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Allergic bronchopulmonary aspergillosis in a lung transplant recipient treated with mepolizumab 一名肺移植受者在接受甲泼尼珠单抗治疗后出现过敏性支气管肺曲霉病。
IF 8.6 3区 医学 Q1 Medicine Pub Date : 2024-05-25 DOI: 10.1016/j.clim.2024.110265
Foteini Ioakeim , Christophe Abellan , Alessio Casutt , Benoit Lechartier , Leslie Noirez , Catherine Beigelman-Aubry , John-David Aubert , Zisis Balmpouzis , Angela Koutsokera

Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction to Aspergillus spp. ABPA diagnosis may be challenging due to its non-specific presentation. Standard ABPA treatment consists of systemic corticosteroids and antifungal agents. Mepolizumab, a monoclonal antibody against interleukin-5 seems to be a promising treatment for ABPA. Data about ABPA following lung transplantation (LuTx) are scarce. LuTx recipients are at higher risk for adverse effects of ABPA treatment compared to the general population.

Here we present a case of a LuTx recipient who was successfully treated with mepolizumab for ABPA following LuTx. Prolonged administration of high dose prednisone was thus avoided. To our knowledge, this is the first case describing mepolizumab administration following LuTx. Mepolizumab seems particularly attractive as a corticosteroid-sparing agent or as an alternative option to antifungal treatments, because of its excellent safety profile and low risk of drug interactions.

过敏性支气管肺曲霉菌病(ABPA)是一种对曲霉菌属的复杂超敏反应。标准的 ABPA 治疗包括全身使用皮质类固醇激素和抗真菌药物。抗白细胞介素-5 的单克隆抗体 Mepolizumab 似乎是治疗 ABPA 的一种很有前景的方法。有关肺移植(LuTx)后 ABPA 的数据很少。与普通人群相比,肺移植受者出现 ABPA 治疗不良反应的风险更高。在此,我们介绍了一例在肺移植术后使用甲泼尼单抗成功治疗 ABPA 的病例。因此避免了长期使用大剂量泼尼松。据我们所知,这是第一例描述 LuTx 术后使用美妥珠单抗的病例。由于美妥珠单抗具有极佳的安全性和较低的药物相互作用风险,因此作为一种皮质类固醇替代药物或抗真菌治疗的替代选择似乎特别有吸引力。
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引用次数: 0
Immune reconstitution and survival, following hematopoietic stem cell transplantation in Omani patients with inborn errors of immunity 阿曼先天性免疫错误患者造血干细胞移植后的免疫重建和存活率
IF 8.6 3区 医学 Q1 Medicine Pub Date : 2024-05-23 DOI: 10.1016/j.clim.2024.110263
Salem Al-Tamemi , Abdulhakim Al-Rawas , Murtadha Al-Khabori , Khalil Al-Farsi , Mohammed Al-Huneini , Amr Abdalla , Salam Al-Kindi , David Dennison

Background

Hematopoietic stem cell transplantation (HSCT) is a curative treatment for certain inborn errors of immunity.

Methods

A 17-year retrospective cohort study was conducted on 40 immunodeficient patients who underwent HSCT.

Results

The median age at transplant was 11.0 months (4.6–61.0). Donors were primarily matched sibling donors (60%). 90% and 85% of patients received conditioning and graft-versus-host disease (GVHD) prophylaxis, respectively. The mean donor chimerism at the last follow-up was 88.6% ± 17.9% (40–100). Median serum immunoglobulin (Ig) G level, CD4+ T-cell count, and CD19+ B-cell count were 11.7 g/L (9.2–13.6), 0.9 × 109/L 0.6–1.2), and 0.5 × 109/L (0.2–0.7), respectively. 29 patients (72.5%) received intravenous immunoglobulins (IVIG) therapy, with a median duration of 10.0 months (4.0–14.0). The median post-transplant follow-up was 6.5 years (IQR:1.4–11.5). The 10-year overall probability of survival is 84.3%.

Conclusion

Monitoring IRC is important in ensuring adequate disease-free survival.

背景造血干细胞移植(HSCT)是治疗某些先天性免疫错误的一种治愈性疗法。方法对40名接受造血干细胞移植的免疫缺陷患者进行了一项为期17年的回顾性队列研究。供体主要是匹配的同胞供体(60%)。90%和85%的患者分别接受了调理和移植物抗宿主病(GVHD)预防。最后一次随访时的平均供体嵌合率为 88.6% ± 17.9% (40-100)。血清免疫球蛋白(Ig)G水平、CD4+ T细胞计数和CD19+ B细胞计数的中位数分别为11.7克/升(9.2-13.6)、0.9×109/升(0.6-1.2)和0.5×109/升(0.2-0.7)。29名患者(72.5%)接受了静脉注射免疫球蛋白(IVIG)治疗,中位持续时间为10.0个月(4.0-14.0)。移植后随访的中位数为 6.5 年(IQR:1.4-11.5)。结论IRC的监测对于确保足够的无病生存期非常重要。
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引用次数: 0
Effects of anti-CD20 therapy on circulating and intrathecal follicular helper T cell subsets in multiple sclerosis 抗CD20疗法对多发性硬化症患者循环和鞘内滤泡辅助T细胞亚群的影响。
IF 8.6 3区 医学 Q1 Medicine Pub Date : 2024-05-23 DOI: 10.1016/j.clim.2024.110262
Sahla El Mahdaoui , Marie Mathilde Hansen , Malene Bredahl Hansen , Victoria Hyslop Hvalkof , Helle Bach Søndergaard , Mie Reith Mahler , Jeppe Romme Christensen , Finn Sellebjerg , Marina Rode von Essen

Follicular helper T (Tfh) cells and their interplay with B cells likely contribute to the pathogenesis of relapsing-remitting multiple sclerosis (RRMS). Tfh cells are enriched in cerebrospinal fluid (CSF) in RRMS, but effects of anti-CD20 therapy are unknown. We investigated Tfh cells in controls, untreated and anti-CD20-treated patients with RRMS using flow cytometry. CSF Tfh cells were increased in untreated patients. Compared to paired blood samples, CD25 Tfh cells were enriched in CSF in RRMS, but not in controls. Contrast-enhancing brain MRI lesions and IgG index correlated with CSF CD25 Tfh cell frequency in untreated patients with RRMS. Anti-CD20 therapy reduced the numbers of circulating PD1+ Tfh cells and CD25 Tfh cells, and the frequency of CSF CD25 Tfh cells. The study suggests that CD25 Tfh cells are recruited to the CSF in RRMS, associated with focal inflammation, and are reduced by anti-CD20 therapy.

滤泡辅助T细胞(Tfh)及其与B细胞的相互作用可能是复发缓解型多发性硬化症(RRMS)的发病机制之一。Tfh细胞在RRMS患者的脑脊液(CSF)中富集,但抗CD20治疗的效果尚不清楚。我们使用流式细胞术研究了对照组、未接受治疗和接受抗 CD20 治疗的 RRMS 患者的 Tfh 细胞。在未经治疗的患者中,CSF Tfh细胞有所增加。与配对血液样本相比,CD25- Tfh细胞在RRMS患者的CSF中富集,而在对照组中则没有富集。在未经治疗的RRMS患者中,对比增强的脑MRI病变和IgG指数与CSF中CD25- Tfh细胞的频率相关。抗CD20疗法减少了循环中PD1+ Tfh细胞和CD25- Tfh细胞的数量,也降低了CSF CD25- Tfh细胞的频率。该研究表明,CD25- Tfh细胞被招募到RRMS的CSF中,与病灶炎症有关,并通过抗CD20治疗而减少。
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引用次数: 0
A proximal enhancer regulates RORA expression during early human Th17 cell differentiation 近端增强子在人类 Th17 细胞早期分化过程中调控 RORA 的表达。
IF 8.6 3区 医学 Q1 Medicine Pub Date : 2024-05-22 DOI: 10.1016/j.clim.2024.110261
Ubaid Ullah Kalim , Rahul Biradar , Sini Junttila , Mohd Moin Khan , Subhash Tripathi , Meraj Hasan Khan , Johannes Smolander , Kartiek Kanduri , Tapio Envall , Asta Laiho , Alexander Marson , Omid Rasool , Laura L. Elo , Riitta Lahesmaa

Gene regulatory elements, such as enhancers, greatly influence cell identity by tuning the transcriptional activity of specific cell types. Dynamics of enhancer landscape during early human Th17 cell differentiation remains incompletely understood. Leveraging ATAC-seq-based profiling of chromatin accessibility and comprehensive analysis of key histone marks, we identified a repertoire of enhancers that potentially exert control over the fate specification of Th17 cells. We found 23 SNPs associated with autoimmune diseases within Th17-enhancers that precisely overlapped with the binding sites of transcription factors actively engaged in T-cell functions. Among the Th17-specific enhancers, we identified an enhancer in the intron of RORA and demonstrated that this enhancer positively regulates RORA transcription. Moreover, CRISPR-Cas9-mediated deletion of a transcription factor binding site-rich region within the identified RORA enhancer confirmed its role in regulating RORA transcription. These findings provide insights into the potential mechanism by which the RORA enhancer orchestrates Th17 differentiation.

背景:基因调控元件(如增强子)通过调整特定细胞类型的转录活性,对细胞特性产生极大影响。人类Th17细胞早期分化过程中增强子景观的动态变化仍不完全清楚。利用基于 ATAC-seq 的染色质可及性分析和关键组蛋白标记的综合分析,我们发现了一系列潜在的增强子,这些增强子可能对 Th17 细胞的命运规范产生控制作用。我们在 Th17 增强子中发现了 23 个与自身免疫性疾病相关的 SNPs,这些 SNPs 与活跃参与 T 细胞功能的转录因子的结合位点精确重叠。在Th17特异性增强子中,我们发现了RORA内含子中的一个增强子,并证明该增强子能正向调控RORA的转录。此外,CRISPR-Cas9介导的删除RORA增强子中一个富含转录因子结合位点的区域证实了它在调节RORA转录中的作用。这些发现深刻揭示了 RORA 增强子协调 Th17 分化的潜在机制。
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引用次数: 0
IL-27 promotes pathogenic T cells in a mouse model of Sjögren's disease IL-27 可促进斯约戈伦病小鼠模型中致病性 T 细胞的生长
IF 8.6 3区 医学 Q1 Medicine Pub Date : 2024-05-22 DOI: 10.1016/j.clim.2024.110260
Ivy L. Debreceni , Jennifer Y. Barr , Ellen M. Upton , Yi-Guang Chen , Scott M. Lieberman

Sjögren's disease (SjD) is a chronic autoimmune disease characterized by focal lymphocytic inflammation in lacrimal and salivary glands. We recently identified IL-27 as a requisite signal for the spontaneous SjD-like manifestations in nonobese diabetic (NOD) mice. Here, we define T cell-intrinsic effects of IL-27 in lacrimal gland disease in NOD mice. IL-27 receptor was required by both CD4 T effector (Te) cells and CD8 T cells to mediate focal inflammation. Intrinsic IL-27 signaling was associated with PD-1 and ICOS expressing T follicular helper (Tfh)-like CD4 Te cells within lacrimal glands, including subsets defined by CD73 or CD39 expression. CD8 T cells capable of IL-27 signaling also expressed PD-1 with subsets expressing ICOS and CD73 demonstrating a T follicular cytotoxic (Tfc)-like cell phenotype and others expressing a CD39hi exhausted-like phenotype. These findings suggest IL-27 is a key early signal driving a follicular-type response in lacrimal gland inflammation in NOD mice.

斯约格伦病(SjD)是一种慢性自身免疫性疾病,其特征是泪腺和唾液腺的局灶性淋巴细胞炎症。我们最近发现 IL-27 是非肥胖糖尿病(NOD)小鼠自发 SjD 样表现的必要信号。在这里,我们确定了 IL-27 在 NOD 小鼠泪腺疾病中的 T 细胞内在效应。CD4 T效应(Te)细胞和CD8 T细胞都需要IL-27受体来介导病灶炎症。内在的IL-27信号与泪腺中表达PD-1和ICOS的T滤泡辅助细胞(Tfh)类CD4 Te细胞有关,包括由CD73或CD39表达所定义的亚群。能发出IL-27信号的CD8 T细胞也表达PD-1,其中表达ICOS和CD73的亚群表现出T滤泡细胞毒性(Tfc)样细胞表型,其他亚群则表现出CD39hi衰竭样表型。这些发现表明,IL-27 是驱动 NOD 小鼠泪腺炎症中滤泡型反应的关键早期信号。
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引用次数: 0
Itaconate reduces proliferation and migration of fibroblast-like synoviocytes and ameliorates arthritis models 伊塔康酸可减少成纤维细胞样滑膜细胞的增殖和迁移,改善关节炎模型。
IF 8.6 3区 医学 Q1 Medicine Pub Date : 2024-05-18 DOI: 10.1016/j.clim.2024.110255
Maria Tada , Yuki Kudo , Michihito Kono , Masatoshi Kanda , Shuhei Takeyama , Kodai Sakiyama , Hotaka Ishizu , Tomohiro Shimizu , Tsutomu Endo , Ryo Hisada , Yuichiro Fujieda , Masaru Kato , Olga Amengual , Norimasa Iwasaki , Tatsuya Atsumi

Fibroblast-like synoviocytes (FLS) play critical roles in rheumatoid arthritis (RA). Itaconate (ITA), an endogenous metabolite derived from the tricarboxylic acid (TCA) cycle, has attracted attention because of its anti-inflammatory, antiviral, and antimicrobial effects. This study evaluated the effect of ITA on FLS and its potential to treat RA. ITA significantly decreased FLS proliferation and migration in vitro, as well as mitochondrial oxidative phosphorylation and glycolysis measured by an extracellular flux analyzer. ITA accumulates metabolites including succinate and citrate in the TCA cycle. In rats with type II collagen-induced arthritis (CIA), intra-articular injection of ITA reduced arthritis and bone erosion. Irg1-deficient mice lacking the ability to produce ITA had more severe arthritis than control mice in the collagen antibody-induced arthritis. ITA ameliorated CIA by inhibiting FLS proliferation and migration. Thus, ITA may be a novel therapeutic agent for RA.

成纤维细胞样滑膜细胞(FLS)在类风湿性关节炎(RA)中起着至关重要的作用。伊塔康酸(ITA)是从三羧酸(TCA)循环中提取的一种内源性代谢物,因其抗炎、抗病毒和抗菌作用而备受关注。本研究评估了 ITA 对 FLS 的影响及其治疗 RA 的潜力。ITA在体外明显减少了FLS的增殖和迁移,并通过细胞外通量分析仪测量了线粒体氧化磷酸化和糖酵解。在 TCA 循环中,ITA 会积累包括琥珀酸盐和柠檬酸盐在内的代谢物。在Ⅱ型胶原诱导的关节炎(CIA)大鼠中,关节内注射ITA可减少关节炎和骨侵蚀。在胶原抗体诱导的关节炎中,缺乏产生ITA能力的Irg1缺陷小鼠的关节炎比对照小鼠更严重。ITA通过抑制FLS的增殖和迁移改善了CIA。因此,ITA可能是一种治疗RA的新型药物。
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引用次数: 0
A bispecific antibody targeting HLA-DQ2.5-gluten peptides potently blocks gluten-specific T cells induced by gluten ingestion in patients with celiac disease 针对 HLA-DQ2.5 谷蛋白肽的双特异性抗体能有效阻断乳糜泻患者因摄入谷蛋白而诱导的谷蛋白特异性 t 细胞。
IF 8.6 3区 医学 Q1 Medicine Pub Date : 2024-05-18 DOI: 10.1016/j.clim.2024.110259
M.Y. Hardy , L.M. Henneken , A.K. Russell , Y. Okura , A. Mizoroki , Y. Ozono , S. Kobayashi , Y. Murakami , J.A. Tye-Din

The gluten-free diet for celiac disease (CeD) is restrictive and often fails to induce complete symptom and/or mucosal disease remission. Central to CeD pathogenesis is the gluten-specific CD4+ T cell that is restricted by HLA-DQ2.5 in over 85% of CeD patients, making HLA-DQ2.5 an attractive target for suppressing gluten-dependent immunity. Recently, a novel anti-HLA-DQ2.5 antibody that specifically recognizes the complexes of HLA-DQ2.5 and multiple gluten epitopes was developed (DONQ52).

Objective

To assess the ability of DONQ52 to inhibit CeD patient-derived T-cell responses to the most immunogenic gluten peptides that encompass immunodominant T cell epitopes.

Methods

We employed an in vivo gluten challenge model in patients with CeD that affords a quantitative readout of disease-relevant gluten-specific T-cell responses. HLA-DQ2.5+ CeD patients consumed food containing wheat, barley, or rye for 3 days with collection of blood before (D1) and 6 days after (D6) commencing the challenge. Peripheral blood mononuclear cells were isolated and assessed in an interferon (IFN)-γ enzyme-linked immunosorbent spot assay (ELISpot) testing responses to gluten peptides encompassing a series of immunodominant T cell epitopes. The inhibitory effect of DONQ52 (4 or 40 μg/mL) was assessed and compared to pan-HLA-DQ blockade (SPVL3 antibody).

Results

In HLA-DQ2.5+ CeD patients, DONQ52 reduced T cell responses to all wheat gluten peptides to an equivalent or more effective degree than pan-HLA-DQ antibody blockade. It reduced T cell responses to a cocktail of the most immunodominant wheat epitopes by a median of 87% (IQR 72–92). Notably, DONQ52 also substantially reduced T-cell responses to dominant barley hordein and rye secalin derived peptides. DONQ52 had no effect on T-cell responses to non-gluten antigens.

Conclusion

DONQ52 can significantly block HLA-DQ2.5-restricted T cell responses to the most highly immunogenic gluten peptides in CeD. Our findings support in vitro data that DONQ52 displays selectivity and broad cross-reactivity against multiple gluten peptide:HLA-DQ2.5 complexes. This work provides proof-of-concept multi-specific antibody blockade has the potential to meaningfully inhibit pathogenic gluten-specific T-cell responses in CeD and supports ongoing therapeutic development.

治疗乳糜泻(Ceeliac disease,CeD)的无麸质饮食是一种限制性饮食,往往不能诱导症状和/或粘膜疾病的完全缓解。麸质过敏症发病机制的核心是麸质特异性 CD4+ T 细胞,85% 以上的麸质过敏症患者的 CD4+ T 细胞受到 HLA-DQ2.5 的限制,这使得 HLA-DQ2.5 成为抑制麸质依赖性免疫的一个有吸引力的靶点。最近,一种新型抗HLA-DQ2.5抗体(DONQ52)被开发出来,它能特异性识别HLA-DQ2.5和多个麸质表位的复合物:目的:评估DONQ52抑制CeD患者T细胞对包含免疫优势T细胞表位的最具免疫原性的麸质多肽反应的能力:方法:我们在CeD患者中采用了体内麸质挑战模型,该模型可定量读出与疾病相关的麸质特异性T细胞反应。HLA-DQ2.5+ CeD 患者食用含有小麦、大麦或黑麦的食物 3 天,并在开始挑战前(D1)和挑战后 6 天(D6)采集血液。分离外周血单核细胞,并用干扰素(IFN)-γ 酶联免疫吸附点测定法(ELISpot)评估其对包含一系列免疫优势 T 细胞表位的麸质肽的反应。评估了 DONQ52(4 或 40 μg/mL)的抑制作用,并与泛 HLA-DQ 阻断(SPVL3 抗体)进行了比较:结果:在HLA-DQ2.5+ CeD患者中,DONQ52能降低T细胞对所有麦麸肽的反应,其效果等同于或高于泛HLA-DQ抗体阻断。它能将T细胞对最具有免疫优势的小麦表位的反应降低87.3%(IQR 72.4-92.4)。值得注意的是,DONQ52 还大大降低了 T 细胞对优势大麦角蛋白和黑麦鞘氨醇衍生肽的反应。DONQ52 对非麸质抗原的 T 细胞反应没有影响:结论:DONQ52 能显著阻断 HLA-DQ2.5 限制的 T 细胞对 CeD 中免疫原性最强的麸质多肽的反应。我们的研究结果支持体外数据,即 DONQ52 对多种谷蛋白肽:HLA-DQ2.5 复合物具有选择性和广泛的交叉反应性。这项工作提供了多特异性抗体阻断可能有效抑制 CeD 中致病性麸质特异性 T 细胞反应的概念证明,并为正在进行的治疗开发提供了支持。
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引用次数: 0
Regarding the “Renal dysfunction in AQP4 NMOSD and MS; a potential predictor of relapse and prognosis” 关于 "AQP4 NMOSD 和多发性硬化症的肾功能障碍;复发和预后的潜在预测因素
IF 8.6 3区 医学 Q1 Medicine Pub Date : 2024-05-17 DOI: 10.1016/j.clim.2024.110257
Jianfang Liao, Juan Cao
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引用次数: 0
Reconstruction of Sjögren's syndrome-like sialadenitis by a defined disease specific gut-reactive single TCR and an autoantibody 通过明确的疾病特异性肠道反应性单个 TCR 和自身抗体重建类似于 Sjögren's 综合征的唾液腺炎。
IF 8.6 3区 医学 Q1 Medicine Pub Date : 2024-05-16 DOI: 10.1016/j.clim.2024.110258
Mana Iizuka-Koga , Minako Ito , Noriko Yumoto , Setsuko Mise-Omata , Taeko Hayakawa , Kyoko Komai , Shunsuke Chikuma , Satoru Takahashi , Isao Matsumoto , Takayuki Sumida , Akihiko Yoshimura

Lymphocytes such as CD4+ T cells and B cells mainly infiltrate the salivary glands; however, the precise roles and targets of autoreactive T cells and autoantibodies in the pathogenesis of Sjögren's Syndrome (SS) remain unclear. This study was designed to clarify the role of autoreactive T cells and autoantibodies at the single-cell level involved in the development of sialadenitis. Infiltrated CD4+ T and B cells in the salivary glands of a mouse model resembling SS were single-cell-sorted, and their T cell receptor (TCR) and B cell receptor (BCR) sequences were analyzed. The predominant TCR and BCR clonotypes were reconstituted in vitro, and their pathogenicity was evaluated by transferring reconstituted TCR-expressing CD4+ T cells into Rag2−/− mice and administering recombinant IgG in vivo. The reconstitution of Th17 cells expressing TCR (#G) in Rag2−/− mice resulted in the infiltration of T cells into the salivary glands and development of sialadenitis, while an autoantibody (IgGr22) was observed to promote the proliferation of pathogenic T cells. IgGr22 specifically recognizes double-stranded RNA (dsRNA) and induces the activation of dendritic cells, thereby enhancing the expression of IFN signature and inflammatory genes. TCR#G recognizes antigens related to the gut microbiota. Antibiotic treatment severely reduces the activation of TCR#G-expressing Th17 cells and suppresses sialadenitis development. These data suggest that the anti-dsRNA antibodies and, TCR recognizing the gut microbiota involved in the development of sialadenitis like SS. Thus, our model provides a novel strategy for defining the roles of autoreactive TCR and autoantibodies in the development and pathogenesis of SS.

CD4+ T细胞和B细胞等淋巴细胞主要浸润唾液腺;然而,自反应性T细胞和自身抗体在斯约格伦综合征(SS)发病机制中的确切作用和靶点仍不清楚。本研究旨在阐明自反应 T 细胞和自身抗体在单细胞水平上参与唾液腺炎发病的作用。对类似 SS 的小鼠模型唾液腺中浸润的 CD4+ T 细胞和 B 细胞进行了单细胞分选,并分析了它们的 T 细胞受体(TCR)和 B 细胞受体(BCR)序列。体外重组了主要的TCR和BCR克隆型,并通过将重组的TCR表达CD4+ T细胞转移到Rag2-/-小鼠体内和体内注射重组IgG来评估它们的致病性。在Rag2-/-小鼠体内重组表达TCR(#G)的Th17细胞会导致T细胞浸润唾液腺并引发唾液腺炎,同时观察到一种自身抗体(IgGr22)会促进致病性T细胞的增殖。IgGr22 能特异性识别双链 RNA(dsRNA)并诱导树突状细胞活化,从而增强 IFN 标志和炎症基因的表达。TCR#G 可识别与肠道微生物群相关的抗原。抗生素治疗严重降低了表达 TCR#G 的 Th17 细胞的活化,抑制了唾液腺炎的发展。这些数据表明,抗dsRNA抗体和识别肠道微生物群的TCR参与了类似SS的唾液腺炎的发生。因此,我们的模型为确定自反应性 TCR 和自身抗体在 SS 的发展和发病机制中的作用提供了一种新策略。
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引用次数: 0
Ionic reverberation modulates the cellular fate of CD8+tissue resident memory T cells (TRMs) in patients with renal cell carcinoma: A novel mechanism 离子混响调节肾细胞癌患者 CD8+ 组织驻留记忆 T 细胞 (TRM) 的细胞命运:一种新的机制。
IF 8.6 3区 医学 Q1 Medicine Pub Date : 2024-05-16 DOI: 10.1016/j.clim.2024.110256
Ashu Singh , Saumitra Dey Choudhury , Prabhjot Singh , Vishwendra Vikram Singh , Som Nath Singh , Alpana Sharma

In metastatic renal cell carcinoma (mRCC), existing treatments including checkpoint inhibitors are failed to cure and/or prevent recurrence of the disease. Therefore, in-depth understanding of tumor tissue resident memory T cells (TRMs) dysfunction are necessitated to enrich efficacy of immunotherapies and increasing disease free survival in treated patients. In patients, we observed dysregulation of K+, Ca2+, Na2+ and Zn2+ ion channels leads to excess infiltration of their respective ions in tumor TRMs, thus ionic gradients are disturbed and cells became hyperpolarized. Moreover, overloaded intramitochondrial calcium caused mitochondrial depolarization and trigger apoptosis of tumor TRMs. Decreased prevalence of activated tumor TRMs reflected our observations. Furthermore, disruptions in ionic concentrations impaired the functional activities and/or suppressed anti-tumor action of circulating and tumor TRMs in RCC. Collectively, these findings revealed novel mechanism behind dysfunctionality of tumor TRMs. Implicating enrichment of activated TRMs within tumor would be beneficial for better management of RCC patients.

对于转移性肾细胞癌(mRCC),包括检查点抑制剂在内的现有治疗方法都无法治愈和/或预防疾病复发。因此,有必要深入了解肿瘤组织常驻记忆 T 细胞(TRMs)的功能障碍,以丰富免疫疗法的疗效,提高患者的无病生存率。在患者体内,我们观察到 K+、Ca2+、Na2+ 和 Zn2+ 离子通道失调,导致各自离子在肿瘤 TRMs 中过度渗透,从而扰乱了离子梯度,使细胞极化过度。此外,线粒体内过量的钙离子导致线粒体去极化,并引发肿瘤 TRM 的凋亡。活化的肿瘤 TRMs 的减少反映了我们的观察结果。此外,离子浓度的紊乱损害了循环和肿瘤 TRMs 在 RCC 中的功能活性和/或抑制了其抗肿瘤作用。总之,这些发现揭示了肿瘤TRMs功能失调背后的新机制。在肿瘤内富集活化的TRMs将有利于更好地治疗RCC患者。
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引用次数: 0
期刊
Clinical immunology
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