title: Interferon and alternative activation of monocyte/macrophages in systemic sclerosis-associated pulmonary arterial hypertension.
abstract: OBJECTIVE
  To explore the relationship between biomarkers of pulmonary arterial hypertension (PAH), interferon (IFN)-regulated gene expression, and the alternative activation pathway in systemic sclerosis (SSc).
  
  
  METHODS
  Peripheral blood mononuclear cells (PBMCs) were purified from healthy controls, patients with idiopathic PAH, and SSc patients (classified as having diffuse cutaneous SSc, limited cutaneous SSc [lcSSc] without PAH, and lcSSc with PAH). IFN-regulated and "PAH biomarker" genes were compared after supervised hierarchical clustering. Messenger RNA levels of selected IFN-regulated genes (Siglec1 and MX1), biomarker genes (IL13RA1, CCR1, and JAK2), and the alternative activation marker gene (MRC1) were analyzed on PBMCs and on CD14- and CD14+ cell populations. Interleukin-13 (IL-13) and IL-4 concentrations were measured in plasma by immunoassay. CD14, MRC1, and IL13RA1 surface expression was analyzed by flow cytometry.
  
  
  RESULTS
  Increased PBMC expression of both IFN-regulated and biomarker genes distinguished SSc patients from healthy controls. Expression of genes in the biomarker cluster, but not in the IFN-regulated cluster, distinguished lcSSc with PAH from lcSSc without PAH. The genes CCR1 (P<0.001) and JAK2 (P<0.001) were expressed more highly in lcSSc patients with PAH compared with controls and mainly by CD14+ cells. MRC1 expression was increased exclusively in lcSSc patients with PAH (P<0.001) and correlated strongly with pulmonary artery pressure (r=0.52, P=0.03) and higher mortality (P=0.02). MRC1 expression was higher in CD14+ cells and was greatly increased by stimulation with IL-13. IL-13 concentrations in plasma were most highly increased in lcSSc patients with PAH (P<0.001).
  
  
  CONCLUSIONS
  IFN-regulated and biomarker genes represent distinct, although related, clusters in lcSSc patients with PAH. MRC1, a marker for the effect of IL-13 on alternative monocyte/macrophage activation, is associated with this severe complication and is related to mortality.
authors.affiliation: Boston University School of Medicine, E501 Arthritis Center, Boston, Massachusetts 02118-2526, USA.
authors.forename: Romy B
authors.initials: RB
authors.lastname: Christmann
authors.forename: Everett
authors.initials: E
authors.lastname: Hayes
authors.forename: Sarah
authors.initials: S
authors.lastname: Pendergrass
authors.forename: Cristina
authors.initials: C
authors.lastname: Padilla
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Farina
authors.forename: Alsya J
authors.initials: AJ
authors.lastname: Affandi
authors.forename: Michael L
authors.initials: ML
authors.lastname: Whitfield
authors.forename: Harrison W
authors.initials: HW
authors.lastname: Farber
authors.forename: Robert
authors.initials: R
authors.lastname: Lafyatis
mesh_terms: D000328:Adult; D000368:Aged; D065627:Familial Primary Pulmonary Hypertension; D019204:GTP-Binding Proteins / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000276:immunology / Q000401:mortality; D007372:Interferons / Q000276:immunology*; D018793:Interleukin-13 / Q000097:blood; D053661:Interleukin-13 Receptor alpha1 Subunit / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000097:blood; D053614:Janus Kinase 2 / Q000235:genetics / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D008875:Middle Aged; D064547:Myxovirus Resistance Proteins; D054389:Receptors, CCR1 / Q000235:genetics / Q000276:immunology; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology; D012595:Scleroderma, Systemic / Q000150:complications / Q000276:immunology*; D063267:Sialic Acid Binding Ig-like Lectin 1
chemical_list: C515300:CCR1 protein, human; C508181:IL13RA1 protein, human; C508598:IL4 protein, human; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D064547:Myxovirus Resistance Proteins; D054389:Receptors, CCR1; D011971:Receptors, Immunologic; C571166:SIGLEC1 protein, human; D063267:Sialic Acid Binding Ig-like Lectin 1; D015847:Interleukin-4; D007372:Interferons; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D019204:GTP-Binding Proteins