Frontiers in Immunology (Jul 2022)

Soluble markers of B cell activation suggest a role of B cells in the pathogenesis of systemic sclerosis-associated pulmonary arterial hypertension

  • Sébastien Sanges,
  • Sébastien Sanges,
  • Sébastien Sanges,
  • Sébastien Sanges,
  • Sébastien Sanges,
  • Thomas Guerrier,
  • Thomas Guerrier,
  • Thomas Guerrier,
  • Alain Duhamel,
  • Lucile Guilbert,
  • Lucile Guilbert,
  • Lucile Guilbert,
  • Carine Hauspie,
  • Carine Hauspie,
  • Carine Hauspie,
  • Alexis Largy,
  • Alexis Largy,
  • Maïté Balden,
  • Maïté Balden,
  • Maïté Balden,
  • Céline Podevin,
  • Guillaume Lefèvre,
  • Guillaume Lefèvre,
  • Guillaume Lefèvre,
  • Manel Jendoubi,
  • Manel Jendoubi,
  • Silvia Speca,
  • Silvia Speca,
  • Éric Hachulla,
  • Éric Hachulla,
  • Éric Hachulla,
  • Éric Hachulla,
  • Éric Hachulla,
  • Vincent Sobanski,
  • Vincent Sobanski,
  • Vincent Sobanski,
  • Vincent Sobanski,
  • Vincent Sobanski,
  • Sylvain Dubucquoi,
  • Sylvain Dubucquoi,
  • Sylvain Dubucquoi,
  • David Launay,
  • David Launay,
  • David Launay,
  • David Launay,
  • David Launay

DOI
https://doi.org/10.3389/fimmu.2022.954007
Journal volume & issue
Vol. 13

Abstract

Read online

IntroductionSoluble markers of B cell activation are interesting diagnostic and prognostic tools in autoimmune diseases. Data in systemic sclerosis (SSc) are scarce and few studies focused on their association with disease characteristics.Methods1. Serum levels of 14 B cell biomarkers (β2-microglobulin, rheumatoid factor (RF), immunoglobulins (Ig) G, IgA, IgM, BAFF, APRIL, soluble (s)TACI, sBCMA sCD21, sCD23, sCD25, sCD27, CXCL13) were measured in SSc patients and healthy controls (HC). 2. Associations between these biomarkers and SSc characteristics were assessed. 3. The pathophysiological relevance of identified associations was explored by studying protein production in B cell culture supernatant.ResultsIn a discovery panel of 80 SSc patients encompassing the broad spectrum of disease manifestations, we observed a higher frequency of RF positivity, and increased levels of β2-microglobulin, IgG and CXCL13 compared with HC. We found significant associations between several biomarkers and SSc characteristics related to disease phenotype, activity and severity. Especially, serum IgG levels were associated with pulmonary hypertension (PH); β2-microglobulin with Nt-pro-BNP and DLCO; and BAFF with peak tricuspid regurgitation velocity (TRV). In a validation cohort of limited cutaneous SSc patients without extensive ILD, we observed lower serum IgG levels, and higher β2-microglobulin, sBCMA, sCD23 and sCD27 levels in patients with pulmonary arterial hypertension (PAH). BAFF levels strongly correlated with Nt-pro-BNP levels, FVC/DLCO ratio and peak TRV in SSc-PAH patients. Cultured SSc B cells showed increased production of various angiogenic factors (angiogenin, angiopoietin-1, VEGFR-1, PDGF-AA, MMP-8, TIMP-1, L-selectin) and decreased production of angiopoietin-2 compared to HC.ConclusionSoluble markers of B cell activation could be relevant tools to assess organ involvements, activity and severity in SSc. Their associations with PAH could plead for a role of B cell activation in the pathogenesis of pulmonary microangiopathy. B cells may contribute to SSc vasculopathy through production of angiogenic mediators.

Keywords