美国华盛顿大学Jonathan Kipnis课题组报道，内源性自身肽维护中枢神经系统（CNS）的免疫特性。该项研究成果发表在2024年10月30日出版的《自然》上。

研究人员表示，尽管中枢神经系统具有保护性的解剖屏障，但它并非完全与免疫系统隔绝。事实上，中枢神经系统与外周免疫系统保持着物理联系，并可能受到外周免疫系统的影响。尚不清楚中枢神经系统如何在保持免疫独特性的同时保持这种反应性。

在寻找中枢神经系统内使得其与免疫系统直接交流的分子时，研究人员发现，中枢神经系统中存在源于中枢神经系统的内源性调节自身肽，这些自身肽位于中枢神经系统边界的主要组织相容性复合体（MHC）II分子上。

在平衡状态时，这些调节性自身肽，通过从大脑到周围脑膜及其引流颈淋巴结的整个淋巴引流路径中，与MHC II分子结合。然而，随着神经炎性疾病的发生，调节性自身肽的递呈减少。

当这些调节性自身肽呈递量增加时，抑制性CD4⁺ T细胞群出现扩增，从而以一种CTLA-4和TGFβ依赖的方式控制中枢神经系统自身免疫。

中枢神经系统中自身性免疫自身肽，可能是中枢神经系统与免疫系统保持持续对话，同时平衡明显自身反应的分子关键。这为人们从概念上思考和治疗，神经炎症和神经退行性疾病提供了新的思路。

附：英文原文

Title: Endogenous self-peptides guard immune privilege of the central nervous system

Author: Kim, Min Woo, Gao, Wenqing, Lichti, Cheryl F., Gu, Xingxing, Dykstra, Taitea, Cao, Jay, Smirnov, Igor, Boskovic, Pavle, Kleverov, Denis, Salvador, Andrea F. M., Drieu, Antoine, Kim, Kyungdeok, Blackburn, Susan, Crewe, Clair, Artyomov, Maxim N., Unanue, Emil R., Kipnis, Jonathan

Issue&Volume: 2024-10-30

Abstract: The central nervous system (CNS), despite the presence of strategically positioned anatomical barriers designed to protect it, is not entirely isolated from the immune system1,2. In fact, it remains physically connected to and can be influenced by the peripheral immune system1. How the CNS retains such responsiveness while maintaining an immunologically unique status remains an outstanding conundrum. In searching for molecular cues that derive from the CNS and allow its direct communication with the immune system, we discovered an endogenous repertoire of CNS-derived regulatory self-peptides presented on major histocompatibility complex (MHC) II molecules at the CNS borders. During homeostasis, these regulatory self-peptides were found to be bound to MHC II molecules throughout the path of lymphatic drainage from the brain to its surrounding meninges and its draining cervical lymph nodes. With neuroinflammatory disease, however, the presentation of regulatory self-peptides diminished. Upon boosting the presentation of these regulatory self-peptides, a population of suppressor CD4+ T cells was expanded, controlling CNS autoimmunity in a CTLA-4 and TGFβ dependent manner. This unexpected discovery of CNS-derived autoimmune self-peptides may be the molecular key adapting the CNS to maintain continuous dialogue with the immune system while balancing overt autoreactivity. This sheds new light on how we conceptually think about and therapeutically target neuroinflammatory and neurodegenerative diseases.

DOI: 10.1038/s41586-024-08279-y

Source: https://www.nature.com/articles/s41586-024-08279-y