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Original research
Plasma collagen neoepitopes are associated with multiorgan disease in the ACCESS and GRADS sarcoidosis cohorts
  1. Jannie Marie Bülow Sand1,
  2. Henrik Jessen1,
  3. Diana Julie Leeming1,
  4. Sheeline Yu2,
  5. Chris J Lee2,
  6. Buqu Hu2,
  7. Ying Sun2,
  8. Taylor Adams3,
  9. Taylor Pivarnik4,
  10. Angela Liu2,
  11. Samuel Woo2,
  12. John R McGovern2,
  13. Vitória Fiorini2,
  14. Tina Saber2,
  15. Jean Paul Higuero-Sevilla2,
  16. Mridu Gulati2,
  17. Naftali Kaminski2,
  18. William Damsky2,
  19. Albert C Shaw5,
  20. Subhasis Mohanty5,
  21. Gillian Goobie6,7,
  22. Yingze Zhang8,
  23. Erica Lyndrup Herzog9,
  24. Changwan Ryu10
  1. 1Nordic Bioscience, Herlev, Denmark
  2. 2Yale School of Medicine, New Haven, Connecticut, USA
  3. 3Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
  4. 4Medicine, Yale University, New Haven, Connecticut, USA
  5. 5Infectious Disease, Yale School of Medicine, New Haven, Connecticut, USA
  6. 6University of Pittsburgh Medical Center Health System, Pittsburgh, Pennsylvania, USA
  7. 7The University of British Columbia, Vancouver, British Columbia, Canada
  8. 8Pulmonary, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  9. 9Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
  10. 10Medicine, Yale School of Medicine, New Haven, Connecticut, USA
  1. Correspondence to Dr Changwan Ryu, Medicine, Yale School of Medicine, New Haven, CT 06510, USA; changwan.ryu{at}yale.edu

Abstract

Introduction The pathogenesis of sarcoidosis involves tissue remodelling mediated by the accumulation of abnormal extracellular matrix, which is partly the result of an imbalance in collagen synthesis, cross-linking and degradation. During this process, collagen fragments or neoepitopes, are released into the circulation. The significance of these circulating collagen neoepitopes in sarcoidosis remains unknown.

Methods We employed plasma samples from patients with sarcoidosis enrolled in A Case Control Etiologic Study of Sarcoidosis (ACCESS) and Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS), and healthy control patients recruited from the Yale community. Plasma concentrations of type III and VI collagen degradation (C3M and C6M) and formation (PRO-C3 and PRO-C6) were quantified via neoepitope-specific competitive ELISA, and statistical associations were sought with clinical phenotypes.

Results Relative to healthy controls, the plasma of both sarcoidosis cohorts was enriched for C3M and C6M, irrespective of corticosteroid use and disease duration. While circulating collagen neoepitopes were independent of Scadding stage, there was a significant association between multiorgan disease and PRO-C3, PRO-C6 and C3M in the ACCESS cohort; PRO-C3 and C6M displayed this property in GRADS. These findings were unrelated to plasma levels of interleukin-4 (IL-4), IL-5, IL-6, IL-9, IL-10 and IL-13. Moreover, PRO-C3 was associated with dermatological disease in both cohorts.

Discussion In two well-characterised sarcoidosis cohorts, we discovered that the plasma is enriched for neoepitopes of collagen degradation (C3M and C6M). In multiorgan disease, there was an association with circulating neoepitopes of type III formation (PRO-C3), perhaps mediated by dermatological sarcoidosis. Further investigation in this arena has the potential to foster new insights into the pathogenic mechanisms of this complex disease.

  • sarcoidosis

Data availability statement

Data are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request.

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Footnotes

  • X @kaminskimed, @yingzezhang, @wonnie1981

  • Contributors JMBS, HJ and DJL performed the investigation, conducted the methodology and provided conceptualisation. SY, CJL, BH, YS, TA, TP, AL, SW, JRM, VF, TS, JPH-S, MG, NK, WD, ACS and SM performed the investigation. GG and YZ performed the investigation and provided conceptualisation. ELH and CR provided conceptualisation, resources, supervision, project administration and funding acquisition. All authors participated in manuscript preparation and provided final approval of the submitted work. Guarantor: CR.

  • Funding VF was supported by the Yale ILD Center of Excellence Translational Research Award (no award number). ELH was supported R01HL125850, R01HL152677, and grants from the Gabriel and Alma Elias Research Fund (no award number) and the Greenfield Foundation (no award number). NK was supported by R01HL127349, UG3TR002445, U01HL145567, U01HL122626 and U54HG008540. CR was supported by K08HL151970-01 and grants from the Foundation for Sarcoidosis Research (no award number) and the Chest Foundation (no award number).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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