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The effects of age, origin, and biological sex on rodent mast cell (BMMC and MC/9) and basophil (RBL-2H3) phenotype and function 年龄、来源和生物性别对鼠类肥大细胞(BMMC和MC/9)和嗜碱性粒细胞(RBL-2H3)表型和功能的影响
IF 4.3 4区 医学 Q2 CELL BIOLOGY Pub Date : 2023-09-01 DOI: 10.1016/j.cellimm.2023.104751
Ashley Wagner , Syed Benazir Alam , Marianna Kulka

Mast cells initiate allergic inflammatory immune responses and play a role in disease by releasing various inflammatory and immunomodulatory mediators. Several mast cell-lines and primary cultured cells have been used as mast cell models with inconsistent results among research groups. Bone marrow-derived mast cells (BMMC) cultured from mouse bone marrow progenitor cells are often used as a representative model of mucosal mast cell behaviour, however their reported phenotype is variable due to inconsistent culture protocols. RBL-2H3 is a rat basophilic histamine-releasing cell line that has some characteristics of both mast cells and basophils but is not a true representation of either cell type. The murine mast cell line MC/9 is an IL-3-dependent mucosal mast cell model but has limited mast cell characteristics. In this study, we have compared the response of BMMC (derived from C57BL/6 male or female mice), two sources of RBL-2H3 (purchased directly from ATCC and a lab curated culture), and MC/9 (ATCC) at several critical stages to some common stimuli (IgE/Ag, A23187) and analyzed mast cell morphology, expression level of common mast cell surface markers (CD117 and FcεRI), protease expression, and function (growth kinetics, viability, ROS production, degranulation, cytokine release and FcεRI signaling). The objective of this study was to provide insight into the effects of culture conditions, biological sex, and age of the cells on variability among reported phenotypes and, to determine optimal conditions for activation of these cells. Our data show that factors that are often overlooked such as source, age and biological sex of mast cells play an integral role in phenotypic outcomes and may account for the reported variability in their function.

肥大细胞启动过敏性炎症免疫反应,并通过释放各种炎症和免疫调节介质在疾病中发挥作用。一些肥大细胞系和原代培养细胞已被用作肥大细胞模型,研究小组之间的结果不一致。从小鼠骨髓祖细胞培养的骨髓源性肥大细胞(BMMC)通常被用作粘膜肥大细胞行为的代表性模型,然而,由于培养方案不一致,其报告的表型是可变的。RBL-2H3是一种大鼠嗜碱性组胺释放细胞系,具有肥大细胞和嗜碱性细胞的一些特征,但不是这两种细胞类型的真实代表。小鼠肥大细胞系MC/9是IL-3依赖性粘膜肥大细胞模型,但具有有限的肥大细胞特性。在本研究中,我们比较了BMMC(来源于C57BL/6雄性或雌性小鼠)、RBL-2H3的两种来源(直接从ATCC和实验室策划的培养物购买)和MC/9(ATCC)在几个关键阶段对一些常见刺激(IgE/Ag,A23187)的反应,并分析了肥大细胞形态、常见肥大细胞表面标记物(CD117和FcεRI)的表达水平、蛋白酶表达,和功能(生长动力学、活力、ROS产生、脱颗粒、细胞因子释放和FcεRI信号传导)。本研究的目的是深入了解培养条件、生物性别和细胞年龄对所报道表型变异性的影响,并确定激活这些细胞的最佳条件。我们的数据表明,经常被忽视的因素,如肥大细胞的来源、年龄和生物学性别,在表型结果中发挥着不可或缺的作用,并可能解释了其功能的变异性。
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引用次数: 1
Crosstalk between peripheral immunity and central nervous system in Alzheimer’s disease 阿尔茨海默病中外周免疫与中枢神经系统的串扰
IF 4.3 4区 医学 Q2 CELL BIOLOGY Pub Date : 2023-09-01 DOI: 10.1016/j.cellimm.2023.104743
Hanchen Yang , Qi Qin , Meng Wang , Yunsi Yin , Ruiyang Li , Yi Tang

The significance of peripheral immunity in the pathogenesis and progression of Alzheimer’s diseases (AD) has been recognized. Brain-infiltrated peripheral immune components transporting across the blood–brain barrier (BBB) may reshape the central immune environment. However, mechanisms of how these components open the BBB for AD occurrence and development and correlations between peripheral and central immunity have not been fully explored. Herein, we formulate a hypothesis whereby peripheral immunity as a critical factor allows AD to progress. Peripheral central immune cell crosstalk is associated with early AD pathology and related risk factors. The damaged BBB permits peripheral immune cells to enter the central immune system to deprive its immune privilege promoting the progression toward developing AD. This review summarizes the influences of risk factors on peripheral immunity, alongside their functions, highlighting the concept of peripheral and central immunity as an integrated system in AD pathogenesis, which has received scant attention before.

外周免疫在阿尔茨海默病(AD)的发病机制和进展中的意义已被公认。脑浸润的外周免疫成分通过血脑屏障(BBB)转运可能重塑中枢免疫环境。然而,这些成分如何打开AD发生和发展的血脑屏障的机制以及外周免疫和中枢免疫之间的相关性尚未得到充分探索。在此,我们提出了一个假设,即外周免疫作为一个关键因素可以使AD发展。外周中枢免疫细胞串扰与早期AD病理学及相关危险因素有关。受损的血脑屏障允许外周免疫细胞进入中枢免疫系统,剥夺其免疫特权,从而促进AD的发展。本文综述了危险因素对外周免疫的影响及其功能,强调了外周免疫和中枢免疫作为AD发病机制中的一个综合系统的概念,这在以前很少受到关注。
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引用次数: 0
Piperine suppresses inflammatory fibroblast-like synoviocytes derived from rheumatoid arthritis patients Via NF-κB inhibition 胡椒碱通过抑制NF-κB抑制类风湿关节炎患者炎性成纤维细胞样滑膜细胞
IF 4.3 4区 医学 Q2 CELL BIOLOGY Pub Date : 2023-09-01 DOI: 10.1016/j.cellimm.2023.104752
Qoyama Noel Baito, Halmat M. Jaafar, Talar Ahmad Merza Mohammad

Rheumatoid Arthritis (RA) is a common autoimmune disease recognized by hyperplasia of synoviocytes and chronic joint inflammation. Activation of fibroblast-like synoviocytes (FLSs) is one of the main features of RA which can trigger inflammation leading to articular cartilage and joint destruction. Aberrant activation of NF-κB signaling cascade was found to be responsible for the high proliferation and defective apoptosis of FLSs and subsequent inflammation in RA. Piperine is a principal constituent of piper species frequently used as antitumor and anti-inflammatory natural compound. In this study we aimed to assess the anti-inflammatory effect of piperine on RA-FLS through NF-κB inhibition.

FLSs were isolated from 68 RA patients and 30 healthy controls and were exposed to piperine. The main assays were MTT assay, flow cytometric analysis, PI staining, reverse transcription-PCR (RT-PCR), and ELISA.

Results showed that piperine can induce the apoptosis and reduce the proliferation of RA-FLSs in vitro. Moreover, piperine directly reduced the phosphorylation of NF-kB and the expression of NF-κB target genes related to RA-FLSs proliferation (c-Myc and Cycline D1), apoptosis inhibition (Bcl2 and Bcl-xl) and inflammation (COX2, IL-1β, TNF-α,IL-6, CCL5 and CXCL10) while increasing the expression of apoptosis related ones (Bax) in vitro. Piperine also reduced the protein levels of cytokines and chemokines secreted by FLSs as a result of NF-κB inhibition.

In conclusion, our results provide evidence for the anti-inflammatory capacity of piperine through inhibition of NF-κB pathway in FLSs proposing this compound as a suitable alternative for chemical treatment of RA.

类风湿性关节炎(RA)是一种常见的自身免疫性疾病,由滑膜细胞增生和慢性关节炎症引起。成纤维细胞样滑膜细胞(FLSs)的激活是RA的主要特征之一,可引发炎症,导致关节软骨和关节破坏。NF-κB信号级联的异常激活被发现是FLSs的高增殖和缺陷性凋亡以及随后RA炎症的原因。胡椒碱是胡椒属植物的主要成分,常用作抗肿瘤和抗炎的天然化合物。在本研究中,我们旨在通过抑制NF-κB来评估胡椒碱对RA-FLS的抗炎作用。从68名RA患者和30名健康对照中分离出FLS,并暴露于胡椒碱。主要检测方法为MTT法、流式细胞仪、PI染色、逆转录聚合酶链式反应(RT-PCR)和ELISA。此外,哌啶在体外直接降低了NF-kB的磷酸化和NF-κB靶基因的表达,这些靶基因与RA FLSs增殖(c-Myc和Cycline D1)、细胞凋亡抑制(Bcl2和Bcl-xl)和炎症(COX2、IL-1β、TNF-α、IL-6、CCL5和CXCL10)有关,同时增加了细胞凋亡相关基因(Bax)的表达。胡椒碱还降低了FLSs分泌的细胞因子和趋化因子的蛋白质水平,这是NF-κB抑制的结果。总之,我们的研究结果通过抑制FLSs中的NF-κB途径为哌啶的抗炎能力提供了证据,提出该化合物是化学治疗RA的合适替代品。
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引用次数: 0
Phloretin suppresses intestinal inflammation and maintained epithelial tight junction integrity by modulating cytokines secretion in in vitro model of gut inflammation 在体外肠道炎症模型中,根皮素通过调节细胞因子分泌抑制肠道炎症,维持上皮紧密连接的完整性
IF 4.3 4区 医学 Q2 CELL BIOLOGY Pub Date : 2023-09-01 DOI: 10.1016/j.cellimm.2023.104754
Smita Kapoor , Yogendra S. Padwad

Ulcerative colitis is a type of inflammatory bowel disease which in long run can lead to colorectal cancer (CRC). Chronic inflammation can be a key factor for the occurrence of CRC thus mitigating an inflammation can be a preventive strategy for the occurrence of CRC. In this study we have explored the anti-inflammatory potential of phloretin, in in vitro gut inflammation model, developed by co-culture of Caco2 (intestinal epithelial) cells and RAW264.7 macrophages (immune cells). Phloretin is a dihydrochalcone present in apple, pear and strawberries. An anti-inflammatory effect of phloretin in reducing LPS induced inflammation and maintenance of transepithelial electric resistance (TEER) in Caco2 cells was examined. Paracellular permeability assay was performed using Lucifer yellow dye to evaluate the effect of phloretin in inhibiting gut leakiness caused by inflammatory mediators secreted by activated macrophages. Phloretin attenuated LPS induced nitric oxide levels, oxidative stress, depolarization of mitochondrial membrane potential in Caco2 cells as evidenced by reduction in reactive oxygen species (ROS), and enhancement of MMP, and decrease in inflammatory cytokines IL8, TNFα, IL1β and IL6. It exhibited anti-inflammatory activity by inhibiting the expression of NFκB, iNOS and Cox2. Phloretin maintained the epithelial integrity by regulating the expression of tight junction proteins ZO1, occludin, Claudin1 and JAM. Phloretin reduced LPS induced levels of Cox2 along with the reduction in Src expression which further regulated an expression of tight junction protein occludin. Phloretin in combination to sodium pyruvate exhibited potential anti-inflammatory activity via targeting NFkB signaling. Our findings paved a way to position phloretin as nutraceutical in preventing the occurrence of colitis and culmination of disease into colitis associated colorectal cancer.

溃疡性结肠炎是一种炎症性肠病,长期可导致结直肠癌。慢性炎症可能是CRC发生的关键因素,因此减轻炎症可以成为CRC发生的预防策略。在本研究中,我们探索了根皮素的抗炎潜力,根皮素是通过共培养Caco2(肠上皮)细胞和RAW264.7巨噬细胞(免疫细胞)开发的体外肠道炎症模型。Phloretin是一种存在于苹果、梨和草莓中的二氢查尔酮。研究根皮素在减少LPS诱导的Caco2细胞炎症和维持跨上皮电阻(TEER)中的抗炎作用。使用路西法黄色染料进行细胞旁渗透性测定,以评估根皮素在抑制由活化巨噬细胞分泌的炎症介质引起的肠道渗漏中的作用。Phloretin减弱了LPS诱导的Caco2细胞中一氧化氮水平、氧化应激、线粒体膜电位的去极化,表现为活性氧(ROS)的减少、MMP的增强以及炎性细胞因子IL8、TNFα、IL1β和IL6的减少。它通过抑制NFκB、iNOS和Cox2的表达而表现出抗炎活性。Phloretin通过调节紧密连接蛋白ZO1、occludin、Claudin1和JAM的表达来维持上皮完整性。Phloretin降低了LPS诱导的Cox2水平,同时降低了Src表达,这进一步调节了紧密连接蛋白occludin的表达。Phloretin与丙酮酸钠的组合通过靶向NFkB信号显示出潜在的抗炎活性。我们的研究结果为将根皮素定位为预防结肠炎和结肠炎相关结直肠癌的营养药物铺平了道路。
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引用次数: 1
A mAb to SIRPα downregulates the priming of naive CD4 + T cell in Primary immune thrombocytopenia 对SIRPα的单抗下调原发性免疫性血小板减少症患者初始CD4 + T细胞的启动
IF 4.3 4区 医学 Q2 CELL BIOLOGY Pub Date : 2023-09-01 DOI: 10.1016/j.cellimm.2023.104757
Dongmei Xie, Zhihui Feng, Wen Yang, Yacan Wang, Renxia Li, Shiqi Zhang, Zeping Zhou

SIRPα is a transmembrane protein that binds the protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region and is abundantly expressed on monocytes, dendritic cells, and macrophages. Studies recently showed that SIRPα is essential for priming of CD4 + T cells by DCs and for development of Th17 cell-mediated autoimmune diseases. We have now further evaluated the importance of SIRPα and that of its ligand CD47 in primary immune thrombocytopenia (ITP). In this study, we show that there was a low expression state of SIRPα on the surface of monocytes. Treatment of cells culture from ITP patients with a mAb to SIRPα that blocks the binding of SIRPα to CD47 downregulated the ITP response. The abilities of monocytes from ITP patients to stimulate an allogenic MLR were reduced. The proliferation of, and production of IL-2, by CD4 + T cells from ITP patients were inhibited, the Treg cell numbers and the production of IL-10 pairs were upregulated, and the production of TGF-β not was inhibited, by a mAb to SIRPα. Moreover, a mAb to SIRPα, the expression of HLA-DR and CD86 were markedly inhibited and the expression of CD80 was slightly upregulated, on the surface of CD14 + monocytes from ITP patients as compared with healthy subjects. However, blockade of SIRPα increased the secretion of TLR-dependent cytokines TNF-α, IL-6 and IL-1β by PBMCs, which may be considered as a reserve in response to danger signals. These results suggest that SIRPα on monocytes is essential for the priming of naive T cells and the development of ITP. Therefore, SIRPα is a potential therapeutic target for ITP and other autoimmune diseases.

SIRPα是一种跨膜蛋白,通过其细胞质区域结合蛋白酪氨酸磷酸酶SHP-1和SHP-2,并在单核细胞、树突状细胞和巨噬细胞上大量表达。最近的研究表明,SIRPα对于DC启动CD4+T细胞和Th17细胞介导的自身免疫性疾病的发展至关重要。我们现在已经进一步评估了SIRPα及其配体CD47在原发性免疫性血小板减少症(ITP)中的重要性。在本研究中,我们发现单核细胞表面存在SIRPα的低表达状态。用阻断SIRPα与CD47结合的SIRPα单克隆抗体治疗ITP患者的细胞培养物可下调ITP反应。ITP患者的单核细胞刺激同种异体MLR的能力降低。SIRPα单克隆抗体抑制ITP患者CD4+T细胞的增殖和IL-2的产生,上调Treg细胞数量和IL-10对的产生,抑制TGF-β的产生。此外,与健康受试者相比,ITP患者的CD14+单核细胞表面的SIRPαmAb、HLA-DR和CD86的表达受到显著抑制,CD80的表达略有上调。然而,SIRPα的阻断增加了PBMC分泌TLR依赖性细胞因子TNF-α、IL-6和IL-1β,这可能被认为是对危险信号的反应储备。这些结果表明,单核细胞上的SIRPα对幼稚T细胞的启动和ITP的发展至关重要。因此,SIRPα是ITP和其他自身免疫性疾病的潜在治疗靶点。
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引用次数: 0
Potential role for oral tolerance in gene therapy 口腔耐受在基因治疗中的潜在作用。
IF 4.3 4区 医学 Q2 CELL BIOLOGY Pub Date : 2023-09-01 DOI: 10.1016/j.cellimm.2023.104742
John S.S. Butterfield , Xin Li , Sreevani Arisa , Kwang-Chul Kwon , Henry Daniell , Roland W. Herzog

Oral immunotherapies are being developed for various autoimmune diseases and allergies to suppress immune responses in an antigen-specific manner. Previous studies have shown that anti-drug antibody (inhibitor) formation in protein replacement therapy for the inherited bleeding disorder hemophilia can be prevented by repeated oral delivery of coagulation factor antigens bioencapsulated in transplastomic lettuce cells. Here, we find that this approach substantially reduces antibody development against factor VIII in hemophilia A mice treated with adeno-associated viral gene transfer. We propose that the concept of oral tolerance can be applied to prevent immune responses against therapeutic transgene products expressed in gene therapy.

目前正在开发针对各种自身免疫性疾病和过敏的口服免疫疗法,以抗原特异性的方式抑制免疫反应。先前的研究表明,在遗传性出血性疾病血友病的蛋白质替代治疗中,通过反复口服生物胶囊化的凝血因子抗原,可以防止抗药物抗体(抑制剂)的形成。在这里,我们发现这种方法显著减少了接受腺相关病毒基因转移治疗的血友病A小鼠中针对因子VIII的抗体产生。我们提出,口服耐受的概念可以应用于预防针对基因治疗中表达的治疗性转基因产物的免疫反应。
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引用次数: 2
Tandem CAR-T cells targeting MUC1 and PSCA combined with anti-PD-1 antibody exhibit potent preclinical activity against non-small cell lung cancer 靶向MUC1和PSCA的串联CAR-T细胞结合抗pd -1抗体对非小细胞肺癌表现出强大的临床前活性
IF 4.3 4区 医学 Q2 CELL BIOLOGY Pub Date : 2023-09-01 DOI: 10.1016/j.cellimm.2023.104760
Aying Wang , Tangfeng Lv , Yong Song

Chimeric antigen receptor (CAR)-T cells encounter many issues when treating solid tumors, including tumor antigen heterogeneity and immunosuppression. United targeting of two tumor-associated antigens (TAAs) and blocking of PD-1 may solve this problem and enhance the function of CAR-T. Mucin 1 (MUC1) and prostate stem cell antigen (PSCA) are overexpressed in non-small cell lung cancer (NSCLC). Here, we constructed a bivalent tandem CAR-T (Tan CAR-T), which can simultaneously target MUC1 and PSCA and evaluated its effects of inhibiting non-small cell lung cancer (NSCLC) in vitro and in vivo. Results indicated that the tumor killing effect of these Tan CAR-T was more effective than that of single-target CAR-T, its antitumor efficacy could be further strengthened by anti-PD-1 antibody. Our study reported a previously unstudied therapeutic effect of a Tan CAR-T in NSCLC, providing a preclinical rationale for anti-PD-1 antibody combined with Tan CAR-T targeting MUC1 and PSCA in the treatment of NSCLC.

嵌合抗原受体(CAR)-T细胞在治疗实体瘤时遇到许多问题,包括肿瘤抗原异质性和免疫抑制。两种肿瘤相关抗原(TAAs)的联合靶向和PD-1的阻断可以解决这个问题并增强CAR-T的功能。粘蛋白1(MUC1)和前列腺干细胞抗原(PSCA)在非小细胞肺癌癌症中过表达。在此,我们构建了一种二价串联CAR-T(Tan CAR-T),它可以同时靶向MUC1和PSCA,并在体外和体内评估了它对非小细胞肺癌癌症(NSCLC)的抑制作用。结果表明,Tan CAR-T的抑瘤效果优于单靶点CAR-T,抗PD-1抗体可进一步增强其抗肿瘤作用。我们的研究报道了Tan CAR-T在NSCLC中的先前未研究的治疗效果,为抗PD-1抗体与靶向MUC1和PSCA的Tan CART联合治疗NSCLC提供了临床前基础。
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引用次数: 0
HIF-1α regulates the expression of the non-conventional isoform of the cd5 gene in T cells under the hypoxic condition: A potential mechanism for CD5neg/low phenotype of infiltrating cells in solid tumors HIF-1α在低氧条件下调节T细胞中cd5基因非常规亚型的表达:实体瘤浸润细胞CD5neg/low表型的潜在机制
IF 4.3 4区 医学 Q2 CELL BIOLOGY Pub Date : 2023-09-01 DOI: 10.1016/j.cellimm.2023.104755
Smita Kumari, Srishti Sahu, Bharat Singh, Swarnima Gupta, Amit Kumar Kureel, Ankit Srivastava, Deeksha Rikhari, Sameer Srivastava, Ambak Kumar Rai

CD5, a T-cell receptor (TCR) negative regulator, is reduced on the surface of CD8+ lymphocytes in the tumor microenvironment (TME). Reduced surface CD5 expression (sCD5) occurs due to the preferential transcription of HERV-E derived exon E1B, i.e., a non-conventional form of the cd5 gene instead of its conventional exon E1A. A tumor employs several mechanisms to evade anti-tumor response, and hypoxia is one such mechanism that prevails in the TME and modulates the infiltrated T lymphocytes. We identified hypoxia response elements (HREs) upstream of E1B. We showed binding of HIF-1α onto these HREs and increased E1B mRNA expression in hypoxic T cells. This results in decreased sCD5 expression and increased cytoplasmic accumulation in T cells. We also validated our study in a solid tumor, i.e., colorectal cancer (CRC) patient samples. This hypoxia-driven mechanism reduces the surface CD5 expression on infiltrated T-cells in solid tumors.

CD5是一种T细胞受体(TCR)阴性调节因子,在肿瘤微环境(TME)中的CD8+淋巴细胞表面被还原。表面CD5表达减少(sCD5)是由于HERV-E衍生的外显子E1B的优先转录而发生的,即CD5基因的非常规形式而不是其常规外显子E1 a。肿瘤采用多种机制来逃避抗肿瘤反应,缺氧是TME中普遍存在并调节浸润的T淋巴细胞的机制之一。我们鉴定了E1B上游的缺氧反应元件(HRE)。我们发现HIF-1α与这些HRE结合,并增加缺氧T细胞中E1B mRNA的表达。这导致T细胞中sCD5表达降低和细胞质积累增加。我们还在实体瘤,即癌症(CRC)患者样本中验证了我们的研究。这种缺氧驱动的机制降低了实体瘤中浸润的T细胞表面CD5的表达。
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引用次数: 0
Autoimmune susceptible HLA class II motifs facilitate the presentation of modified neoepitopes to potentially autoreactive T cells 自身免疫易感的HLA II类基序促进修饰的新表位向潜在的自身反应性T细胞呈递
IF 4.3 4区 医学 Q2 CELL BIOLOGY Pub Date : 2023-08-01 DOI: 10.1016/j.cellimm.2023.104729
Antonis K. Moustakas , Hai Nguyen , Eddie A. James , George K. Papadopoulos

Rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes (T1D), and celiac disease (CD), are strongly associated with susceptible HLA class II haplotypes. The peptide-binding pockets of these molecules are polymorphic, thus each HLA class II protein presents a distinct set of peptides to CD4+ T cells. Peptide diversity is increased through post-translational modifications, generating non-templated sequences that enhance HLA binding and/or T cell recognition. The high-risk HLA-DR alleles that confer susceptibility to RA are notable for their ability to accommodate citrulline, promoting responses to citrullinated self-antigens. Likewise, HLA-DQ alleles associated with T1D and CD favor the binding of deamidated peptides. In this review, we discuss structural features that promote modified self-epitope presentation, provide evidence supporting the relevance of T cell recognition of such antigens in disease processes, and make a case that interrupting the pathways that generate such epitopes and reprogramming neoepitope-specific T cells are key strategies for effective therapeutic intervention.

类风湿性关节炎(RA)、多发性硬化症(MS)、1型糖尿病(T1D)和乳糜泻(CD)与易感HLA II类单倍型密切相关。这些分子的肽结合口袋是多态的,因此每个HLA II类蛋白向CD4+T细胞呈现一组不同的肽。肽多样性通过翻译后修饰增加,产生增强HLA结合和/或T细胞识别的非模板化序列。赋予RA易感性的高危HLA-DR等位基因因其适应瓜氨酸的能力而引人注目,从而促进对瓜氨酸化自身抗原的反应。同样,与T1D和CD相关的HLA-DQ等位基因有利于脱酰胺肽的结合。在这篇综述中,我们讨论了促进修饰的自身表位呈递的结构特征,提供了支持T细胞识别此类抗原在疾病过程中的相关性的证据,并证明阻断产生此类表位的途径和重新编程新表位特异性T细胞是有效治疗干预的关键策略。
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引用次数: 1
Chronic IFNα treatment induces leukopoiesis, increased plasma succinate and immune cell metabolic rewiring 慢性IFNα治疗诱导白细胞生成,血浆琥珀酸增加和免疫细胞代谢重接线
IF 4.3 4区 医学 Q2 CELL BIOLOGY Pub Date : 2023-08-01 DOI: 10.1016/j.cellimm.2023.104741
Anjali S. Yennemadi , Gráinne Jameson , Mary Glass , Carolina De Pasquale , Joseph Keane , Massimiliano Bianchi , Gina Leisching

Although clinically effective, the actions of IFNα, either produced endogenously or by therapeutic delivery, remain poorly understood. Emblematic of this research gap is the disparate array of notable side effects that occur in susceptible individuals, such as neuropsychiatric consequences, autoimmune phenomena, and infectious complications. We hypothesised that these complications are driven at least in part by dysregulated cellular metabolism. Male Wistar rats were treated with either 170,000 IU/kg human recombinant IFNα-2a or BSA/saline (0.9% NaCl) three times per week for three weeks. Bone marrow (BM) immune cells were isolated from the excised femurs for glycolytic rate and mitochondrial function assessment using Agilent Seahorse Technology. Frequencies of immune cell populations were assessed by flow cytometry to determine whether leukopoietic changes had occurred in both blood and BM. Plasma levels of lactate and succinate were also determined. BMDMs were metabolically assessed as above, as well as their metabolic response to an antigenic stimulus (iH37Rv). We observed that BM immune cells from IFN-treated rats exhibit a hypermetabolic state (increased basal OCR/GlycoPER) with decreased mitochondrial metabolic respiration and increased non-mitochondrial OCR. Flow cytometry results indicated an increase in immature granulocytes (RP1- SSChi CD45lo) only in the blood, together with increased succinate levels in the plasma. BMDMs from IFN-treated rats retained the hypermetabolic phenotype after differentiation and failed to induce a step-up in glycolysis and mitochondrial respiration after bacterial stimulation. This work provides the first evidence of the effects of IFNα treatment in inducing hypermetabolic immune features that are associated with markers of inflammation, leukopoiesis, and defective responses to bacterial stimulation.

尽管临床上有效,IFNα的作用,无论是内源性还是通过治疗性递送,仍然知之甚少。这一研究差距的标志是易感个体出现的一系列不同的显著副作用,如神经精神后果、自身免疫现象和感染并发症。我们假设这些并发症至少部分是由细胞代谢失调引起的。雄性Wistar大鼠每周用170000IU/kg人重组IFNα-2a或BSA/生理盐水(0.9%NaCl)处理三次,持续三周。从切除的股骨中分离骨髓(BM)免疫细胞,使用安捷伦海马技术进行糖酵解速率和线粒体功能评估。通过流式细胞术评估免疫细胞群的频率,以确定血液和骨髓中是否发生了白细胞生成变化。还测定了血浆乳酸和琥珀酸的水平。BMDM如上所述进行代谢评估,以及它们对抗原刺激(iH37Rv)的代谢反应。我们观察到,来自IFN处理的大鼠的BM免疫细胞表现出高代谢状态(基础OCR/GlycoPER增加),线粒体代谢呼吸减少,非线粒体OCR增加。流式细胞术结果显示,血液中未成熟粒细胞(RP1-SSChi CD45lo)增加,血浆中琥珀酸盐水平增加。来自IFN处理的大鼠的BMDM在分化后保留了高代谢表型,并且在细菌刺激后未能诱导糖酵解和线粒体呼吸的增加。这项工作首次证明了IFNα治疗在诱导与炎症、白细胞生成和对细菌刺激的缺陷反应相关的高代谢免疫特征方面的作用。
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Cellular immunology
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