期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 48, 期 5, 页码 874-884出版社
WILEY
DOI: 10.1002/eji.201747460
关键词
Antibodies; Autoimmunity; B cells; Clinical immunology; VDJ recombination
类别
资金
- NIH [R01HL138473-01, R01 HL122887-01A1, 2P01 HL014985-41A1, K12 RFA-HL-07-004:CDP, T32 AR050942]
- Vera Moulton Wall Center for Pulmonary Vascular Diseases
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL108797, K12HL120001, P01HL014985, K12HL089989, R01HL122887, R01HL138473] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [T32AI007290] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [T32AR050942] Funding Source: NIH RePORTER
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.
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