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Eur J Immunol. 2018 May;48(5):874-884. doi: 10.1002/eji.201747460. Epub 2018 Feb 22.

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

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Stanford University School of Medicine, Division of Immunology and Rheumatology, Stanford, CA, USA.
VA Palo Alto Health Care System, Palo Alto, CA, USA.
Stanford University Medical Center, Division of Pulmonary and Critical Care Medicine, Stanford, CA, USA.


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.


Antibodies; Autoimmunity; B cells; Clinical immunology; VDJ recombination

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