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

• Published in: European journal of immunology Vol. 48; no. 5; pp. 874 - 884
• Main Authors: Blum, Lisa K., Cao, Richard R.L., Sweatt, Andrew J., Bill, Matthew, Lahey, Lauren J., Hsi, Andrew C., Lee, Casey S., Kongpachith, Sarah, Ju, Chia‐Hsin, Mao, Rong, Wong, Heidi H., Nicolls, Mark R., Zamanian, Roham T., Robinson, William H.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.05.2018
• Subjects: Adhesion; Antibodies; Antibody Formation - immunology; Autoantibodies; Autoantibodies - immunology; Autoimmune diseases; Autoimmunity; Autoimmunity - immunology; B cells; Cell adhesion molecules; Clinical immunology; Cytokines; Cytokines - biosynthesis; Endothelial cells; Endothelial Cells - immunology; Familial Primary Pulmonary Hypertension - blood; Familial Primary Pulmonary Hypertension - immunology; Familial Primary Pulmonary Hypertension - pathology; Female; Human Umbilical Vein Endothelial Cells - immunology; Humans; Hypertension; Immunoglobulin A; Immunoglobulins; Inflammation; Intercellular Adhesion Molecule-1 - biosynthesis; Lung diseases; Lymphocyte Activation - immunology; Lymphocytes B; Male; Middle Aged; Molecular chains; Pathogenesis; Plasma Cells - cytology; Plasma Cells - immunology; Pulmonary hypertension; Therapeutic applications; Umbilical vein; Vascular diseases; VDJ recombination; Autoimmunity; Antibodies; Clinical immunology; B cells; VDJ recombination
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201747460

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. Idiopathic pulmonary arterial hypertension (IPAH) is a rare but deadly pulmonary vascular disease. We report that IgA‐producing blood plasmablasts are elevated in IPAH, and that antibodies derived from sequencing these plasmablasts stimulate endothelial cell production of inflammatory mediators. Our findings suggest that mucosally‐driven autoimmunity contributes to the pathogenesis of IPAH.