title: Endothelial progenitor dysfunction associates with a type I interferon signature in primary antiphospholipid syndrome.
abstract: OBJECTIVE
  Patients with antiphospholipid syndrome (APS) are at risk for subclinical endothelial injury, as well as accelerated atherosclerosis. In the related disease systemic lupus erythematosus, there is a well-established defect in circulating endothelial progenitors, which leads to an accrual of endothelial damage over time. This defect has been at least partially attributed to exaggerated expression of type I interferons (IFNs). We sought to determine whether these pathways are important in APS.
  
  
  METHODS
  We studied 68 patients with primary APS. Endothelial progenitors were assessed by flow cytometry and functional assay. Type I IFN activity was determined by a well-accepted bioassay, while peripheral blood mononuclear cells were scored for expression of IFN-responsive genes.
  
  
  RESULTS
  Endothelial progenitors from patients with APS demonstrated a marked defect in the ability to differentiate into endothelial cells, a phenotype which could be mimicked by treating control progenitors with APS sera. Elevated type I IFN activity was detected in the circulation of patients with APS (a finding that was then replicated in an independent cohort). While IgG depletion from APS sera did not rescue endothelial progenitor function, the dysfunction was successfully reversed by a type I IFN receptor-neutralising antibody.
  
  
  CONCLUSIONS
  We describe, for the first time to our knowledge, an IFN signature in primary APS and show that this promotes impaired endothelial progenitor function. This work opens the door to novel approaches that may mitigate vascular damage in APS, such as anti-IFN drugs.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Grenn
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Srilakshmi
authors.initials: S
authors.lastname: Yalavarthi
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Alex A
authors.initials: AA
authors.lastname: Gandhi
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Nayef M
authors.initials: NM
authors.lastname: Kazzaz
authors.affiliation: Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
authors.forename: Carlos
authors.initials: C
authors.lastname: Núñez-Álvarez
authors.affiliation: Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
authors.forename: Diego
authors.initials: D
authors.lastname: Hernández-Ramírez
authors.affiliation: Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.|Division of Rheumatology, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Antonio R
authors.initials: AR
authors.lastname: Cabral
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: W Joseph
authors.initials: WJ
authors.lastname: McCune
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Paula L
authors.initials: PL
authors.lastname: Bockenstedt
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Knight
mesh_terms: D000328:Adult; D000368:Aged; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D016736:Antiphospholipid Syndrome / Q000276:immunology* / Q000503:physiopathology; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D066026:Endothelial Progenitor Cells / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007370:Interferon Type I / Q000276:immunology; D016898:Interferon-alpha / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D053633:Receptor, Interferon alpha-beta / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; C508033:IFNAR2 protein, human; D007370:Interferon Type I; D016898:Interferon-alpha; D053633:Receptor, Interferon alpha-beta
keywords: Antiphospholipid Syndrome; Atherosclerosis; Cytokines