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November 2021; 8 (6) ArticleOpen Access

T-Cell Specificity Influences Disease Heterogeneity in Multiple Sclerosis

Carolina Cruciani, Marco Puthenparampil, Paula Tomas-Ojer, Ivan Jelcic, Maria Jose Docampo, Raquel Planas, Praveena Manogaran, Roland Opfer, Carla Wicki, Markus Reindl, Ilijas Jelcic, Andreas Lutterotti, Roland Martin, Mireia Sospedra
First published September 17, 2021, DOI: https://doi.org/10.1212/NXI.0000000000001075
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Article Information

vol. 8 no. 6 e1075
DOI: 
https://doi.org/10.1212/NXI.0000000000001075
PubMed: 
34535569
Published By: 
Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology
Online ISSN: 
2332-7812
History: 
  • Received April 26, 2021
  • Accepted in final form July 15, 2021
  • First Published September 17, 2021.
Copyright & Usage: 
Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Author Disclosures

    1. Carolina Cruciani, PhD* (carolina.cruciani{at}gmail.com),
    2. Marco Puthenparampil, MD, PhD* (marco.puthenparampil{at}unipd.it),
    3. Paula Tomas-Ojer (paulatomasojer{at}gmail.com),
    4. Ivan Jelcic, PhD (ivan.jelcic.private{at}gmail.com),
    5. Maria Jose Docampo, PhD (maria.docampo{at}usz.ch),
    6. Raquel Planas, PhD (raquel.planasbas{at}gmail.com),
    7. Praveena Manogaran, PhD (praveena.manogaran{at}roche.com),
    8. Roland Opfer (roland.opfer{at}jung-diagnostics.de),
    9. Carla Wicki, PhD (wickic{at}student.ethz.ch),
    10. Markus Reindl, PhD (markus.reindl{at}i-med.ac.at),
    11. Ilijas Jelcic, MD, PhD (ilijas.jelcic{at}usz.ch),
    12. Andreas Lutterotti, MD (andreas.lutterotti{at}usz.ch),
    13. Roland Martin, MD, PhD (roland.martin{at}usz.ch) and
    14. Mireia Sospedra, PhD
  1. Carolina Cruciani, PhD* (carolina.cruciani{at}gmail.com),
    2. Scientific Advisory Boards:

    1. None

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. None

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. None

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  2. Marco Puthenparampil, MD, PhD* (marco.puthenparampil{at}unipd.it),
    3. Scientific Advisory Boards:

    1. Puthenparampil Marco has been consultant for Genzyme, and Novartis.

    Gifts:

    1. Puthenparampil Marco has been consultant for Novartis.

    Funding for Travel or Speaker Honoraria:

    1. Puthenparampil Marco received travel grant from Novartis, Genzyme, Biogen Idec, Teva, Almirall and Sanofi Aventis.

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. None

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  3. Paula Tomas-Ojer (paulatomasojer{at}gmail.com),
    4. Scientific Advisory Boards:

    1. None

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. None

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. 1. MSD Merck Sharp & Dohme, Clinical Research Associate, 1 year

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. None

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  4. Ivan Jelcic, PhD (ivan.jelcic.private{at}gmail.com),
    5. Scientific Advisory Boards:

    1. None

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. None

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. (1) Ivan Jelcic is currently employee of Hoffmann-La Roche Ltd, Senior Scientist, since June 2020. However, the employment at Roche is not related to the submitted manuscript/data and contribution is only based on work previously performed as a group member at the University Hospital Zurich.

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. None

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  5. Maria Jose Docampo, PhD (maria.docampo{at}usz.ch),
    6. Scientific Advisory Boards:

    1. None

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. None

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. None

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  6. Raquel Planas, PhD (raquel.planasbas{at}gmail.com),
    7. Scientific Advisory Boards:

    1. None

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. None

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. None

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  7. Praveena Manogaran, PhD (praveena.manogaran{at}roche.com),
    8. Scientific Advisory Boards:

    1. NONE

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. I am currently employed by F. Hoffmann-La Roche AG. No part of my contribution to this paper was completed while employed at F. Hoffmann-La Roche AG.

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  8. Roland Opfer (roland.opfer{at}jung-diagnostics.de),
    9. Scientific Advisory Boards:

    1. None

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. None

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. jung diagnostics GmbH, Hamburg, GermanyResearch director since 2013

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. None

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  9. Carla Wicki, PhD (wickic{at}student.ethz.ch),
    10. Scientific Advisory Boards:

    1. None

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. (1) Teva, funding for travel to ECTRIMS congress 2017(2) Merck Sereno, funding for travel to ECTRIMS congress 2018

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. None

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  10. Markus Reindl, PhD (markus.reindl{at}i-med.ac.at),
    11. Scientific Advisory Boards:

    1. NONE

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. PLOS ONE, academic editor, 2012,

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other activities:

    1. The University Hospital and Medical University of Innsbruck (Austria, Markus Reindl) receive payments for antibody assays (NMDAR, AQP4 and other autoantibodies) and for MOG and AQP4 antibody validation experiments organized by Euroimmun (Luebeck, Germany).

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. Euroimmun AG, Germany; Roche, Switzerland

    Research Support, Government Entities:

    1. (1) Austrian Science Funds (FWF), project P32699, PI, 2019-2022 (2) Austrian Research promotion Agency (FFG), Bridge 1 project Nr. 853209, PI, 2016-2018 (3) Austrian Science Funds (FWF), project W1206, PI, 2007-2018

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  11. Ilijas Jelcic, MD, PhD (ilijas.jelcic{at}usz.ch),
    12. Scientific Advisory Boards:

    1. (1) Neuway (2) Merck (3) Novartis (4) Celgene (5) Bristol Myers Squibb (6) Sanofi-Aventis

    Gifts:

    1. NONE

    Funding for travel or speaker honoraria:

    1. Novartis, speaker honoraria Sanofi-Aventis, speaker honoraria

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  12. Andreas Lutterotti, MD (andreas.lutterotti{at}usz.ch),
    13. Scientific Advisory Boards:

    1. Almirall, Bayer, Biogen, Merck, Novartis, SanofiGenzyme, Roche, Celgene

    Gifts:

    1. NONE

    Funding for travel or speaker honoraria:

    1. Travel support from European Charcot Foundation, Fundacio GAEM Biogen, Merck, Novartis, SanofiGenzyme, BMS/Celgene, Roche

    Editorial Boards:

    1. NONE

    Patents:

    1. Listed as an author on a University of Zurich patent on

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other activities:

    1. Co-founder and shareholder of Cellerys, a Spin-off company of the University of Zurich pursuing antigen-specific immune tolerance in MS.

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. Wyss Zurich, Swiss MS Society

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  13. Roland Martin, MD, PhD (roland.martin{at}usz.ch) and
    14. Scientific Advisory Boards:

    1. RM received unrestricted grants from Biogen, Novartis, Roche and Third Rock Ventures, personal compensation for lecture or advisory board functions from Biogen, Merck, Novartis, Roche, Sanofi Aventis, Teva, Cell-Protect, Neuway and Third Rock Ventures.

    Gifts:

    1. NONE

    Funding for travel or speaker honoraria:

    1. I have received personal compensation/honoraria for speaking at workshops or small meetings by Biogen and Merck & Serono, Novartis, Roche, Genzyme, Teva, Sanofi-Aventis.

    Editorial Boards:

    1. NONE

    Patents:

    1. Together with B. Bielekova, H. McFarland and T. Waldmann I am a coholder of a patent claiming the therapeutic efficacy of anti-CD25 monoclonal antibody treatment in combination with IFN-b in MS. This patent is owned by NIH, but the patent holders receive periodic royalties. I have received royalties in the last five years. I am also inventor or co-inventor on University Zurich-held patents in the context of antigen-specific tolerization with peptide-coupled cells and for vaccination methods against progressive multifocal leukoencephalopathy.

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. I have been consulting for the Myelin Repair Foundation, The Weatherall Institute for Molecular Studies, University of Oxford, the German Research Society, the Swiss National Science Foundation, and the Hertie Foundation. These are all non-profit academic or private institutions, foundations. I am a member of the Kuratorium of the Jung Foundation for Science, Hamburg, Germany, also a non-profit organization; the Swiss Multiple Sclerosis Society, also non-profit, and several other national MS societies, in each case non-profit.

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. Novartis has given us financial support (unrestricted grant) to examine the effects of fingolimod on immune responses against herpes viruses. Biogen has given us financial support (unrestricted grant) to study the effects of natalizumab on the intrathecal antibody response in MS. We have also received unrestricted support for the department of neuroimmunology and MS research from Roche and Third Rock Ventures.

    Research Support, Government Entities:

    1. Swiss National Science Foundation (throughout last 8 years). European Union Seventh Framework Program. European Research Council Advanced Grant. Clinical Research Priority Program Multiple Sclerosis of the University Zurich for the last 6 years.

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. I hold stock of Cellerys, a company aiming at antigen-specific tolerization, and of Abata Therapeutics, a company developing adoptive Treg therapy. If have not received any returns from the stock of these two entities.

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. I had received royalty payments (periodically) from a NIH- Held patent on the use of anti-CD25 (daclizumab) in multiple sclerosis.

    Stock/Stock Options, Research Sponsor:

    1. I am Co-Founder and Co-Owner of Cellerys (founded 2015), a startup company out of Univ. Zurich, which is pursuing antigen-specific tolerization. I am a Co-Founder of Abata Therapeutics, Cambridge, MA (founded 2021).

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  14. Mireia Sospedra, PhD
    15. Scientific Advisory Boards:

    1. None

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. None

    Editorial Boards:

    1. Invited editor of the special issue `Understanding andElucidation of the Specificity of αβ-T cells`in Frontiersin Immunology

    Patents:

    1. Sospedra, M., Martin, R., Planas, R., Jelcic, I., Santos,R., Pinilla, C. IMMUNODOMINANT PROTEINS AND FRAGMENTS INAUTOIMMUNE DISEASES. EP18180326.3 (2018).Jelcic, I., Martin, R., Schippling, S., Sospedra, M.,Yousef, S. POLYOMA VIRUS JC PEPTIDES AND PROTEINS INVACCINATION AND DIAGNOSTIC APPLICATIONS WO Patent2,013,014,134 (2013)

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. None

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  1. From the Neuroimmunology and MS Research (NIMS) (C.C., M.P., P.T.O., I.J., M.J.D., R.P., P.M., C.W., I.J., A.L., R.M., M.S.), Department of Neurology, University Hospital and University Zurich, Switzerland; Department of Neuroscience DNS (M.P.), University-Hospital of Padova, Italy; Jung Diagnostics GmbH (R.O.), HIP - Health Innovation Port, Germany; Department of Health Sciences and Technology (C.W.), ETH Zurich, Switzerland; and Clinical Department of Neurology (M.R.), Medical University of Innsbruck, Austria.
  1. Correspondence
    Dr. Sospedra mireia.sospedraramos{at}usz.ch

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