FRI0353 MISREGULATION OF BMP/TGFβ SHEDS LIGHT ON THE PATHOGENICITY OF HLA-B27 IN SPONDYLOARTHRITIS
Authors: Benjamin Grandon, Auroe Rincheval, Nadège Jah, Jean-Marc Corsi, Luiza M. Araujo, Simon Glatigny, Delphine Roche, Gilles Chiocchia, Isabelle Guénal, Sébastein Gaumer, Maxime Breban
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> The class I MHC allele, HLA-B27 is the main genetic factor predisposing to ankylosing spondylitis (AS) and related spondyloarthritis (SpA), a group of osteo-articular disorders combining inflammation with ossification. Until now, hypotheses to explain such striking association discovered 45 years have speculated either on the presentation of particular peptides to CD8<sup>+</sup> T cells or on aberrant behaviors of the HLA-B27 molecule independent of its antigen presenting function, including slow folding and homodimers formation <h3>Objectives</h3> To unravel aberrant function(s) of HLA-B27 independent of antigen presentation that may explain its pathogenicity. <h3>Methods</h3> <i>Drosophila</i> transgenic for SpA-associated HLA-B*27:04 or HLA-B*27:05 or non-SpA -associated HLA-B*07:02, alone or in combination with human β2-microglobulin (hβ2m) were produced. Genetic interaction tests were used to identify altered pathway(s). Protein-protein interactions were evidenced by proximity ligation assay. Phosphorylation of Smad2/3 was tested on CD4+ T cells from HLA-B27+ SpA patients and HLA-B27-neg healthy controls (6-10/group) by PhosFlow. <h3>Results</h3> <i>Drosophila</i> transgenic for HLA-B*27:04 or HLA-B*27:05 but not for control HLA-B*07:02 allele, in the presence of hβ2m that allows expression of well-folded HLA-B molecules at the cell surface, developed <i>crossveinless</i> phenotype. This was due to a disturbance of BMP signaling by HLA-B27/hβ2m which repressed Saxophone (Sax) BMP type I receptor (BMPR1) function, resulting in widening of phosphorylated Mad, the <i>Drosophila</i> receptor-mediated Smad, gradient, and increased expression of its target genes <i>dpp</i> and <i>omb</i>. Consistently, HLA-B27/hβ2m well-folded conformers co-localized with Sax at the surface of <i>Drosophila</i> cells and also with Sax mammal ortholog ALK2, on immune cells from SpA patients. As predicted, given that Sax orthologs ALK1 and ALK2 are known to exert antagonistic function on TGFβ/BMP signaling, we found heighthened p-Smad in response to TGFβ or Activin A in CD4+ T cells from HLA-B27+ SpA patients (p&lt;0.05). <h3>Conclusion</h3> The pathogenic role of HLA-B27 in SpA may result from a TGFβ/BMP signaling misregulation due to specific antagonistic interaction with ALK1/ALK2 BMPR1, at the crosstalk between inflammation and ossification. Interestingly, ALK2 mutations are responsible for the rare mendelian disorder, Fibrodysplasia Ossifians Prgogressiva that mimicks AS (Ref). <h3>References</h3> [1] Hatsell, S. J. et al. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin. Science Translational Medicine7, 303ra137-303ra137 (2015). <h3>Disclosure of Interests</h3> Benjamin Grandon: None declared, Auroe Rincheval: None declared, Nadège Jah: None declared, Jean-Marc Corsi: None declared, Luiza M. Araujo: None declared, Simon Glatigny: None declared, Delphine Roche: None declared, Gilles Chiocchia: None declared, Isabelle Guénal: None declared, Sébastein Gaumer: None declared, Maxime Breban Grant/research support from: Pfizer, UCB, Novartis, MSD, Consultant for: UCB