@article{c2b0949a00ad4e48ab8fda0cedc20d02,
title = "Autoimmunity Is a Significant Feature of Idiopathic Pulmonary Arterial Hypertension",
abstract = "Rationale: Autoimmunity is believed to play a role in idiopathic pulmonary arterial hypertension (IPAH). It is not clear whether this is causative or a bystander of disease and if it carries any prognostic or treatment significance. Objectives: To study autoimmunity in IPAH using a large cross-sectional cohort. Methods: Assessment of the circulating immune cell phenotype was undertaken using flow cytometry, and the profile of serum immunoglobulins was generated using a standardized multiplex array of 19 clinically validated autoantibodies in 473 cases and 946 control subjects. Additional glutathione S-transferase fusion array and ELISA data were used to identify a serum autoantibody to BMPR2 (bone morphogenetic protein receptor type 2). Clustering analyses and clinical correlations were used to determine associations between immunogenicity and clinical outcomes. Measurements and Main Results: Flow cytometric immune profiling demonstrates that IPAH is associated with an altered humoral immune response in addition to raised IgG3. Multiplexed autoantibodies were significantly raised in IPAH, and clustering demonstrated three distinct clusters: “high autoantibody,” “low autoantibody,” and a small “intermediate” cluster exhibiting high concentrations of ribonucleic protein complex. The high-autoantibody cluster had worse hemodynamics but improved survival. A small subset of patients demonstrated immunoglobulin reactivity to BMPR2. Conclusions: This study establishes aberrant immune regulation and presence of autoantibodies as key features in the profile of a significant proportion of patients with IPAH and is associated with clinical outcomes.",
keywords = "autoantibodies, autoimmune, BMPR2, IPAH, pulmonary arterial hypertension",
author = "{the UK National Cohort Study of Idiopathic and Heritable PAH Consortium} and Jones, {Rowena J.} and {De Bie}, {Eckart M.D.D.} and Emily Groves and Zalewska, {Kasia I.} and Swietlik, {Emilia M.} and Treacy, {Carmen M.} and Martin, {Jennifer M.} and Gary Polwarth and Wei Li and Jingxu Guo and Baxendale, {Helen E.} and Stephen Coleman and Natalia Savinykh and Coghlan, {J. Gerry} and Corris, {Paul A.} and Howard, {Luke S.} and Johnson, {Martin K.} and Colin Church and Kiely, {David G.} and Allan Lawrie and Lordan, {James L.} and {Mackenzie Ross}, {Robert V.} and Zaba, {Joanna Pepke} and Wilkins, {Martin R.} and Wort, {S. John} and Edoardo Fiorillo and Valeria Orr{\'u} and Francesco Cucca and Rhodes, {Christopher J.} and Stefan Gr{\"a}f and Morrell, {Nicholas W.} and McKinney, {Eoin F.} and Chris Wallace and Mark Toshner and Marta Bleda and Charaka Hadinnapola and Matthias Haimel and Kate Auckland and Tobias Tilly and Martin, {Jennifer M.} and Katherine Yates and Treacy, {Carmen M.} and Margaret Day and Alan Greenhalgh and Debbie Shipley and Golden Jubilee and Val Irvine and Fiona Kennedy and Shahin Moledina and Richard Trembath",
note = "Funding Information: Supported by the National Institute for Health Research (NIHR) Biomedical Research Centre Cambridge, Medical Research Council (MC_UU_00002/4), and Wellcome Trust (WT107881) (salary costs). The Dinosaur Trust provided funding for a Ph.D. studentship. The UK National Cohort Study of Idiopathic and Heritable PAH is supported by the NIHR, the British Heart Foundation (BHF; SP/12/12/29836), the BHF Imperial Centre of Cardiovascular Research Excellence (RE/18/4/34215), the BHF Cambridge Centre of Cardiovascular Research Excellence, the UK Medical Research Council (MR/K020919/1), the Dinosaur Trust, the NIHR Great Ormond Street Hospital Biomedical Research Centre, and Great Ormond Street Hospital Charity. A.L. is supported by a BHF Senior Basic Science Research Fellowship (FS/18/52/33808). All funders were restricted to financial support. Funding Information: Acknowledgment: The authors thank all the patients and control volunteers who donated to this research. They also thank the UK National Cohort Study of Idiopathic and Heritable PAH and the research nurses and coordinators at the specialist pulmonary hypertension centers involved in this study. The authors acknowledge the National Institute for Health Research BioResource and National Institute for Health Research Cardiorespiratory Biomedical Research Centre, which supported this work. Publisher Copyright: Copyright {\textcopyright} 2022 by the American Thoracic Society",
year = "2022",
month = jul,
day = "1",
doi = "10.1164/rccm.202108-1919OC",
language = "English",
volume = "206",
pages = "81--93",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "1",
}
