Skip to main content
  • Submit
  • About
    • Editorial Board
    • PNAS Staff
    • FAQ
    • Accessibility Statement
    • Rights and Permissions
    • Site Map
  • Contact
  • Journal Club
  • Subscribe
    • Subscription Rates
    • Subscriptions FAQ
    • Open Access
    • Recommend PNAS to Your Librarian
  • Log in
  • My Cart

Main menu

  • Home
  • Articles
    • Current
    • Special Feature Articles - Most Recent
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • List of Issues
  • Front Matter
  • News
    • For the Press
    • This Week In PNAS
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Editorial and Journal Policies
    • Submission Procedures
    • Fees and Licenses
  • Submit
  • About
    • Editorial Board
    • PNAS Staff
    • FAQ
    • Accessibility Statement
    • Rights and Permissions
    • Site Map
  • Contact
  • Journal Club
  • Subscribe
    • Subscription Rates
    • Subscriptions FAQ
    • Open Access
    • Recommend PNAS to Your Librarian

User menu

  • Log in
  • My Cart

Search

  • Advanced search
Home
Home

Advanced Search

  • Home
  • Articles
    • Current
    • Special Feature Articles - Most Recent
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • List of Issues
  • Front Matter
  • News
    • For the Press
    • This Week In PNAS
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Editorial and Journal Policies
    • Submission Procedures
    • Fees and Licenses

New Research In

Physical Sciences

Featured Portals

  • Physics
  • Chemistry
  • Sustainability Science

Articles by Topic

  • Applied Mathematics
  • Applied Physical Sciences
  • Astronomy
  • Computer Sciences
  • Earth, Atmospheric, and Planetary Sciences
  • Engineering
  • Environmental Sciences
  • Mathematics
  • Statistics

Social Sciences

Featured Portals

  • Anthropology
  • Sustainability Science

Articles by Topic

  • Economic Sciences
  • Environmental Sciences
  • Political Sciences
  • Psychological and Cognitive Sciences
  • Social Sciences

Biological Sciences

Featured Portals

  • Sustainability Science

Articles by Topic

  • Agricultural Sciences
  • Anthropology
  • Applied Biological Sciences
  • Biochemistry
  • Biophysics and Computational Biology
  • Cell Biology
  • Developmental Biology
  • Ecology
  • Environmental Sciences
  • Evolution
  • Genetics
  • Immunology and Inflammation
  • Medical Sciences
  • Microbiology
  • Neuroscience
  • Pharmacology
  • Physiology
  • Plant Biology
  • Population Biology
  • Psychological and Cognitive Sciences
  • Sustainability Science
  • Systems Biology
Research Article

Transfer of complex regional pain syndrome to mice via human autoantibodies is mediated by interleukin-1–induced mechanisms

Zsuzsanna Helyes, Valéria Tékus, Nikolett Szentes, View ORCID ProfileKrisztina Pohóczky, Bálint Botz, Tamás Kiss, Ágnes Kemény, Zsuzsanna Környei, View ORCID ProfileKrisztina Tóth, View ORCID ProfileNikolett Lénárt, Hajnalka Ábrahám, Emmanuel Pinteaux, Sheila Francis, Serena Sensi, Ádám Dénes, and View ORCID ProfileAndreas Goebel
PNAS June 25, 2019 116 (26) 13067-13076; first published June 10, 2019; https://doi.org/10.1073/pnas.1820168116
Zsuzsanna Helyes
aDepartment of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624, Pécs, Hungary;
bJános Szentágothai Research Centre & Centre for Neuroscience, University of Pécs, H-7624, Pécs, Hungary;
cPharmInVivo Ltd., H-7629, Pécs, Hungary;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: zsuzsanna.helyes@aok.pte.hu denes.adam@koki.mta.hu andreasgoebel@rocketmail.com
Valéria Tékus
aDepartment of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624, Pécs, Hungary;
bJános Szentágothai Research Centre & Centre for Neuroscience, University of Pécs, H-7624, Pécs, Hungary;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nikolett Szentes
aDepartment of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624, Pécs, Hungary;
bJános Szentágothai Research Centre & Centre for Neuroscience, University of Pécs, H-7624, Pécs, Hungary;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Krisztina Pohóczky
aDepartment of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624, Pécs, Hungary;
bJános Szentágothai Research Centre & Centre for Neuroscience, University of Pécs, H-7624, Pécs, Hungary;
dFaculty of Pharmacy, Department of Pharmacology, University of Pécs, H-7624, Pécs, Hungary;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Krisztina Pohóczky
Bálint Botz
aDepartment of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624, Pécs, Hungary;
bJános Szentágothai Research Centre & Centre for Neuroscience, University of Pécs, H-7624, Pécs, Hungary;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tamás Kiss
aDepartment of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624, Pécs, Hungary;
bJános Szentágothai Research Centre & Centre for Neuroscience, University of Pécs, H-7624, Pécs, Hungary;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ágnes Kemény
aDepartment of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624, Pécs, Hungary;
bJános Szentágothai Research Centre & Centre for Neuroscience, University of Pécs, H-7624, Pécs, Hungary;
eDepartment of Biology and Electron Microscopy, Medical School, University of Pécs, H-7624, Pécs, Hungary;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Zsuzsanna Környei
fMomentum Laboratory of Neuroimmunology, Institute of Experimental Medicine, H-1083, Budapest, Hungary;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Krisztina Tóth
fMomentum Laboratory of Neuroimmunology, Institute of Experimental Medicine, H-1083, Budapest, Hungary;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Krisztina Tóth
Nikolett Lénárt
fMomentum Laboratory of Neuroimmunology, Institute of Experimental Medicine, H-1083, Budapest, Hungary;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Nikolett Lénárt
Hajnalka Ábrahám
eDepartment of Biology and Electron Microscopy, Medical School, University of Pécs, H-7624, Pécs, Hungary;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Emmanuel Pinteaux
gDivision of Neuroscience and Experimental Psychology, University of Manchester, Manchester M13 9PT, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sheila Francis
hDepartment of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2RX, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Serena Sensi
iDepartment of Translational Medicine, University of Liverpool, Liverpool L9 7AL, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ádám Dénes
fMomentum Laboratory of Neuroimmunology, Institute of Experimental Medicine, H-1083, Budapest, Hungary;
gDivision of Neuroscience and Experimental Psychology, University of Manchester, Manchester M13 9PT, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: zsuzsanna.helyes@aok.pte.hu denes.adam@koki.mta.hu andreasgoebel@rocketmail.com
Andreas Goebel
iDepartment of Translational Medicine, University of Liverpool, Liverpool L9 7AL, United Kingdom;
jDepartment of Pain Medicine, The Walton Centre National Health Service Foundation Trust, Liverpool L9 7LJ, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Andreas Goebel
  • For correspondence: zsuzsanna.helyes@aok.pte.hu denes.adam@koki.mta.hu andreasgoebel@rocketmail.com
  1. Edited by David Julius, University of California, San Francisco, CA, and approved May 13, 2019 (received for review December 1, 2018)

This article has a Correction. Please see:

  • Correction for Helyes et al., Transfer of complex regional pain syndrome to mice via human autoantibodies is mediated by interleukin-1–induced mechanisms - July 08, 2019
  • Article
  • Figures & SI
  • Info & Metrics
  • PDF
Loading

Significance

Complex regional pain syndrome (CRPS) is a poorly understood painful condition, which typically arises after distal limb trauma; 20% of patients may develop lifelong severe incessant pain with few therapeutic options. In this study, we show that immunoglobulin G autoantibodies from patients with severe, persistent CRPS, on transfer to hind paw-injured mice, elicit important features of the clinical condition and profound glial activation in pain-related brain regions. Blockade of the proinflammatory cytokine interleukin-1 (IL-1) both prevents and reverses these changes. Our findings suggest that antibody-mediated autoimmunity contributes to the development of severe CRPS after injury and that blockade of IL-1 actions may be an attractive therapeutic prospect. Investigation of autoantibody contribution to other unexplained chronic pain syndromes seems warranted.

Abstract

Neuroimmune interactions may contribute to severe pain and regional inflammatory and autonomic signs in complex regional pain syndrome (CRPS), a posttraumatic pain disorder. Here, we investigated peripheral and central immune mechanisms in a translational passive transfer trauma mouse model of CRPS. Small plantar skin–muscle incision was performed in female C57BL/6 mice treated daily with purified serum immunoglobulin G (IgG) from patients with longstanding CRPS or healthy volunteers followed by assessment of paw edema, hyperalgesia, inflammation, and central glial activation. CRPS IgG significantly increased and prolonged swelling and induced stable hyperalgesia of the incised paw compared with IgG from healthy controls. After a short-lasting paw inflammatory response in all groups, CRPS IgG-injected mice displayed sustained, profound microglia and astrocyte activation in the dorsal horn of the spinal cord and pain-related brain regions, indicating central sensitization. Genetic deletion of interleukin-1 (IL-1) using IL-1αβ knockout (KO) mice and perioperative IL-1 receptor type 1 (IL-1R1) blockade with the drug anakinra, but not treatment with the glucocorticoid prednisolone, prevented these changes. Anakinra treatment also reversed the established sensitization phenotype when initiated 8 days after incision. Furthermore, with the generation of an IL-1β floxed(fl/fl) mouse line, we demonstrated that CRPS IgG-induced changes are in part mediated by microglia-derived IL-1β, suggesting that both peripheral and central inflammatory mechanisms contribute to the transferred disease phenotype. These results indicate that persistent CRPS is often contributed to by autoantibodies and highlight a potential therapeutic use for clinically licensed antagonists, such as anakinra, to prevent or treat CRPS via blocking IL-1 actions.

  • CRPS
  • autoantibody
  • complex regional pain syndrome
  • interleukin-1
  • anakinra

Footnotes

  • ↵1Z.H., V.T., and N.S. contributed equally to this work.

  • ↵2To whom correspondence may be addressed. Email: zsuzsanna.helyes{at}aok.pte.hu, denes.adam{at}koki.mta.hu, or andreasgoebel{at}rocketmail.com.
  • ↵3Á.D. and A.G. contributed equally to this work.

  • Author contributions: Z.H., V.T., E.P., Á.D., and A.G. designed research; Z.H., V.T., N.S., K.P., B.B., T.K., Á.K., Z.K., K.T., N.L., H.Á., S.F., S.S., Á.D., and A.G. performed research; Z.K., K.T., N.L., E.P., S.F., and Á.D. contributed new reagents/analytic tools; Z.H., V.T., N.S., K.P., B.B., H.Á., E.P., Á.D., and A.G. analyzed data; and Z.H., N.S., K.P., E.P., S.F., Á.D., and A.G. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1820168116/-/DCSupplemental.

Published under the PNAS license.

View Full Text
PreviousNext
Back to top
Article Alerts
Email Article

Thank you for your interest in spreading the word on PNAS.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Transfer of complex regional pain syndrome to mice via human autoantibodies is mediated by interleukin-1–induced mechanisms
(Your Name) has sent you a message from PNAS
(Your Name) thought you would like to see the PNAS web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Transfer of complex regional pain syndrome to mice via human autoantibodies is mediated by interleukin-1–induced mechanisms
Zsuzsanna Helyes, Valéria Tékus, Nikolett Szentes, Krisztina Pohóczky, Bálint Botz, Tamás Kiss, Ágnes Kemény, Zsuzsanna Környei, Krisztina Tóth, Nikolett Lénárt, Hajnalka Ábrahám, Emmanuel Pinteaux, Sheila Francis, Serena Sensi, Ádám Dénes, Andreas Goebel
Proceedings of the National Academy of Sciences Jun 2019, 116 (26) 13067-13076; DOI: 10.1073/pnas.1820168116

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Transfer of complex regional pain syndrome to mice via human autoantibodies is mediated by interleukin-1–induced mechanisms
Zsuzsanna Helyes, Valéria Tékus, Nikolett Szentes, Krisztina Pohóczky, Bálint Botz, Tamás Kiss, Ágnes Kemény, Zsuzsanna Környei, Krisztina Tóth, Nikolett Lénárt, Hajnalka Ábrahám, Emmanuel Pinteaux, Sheila Francis, Serena Sensi, Ádám Dénes, Andreas Goebel
Proceedings of the National Academy of Sciences Jun 2019, 116 (26) 13067-13076; DOI: 10.1073/pnas.1820168116
Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Mendeley logo Mendeley
Proceedings of the National Academy of Sciences: 116 (26)
Table of Contents

Submit

Sign up for Article Alerts

Article Classifications

  • Biological Sciences
  • Neuroscience

Jump to section

  • Article
    • Abstract
    • Results
    • Discussion
    • Materials and Methods
    • Acknowledgments
    • Footnotes
    • References
  • Figures & SI
  • Info & Metrics
  • PDF

You May Also be Interested in

Surgeons hands during surgery
Inner Workings: Advances in infectious disease treatment promise to expand the pool of donor organs
Despite myriad challenges, clinicians see room for progress.
Image credit: Shutterstock/David Tadevosian.
Setting sun over a sun-baked dirt landscape
Core Concept: Popular integrated assessment climate policy models have key caveats
Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
Double helix
Journal Club: Noncoding DNA shown to underlie function, cause limb malformations
Using CRISPR, researchers showed that a region some used to label “junk DNA” has a major role in a rare genetic disorder.
Image credit: Nathan Devery.
Steamboat Geyser eruption.
Eruption of Steamboat Geyser
Mara Reed and Michael Manga explore why Yellowstone's Steamboat Geyser resumed erupting in 2018.
Listen
Past PodcastsSubscribe
Multi-color molecular model
Enzymatic breakdown of PET plastic
A study demonstrates how two enzymes—MHETase and PETase—work synergistically to depolymerize the plastic pollutant PET.
Image credit: Aaron McGeehan (artist).

Similar Articles

Site Logo
Powered by HighWire
  • Submit Manuscript
  • Twitter
  • Facebook
  • RSS Feeds
  • Email Alerts

Articles

  • Current Issue
  • Special Feature Articles – Most Recent
  • List of Issues

PNAS Portals

  • Anthropology
  • Chemistry
  • Classics
  • Front Matter
  • Physics
  • Sustainability Science
  • Teaching Resources

Information

  • Authors
  • Editorial Board
  • Reviewers
  • Librarians
  • Press
  • Site Map
  • PNAS Updates

Feedback    Privacy/Legal

Copyright © 2021 National Academy of Sciences. Online ISSN 1091-6490