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HLA-B27 alters BMP/TGFβ signalling in Drosophila, revealing putative pathogenic mechanism for spondyloarthritis
  1. Benjamin Grandon1,2,
  2. Aurore Rincheval-Arnold1,
  3. Nadège Jah2,
  4. Jean-Marc Corsi1,
  5. Luiza M Araujo2,
  6. Simon Glatigny2,
  7. Erwann Prevost1,2,
  8. Delphine Roche1,
  9. Gilles Chiocchia2,
  10. Isabelle Guénal1,
  11. Sébastien Gaumer1,
  12. Maxime Breban2,3
  1. 1 LGBC, EA4589, UVSQ/Université Paris-Saclay, EPHE/PSL Research University, Montigny-le-Bretonneux, France
  2. 2 Infection & Inflammation, UMR 1173, Inserm, UVSQ/ Université Paris Saclay, Montigny-le-Bretonneux, France
  3. 3 Rheumatology, Ambroise Paré Hospital, Boulogne Billancourt, France
  1. Correspondence to Professor Maxime Breban, Rheumatology, Ambroise Paré Hospital, Boulogne Billancourt, France; maxime.breban{at}aphp.fr

Abstract

Objectives The human leucocyte antigen (HLA)-B27 confers an increased risk of spondyloarthritis (SpA) by unknown mechanism. The objective of this work was to uncover HLA-B27 non-canonical properties that could explain its pathogenicity, using a new Drosophila model.

Methods We produced transgenic Drosophila expressing the SpA-associated HLA-B*27:04 or HLA-B*27:05 subtypes, or the non-associated HLA-B*07:02 allele, alone or in combination with human β2-microglobulin (hβ2m), under tissue-specific drivers. Consequences of transgenes expression in Drosophila were examined and affected pathways were investigated by the genetic interaction experiments. Predictions of the model were further tested in immune cells from patients with SpA.

Results Loss of crossveins in the wings and a reduced eye phenotype were observed after expression of HLA-B*27:04 or HLA-B*27:05 in Drosophila but not in fruit flies expressing the non-associated HLA-B*07:02 allele. These HLA-B27-induced phenotypes required the presence of hβ2m that allowed expression of well-folded HLA-B conformers at the cell surface. Loss of crossveins resulted from a dominant negative effect of HLA-B27 on the type I bone morphogenetic protein (BMP) receptor saxophone (Sax) with which it interacted, resulting in elevated mothers against decapentaplegic (Mad, a Drosophila receptor-mediated Smad) phosphorylation. Likewise, in immune cells from patients with SpA, HLA-B27 specifically interacted with activin receptor-like kinase-2 (ALK2), the mammalian Sax ortholog, at the cell surface and elevated Smad phosphorylation was observed in response to activin A and transforming growth factor β (TGFβ).

Conclusions Antagonistic interaction of HLA-B27 with ALK2, which exerts inhibitory functions on the TGFβ/BMP signalling pathway at the cross-road between inflammation and ossification, could adequately explain SpA development.

  • ankylosing spondylitis
  • spondyloarthritis
  • HLA-B27
  • TGFβ
  • BMP
  • ALK2
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Footnotes

  • IG, SG and MB are joint senior authors.

  • Handling editor Josef S Smolen

  • Presented at This work has been presented at the 2019 EULAR Congress (Abstract FRI0353; Madrid, Spain, June 2019).

  • Correction notice This article has been corrected since it published Online First. The senior authorship statement has been added and the sixth author's name has been corrected as well as affiliations one and two.

  • Contributors BG, AR-A and NJ designed and performed all Drosophila experiments and analysed the data. J-MC, EP and DR performed PLA and Western blot on human cells. LMA and SG designed and performed human cells experiments. BG, AR-A, IG, SG and MB wrote the manuscript with input from all the coauthors. GC, IG, SG and MB supervised the research and contributed to experimental design.

  • Funding This work was supported by a grant from Société Française de Rhumatologie (SFR). NJ was in part supported by grant ING20130526783 from the French 'Fondation pour la Recherche Médicale' (FRM). We thank the genomics and CYMAGES imaging facilities of the Simone Veil faculty (University of Versailles Saint-Quentin and Paris-Saclay) for its logistic and technical support.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval This study was approved by the institutional ethical committee of Ile-de-France XI (Saint-Germain-en-Laye France).

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

  • Data availability statement All data relevant to the study are included in the article or uploaded as online supplementary information.

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