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Stage-dependent immunity orchestrates AQP4 antibody-guided NMOSD pathology: a role for netting neutrophils with resident memory T cells in situ

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Abstract

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the CNS characterized by the production of disease-specific autoantibodies against aquaporin-4 (AQP4) water channels. Animal model studies suggest that anti-AQP4 antibodies cause a loss of AQP4-expressing astrocytes, primarily via complement-dependent cytotoxicity. Nonetheless, several aspects of the disease remain unclear, including: how anti-AQP4 antibodies cross the blood–brain barrier from the periphery to the CNS; how NMOSD expands into longitudinally extensive transverse myelitis or optic neuritis; how multiphasic courses occur; and how to prevent attacks without depleting circulating anti-AQP4 antibodies, especially when employing B-cell-depleting therapies. To address these knowledge gaps, we conducted a comprehensive ‘stage-dependent’ investigation of immune cell elements in situ in human NMOSD lesions, based on neuropathological techniques for autopsied/biopsied CNS materials. The present study provided three major findings. First, activated or netting neutrophils and melanoma cell adhesion molecule-positive (MCAM+) helper T (TH) 17/cytotoxic T (TC) 17 cells are prominent, and the numbers of these correlate with the size of NMOSD lesions in the initial or early-active stages. Second, forkhead box P3-positive (FOXP3+) regulatory T (Treg) cells are recruited to NMOSD lesions during the initial, early-active or late-active stages, suggesting rapid suppression of proinflammatory autoimmune events in the active stages of NMOSD. Third, compartmentalized resident memory immune cells, including CD103+ tissue-resident memory T (TRM) cells with long-lasting inflammatory potential, are detected under “standby” conditions in all stages. Furthermore, CD103+ TRM cells express high levels of granzyme B/perforin-1 in the initial or early-active stages of NMOSD in situ. We infer that stage-dependent compartmentalized immune traits orchestrate the pathology of anti-AQP4 antibody-guided NMOSD in situ. Our work further suggests that targeting activated/netting neutrophils, MCAM+ TH17/TC17 cells, and CD103+ TRM cells, as well as promoting the expansion of FOXP3+ Treg cells, may be effective in treating and preventing relapses of NMOSD.

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Data availability

Data that support the conclusion of the study are included in the main manuscript and supplementary materials. Additional data are available on reasonable request to the corresponding author.

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Acknowledgements

We thank S. Kawaguchi, T. Yahata, and M. Kaneko (Department of Neurology, Brain Research Institute, Niigata University, Japan) for technical assistance with neuropathological and immunological investigations and BP Morgan (School of Medicine, Cardiff University, UK) for providing the complement antibody.

Funding

This work was supported in part by JSPS KAKENHI Grant Numbers JP20K07899 (IK), JP23K06923 (IK) and JP21K07412 (ES), and by the MHLW Research Program on Rare and Intractable Diseases, Grant/Award (JPMH 20FC1030, JPMH 23FC1009) (IK).

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Author notes

  1. Akihiro Nakajima and Fumihiro Yanagimura contributed equally.

Authors and Affiliations

  1. Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi, Chuo-Ku, Niigata, 951-8585, Japan

    Akihiro Nakajima, Fumihiro Yanagimura, Etsuji Saji, Kaori Yanagawa, Musashi Arakawa, Mariko Hokari, Akiko Yokoseki, Takahiro Wakasugi, Masatoyo Nishizawa, Osamu Onodera & Izumi Kawachi

  2. Department of Neurology, NHO Niigata National Hospital, 3-52 Akasakamachi, Kashiwazaki, Niigata, 945-8585, Japan

    Fumihiro Yanagimura

  3. Department of Pathology, Brain Research Institute, Niigata University, 1-757 Asahimachi, Chuo-Ku, Niigata, 951-8585, Japan

    Hiroshi Shimizu, Yasuko Toyoshima, Hitoshi Takahashi & Akiyoshi Kakita

  4. Department of Neurology, Brain Disease Center, Agano Hospital, 6317-15 Yasuda, Agano, Niigata, 959-2221, Japan

    Yasuko Toyoshima

  5. Musashi Clinic, 20-1 Hakusanura 2, Chuo-Ku, Niigata, 951-8131, Japan

    Musashi Arakawa

  6. Department of Neurology, Niigata Medical Center, 27-11 Kobari 3, Nishi-Ku, Niigata, 950-2022, Japan

    Akiko Yokoseki

  7. Department of Neurology, NHO Nishiniigata Chuo Hospital, 14-1 Masago 1, Nishi-Ku, Niigata, 950-2085, Japan

    Takahiro Wakasugi

  8. Department of Neurosurgery, Brain Research Institute, Niigata University, 1-757 Asahimachi, Chuo-Ku, Niigata, 951-8585, Japan

    Kouichirou Okamoto

  9. Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi, Chuo-Ku, Niigata, 951-8510, Japan

    Hirohide Takebayashi

  10. Department of Neurology, Kansai Medical University Medical Center, 10-15 Fumizonocho, Moriguchi, Osaka, 570-8507, Japan

    Chihiro Fujii

  11. Department of Neurology, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, 465 Kajii-Cho, Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan

    Chihiro Fujii

  12. Department of Pathology and Applied Neurobiology, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, 465 Kajii-Cho, Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan

    Kyoko Itoh

  13. Department of Neurology, NHO Matsumoto Medical Center, 2-20-30 Muraimachi-Minami, Matsumoto, Nagano, 399-8701, Japan

    Yo-ichi Takei & Shinji Ohara

  14. Department of Neurology, Iida Hospital, 1-15 Odori, Iida, Nagano, 395-8505, Japan

    Shinji Ohara

  15. Department of Brain Disease Research, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan

    Mitsunori Yamada

  16. Department of Pathology and Laboratory Medicine, Niigata Neurosurgical Hospital, 3057 Yamada, Nishi-Ku, Niigata, 950-1101, Japan

    Hitoshi Takahashi

  17. Niigata University of Health and Welfare, 1398 Shimami-Cho, Kita-Ku, Niigata, 950-3198, Japan

    Masatoyo Nishizawa

  18. Center for Integrated Human Brain Science, Brain Research Institute, Niigata University, 1-757 Asahimachi, Chuo-Ku, Niigata, 951-8585, Japan

    Hironaka Igarashi

  19. Medical Education Center, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi, Chuo-Ku, Niigata, 951-8510, Japan

    Izumi Kawachi

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  1. Akihiro Nakajima
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  2. Fumihiro Yanagimura
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Contributions

Conception and design: ES, MN, IK; acquisition of data; AN, FY, ES, HS, YT, KY, MA, MH, AY, TW, KO, H. Takebayashi, CF, KI, YT, SO, MY, H. Takahashi, MN, HI, AK, OO, IK; statistical analysis; AN, FY, ES, IK; interpretation of data: AN, FY, ES, HS, YT, KY, MA, MH, AY, TW, KO, H. Takebayashi, MY, H. Takahashi, MN, HI, AK, OO, IK; critical review for important intellectual content: all authors; all authors have approved the final version of the manuscript.

Corresponding author

Correspondence to Izumi Kawachi.

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Conflict of interest

AN, FY, ES, HS, YT, KY, MA, MH, AY, TW, KO, H.Takebayashi, CF, KI, YT, SO, MY, H. Takahashi, MN, HI, AK, and OO have no competing interests to disclose. IK reports receiving funding for research, travel, and/or speaker’s honoraria from Chugai Pharmaceuticals, Novartis Pharma, Biogen, Alexion Pharmaceuticals, Mitsubishi Tanabe Pharma, Takeda Pharmaceutical Company, Teijin Pharma, Argenx, and Daiichi-Sankyo and is a scientific advisory board member for Mitsubishi Tanabe Pharma and Chugai Pharmaceuticals.

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Nakajima, A., Yanagimura, F., Saji, E. et al. Stage-dependent immunity orchestrates AQP4 antibody-guided NMOSD pathology: a role for netting neutrophils with resident memory T cells in situ. Acta Neuropathol 147, 76 (2024). https://doi.org/10.1007/s00401-024-02725-x

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