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Compartmentalized ocular lymphatic system mediates eye–brain immunity

Author

Listed:
  • Xiangyun Yin

    (Yale School of Medicine
    Yale School of Medicine)

  • Sophia Zhang

    (Yale School of Medicine)

  • Ju Hyun Lee

    (Yale School of Engineering and Applied Science)

  • Huiping Dong

    (Yale School of Medicine)

  • George Mourgkos

    (Yale School of Medicine)

  • Gordon Terwilliger

    (Yale School of Medicine)

  • Aurora Kraus

    (University of New Mexico)

  • Luiz Henrique Geraldo

    (Yale School of Medicine
    Yale School of Medicine)

  • Mathilde Poulet

    (Yale School of Medicine
    Yale School of Medicine)

  • Suzanne Fischer

    (Yale School of Medicine)

  • Ting Zhou

    (Yale School of Medicine
    Westlake University)

  • Farrah Shalima Mohammed

    (Yale School of Engineering and Applied Science
    Yale School of Medicine)

  • Jiangbing Zhou

    (Yale School of Engineering and Applied Science
    Yale School of Medicine)

  • Yongfu Wang

    (Stowers Institute for Medical Research)

  • Seth Malloy

    (Stowers Institute for Medical Research)

  • Nicolas Rohner

    (Stowers Institute for Medical Research)

  • Lokesh Sharma

    (Yale School of Medicine)

  • Irene Salinas

    (University of New Mexico)

  • Anne Eichmann

    (Yale School of Medicine
    Yale School of Medicine
    Université de Paris, INSERM, PARCC)

  • Jean-Leon Thomas

    (Yale School of Medicine
    Sorbonne Université)

  • W. Mark Saltzman

    (Yale School of Engineering and Applied Science
    Yale School of Medicine
    Yale School of Engineering and Applied Science
    Yale School of Medicine)

  • Anita Huttner

    (Yale School of Medicine)

  • Caroline Zeiss

    (Yale School of Medicine)

  • Aaron Ring

    (Yale School of Medicine)

  • Akiko Iwasaki

    (Yale School of Medicine
    Howard Hughes Medical Institute)

  • Eric Song

    (Yale School of Medicine
    Yale School of Medicine)

Abstract

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 retina1. 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.

Suggested Citation

  • Xiangyun Yin & Sophia Zhang & Ju Hyun Lee & Huiping Dong & George Mourgkos & Gordon Terwilliger & Aurora Kraus & Luiz Henrique Geraldo & Mathilde Poulet & Suzanne Fischer & Ting Zhou & Farrah Shalima , 2024. "Compartmentalized ocular lymphatic system mediates eye–brain immunity," Nature, Nature, vol. 628(8006), pages 204-211, April.
  • Handle: RePEc:nat:nature:v:628:y:2024:i:8006:d:10.1038_s41586-024-07130-8
    DOI: 10.1038/s41586-024-07130-8
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    Cited by:

    1. Bingxin Zhao & Yujue Li & Zirui Fan & Zhenyi Wu & Juan Shu & Xiaochen Yang & Yilin Yang & Xifeng Wang & Bingxuan Li & Xiyao Wang & Carlos Copana & Yue Yang & Jinjie Lin & Yun Li & Jason L. Stein & Joa, 2024. "Eye-brain connections revealed by multimodal retinal and brain imaging genetics," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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