健康な脳は不適切な免疫反応を抑制する(Healthy brains suppress inappropriate immune responses)

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2024-10-30 ワシントン大学セントルイス校

健康な脳は不適切な免疫反応を抑制する(Healthy brains suppress inappropriate immune responses)
Researchers at WashU Medicine have found a process by which the brain guards against attack by the immune system. In mice with multiple sclerosis, such “guardian” proteins that train the immune system were drastically depleted, and replenishing them improved symptoms, according to a study in Nature. (Image: Getty Images)

ワシントン大学医学部の研究者は、脳が免疫系と対話し、過剰な免疫反応を抑制する「ガーディアンペプチド」を発見しました。このペプチドは、脳と脊髄で生成され、免疫系の調整に寄与します。多発性硬化症(MS)のマウスモデルでは、これらのペプチドが減少しており、補充することで症状の改善が見られました。この発見は、MSやアルツハイマー病などの神経炎症性疾患の新たな治療法開発に繋がる可能性があります。

<関連情報>

内因性自己ペプチドが中枢神経系の免疫特権を守る Endogenous self-peptides guard immune privilege of the central nervous system

Min Woo Kim,Wenqing Gao,Cheryl F. Lichti,Xingxing Gu,Taitea Dykstra,Jay Cao,Igor Smirnov,Pavle Boskovic,Denis Kleverov,Andrea F. M. Salvador,Antoine Drieu,Kyungdeok Kim,Susan Blackburn,Clair Crewe,Maxim N. Artyomov,Emil R. Unanue & Jonathan Kipnis
Nature  Published:30 October 2024
DOI:https://doi.org/10.1038/s41586-024-08279-y

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

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.

医療・健康
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