Anti-aquaporin-4 immune complex stimulates complement-dependent Th17 cytokine release in neuromyelitis optica spectrum disorders

Shuhei Nishiyama; Jin Myong Seok; Amy E. Wright; Itay Lotan; Takahisa Mikami; Natalia C. Drosu; Natasha Bobrowski-Khoury; Monique R. Anderson; Philippe A. Bilodeau; Patrick Schindler; Friedemann Paul; Masashi Aoki; Michael R. Yeaman; Michael Levy; Jacinta M. Behne; Megan K. Behne; Jeffrey L. Bennett; Terrence F. Blaschke; Tanuja Chitnis; Lawrence J. Cook; Michael Levy; Sarah M. Planchon; Pavle Repovic; Claire S. Riley; Terry J. Smith; Anthony Traboulsee; Michael R. Yeaman

doi:10.1038/s41598-024-53661-5

Anti-aquaporin-4 immune complex stimulates complement-dependent Th17 cytokine release in neuromyelitis optica spectrum disorders

Shuhei Nishiyama, Jin Myong Seok, Amy E. Wright, Itay Lotan, Takahisa Mikami, Natalia C. Drosu, Natasha Bobrowski-Khoury, Monique R. Anderson, Philippe A. Bilodeau, Patrick Schindler, Friedemann Paul, Masashi Aoki, Michael R. Yeaman, Michael Levy, Jacinta M. Behne, Megan K. Behne, Jeffrey L. Bennett, Terrence F. Blaschke, Tanuja Chitnis, Lawrence J. CookMichael Levy, Sarah M. Planchon, Pavle Repovic, Claire S. Riley, Terry J. Smith, Anthony Traboulsee, Michael R. Yeaman

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Abstract

Proinflammatory cytokines, such as (IL: interleukin) IL-6 and IL-17A, and complement fixation are critical in the immunopathogenesis of neuromyelitis optica spectrum disorders (NMOSD). Blocking the IL-6 receptor or the C5 complement pathway reduces relapse risk. However, the role of interleukin (IL)-6 and complement in aquaporin-4 (AQP4) autoimmunity remains unclear. To investigate the role of the anti-AQP4 immunoglobulin (AQP4-IgG)/AQP4 immunocomplex on the induction and profile of ex vivo cytokine and surface marker expression in peripheral blood mononuclear cells (PBMC) culture. Isolated PBMCs obtained from 18 patients with AQP4-IgG-seropositive-NMOSD (8 treatment-naive, 10 rituximab-treated) or ten healthy controls were cultured with AQP4-immunocomplex with or without complement. Changes in PBMC surface markers and cytokine expression were profiled using flow cytometry and ELISA. PBMCs derived from treatment-naive NMOSD patients stimulated with a complex mixture of serum complement proteins produced significant elevations of IL-17A and IL-6. Rituximab-treated patients also exhibited higher IL-6 but not IL-17A release. IL-6 and IL-17A elevations are not observed without complement. Co-stimulation of PBMCs with AQP4-IgG/AQP4 immunocomplex and complement prompts a Th17-biased response consistent with the inflammatory paradigm observed in NMOSD. A possible inflammation model is proposed via antigen-specific autoreactive peripheral blood cells, including NK/NKT cells.

Original language	English
Article number	3146
Journal	Scientific Reports
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41598-024-53661-5
State	Published - Dec 2024
Externally published	Yes

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Nishiyama, S., Seok, J. M., Wright, A. E., Lotan, I., Mikami, T., Drosu, N. C., Bobrowski-Khoury, N., Anderson, M. R., Bilodeau, P. A., Schindler, P., Paul, F., Aoki, M., Yeaman, M. R., Levy, M., Behne, J. M., Behne, M. K., Bennett, J. L., Blaschke, T. F., Chitnis, T., ... R. Yeaman, M. (2024). Anti-aquaporin-4 immune complex stimulates complement-dependent Th17 cytokine release in neuromyelitis optica spectrum disorders. Scientific Reports, 14(1), Article 3146. https://doi.org/10.1038/s41598-024-53661-5

@article{73dc7a334baa4654b9c166db16e7f4de,

title = "Anti-aquaporin-4 immune complex stimulates complement-dependent Th17 cytokine release in neuromyelitis optica spectrum disorders",

abstract = "Proinflammatory cytokines, such as (IL: interleukin) IL-6 and IL-17A, and complement fixation are critical in the immunopathogenesis of neuromyelitis optica spectrum disorders (NMOSD). Blocking the IL-6 receptor or the C5 complement pathway reduces relapse risk. However, the role of interleukin (IL)-6 and complement in aquaporin-4 (AQP4) autoimmunity remains unclear. To investigate the role of the anti-AQP4 immunoglobulin (AQP4-IgG)/AQP4 immunocomplex on the induction and profile of ex vivo cytokine and surface marker expression in peripheral blood mononuclear cells (PBMC) culture. Isolated PBMCs obtained from 18 patients with AQP4-IgG-seropositive-NMOSD (8 treatment-naive, 10 rituximab-treated) or ten healthy controls were cultured with AQP4-immunocomplex with or without complement. Changes in PBMC surface markers and cytokine expression were profiled using flow cytometry and ELISA. PBMCs derived from treatment-naive NMOSD patients stimulated with a complex mixture of serum complement proteins produced significant elevations of IL-17A and IL-6. Rituximab-treated patients also exhibited higher IL-6 but not IL-17A release. IL-6 and IL-17A elevations are not observed without complement. Co-stimulation of PBMCs with AQP4-IgG/AQP4 immunocomplex and complement prompts a Th17-biased response consistent with the inflammatory paradigm observed in NMOSD. A possible inflammation model is proposed via antigen-specific autoreactive peripheral blood cells, including NK/NKT cells.",

author = "Shuhei Nishiyama and Seok, {Jin Myong} and Wright, {Amy E.} and Itay Lotan and Takahisa Mikami and Drosu, {Natalia C.} and Natasha Bobrowski-Khoury and Anderson, {Monique R.} and Bilodeau, {Philippe A.} and Patrick Schindler and Friedemann Paul and Masashi Aoki and Yeaman, {Michael R.} and Michael Levy and Behne, {Jacinta M.} and Behne, {Megan K.} and Bennett, {Jeffrey L.} and Blaschke, {Terrence F.} and Tanuja Chitnis and Cook, {Lawrence J.} and Michael Levy and Planchon, {Sarah M.} and Pavle Repovic and Riley, {Claire S.} and Smith, {Terry J.} and Anthony Traboulsee and {R. Yeaman}, Michael",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1038/s41598-024-53661-5",

language = "English",

volume = "14",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

number = "1",

}

Nishiyama, S, Seok, JM, Wright, AE, Lotan, I, Mikami, T, Drosu, NC, Bobrowski-Khoury, N, Anderson, MR, Bilodeau, PA, Schindler, P, Paul, F, Aoki, M, Yeaman, MR, Levy, M, Behne, JM, Behne, MK, Bennett, JL, Blaschke, TF, Chitnis, T, Cook, LJ, Levy, M, Planchon, SM, Repovic, P, Riley, CS, Smith, TJ, Traboulsee, A & R. Yeaman, M 2024, 'Anti-aquaporin-4 immune complex stimulates complement-dependent Th17 cytokine release in neuromyelitis optica spectrum disorders', Scientific Reports, vol. 14, no. 1, 3146. https://doi.org/10.1038/s41598-024-53661-5

TY - JOUR

T1 - Anti-aquaporin-4 immune complex stimulates complement-dependent Th17 cytokine release in neuromyelitis optica spectrum disorders

AU - Nishiyama, Shuhei

AU - Seok, Jin Myong

AU - Wright, Amy E.

AU - Lotan, Itay

AU - Mikami, Takahisa

AU - Drosu, Natalia C.

AU - Bobrowski-Khoury, Natasha

AU - Anderson, Monique R.

AU - Bilodeau, Philippe A.

AU - Schindler, Patrick

AU - Paul, Friedemann

AU - Aoki, Masashi

AU - Yeaman, Michael R.

AU - Levy, Michael

AU - Behne, Jacinta M.

AU - Behne, Megan K.

AU - Bennett, Jeffrey L.

AU - Blaschke, Terrence F.

AU - Chitnis, Tanuja

AU - Cook, Lawrence J.

AU - Levy, Michael

AU - Planchon, Sarah M.

AU - Repovic, Pavle

AU - Riley, Claire S.

AU - Smith, Terry J.

AU - Traboulsee, Anthony

AU - R. Yeaman, Michael

PY - 2024/12

Y1 - 2024/12

N2 - Proinflammatory cytokines, such as (IL: interleukin) IL-6 and IL-17A, and complement fixation are critical in the immunopathogenesis of neuromyelitis optica spectrum disorders (NMOSD). Blocking the IL-6 receptor or the C5 complement pathway reduces relapse risk. However, the role of interleukin (IL)-6 and complement in aquaporin-4 (AQP4) autoimmunity remains unclear. To investigate the role of the anti-AQP4 immunoglobulin (AQP4-IgG)/AQP4 immunocomplex on the induction and profile of ex vivo cytokine and surface marker expression in peripheral blood mononuclear cells (PBMC) culture. Isolated PBMCs obtained from 18 patients with AQP4-IgG-seropositive-NMOSD (8 treatment-naive, 10 rituximab-treated) or ten healthy controls were cultured with AQP4-immunocomplex with or without complement. Changes in PBMC surface markers and cytokine expression were profiled using flow cytometry and ELISA. PBMCs derived from treatment-naive NMOSD patients stimulated with a complex mixture of serum complement proteins produced significant elevations of IL-17A and IL-6. Rituximab-treated patients also exhibited higher IL-6 but not IL-17A release. IL-6 and IL-17A elevations are not observed without complement. Co-stimulation of PBMCs with AQP4-IgG/AQP4 immunocomplex and complement prompts a Th17-biased response consistent with the inflammatory paradigm observed in NMOSD. A possible inflammation model is proposed via antigen-specific autoreactive peripheral blood cells, including NK/NKT cells.

AB - Proinflammatory cytokines, such as (IL: interleukin) IL-6 and IL-17A, and complement fixation are critical in the immunopathogenesis of neuromyelitis optica spectrum disorders (NMOSD). Blocking the IL-6 receptor or the C5 complement pathway reduces relapse risk. However, the role of interleukin (IL)-6 and complement in aquaporin-4 (AQP4) autoimmunity remains unclear. To investigate the role of the anti-AQP4 immunoglobulin (AQP4-IgG)/AQP4 immunocomplex on the induction and profile of ex vivo cytokine and surface marker expression in peripheral blood mononuclear cells (PBMC) culture. Isolated PBMCs obtained from 18 patients with AQP4-IgG-seropositive-NMOSD (8 treatment-naive, 10 rituximab-treated) or ten healthy controls were cultured with AQP4-immunocomplex with or without complement. Changes in PBMC surface markers and cytokine expression were profiled using flow cytometry and ELISA. PBMCs derived from treatment-naive NMOSD patients stimulated with a complex mixture of serum complement proteins produced significant elevations of IL-17A and IL-6. Rituximab-treated patients also exhibited higher IL-6 but not IL-17A release. IL-6 and IL-17A elevations are not observed without complement. Co-stimulation of PBMCs with AQP4-IgG/AQP4 immunocomplex and complement prompts a Th17-biased response consistent with the inflammatory paradigm observed in NMOSD. A possible inflammation model is proposed via antigen-specific autoreactive peripheral blood cells, including NK/NKT cells.

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U2 - 10.1038/s41598-024-53661-5

DO - 10.1038/s41598-024-53661-5

M3 - Article

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AN - SCOPUS:85184728765

SN - 2045-2322

VL - 14

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 3146

ER -

Anti-aquaporin-4 immune complex stimulates complement-dependent Th17 cytokine release in neuromyelitis optica spectrum disorders

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