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Cathepsin C exacerbates EAE by promoting the expansion of Tfh cells and the formation of TLSs in the CNS Cathepsin C能促进中枢神经系统中Tfh细胞的扩增和TLS的形成,从而加剧EAE。
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-05 DOI: 10.1016/j.bbi.2024.09.004
Shuang Liu , Xiaohan Yang , Henan Zhao , Xinnan Zhao , Kai Fan , Gang Liu , Xia Li , Cong Du , Jing Liu , Jianmei Ma

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) mediated by CD4+ T helper (Th) cells, and characterized by immune cell infiltration, demyelination and neurodegeneration, with no definitive cure available. Thus, it is pivotal and imperative to acquire more profound comprehension of the underlying mechanisms implicated in MS. Dysregulated immune responses are widely believed to play a primary role in the pathogenesis of MS. Recently, a plethora of studies have demonstrated the involvement of T follicular helper (Tfh) cells and tertiary lymphoid-like structures (TLSs) in the pathogenesis and progression of MS. Cathepsin C (CatC) is a cysteine exopeptidase which is crucial for the activation of immune-cell-associated serine proteinases in many inflammatory diseases in peripheral system, such as rheumatoid arthritis and septicemia. We have previously demonstrated that CatC is involved in neuroinflammation and exacerbates demyelination in both cuprizone-induced and experimental autoimmune encephalomyelitis (EAE) mouse models. However, the underlying immunopathological mechanism remains elusive. In the present study, we established a recombinant myelin oligodendrocyte glycoprotein 35–55 peptide-induced EAE model using conditional CatC overexpression mice to investigate the effects of CatC on the alteration of CD4+ Th subsets, including Th1, Th2, Th17, Tfh and T regulatory cells. Our findings demonstrated that CatC particularly enhanced the population of Tfh cell in the brain, resulting in the earlier onset and more severe chronic syndrome of EAE. Furthermore, CatC promoted the formation of TLSs in the brain, leading to persistent neuroinflammation and exacerbating the severity of EAE in the chronic phase. Conversely, treatment with AZD7986, a specific inhibitor of CatC, effectively attenuated the syndrome of EAE and its effects caused by CatC both in vivo and in vitro. These findings provide a novel insight into the critical role of CatC in innate and adaptive immunity in EAE, and specific inhibitor of CatC, AZD7986, may contribute to potential therapeutic strategies for MS.

多发性硬化症(MS)是一种由 CD4+ T 辅助细胞(Th)介导的中枢神经系统(CNS)慢性自身免疫性疾病,以免疫细胞浸润、脱髓鞘和神经变性为特征,目前尚无根治方法。因此,更深入地了解多发性硬化症的内在机制至关重要,势在必行。人们普遍认为,失调的免疫反应在多发性硬化症的发病机制中起着主要作用。最近,大量研究表明,T 滤泡辅助细胞(Tfh)和三级淋巴样结构(TLSs)参与了多发性硬化症的发病和进展。Cathepsin C(CatC)是一种半胱氨酸外肽酶,在类风湿性关节炎和败血症等许多外周系统炎症性疾病中,它是激活免疫细胞相关丝氨酸蛋白酶的关键。我们之前已经证明,CatC 参与了铜绿素诱导的神经炎症,并加剧了实验性自身免疫性脑脊髓炎(EAE)小鼠模型的脱髓鞘。然而,其潜在的免疫病理机制仍然难以捉摸。在本研究中,我们利用条件性CatC过表达小鼠建立了重组髓鞘少突胶质细胞糖蛋白35-55肽诱导的EAE模型,研究了CatC对CD4+ Th亚群(包括Th1、Th2、Th17、Tfh和T调节细胞)改变的影响。我们的研究结果表明,CatC特别增强了脑内Tfh细胞的数量,导致EAE慢性综合征发病更早、更严重。此外,CatC还能促进脑内TLS的形成,导致持续性神经炎症,加重慢性期EAE的严重程度。相反,CatC的特异性抑制剂AZD7986能有效减轻EAE综合征及其在体内和体外由CatC引起的影响。这些研究结果提供了一个新的视角,让我们了解到CatC在EAE的先天性免疫和适应性免疫中的关键作用,而CatC的特异性抑制剂AZD7986可能有助于多发性硬化症的潜在治疗策略。
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引用次数: 0
TNFR2 signaling in oligodendrocyte precursor cells suppresses their immune-inflammatory function and detrimental microglia activation in CNS demyelinating disease 在中枢神经系统脱髓鞘疾病中,少突胶质前体细胞中的 TNFR2 信号可抑制其免疫炎症功能和有害的小胶质细胞激活。
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-05 DOI: 10.1016/j.bbi.2024.09.002
Haritha L. Desu , Estrid Thougaard , Brianna N. Carney , Placido Illiano , Melanie J. Plastini , Yoleinny Florimon , Antonella Mini , Chelsea Guastucci , Brian Kang , Jae K. Lee , Kate L. Lambertsen , Roberta Brambilla

Multiple Sclerosis (MS) is a chronic degenerative disease of the central nervous system (CNS) characterized by inflammation, demyelination, and progressive neurodegeneration. These processes, combined with the failure of reparative remyelination initiated by oligodendrocyte precursor cells (OPCs), lead to irreversible neurological impairment. The cytokine tumor necrosis factor (TNF) has been implicated in CNS repair via activation of its cognate receptor TNFR2 in glia. Here, we demonstrate the important role of TNFR2 in regulating OPC function in vivo during demyelinating disease, and that TNFR2 expressed in OPCs modulates OPC-microglia interactions. In PdgfrαCreERT:Tnfrsf1bfl/fl:Eyfp mice with selective TNFR2 ablation in OPCs, we observed an earlier onset and disease peak in experimental autoimmune encephalomyelitis (EAE). This was associated with accelerated immune cell infiltration and increased microglia activation in the spinal cord. Similarly, PdgfrαCreERT:Tnfrsf1bfl/fl:Eyfp mice showed rapid and increased microglia reactivity compared to control mice in the corpus callosum after cuprizone-induced demyelination, followed by chronic reduction in the number of mature myelinating oligodendrocytes (OLs). With EAE and cuprizone models combined, we uncovered that TNFR2 does not have a cell autonomous role in OPC differentiation, but may be important for survival of newly formed mature OLs. Finally, using an in vitro approach, we demonstrated that factors released by Tnfrsf1b ablated OPCs drove microglia to develop an exacerbated “foamy” phenotype when incubated with myelin-rich spinal cord homogenate, aberrantly increasing lysosomal lipid accumulation. Together, our data indicate that TNFR2 signaling in OPCs is protective by dampening their immune-inflammatory activation and by suppressing neurotoxic microglia reactivity. This suggests that boosting TNFR2 activation or its downstream cascades could be an effective strategy to restore OPC reparative capacity in neuroimmune and demyelinating disease.

多发性硬化症(MS)是中枢神经系统(CNS)的一种慢性退行性疾病,以炎症、脱髓鞘和进行性神经变性为特征。这些过程加上少突胶质细胞前体细胞(OPCs)启动的修复性再髓鞘化失败,导致不可逆转的神经损伤。细胞因子肿瘤坏死因子(TNF)通过激活神经胶质中的同源受体 TNFR2 而参与中枢神经系统的修复。在这里,我们证明了 TNFR2 在脱髓鞘疾病期间调节体内 OPC 功能的重要作用,并证明在 OPC 中表达的 TNFR2 可调节 OPC 与小胶质细胞之间的相互作用。在选择性消减OPCs中TNFR2的PdgfrαCreERT:Tnfrsf1bfl/fl:Eyfp小鼠中,我们观察到实验性自身免疫性脑脊髓炎(EAE)的发病时间和疾病高峰提前。这与脊髓中免疫细胞浸润加速和小胶质细胞活化增加有关。同样,与对照组小鼠相比,PdgfrαCreERT:Tnfrsf1bfl/fl:Eyfp小鼠在铜绿素诱导脱髓鞘后,胼胝体中的小胶质细胞反应性迅速增强,随后成熟的髓鞘化少突胶质细胞(OLs)数量长期减少。结合EAE和铜绿素模型,我们发现TNFR2在OPC分化中没有细胞自主作用,但可能对新形成的成熟OLs的存活很重要。最后,我们利用体外方法证明,当与富含髓鞘的脊髓匀浆一起培养时,Tnfrsf1b 消减的 OPCs 释放的因子会促使小胶质细胞形成加剧的 "泡沫 "表型,并异常增加溶酶体脂质的积累。总之,我们的数据表明,OPCs 中的 TNFR2 信号通过抑制其免疫炎症活化和抑制神经毒性小胶质细胞反应性而起到保护作用。这表明,在神经免疫和脱髓鞘疾病中,促进 TNFR2 或其下游级联的活化可能是恢复 OPC 修复能力的有效策略。
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引用次数: 0
Long-term characterisation of the relationship between change in depression severity and change in inflammatory markers following inflammation-stratified treatment with vortioxetine augmented with celecoxib or placebo 在使用伏替西汀和塞来昔布或安慰剂进行炎症分层治疗后,抑郁症严重程度的变化与炎症标志物变化之间的长期关系。
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-05 DOI: 10.1016/j.bbi.2024.09.003
Emma Sampson , Natalie T. Mills , Hikaru Hori , Micah Cearns , Kathrin Schwarte , Christa Hohoff , K. Oliver Schubert , Célia Fourrier , Bernhard T. Baune
<div><h3>Background</h3><p>Major depressive disorder (MDD) is a highly prevalent condition with a substantial incidence of relapse or treatment resistance. A subset of patients show evidence of low-grade inflammation, with these patients having a higher likelihood of more severe or difficult to treat courses of illness. Anti-inflammatory treatment of MDD has been investigated with mixed results, and no known studies have included assessments beyond cessation of the anti-inflammatory agent, meaning it remains unknown if any benefit from treatment persists. The objective of the present study was to investigate treatment outcomes up to 29 weeks post-cessation of celecoxib or placebo augmentation of an antidepressant, and how concentrations of selected inflammatory markers change over the same period.</p></div><div><h3>Methods</h3><p>The PREDDICT parallel-group, randomised, double-blind, placebo-controlled trial (University of Adelaide, Australia) ran from December 2017 to April 2020. Participants with MDD were stratified into normal range or elevated inflammation strata according to screening concentrations of high sensitivity C-reactive protein (hsCRP). Participants were randomised to treatment with vortioxetine and celecoxib or vortioxetine and placebo for six weeks, and vortioxetine alone for an additional 29 weeks (35 total weeks). Following a previous publication of results from the six-week RCT phase, exploratory analyses were performed on Montgomery–Åsberg Depression Rating Scale (MADRS) scores, response and remission outcomes, and selected peripheral inflammatory markers across the entire study duration up to week 35.</p></div><div><h3>Results</h3><p>Participants retained at each observation were baseline N=119, week 2 N=115, week 4 N=103, week 6 N=104, week 8 N=98, week 22 N=81, and week 35 N=60. Those in the elevated hsCRP celecoxib-augmented group had a statistically significantly greater reduction in MADRS score from baseline to week 35 compared to all other groups, demonstrating the greatest clinical improvement long-term, despite no group or strata differences at preceding time points. Response and remission outcomes did not differ by treatment group or hsCRP strata at any time point. Changes in hsCRP between baseline and week 35 and Tumour Necrosis Factor-α (TNF-α) concentrations between baseline and week 6 and baseline and week 35 were statistically significantly associated with MADRS scores observed at week 6 and week 35 respectively, with reducing TNF-α concentrations associated with reducing MADRS scores and vice versa in each case. A post-hoc stratification of the participant cohort by baseline TNF-α concentrations led to significant prediction by the derived strata on clinical response at weeks 6, 8 and 35, with participants with elevated baseline TNF-α less likely to achieve clinical response.</p></div><div><h3>Interpretation</h3><p>The present analysis suggests for the first time a possible longer-term clinical benefit of cele
背景:重度抑郁障碍(MDD)是一种发病率很高的疾病,复发率或耐药性很高。一部分患者有低度炎症的迹象,这些患者更有可能出现更严重或更难治疗的病程。针对 MDD 的抗炎治疗研究结果不一,没有任何已知的研究包括停止使用抗炎药物后的评估,这意味着治疗的益处是否持续存在仍是未知数。本研究的目的是调查塞来昔布或安慰剂增强抗抑郁剂停药后长达29周的治疗效果,以及在此期间某些炎症标志物浓度的变化情况:PREDDICT平行组、随机、双盲、安慰剂对照试验(澳大利亚阿德莱德大学)从2017年12月开始至2020年4月结束。根据高敏C反应蛋白(hsCRP)的筛查浓度,将患有MDD的参与者分为正常范围和炎症升高两层。参与者被随机分配接受为期六周的伏替西汀和塞来昔布或伏替西汀和安慰剂治疗,以及为期29周(共35周)的单独伏替西汀治疗。在之前发表了为期六周的 RCT 阶段研究结果后,我们对蒙哥马利-阿斯伯格抑郁量表 (MADRS) 评分、反应和缓解结果以及直至第 35 周的整个研究期间的部分外周炎症标志物进行了探索性分析:每次观察保留的参与者人数分别为:基线119人,第2周115人,第4周103人,第6周104人,第8周98人,第22周81人,第35周60人。从基线到第35周,hsCRP升高的塞来昔布增强组患者的MADRS评分下降幅度在统计学上显著高于其他所有组别,尽管在前几个时间点没有组别或分层差异,但长期临床改善幅度最大。各治疗组或 hsCRP 分层在任何时间点的反应和缓解结果均无差异。基线与第35周之间的hsCRP变化以及基线与第6周之间和基线与第35周之间的肿瘤坏死因子-α(TNF-α)浓度变化分别与第6周和第35周观察到的MADRS评分有显著统计学相关性,TNF-α浓度降低与MADRS评分降低相关,反之亦然。根据基线TNF-α浓度对参与者队列进行事后分层后,得出的分层对第6周、第8周和第35周的临床反应有显著预测作用,基线TNF-α升高的参与者获得临床反应的可能性较低:本分析首次表明,在治疗与炎症相关的MDD时,塞来昔布增强伏替西汀可能具有更长期的临床疗效。然而,还需要进一步的研究来证实这一发现,并确定产生这种延迟效应的原因。此外,该试验还表明,与hsCRP相比,TNF-α与抗炎MDD治疗结果的关系可能更密切,因此应进一步研究其潜在的预测作用:澳大利亚新西兰临床试验注册中心(ANZCTR),ACTRN12617000527369p。注册时间:2017年4月11日,http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12617000527369p。
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引用次数: 0
Bi-allelic NRXN1α deletion in microglia derived from iPSC of an autistic patient increases interleukin-6 production and impairs supporting function on neuronal networking 自闭症患者 iPSC 衍生的小胶质细胞中 NRXN1α 的双等位缺失会增加白细胞介素-6 的产生并损害对神经元网络的支持功能。
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-05 DOI: 10.1016/j.bbi.2024.09.001
Raj Bose , Mercedes Posada-Pérez , Eleni Karvela , Martin Skandik , Lily Keane , Anna Falk , Stefan Spulber , Bertrand Joseph , Sandra Ceccatelli

Autism spectrum disorder (ASD) is a set of heterogeneous neurodevelopmental conditions, with a highly diverse genetic hereditary component, including altered neuronal circuits, that has an impact on communication skills and behaviours of the affected individuals. Beside the recognised role of neuronal alterations, perturbations of microglia and the associated neuroinflammatory processes have emerged as credible contributors to aetiology and physiopathology of ASD. Mutations in NRXN1, a member of the neurexin family of cell-surface receptors that bind neuroligin, have been associated to ASD. NRXN1 is known to be expressed by neurons where it facilitates synaptic contacts, but it has also been identified in glial cells including microglia. Asserting the impact of ASD-related genes on neuronal versus microglia functions has been challenging. Here, we present an ASD subject-derived induced pluripotent stem cells (iPSC)-based in vitro system to characterise the effects of the ASD-associated NRXN1 gene deletion on neurons and microglia, as well as on the ability of microglia to support neuronal circuit formation and function. Using this approach, we demonstrated that NRXN1 deletion, impacting on the expression of the alpha isoform (NRXN1α), in microglia leads to microglial alterations and release of IL6, a pro-inflammatory interleukin associated with ASD. Moreover, microglia bearing the NRXN1α-deletion, lost the ability to support the formation of functional neuronal networks. The use of recombinant IL6 protein on control microglia-neuron co-cultures or neutralizing antibody to IL6 on their NRXN1α-deficient counterparts, supported a direct contribution of IL6 to the observed neuronal phenotype. Altogether, our data suggest that, in addition to neurons, microglia are also negatively affected by NRXN1α-deletion, and this significantly contributes to the observed neuronal circuit aberrations.

自闭症谱系障碍(ASD)是一组异质性神经发育疾病,具有高度多样化的遗传因素,包括神经元回路的改变,对患者的交流技能和行为产生影响。除了公认的神经元改变的作用外,小胶质细胞的扰动和相关的神经炎症过程也是导致 ASD 病因学和生理病理学的可信因素。NRXN1是与神经胶质蛋白结合的细胞表面受体神经胶质蛋白家族的成员,其突变与ASD有关。众所周知,NRXN1 在神经元中表达,可促进突触接触,但在包括小胶质细胞在内的胶质细胞中也被发现。确定 ASD 相关基因对神经元和小胶质细胞功能的影响一直是个挑战。在这里,我们提出了一种基于体外系统的 ASD 受试者诱导多能干细胞(iPSC),以描述 ASD 相关 NRXN1 基因缺失对神经元和小胶质细胞的影响,以及对小胶质细胞支持神经元回路形成和功能的能力的影响。利用这种方法,我们证明了 NRXN1 基因缺失会影响小胶质细胞中α异构体(NRXN1α)的表达,从而导致小胶质细胞的改变和 IL6(一种与 ASD 相关的促炎性白细胞介素)的释放。此外,NRXN1α缺失的小胶质细胞失去了支持功能性神经元网络形成的能力。在对照小胶质细胞-神经元共培养物上使用重组IL6蛋白,或在NRXN1α缺失的小胶质细胞-神经元共培养物上使用IL6中和抗体,都证实了IL6对所观察到的神经元表型有直接作用。总之,我们的数据表明,除神经元外,小胶质细胞也受到 NRXN1α 缺失的负面影响,这在很大程度上导致了所观察到的神经元回路畸变。
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引用次数: 0
Chronic glial activation and behavioral alterations induced by acute/subacute pioglitazone treatment in a mouse model of traumatic brain injury 急性/亚急性吡格列酮治疗在脑外伤小鼠模型中诱导的慢性神经胶质激活和行为改变
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-04 DOI: 10.1016/j.bbi.2024.09.006
L. Daniel Estrella, Jane E. Manganaro, Lexi Sheldon, Nashanthea Roland, Austin D. Snyder, Joseph W. George, Katy Emanuel, Benjamin G Lamberty, Kelly L. Stauch

Traumatic brain injury (TBI) is a disabling neurotraumatic condition and the leading cause of injury-related deaths and disability in the United States. Attenuation of neuroinflammation early after TBI is considered an important treatment target; however, while these inflammatory responses can induce secondary brain injury, they are also involved in the repair of the nervous system. Pioglitazone, which activates peroxisome proliferator-activated receptor gamma, has been shown to decrease inflammation acutely after TBI, but the long-term consequences of its use remain unknown. For this reason, the impacts of treatment with pioglitazone during the acute/subacute phase (30 min after injury and each subsequent 24 h for 5 days) after TBI were interrogated during the chronic phase (30- and 274-days post-injury (DPI)) in mice using the controlled cortical impact model of experimental TBI. Acute/subacute pioglitazone treatment after TBI results in long-term deleterious consequences, including disruption of tau homeostasis, chronic glial cell activation, neuronal pathology, and worsened injury severity particularly at 274 DPI, with male mice being more susceptible than female mice. Further, male pioglitazone-treated TBI mice exhibited increased dominant and offensive-like behavior while having a decreased non-social exploring behavior at 274 DPI. After TBI, both sexes exhibited glial activation at 30 DPI when treated with pioglitazone; however, while injury severity was increased in females it was not impacted in male mice. This work reveals that although pioglitazone has been shown to lead to attenuated TBI outcomes acutely, sex-based differences, timing and long-term consequences of treatment with glitazones must be considered and further studied prior to their clinical use for TBI therapy.

创伤性脑损伤(TBI)是一种致残性神经创伤,也是美国因伤致死和致残的主要原因。创伤性脑损伤后早期减轻神经炎症反应被认为是一个重要的治疗目标;然而,虽然这些炎症反应可诱发继发性脑损伤,但它们也参与了神经系统的修复。吡格列酮能激活过氧化物酶体增殖物激活受体γ,已被证明能在创伤性脑损伤后急性期减轻炎症反应,但其长期使用的后果仍不得而知。为此,我们使用实验性创伤性脑损伤的受控皮层撞击模型,在小鼠创伤性脑损伤后的慢性阶段(伤后 30 天和 274 天)(伤后 30 分钟和随后 5 天内的每个 24 小时)对急性/亚急性阶段(伤后 30 分钟和随后 5 天内的每个 24 小时)使用吡格列酮治疗的影响进行了研究。创伤性脑损伤后急性/亚急性吡格列酮治疗会导致长期有害后果,包括tau稳态破坏、神经胶质细胞慢性活化、神经元病理变化和损伤严重程度恶化,尤其是在274 DPI时,雄性小鼠比雌性小鼠更易受影响。此外,雄性吡格列酮处理的创伤性脑损伤小鼠在274 DPI时表现出更多的支配性和攻击性行为,而非社会探索行为则有所减少。使用吡格列酮治疗创伤性脑损伤后,雌雄小鼠在30 DPI时均表现出神经胶质激活;然而,雌性小鼠的损伤严重程度增加,而雄性小鼠则不受影响。这项研究表明,尽管吡格列酮已被证明可减轻急性创伤性脑损伤的后果,但在将其用于临床治疗创伤性脑损伤之前,必须考虑到性别差异、格列酮类药物治疗的时机和长期后果,并对其进行进一步研究。
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引用次数: 0
Association of Weight Status and Waist Circumference with Physical Activity in people with Schizophrenia Spectrum Disorders and healthy controls 精神分裂症谱系障碍患者和健康对照组的体重状况和腰围与体育活动的关系。
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-04 DOI: 10.1016/j.bbi.2024.09.007
Alessandra Martinelli , Silvia Leone , Manuel Zamparini , Martina Carnevale , Ian D. Caterson , Nicholas R. Fuller , Stefano Calza , Giovanni de Girolamo , DiAPAson collaborators

Background

Individuals with Schizophrenia Spectrum Disorders (SSD) often suffer from obesity and do limited Physical Activity (PA). PA has many beneficial effects on a variety of somatic and mental variables and it should be strengthened among people with mental disorders. The relationship between Body Mass Index (BMI), Waist Circumference (WC), and PA in this population is poorly understood, with a lack of precise PA assessment. This study investigates the association between BMI, WC, weight, and PA in individuals with SSD and controls using accelerometers.

Methods

One hundred twenty-six patients with SSD (residents and outpatients) and 110 sex- and age-matched controls were enrolled. Clinical, sociodemographic, and quality-of-life data were collected. PA was measured with a tri-axial ActiGraph GT9X and quantified by Vector Magnitude (VM). Relationships between PA and BMI, WC, and weight changes were analysed using linear regression models.

Results

Patients were more likely to be unmarried, unemployed, and less educated compared to controls (p < 0.001). Residents had more medical comorbidities (p = 0.001), while outpatients had higher BMI, weight, and WC (p < 0.001). Residents reported more severe psychopathology, lower functioning, and greater use of psychopharmacological medications (p < 0.001). Higher PA levels were not significantly associated with lower BMI, WC, or weight. Although not statistically significant, increased PA showed a trend towards lower obesity risk.

Conclusions

Sociodemographic, medical, and clinical characteristics of individuals with SSD define vulnerability factors that can inform tailored interventions to improve PA.

背景:精神分裂症谱系障碍(SSD)患者通常患有肥胖症,而且体育锻炼(PA)有限。体力活动对各种躯体和精神变量都有许多有益的影响,因此应在精神障碍患者中加强体力活动。由于缺乏精确的体力活动评估,人们对这一人群的身体质量指数(BMI)、腰围(WC)和体力活动之间的关系知之甚少。本研究使用加速度计调查了 SSD 患者和对照组的 BMI、WC、体重和 PA 之间的关系:方法:共招募了 126 名 SSD 患者(住院和门诊患者)和 110 名性别和年龄匹配的对照组。收集了临床、社会人口学和生活质量数据。PA 用三轴向 ActiGraph GT9X 测量,并用 Vector Magnitude (VM) 进行量化。采用线性回归模型分析了 PA 与 BMI、WC 和体重变化之间的关系:结果:与对照组相比,患者更有可能未婚、失业和受教育程度较低(P<0.05):SSD患者的社会人口学、医学和临床特征决定了其易受伤害的因素,这些因素可为改善PA的定制干预措施提供依据。
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引用次数: 0
PNIRS Society Announcements PNIRS 协会公告
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-04 DOI: 10.1016/S0889-1591(24)00586-5
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引用次数: 0
Low-dose interleukin-2 in patients with bipolar depression: A phase 2 randomised double-blind placebo-controlled trial 针对双相抑郁症患者的低剂量白细胞介素-2:第二阶段随机双盲安慰剂对照试验。
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-04 DOI: 10.1016/j.bbi.2024.09.005
Marion Leboyer , Marianne Foiselle , Nicolas Tchitchek , Ryad Tamouza , Roberta Lorenzon , Jean-Romain Richard , Raphaele Arrouasse , Philippe Le Corvoisier , Katia Le Dudal , Eric Vicaut , Pierre Ellul , Michelle Rosenzwajg , David Klatzmann

Immune abnormalities including an insufficiency of regulatory T cells (Treg) and increased blood-based inflammatory markers have been observed in bipolar disorders (BD), particularly during depression. As Tregs are pivotal to control inflammation, Treg stimulation by low-dose IL-2 (IL-2LD) could have a therapeutic impact on bipolar depression. We performed a randomized, double-blind, placebo-controlled (2 active: 1 placebo) proof-of-concept trial of add-on IL-2LD in patients with bipolar depression. Patients received a placebo or IL-2LD (1MIU) once a day for 5 days, and then once a week for 4 weeks starting on week 2. The primary objective was to demonstrate a biological Treg response to IL-2LD assessed by fold increase in Treg percentage of CD4 + cells from baseline to day 5. Secondary objectives included safety assessment and mood improvement throughout the study period. This trial is registered with ClinicalTrials.gov, number NCT04133233. Fourteen patients with bipolar depression were included, with 4 receiving placebo and 10 IL-2LD. Baseline clinical and biological characteristics were balanced between groups. The primary evaluation criterion was met, with IL-2LD expanding 1.17 [95 % CI 1.01–1.34] vs 1.01 [95 % CI 0.90–1.12] (p = 0.0421) and activating Tregs. Secondary evaluation criteria were also met with significant improvements of depressive symptoms and global functioning from day-15 onwards in the IL-2LD treated patients. The treatment was well-tolerated, with no serious adverse events related to treatment. This proof-of-concept trial shows that stimulating Tregs in patients with bipolar depression is safe and associated with clinical improvements. This supports a pathophysiological role of inflammation in BD and warrants pursuing the evaluation of IL-2LD as an adjunct treatment of major mood disorders.

在双相情感障碍(BD)中,尤其是在抑郁期间,已观察到包括调节性T细胞(Treg)不足和血液中炎症标志物增加在内的免疫异常。由于Tregs在控制炎症方面起着关键作用,因此通过低剂量IL-2(IL-2LD)刺激Treg可能会对双相抑郁症产生治疗效果。我们在双相抑郁症患者中开展了一项随机、双盲、安慰剂对照(2 项活性:1 项安慰剂)的附加 IL-2LD 概念验证试验。患者接受安慰剂或IL-2LD(1MIU)治疗,每天一次,共5天,然后从第2周开始每周一次,共4周。首要目标是证明IL-2LD的生物Treg反应,评估指标是CD4 +细胞的Treg百分比从基线到第5天的增加倍数。次要目标包括整个研究期间的安全性评估和情绪改善。该试验已在 ClinicalTrials.gov 注册,编号为 NCT04133233。14名双相抑郁症患者参与了该试验,其中4人接受安慰剂治疗,10人接受IL-2LD治疗。各组的基线临床和生物学特征均衡。结果符合主要评估标准,IL-2LD的治疗效果为1.17 [95 % CI 1.01-1.34] vs 1.01 [95 % CI 0.90-1.12] (p = 0.0421),并激活了Tregs。IL-2LD治疗患者的抑郁症状和整体功能自第15天起显著改善,符合二级评估标准。治疗耐受性良好,未出现与治疗相关的严重不良事件。这项概念验证试验表明,刺激双相抑郁症患者体内的Tregs是安全的,并能改善临床症状。这支持了炎症在双相抑郁症中的病理生理作用,值得继续评估IL-2LD作为重性情绪障碍辅助治疗的效果。
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引用次数: 0
Do inflammation and relational motivation coordinate having better sex? The interplay between C-reactive protein and relational approach motivation on sexual well-being 炎症和关系动机能协调更好的性生活吗?C反应蛋白和关系动机对性福的相互作用
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-03 DOI: 10.1016/j.bbi.2024.08.054
Tatum A. Jolink , Baldwin M. Way , Ayana Younge , Sara B. Algoe

Much evidence on heightened inflammation and social behavior focuses on social withdrawal. Building on recent theory (Muscatell and Inagaki, 2021), we focused instead on the socially affiliative experience of sex. We investigated the interplay between immunology and motivation on sexual well-being among 158 individuals in romantic relationships. Inflammation, indexed by C-reactive protein (CRP), and sexual well-being were measured multiple times over a month. Relational approach motivation (i.e., motivation toward rewards in relationships) was measured at study entry. Results revealed significant associations between CRP and sexual satisfaction and partnered orgasms frequency for those most motivated to approach rewards with their partner. Interaction effects were replicated with relationship-focused psychological correlates of sexual well-being (e.g., touch, shared laughter, social support), but not with individual-focused outcomes (e.g., adapting to change, goal progress). This is one of the first human studies to demonstrate the body and mind coordinate to promote satisfying sexual experiences within romantic relationships.

许多关于炎症加剧和社会行为的证据都集中在社会退缩上。基于最近的理论(Muscatell 和 Inagaki,2021 年),我们转而关注性的社会从属体验。我们调查了 158 名处于恋爱关系中的人的免疫学和性动机之间的相互作用。我们在一个月内多次测量了以 C 反应蛋白(CRP)为指标的炎症和性幸福感。在研究开始时测量了关系接近动机(即在关系中获得回报的动机)。结果显示,对于那些最想与伴侣一起获得奖励的人来说,CRP 与性满意度和伴侣性高潮频率之间存在明显的关联。交互效应与以关系为中心的性健康心理相关因素(如抚摸、共享笑声、社会支持)相同,但与以个人为中心的结果(如适应变化、目标进展)不相同。这是第一批证明身体和心理协调促进浪漫关系中令人满意的性体验的人类研究之一。
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引用次数: 0
Constitutive DAMPs in CNS injury: From preclinical insights to clinical perspectives 中枢神经系统损伤中的组成性 DAMPs:从临床前洞察到临床视角。
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-08-31 DOI: 10.1016/j.bbi.2024.07.047
Adrian Castellanos-Molina, Floriane Bretheau, Ana Boisvert, Dominic Bélanger, Steve Lacroix

Damage-associated molecular patterns (DAMPs) are endogenous molecules released in tissues upon cellular damage and necrosis, acting to initiate sterile inflammation. Constitutive DAMPs (cDAMPs) have the particularity to be present within the intracellular compartments of healthy cells, where they exert diverse functions such as regulation of gene expression and cellular homeostasis. However, after injury to the central nervous system (CNS), cDAMPs are rapidly released by stressed, damaged or dying neuronal, glial and endothelial cells, and can trigger inflammation without undergoing structural modifications. Several cDAMPs have been described in the injured CNS, such as interleukin (IL)-1α, IL-33, nucleotides (e.g. ATP), and high-mobility group box protein 1. Once in the extracellular milieu, these molecules are recognized by the remaining surviving cells through specific DAMP-sensing receptors, thereby inducing a cascade of molecular events leading to the production and release of proinflammatory cytokines and chemokines, as well as cell adhesion molecules. The ensuing immune response is necessary to eliminate cellular debris caused by the injury, allowing for damage containment. However, seeing as some molecules associated with the inflammatory response are toxic to surviving resident CNS cells, secondary damage occurs, aggravating injury and exacerbating neurological and behavioral deficits. Thus, a better understanding of these cDAMPs, as well as their receptors and downstream signaling pathways, could lead to identification of novel therapeutic targets for treating CNS injuries such as SCI, TBI, and stroke. In this review, we summarize the recent literature on cDAMPs, their specific functions, and the therapeutic potential of interfering with cDAMPs or their signaling pathways.

损伤相关分子模式(DAMPs)是细胞损伤和坏死时在组织中释放的内源性分子,其作用是引发无菌性炎症。组成型 DAMPs(cDAMPs)存在于健康细胞的细胞内区室中,具有调节基因表达和细胞平衡等多种功能。然而,中枢神经系统(CNS)受伤后,受压、受损或死亡的神经元、神经胶质细胞和内皮细胞会迅速释放 cDAMPs,并在不改变结构的情况下引发炎症。一旦进入细胞外环境,这些分子就会被剩余的存活细胞通过特定的 DAMP 感受器识别,从而诱发一系列分子事件,导致促炎细胞因子和趋化因子以及细胞粘附分子的产生和释放。随之而来的免疫反应是消除损伤造成的细胞碎片所必需的,从而使损伤得到控制。然而,由于一些与炎症反应相关的分子对存活的中枢神经系统驻留细胞具有毒性,因此会造成二次损伤,加重损伤并加剧神经和行为障碍。因此,如果能更好地了解这些 cDAMPs 及其受体和下游信号通路,就能找到治疗 SCI、创伤性脑损伤和中风等中枢神经系统损伤的新型治疗靶点。在这篇综述中,我们总结了有关 cDAMPs、其特定功能以及干扰 cDAMPs 或其信号通路的治疗潜力的最新文献。
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引用次数: 0
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Brain, Behavior, and Immunity
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