Patients with Idiopathic Pulmonary Fibrosis with Antibodies to Heat Shock Protein 70 Have Poor Prognoses

• Published in: American journal of respiratory and critical care medicine Vol. 187; no. 7; pp. 768 - 775
• Main Authors: KAHLOON, Rehan A, JIANMIN XUE, GIBSON, Kevin F, KAMINSKI, Naftali, BANGA, Gunjan, ODDIS, Chester V, PILEWSKI, Joseph M, SCIURBA, Frank C, DONAHOE, Michael, YINGZE ZHANG, DUNCAN, Steven R, BHARGAVA, Arpit, CSIZMADIA, Eva, OTTERBEIN, Leo, KASS, Daniel J, BON, Jessica, SOEJIMA, Makoto, LEVESQUE, Marc C, LINDELL, Kathleen O
• Format: Journal Article
• Language: English
• Published: New York, NY American Thoracic Society 01.04.2013
• Subjects: Aged; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Antibodies; Antigen-Antibody Complex - analysis; Antigen-Antibody Complex - immunology; Antigens; Autoantibodies - analysis; Autoantibodies - blood; Biological and medical sciences; Enzyme-Linked Immunosorbent Assay; Female; Flow cytometry; Fractions; Heat shock proteins; HSP70 Heat-Shock Proteins - immunology; Humans; Idiopathic Pulmonary Fibrosis - immunology; Immunoglobulin G - blood; Immunohistochemistry; Intensive care medicine; Interleukin-4 - immunology; Interleukin-8 - immunology; Leukocytes; Linear Models; Lung - immunology; Lung - pathology; Lung diseases; Lungs; Lymphatic system; Lymphocytes; Male; Medical sciences; Patients; Plasma; Pneumology; Prognosis; Proportional Hazards Models; Pulmonary fibrosis; Respiratory system : syndromes and miscellaneous diseases; Human; Lung disease; Intensive care; Respiratory disease; Antibody; Idiopathic; Patient; B-Lymphocyte; B cells; T cells; Immunity; adaptive immunity; Pulmonary fibrosis; interstitial lung disease; T-Lymphocyte; Heat shock protein; Interstitial pneumonitis; β Cell; Resuscitation
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.201203-0506OC

Diverse autoantibodies are present in most patients with idiopathic pulmonary fibrosis (IPF). We hypothesized that specific autoantibodies may associate with IPF manifestations. To identify clinically relevant, antigen-specific immune responses in patients with IPF. 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. 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. 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.