Follicle on the Roof: Tertiary Lymphoid Structures in Central Nervous System Autoimmunity

IF 7.5 2区 医学 Q1 IMMUNOLOGY
Michelle Zuo, Angela A. Wang, Jennifer L. Gommerman
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引用次数: 0

Abstract

Leptomeningeal tertiary lymphoid structures (TLS) have emerged as a relatively common pathological feature of autoimmune disease, including multiple sclerosis (MS) and particularly in people with progressive and nonremitting MS. These ectopic lymphoid aggregates, observed in the leptomeninges adjacent to so-called “Type 3” sub-pial cortical lesions, are associated with more severe gray matter damage and worse clinical outcomes. Mouse models of MS that recapitulate TLS formation in the central nervous system (CNS) have provided critical insights into the mechanisms driving their development and maintenance. In these models of experimental autoimmune encephalomyelitis (EAE) initiation of TLS is facilitated by Th17 cells, which promote chronic inflammation via cytokines such as IL-17 and GM-CSF. The cell surface expression of lymphotoxin-α and lymphotoxin-β heterotrimers (LTαβ) on lymphocytes, including Th17 cells, elaborates the organization of ectopic lymphoid tissues via LTβR signaling on radio-resistant stromal cells and resident fibroblasts. Ultimately a pro-inflammatory environment characterized by cytokines such as IL-17 and GM-CSF promotes the recruitment of neutrophils which produce proteases and chemokines that sustain a pro-inflammatory milieu. Emerging EAE data suggest that disrupting TLS organization or targeting key pathways involved in their maintenance could represent promising strategies for modulating chronic CNS inflammation in MS. Understanding the cellular and molecular mechanisms regulating TLS dynamics is therefore critical for the development of therapies aimed at halting or reversing nonremitting MS disease.

Abstract Image

顶泡:中枢神经系统自身免疫的三级淋巴结构
轻脑膜三级淋巴样结构(TLS)已成为自身免疫性疾病(包括多发性硬化症(MS),尤其是进行性和非缓解性MS患者)相对常见的病理特征。在所谓的“3型”枕下皮质病变附近的轻脑膜中观察到这些异位淋巴样聚集物,与更严重的灰质损伤和更差的临床结果相关。重现中枢神经系统(CNS) TLS形成的MS小鼠模型为推动其发展和维持的机制提供了重要见解。在这些实验性自身免疫性脑脊髓炎(EAE)模型中,Th17细胞促进TLS的启动,Th17细胞通过IL-17和GM-CSF等细胞因子促进慢性炎症。淋巴细胞(包括Th17细胞)表面淋巴素-α和淋巴素-β异源三聚体(LTαβ)的表达,通过LTβR信号在耐辐射基质细胞和常驻成纤维细胞上的表达,阐述了异位淋巴组织的组织。最终,以IL-17和GM-CSF等细胞因子为特征的促炎环境促进中性粒细胞的募集,中性粒细胞产生蛋白酶和趋化因子,维持促炎环境。新出现的EAE数据表明,破坏TLS组织或靶向参与其维持的关键通路可能是调节MS慢性中枢神经系统炎症的有希望的策略。因此,了解调节TLS动力学的细胞和分子机制对于开发旨在停止或逆转非缓解型MS疾病的疗法至关重要。
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来源期刊
Immunological Reviews
Immunological Reviews 医学-免疫学
CiteScore
16.20
自引率
1.10%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Immunological Reviews is a specialized journal that focuses on various aspects of immunological research. It encompasses a wide range of topics, such as clinical immunology, experimental immunology, and investigations related to allergy and the immune system. The journal follows a unique approach where each volume is dedicated solely to a specific area of immunological research. However, collectively, these volumes aim to offer an extensive and up-to-date overview of the latest advancements in basic immunology and their practical implications in clinical settings.
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