMMUNOLOGY Pub Date : 2023-07-07 DOI: 10.1016/j.jtauto.2023.100206
George A. Karpouzas , Bianca Papotti , Sarah R. Ormseth , Marcella Palumbo , Elizabeth Hernandez , Maria Pia Adorni , Francesca Zimetti , Matthew J. Budoff , Nicoletta Ronda

Objectives

Cholesterol efflux capacity (CEC) is the main antiatherogenic function of high-density lipoprotein (HDL). ATP-binding-cassette A1 (ABCA1) membrane transporter initiates cholesterol export from arterial macrophages to pre-β HDL particles fostering their maturation; in turn, those accept cholesterol through ABCG1-mediated export. Impaired pre-β HDL maturation may disrupt the collaborative function of the two transporters and adversely affect atherosclerosis. Statins exert atheroprotective functions systemically and locally on plaque. We here evaluated associations between ABCA1-CEC, coronary atherosclerosis and cardiovascular risk and the influence of statins on those relationships in rheumatoid arthritis (RA).

Methods

Evaluation with computed tomography angiography was undertaken in 140 patients and repeated in 99 after 6.9 ± 0.3 years. Events comprising cardiovascular death, acute coronary syndromes, stroke, claudication, revascularization and heart failure were recorded. ABCA1-CEC and ABCG1-CEC were evaluated in J774A.1 macrophages and Chinese hamster ovary (CHO) cells respectively and expressed as percentage of effluxed over total intracellular cholesterol. Covariates in all cardiovascular event risk and plaque outcome models included atherosclerotic cardiovascular disease (ASCVD) risk score and high-density lipoprotein cholesterol.

Results

ABCA1-CEC negatively correlated with ABCG1-CEC (r = −0.167, p = 0.049). ABCA1-CEC associated with cardiovascular risk (adjusted hazard ratio 2.05 [95%CI 1.20–3.48] per standard deviation [SD] increment). There was an interaction of ABCA1-CEC with time-varying statin use (p = 0.038) such that current statin use inversely associated with risk only in patients with ABCA1-CEC below the upper tertile. ABCA1-CEC had no main effect on plaque or plaque progression; instead, ABCA1-CEC (per SD) associated with fewer baseline total plaques (adjusted rate ratio [aRR] 0.81, [95%CI 0.65–1.00]), noncalcified plaques (aRR 0.78 [95%CI 0.61–0.98]), and vulnerable low-attenuation plaques (aRR 0.41 [95%CI 0.23–0.74]) in statin users, and more low-attenuation plaques (aRR 1.91 [95%CI 1.18–3.08]) in nonusers (p-for-interaction = 0.018, 0.011, 0.025 and < 0.001 respectively). Moreover, ABCA1-CEC (per SD) associated with greater partially/fully-calcified plaque progression (adjusted odds ratio 3.07 [95%CI 1.20–7.86]) only in patients not exposed to statins during follow-up (p-for-interaction = 0.009).

Conclusion

In patients with RA, higher ABCA1-CEC may reflect a proatherogenic state, associated with enhanced cardiovascular risk. Statin use may unmask the protective impact of ABCA1-mediated cholesterol efflux on plaque formation, progression and cardiovascular risk.

目的胆固醇外排能力(CEC)是高密度脂蛋白(HDL)抗动脉粥样硬化的主要功能。atp结合盒A1 (ABCA1)膜转运体启动胆固醇从动脉巨噬细胞输出到β前HDL颗粒,促进其成熟;反过来,它们通过abcg1介导的输出接受胆固醇。β - HDL成熟受损可能破坏两种转运体的协同功能,并对动脉粥样硬化产生不利影响。他汀类药物对斑块具有全身和局部的动脉粥样硬化保护作用。我们在此评估了ABCA1-CEC、冠状动脉粥样硬化和心血管风险之间的关系,以及他汀类药物对类风湿关节炎(RA)患者这些关系的影响。方法140例患者行ct血管造影评估,99例患者术后6.9±0.3年复查。记录了心血管死亡、急性冠状动脉综合征、中风、跛行、血运重建术和心力衰竭等事件。测定J774A的ABCA1-CEC和ABCG1-CEC。1巨噬细胞和中国仓鼠卵巢(CHO)细胞,并以外排胆固醇占细胞内总胆固醇的百分比表达。所有心血管事件风险和斑块结局模型的协变量包括动脉粥样硬化性心血管疾病(ASCVD)风险评分和高密度脂蛋白胆固醇。结果abca1 - cec与ABCG1-CEC呈负相关(r = - 0.167, p = 0.049)。ABCA1-CEC与心血管风险相关(校正风险比2.05 [95%CI 1.20-3.48] /标准差[SD]增量)。ABCA1-CEC与随时间变化的他汀类药物使用存在相互作用(p = 0.038),因此目前他汀类药物的使用仅在ABCA1-CEC低于上五分位的患者中与风险呈负相关。ABCA1-CEC对斑块或斑块进展无主要影响;相反,ABCA1-CEC(每SD)与他汀类药物使用者较少的基线总斑块(调整比值[aRR] 0.81, [95%CI 0.65-1.00])、非钙化斑块(aRR 0.78 [95%CI 0.61-0.98])和易损性低衰减斑块(aRR 0.41 [95%CI 0.23-0.74])相关,与非他汀类药物使用者较多的低衰减斑块(aRR 1.91 [95%CI 1.18-3.08])相关(相互作用p = 0.018, 0.011, 0.025和<0.001分别)。此外,ABCA1-CEC(每SD)仅在随访期间未暴露于他汀类药物的患者中与更大的部分/完全钙化斑块进展相关(校正优势比3.07 [95%CI 1.20-7.86])(相互作用p = 0.009)。结论在RA患者中,较高的ABCA1-CEC可能反映了动脉粥样硬化状态,与心血管风险增加相关。他汀类药物的使用可能揭示abca1介导的胆固醇外排对斑块形成、进展和心血管风险的保护作用。
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引用次数: 0
The effect of HLA-DRB1*04:01 on a mouse model of atherosclerosis HLA-DRB1*04:01对动脉粥样硬化小鼠模型的影响
IF 3.9 Q2 IMMUNOLOGY Pub Date : 2023-06-21 DOI: 10.1016/j.jtauto.2023.100203
Garth Blackler , James Akingbasote , Ewa Cairns , Christopher Howlett , Patti Kiser , Lillian Barra

Objectives

HLA-DRB1 is associated with an increased risk of cardiovascular disease in patients with rheumatoid arthritis (RA). This study aimed to determine the effect of HLA-DRB1 on atherosclerotic cardiovascular disease (ASCVD) using a novel mouse model.

Methods

Mice transgenic for HLA-DRB1*04:01 (DR4tg) were crossed with low density lipoprotein receptor knock-out (Ldlr−/−) mice that develop atherosclerosis when fed a high fat, high cholesterol (HFHC) diet. Male and female DR4tgLdlr−/− (n = 48), Ldlr−/− (n = 24), DR4tg (n = 24), and C57Bl/6 (B6) background (n = 24) mice were fed HFHC or regular diet (RD) for 12 weeks. Blood samples were analyzed for serum lipoproteins using a colorimetric assay. C-reactive protein (CRP) and oxidized LDL (OxLDL) were measured using ELISA. Atherosclerosis in the aortas was assessed using the lipid stain, Sudan IV. The presence of citrulline in atherosclerotic plaque was determined by immunohistochemistry.

Results

Sera low-density lipoprotein cholesterol (LDL-C) levels were higher in HFHC-fed Ldlr−/− versus DR4tgLdlr−/−-; p = 0.0056, but the aortic plaque burden and degree of citrullination in the plaque were similar for these two strains. The ratio of pro-atherogenic OxLDL to LDL levels was higher in DR4tgLdlr−/− than Ldlr−/−mice; p = 0.0017. All mice had an increase in CRP when fed a HFHC diet, most pronounced for DR4tgLdlr−/−; p = 0.0009. There were no significant sex differences for DR4tgLdlr−/− mice; however, male Ldlr−/− mice had worse atherosclerosis. B6 and DR4tg mice did not have significant elevations in serum cholesterol levels and did not develop atherosclerosis.

Conclusions

Expression of HLA-DRB1 resulted in an elevation of OxLDL and a reduction in the male bias for atherosclerosis, mimicking what is observed in RA.

目的HLA-DRB1与类风湿性关节炎(RA)患者心血管疾病风险增加有关。本研究旨在使用一种新的小鼠模型来确定HLA-DRB1对动脉粥样硬化性心血管疾病(ASCVD)的影响。方法将HLA-DRB1*04:01(DR4tg)转基因小鼠与低密度脂蛋白受体敲除(Ldlr−/-)小鼠杂交,这些小鼠在高脂、高胆固醇(HFHC)饮食中发生动脉粥样硬化。雄性和雌性DR4tgLdlr−/−(n=48)、Ldlr–/−(n=24)、DR4tg(n=24)和C57Bl/6(B6)背景(n=24。使用比色法分析血液样本中的血清脂蛋白。采用ELISA法测定C反应蛋白(CRP)和氧化低密度脂蛋白(OxLDL)。使用脂质染色Sudan IV评估主动脉中的动脉粥样硬化。通过免疫组织化学测定动脉粥样硬化斑块中瓜氨酸的存在。结果HFHC喂养的Ldlr−/−组血清低密度脂蛋白胆固醇(LDL-C)水平高于DR4tgLdlr–/−组;p=0.0056,但这两种菌株的主动脉斑块负荷和斑块中的瓜氨酸化程度相似。DR4tgLdlr−/−小鼠的促动脉粥样硬化OxLDL与LDL水平之比高于Ldlr–/−小鼠;p=0.0017。当喂食HFHC饮食时,所有小鼠的CRP都有所增加,DR4tgLdlr−/−最为显著;p=0.0009。DR4tgLdlr−/−小鼠没有显著的性别差异;然而,雄性Ldlr−/−小鼠的动脉粥样硬化更严重。B6和DR4tg小鼠的血清胆固醇水平没有显著升高,也没有发生动脉粥样硬化。结论HLA-DRB1的表达导致OxLDL的升高和动脉粥样硬化男性偏倚的减少,这与在RA中观察到的相似。
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引用次数: 1
PPAR agonists for the treatment of primary biliary cholangitis: Old and new tales PPAR激动剂治疗原发性胆管炎:新旧故事
IF 3.9 Q2 IMMUNOLOGY Pub Date : 2023-01-01 DOI: 10.1016/j.jtauto.2023.100188
Francesca Colapietro , M. Eric Gershwin , Ana Lleo

Introduction

Primary biliary cholangitis (PBC) is an autoimmune liver disease involving the small intrahepatic bile ducts; when untreated or undertreated, it may evolve to liver fibrosis and cirrhosis. Ursodeoxycholic Acid (UDCA) is the standard of care treatment, Obeticholic Acid (OCA) has been approved as second-line therapy for those non responder or intolerant to UDCA. However, due to moderate rate of UDCA-non responders and to warnings recently issued against OCA use in patients with cirrhosis, further therapies are needed.

Areas covered. Deep investigations into the pathogenesis of PBC is leading to proposal of new therapeutic agents, among which peroxisome proliferator-activated receptor (PPAR) ligands seem to be highly promising given the preliminary, positive results in Phase 2 and 3 trials. Bezafibrate, the most evaluated, is currently used in clinical practice in combination with UDCA in referral centers. We herein describe completed and ongoing trials involving PPAR agonists use in PBC, analyzing pits and falls.

Expert opinion

Testing new therapeutic opportunities in PBC is challenging due to its low prevalence and slow progression. However, new drugs including PPAR agonists, are currently under investigation and should be considered for at-risk PBC patients.

原发性胆汁性胆管炎(PBC)是一种累及肝内小胆管的自身免疫性肝病;如果不治疗或治疗不足,它可能会演变成肝纤维化和肝硬化。熊去氧胆酸(UDCA)是护理治疗的标准,奥贝胆酸(OCA)已被批准为对UDCA无反应或不耐受者的二线治疗。然而,由于UDCA无效率适中,以及最近发布的关于肝硬化患者使用OCA的警告,需要进一步的治疗。覆盖区域。对PBC发病机制的深入研究导致了新的治疗剂的提出,其中过氧化物酶体增殖物激活受体(PPAR)配体似乎非常有希望,因为在2期和3期试验中取得了初步的积极结果。贝扎贝特是评价最高的药物,目前在临床实践中与UDCA一起在转诊中心使用。我们在此描述了涉及PPAR激动剂在PBC中使用的已完成和正在进行的试验,分析凹坑和跌倒。专家意见:由于PBC发病率低,进展缓慢,测试新的治疗机会具有挑战性。然而,包括PPAR激动剂在内的新药目前正在研究中,应考虑用于高危PBC患者。
{"title":"PPAR agonists for the treatment of primary biliary cholangitis: Old and new tales","authors":"Francesca Colapietro ,&nbsp;M. Eric Gershwin ,&nbsp;Ana Lleo","doi":"10.1016/j.jtauto.2023.100188","DOIUrl":"10.1016/j.jtauto.2023.100188","url":null,"abstract":"<div><h3>Introduction</h3><p>Primary biliary cholangitis (PBC) is an autoimmune liver disease involving the small intrahepatic bile ducts; when untreated or undertreated, it may evolve to liver fibrosis and cirrhosis. Ursodeoxycholic Acid (UDCA) is the standard of care treatment, Obeticholic Acid (OCA) has been approved as second-line therapy for those non responder or intolerant to UDCA. However, due to moderate rate of UDCA-non responders and to warnings recently issued against OCA use in patients with cirrhosis, further therapies are needed.</p><p><u>Areas covered.</u> Deep investigations into the pathogenesis of PBC is leading to proposal of new therapeutic agents, among which peroxisome proliferator-activated receptor (PPAR) ligands seem to be highly promising given the preliminary, positive results in Phase 2 and 3 trials. Bezafibrate, the most evaluated, is currently used in clinical practice in combination with UDCA in referral centers. We herein describe completed and ongoing trials involving PPAR agonists use in PBC, analyzing pits and falls.</p></div><div><h3>Expert opinion</h3><p>Testing new therapeutic opportunities in PBC is challenging due to its low prevalence and slow progression. However, new drugs including PPAR agonists, are currently under investigation and should be considered for at-risk PBC patients.</p></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"6 ","pages":"Article 100188"},"PeriodicalIF":3.9,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/12/6b/main.PMC9850184.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10579003","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: 4
Engineering live attenuated vaccines: Old dogs learning new tricks 工程减毒活疫苗:老狗学新把戏。
IF 3.9 Q2 IMMUNOLOGY Pub Date : 2023-01-01 DOI: 10.1016/j.jtauto.2023.100198
Julia Plocica , Fengguang Guo , Jugal Kishore Das , Koichi S. Kobayashi , Thomas A. Ficht , Robert C. Alaniz , Jianxun Song , Paul de Figueiredo

Autoimmune diseases such as rheumatoid arthritis and type 1 diabetes are increasingly common global problems. Concerns about increases in the prevalence of such diseases and the limited efficacy of conventional treatment regimens necessitates new therapies to address these challenges. Autoimmune disease severity and dysbiosis are interconnected. Although probiotics have been established as a therapy to rebalance the microbiome and suppress autoimmune symptoms, these microbes tend to lack a number of advantageous qualities found in non-commensal bacteria. Through attenuation and genetic manipulation, these non-commensal bacteria have been engineered into recombinant forms that offer malleable platforms capable of addressing the immune imbalances found in RA and T1D. Such bacteria have been engineered to express valuable gene products known to suppress autoimmunity such as anti-inflammatory cytokines, autoantigens, and enzymes synthesizing microbial metabolites. This review will highlight current and emerging trends in the field and discuss how they may be used to prevent and control autoimmune diseases.

类风湿性关节炎和1型糖尿病等自身免疫性疾病是越来越常见的全球问题。对此类疾病患病率增加和传统治疗方案疗效有限的担忧,需要新的疗法来应对这些挑战。自身免疫性疾病的严重程度和微生态失调是相互关联的。尽管益生菌已被确定为一种重新平衡微生物组和抑制自身免疫症状的疗法,但这些微生物往往缺乏非共生细菌中发现的一些有利品质。通过衰减和基因操作,这些非共生细菌已被改造成重组形式,提供了能够解决RA和T1D中发现的免疫失衡的可塑性平台。这些细菌已被改造以表达已知抑制自身免疫的有价值的基因产物,如抗炎细胞因子、自身抗原和合成微生物代谢产物的酶。这篇综述将强调该领域的当前和新兴趋势,并讨论如何将其用于预防和控制自身免疫性疾病。
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引用次数: 1
FRTX-02, a selective and potent inhibitor of DYRK1A, modulates inflammatory pathways in mouse models of psoriasis and atopic dermatitis FRTX-02是一种选择性和有效的DYRK1A抑制剂,可调节银屑病和特应性皮炎小鼠模型中的炎症途径
IF 3.9 Q2 IMMUNOLOGY Pub Date : 2023-01-01 DOI: 10.1016/j.jtauto.2022.100185
Soochan Kim , Eunhwa Ko , Hwan Geun Choi , Daekwon Kim , Monica Luchi , Bernard Khor , Sunghwan Kim

Dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) has been proposed as a novel regulator of adaptive immune homeostasis through modulating T cell polarization. Thus, DYRK1A could present a potential target in autoimmune disorders. Here, we identify FRTX-02 as a novel compound exhibiting potent and selective inhibition of DYRK1A. FRTX-02 induced transcriptional activity of the DYRK1A substrate NFAT in T cell lines. Correspondingly, FRTX-02 promoted ex vivo CD4+ polarization into anti-inflammatory Tregs and reduced their polarization into pro-inflammatory Th1 or Th17 cells. We show that FRTX-02 could also limit innate immune responses through negative regulation of the MyD88/IRAK4–NF-κB axis in a mast cell line. Finally, in mouse models of psoriasis and atopic dermatitis, both oral and topical formulations of FRTX-02 reduced inflammation and disease biomarkers in a dose-dependent manner. These results support further studies of DYRK1A inhibitors, including FRTX-02, as potential therapies for chronic inflammatory and autoimmune conditions.

双特异性酪氨酸磷酸化调节激酶1a (DYRK1A)已被认为是一种通过调节T细胞极化来调节适应性免疫稳态的新型调节剂。因此,DYRK1A可能是自身免疫性疾病的潜在靶点。在这里,我们发现FRTX-02是一种新型化合物,表现出对DYRK1A的有效和选择性抑制。FRTX-02诱导T细胞系中DYRK1A底物NFAT的转录活性。相应的,FRTX-02促进体外CD4+极化为抗炎treg细胞,减少其极化为促炎Th1或Th17细胞。我们发现FRTX-02还可以通过负调控肥大细胞系中的MyD88/ IRAK4-NF -κB轴来限制先天免疫反应。最后,在银屑病和特应性皮炎小鼠模型中,口服和外用FRTX-02制剂均以剂量依赖的方式减少炎症和疾病生物标志物。这些结果支持进一步研究DYRK1A抑制剂,包括FRTX-02,作为慢性炎症和自身免疫性疾病的潜在治疗方法。
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引用次数: 0
期刊
Journal of Translational Autoimmunity
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