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

Abstract

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.

Identification of lncRNA–miRNA–mRNA networks in circulating exosomes as potential biomarkers for systemic sclerosis

“…Activated B cells in SSc promote endothelial cells and fibroblasts to secrete proinflammatory and fibrogenic factors, leading to vascular injury and fibrosis ( 53 ). Serum IgM is a soluble marker of B cell activation and one of the diagnostic markers of SSc ( 53 ).…”

“…Activated B cells in SSc promote endothelial cells and fibroblasts to secrete proinflammatory and fibrogenic factors, leading to vascular injury and fibrosis ( 53 ). Serum IgM is a soluble marker of B cell activation and one of the diagnostic markers of SSc ( 53 ). In this study, we found that ENST00000313807 and hsa-miR-29b-3p in the plasma cirexos of patients with SSc were positively correlated with IgM.…”

B-cells in pulmonary arterial hypertension: friend, foe or bystander?

“…The role of the BAFF system in B-cell activation in the context of PAH has yet to be thoroughly investigated. Serum BAFF concentrations have been assessed in several SSc cohorts: while BAFF levels are similar in patients with and without pulmonary hypertension, they strongly correlate with clinical markers of pulmonary hypertension severity in SSc-PAH patients [ 42 – 45 ]. A pathogenic variant in the gene coding for TACI has been identified as a new causative mutation for PAH, possibly by promoting dysregulated vascular inflammation [ 46 ].…”

“…Although not measured in this cohort, previous studies reported elevated IgE levels in iPAH patients, due to skewed isotype switching induced by Th2 cytokines [ 25 , 26 ]. Few data are available regarding patients with CTD-PAH, with conflicting reports of elevated IgA [ 64 ] and decreased IgG [ 45 ] levels in SSc-PAH (compared to SSc without pulmonary hypertension).…”

Serum Biomarkers in Connective Tissue Disease-Associated Pulmonary Arterial Hypertension

“…Increased levels of the acute phase response protein pentraxin-3 (PTX3) were found in patients with PAH, especially CTD-PAH, vs. those of healthy controls and CTD patients without PAH, without any correlation with BNP or CRP levels, identifying PTX3 as an early marker of PAH, especially in CTDs [ 148 ]. Recently, soluble markers of B cell activation were found to be elevated in the serum of SSc patients; in particular, a correlation was shown between serum levels of B-cell activating factor (BAFF), NT-proBNP levels and forced vital capacity (FVC)/DLCO ratio in lcSSc-PAH patients, although, overall, serum BAFF levels were not significantly higher in SSc patients with PAH vs. those without PAH [ 149 ].…”