Compartmentalized ocular lymphatic system mediates eye-brain immunity

• 成果类型: Article
• 署名作者: Yin, Xiangyun; Zhang, Sophia; Lee, Ju Hyun; Dong, Huiping; Mourgkos, George; Terwilliger, Gordon; Kraus, Aurora; Geraldo, Luiz Henrique; Poulet, Mathilde; Fischer, Suzanne; Zhou, Ting; Mohammed, Farrah Shalima; Zhou, Jiangbing; Wang, Yongfu; Malloy, Seth; Rohner, Nicolas; Sharma, Lokesh; Salinas, Irene; Eichmann, Anne; Thomas, Jean-Leon; Saltzman, W. Mark; Huttner, Anita; Zeiss, Caroline; Ring, Aaron; Iwasaki, Akiko; Song, Eric
• 署名单位: Yale University; Yale University; Yale University; Yale University; University of New Mexico; Yale University; Yale University; Westlake Laboratory; Westlake University; Yale University; Stowers Institute for Medical Research; Yale University; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Yale University; Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); Assistance Publique Hopitaux Paris (APHP); Hopital Universitaire Pitie-Salpetriere - APHP; Institut National de la Sante et de la Recherche Medicale (Inserm); Yale University; Yale University; Yale University; Yale University; Howard Hughes Medical Institute
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5722
• DOI: 10.1038/s41586-024-07130-8
• 发表日期: 2024-04-04
• 页码: 204-+
• 关键词: anterior-chamber; antigen; responses; DYNAMICS; antibody; cells; fluid

摘要

The eye, an anatomical extension of the central nervous system (CNS), exhibits many molecular and cellular parallels to the brain. Emerging research demonstrates that changes in the brain are often reflected in the eye, particularly in the retina(1). Still, the possibility of an immunological nexus between the posterior eye and the rest of the CNS tissues remains unexplored. Here, studying immune responses to herpes simplex virus in the brain, we observed that intravitreal immunization protects mice against intracranial viral challenge. This protection extended to bacteria and even tumours, allowing therapeutic immune responses against glioblastoma through intravitreal immunization. We further show that the anterior and posterior compartments of the eye have distinct lymphatic drainage systems, with the latter draining to the deep cervical lymph nodes through lymphatic vasculature in the optic nerve sheath. This posterior lymphatic drainage, like that of meningeal lymphatics, could be modulated by the lymphatic stimulator VEGFC. Conversely, we show that inhibition of lymphatic signalling on the optic nerve could overcome a major limitation in gene therapy by diminishing the immune response to adeno-associated virus and ensuring continued efficacy after multiple doses. These results reveal a shared lymphatic circuit able to mount a unified immune response between the posterior eye and the brain, highlighting an understudied immunological feature of the eye and opening up the potential for new therapeutic strategies in ocular and CNS diseases.