Circulating plasmablasts are elevated and produce pathogenic anti‐endothelial cell autoantibodies in idiopathic pulmonary arterial hypertension

Abstract

Idiopathic pulmonary arterial hypertension (IPAH) is a devastating pulmonary vascular disease in which autoimmune and inflammatory phenomena are implicated. B cells and autoantibodies have been associated with IPAH and identified as potential therapeutic targets. However, the specific populations of B cells involved and their roles in disease pathogenesis are not clearly defined. We aimed to assess the levels of activated B cells (plasmablasts) in IPAH, and to characterize recombinant antibodies derived from these plasmablasts. Blood plasmablasts are elevated in IPAH, remain elevated over time, and produce IgA autoantibodies. Single-cell sequencing of plasmablasts in IPAH revealed repertoires of affinity-matured antibodies with small clonal expansions, consistent with an ongoing autoimmune response. Recombinant antibodies representative of these clonal lineages bound known autoantigen targets and displayed an unexpectedly high degree of polyreactivity. Representative IPAH plasmablast recombinant antibodies stimulated human umbilical vein endothelial cells to produce cytokines and overexpress the adhesion molecule ICAM-1. Together, our results demonstrate an ongoing adaptive autoimmune response involving IgA plasmablasts that produce anti-endothelial cell autoantibodies in IPAH. These antibodies stimulate endothelial cell production of cytokines and adhesion molecules, which may contribute to disease pathogenesis. These findings suggest a role for mucosally-driven autoimmunity and autoimmune injury in the pathogenesis of IPAH.

Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

“…Next to the presence of TLOs in the lung, there is additional evidence supporting the notion that B-cell activation is dysregulated in IPAH and in connective tissue disease associated PAH (CTD-PAH) [84,85]. First, circulating plasma blasts are increased in IPAH patients [86]. Second, autoantibodies are present in approximately 40% of patients with IPAH [87].…”

“…Second, autoantibodies are present in approximately 40% of patients with IPAH [87]. These autoantibodies might be produced by the plasma cells located within TLOs in IPAH lungs [18,86], recognizing endothelial cell surface antigens [88]. Anti-endothelial autoantibodies promote apoptosis of endothelium, which contributes to vascular remodeling [86].…”

“…These autoantibodies might be produced by the plasma cells located within TLOs in IPAH lungs [18,86], recognizing endothelial cell surface antigens [88]. Anti-endothelial autoantibodies promote apoptosis of endothelium, which contributes to vascular remodeling [86]. Furthermore, endothelial-specific IgA can promote cytokine production and the upregulation of adhesion molecules by endothelial cells [86,[88][89][90].…”

“…Anti-endothelial autoantibodies promote apoptosis of endothelium, which contributes to vascular remodeling [86]. Furthermore, endothelial-specific IgA can promote cytokine production and the upregulation of adhesion molecules by endothelial cells [86,[88][89][90]. Anti-endothelial IgG antibodies activate endothelial cells to a pro-adhesive and pro-inflammatory state [91].…”

Robust B Cell Responses Predict Rapid Resolution of Lyme Disease

“…After single-cell sorting, plasmablast cDNA was labeled with oligonucleotide barcode sequences, and paired antibody heavy- and light-chain variable regions were sequenced as previously described ( 20 – 23 ). Well-specific barcode sequences (TruGrade DNA oligos; IDT; Coralville, IA, USA) were added to the cDNA of each cell by template switching (Maxima Reverse Transcriptase, Thermo Fisher Scientific).…”