title: Patients with idiopathic pulmonary fibrosis with antibodies to heat shock protein 70 have poor prognoses.
abstract: BACKGROUND
  Diverse autoantibodies are present in most patients with idiopathic pulmonary fibrosis (IPF). We hypothesized that specific autoantibodies may associate with IPF manifestations.
  
  
  OBJECTIVE
  To identify clinically relevant, antigen-specific immune responses in patients with IPF.
  
  
  METHODS
  Autoantibodies were detected by immunoblots and ELISA. Intrapulmonary immune processes were evaluated by immunohistochemistry. Anti-heat shock protein 70 (HSP70) IgG was isolated from plasma by immunoaffinity. Flow cytometry was used for leukocyte functional studies.
  
  
  RESULTS
  HSP70 was identified as a potential IPF autoantigen in discovery assays. Anti-HSP70 IgG autoantibodies were detected by immunoblots in 3% of 60 control subjects versus 25% of a cross-sectional IPF cohort (n = 122) (P = 0.0004), one-half the patients with IPF who died (P = 0.008), and 70% of those with acute exacerbations (P = 0.0005). Anti-HSP70 autoantibodies in patients with IPF were significantly associated with HLA allele biases, greater subsequent FVC reductions (P = 0.0004), and lesser 1-year survival (40 ± 10% vs. 80 ± 5%; hazard ratio = 4.2; 95% confidence interval, 2.0-8.6; P < 0.0001). HSP70 protein, antigen-antibody complexes, and complement were prevalent in IPF lungs. HSP70 protein was an autoantigen for IPF CD4 T cells, inducing lymphocyte proliferation (P = 0.004) and IL-4 production (P = 0.01). IPF anti-HSP70 autoantibodies activated monocytes (P = 0.009) and increased monocyte IL-8 production (P = 0.049). ELISA confirmed the association between anti-HSP70 autoreactivity and IPF outcome. Anti-HSP70 autoantibodies were also found in patients with other interstitial lung diseases but were not associated with their clinical progression.
  
  
  CONCLUSIONS
  Patients with IPF with anti-HSP70 autoantibodies have more near-term lung function deterioration and mortality. These findings suggest antigen-specific immunoassays could provide useful clinical information in individual patients with IPF and may have implications for understanding IPF progression.
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Rehan A
authors.initials: RA
authors.lastname: Kahloon
authors.forename: Jianmin
authors.initials: J
authors.lastname: Xue
authors.forename: Arpit
authors.initials: A
authors.lastname: Bhargava
authors.forename: Eva
authors.initials: E
authors.lastname: Csizmadia
authors.forename: Leo
authors.initials: L
authors.lastname: Otterbein
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Kass
authors.forename: Jessica
authors.initials: J
authors.lastname: Bon
authors.forename: Makoto
authors.initials: M
authors.lastname: Soejima
authors.forename: Marc C
authors.initials: MC
authors.lastname: Levesque
authors.forename: Kathleen O
authors.initials: KO
authors.lastname: Lindell
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Gibson
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
authors.forename: Gunjan
authors.initials: G
authors.lastname: Banga
authors.forename: Chester V
authors.initials: CV
authors.lastname: Oddis
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Pilewski
authors.forename: Frank C
authors.initials: FC
authors.lastname: Sciurba
authors.forename: Michael
authors.initials: M
authors.lastname: Donahoe
authors.forename: Yingze
authors.initials: Y
authors.lastname: Zhang
authors.forename: Steven R
authors.initials: SR
authors.lastname: Duncan
mesh_terms: D000368:Aged; D000936:Antigen-Antibody Complex / Q000032:analysis / Q000276:immunology*; D001323:Autoantibodies / Q000032:analysis / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood*; D007150:Immunohistochemistry; D015847:Interleukin-4 / Q000276:immunology; D016209:Interleukin-8 / Q000276:immunology; D016014:Linear Models; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008297:Male; D011379:Prognosis; D016016:Proportional Hazards Models
chemical_list: D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D018840:HSP70 Heat-Shock Proteins; D007074:Immunoglobulin G; D016209:Interleukin-8; D015847:Interleukin-4