title: Autoreactivity to glucose regulated protein 78 links emphysema and osteoporosis in smokers.
abstract: BACKGROUND
  Emphysema and osteoporosis are epidemiologically associated diseases of cigarette smokers. The causal mechanism(s) linking these illnesses is unknown. We hypothesized autoimmune responses may be involved in both disorders.
  
  
  OBJECTIVE
  To discover an antigen-specific autoimmune response associated with both emphysema and osteoporosis among smokers.
  
  
  METHODS
  Replicate nonbiased discovery assays indicated that autoimmunity to glucose regulated protein 78 (GRP78), an endoplasmic reticulum chaperone and cell surface signaling receptor, is present in many smokers. Subject assessments included spirometry, chest CT scans, dual x-ray absorptiometry, and immunoblots for anti-GRP78 IgG. Anti-GRP78 autoantibodies were isolated from patient plasma by affinity chromatography, leukocyte functions assessed by flow cytometry, and soluble metabolites and mediators measured by immunoassays.
  
  
  RESULTS
  Circulating anti-GRP78 IgG autoantibodies were detected in plasma specimens from 86 (32%) of the 265 smoking subjects. Anti-GRP78 autoantibodies were singularly prevalent among subjects with radiographic emphysema (OR 3.1, 95%CI 1.7-5.7, p = 0.003). Anti-GRP78 autoantibodies were also associated with osteoporosis (OR 4.7, 95%CI 1.7-13.3, p = 0.002), and increased circulating bone metabolites (p = 0.006). Among emphysematous subjects, GRP78 protein was an autoantigen of CD4 T-cells, stimulating lymphocyte proliferation (p = 0.0002) and IFN-gamma production (p = 0.03). Patient-derived anti-GRP78 autoantibodies had avidities for osteoclasts and macrophages, and increased macrophage NFkB phosphorylation (p = 0.005) and productions of IL-8, CCL-2, and MMP9 (p = 0.005, 0.007, 0.03, respectively).
  
  
  CONCLUSIONS
  Humoral and cellular GRP78 autoimmune responses in smokers have numerous biologically-relevant pro-inflammatory and other deleterious actions, and are associated with emphysema and osteoporosis. These findings may have relevance for the pathogenesis of smoking-associated diseases, and development of biomarker immunoassays and/or novel treatments for these disorders.
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Jessica
authors.initials: J
authors.lastname: Bon
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Rehan
authors.initials: R
authors.lastname: Kahloon
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Yingze
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Xue
authors.affiliation: Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Carl R
authors.initials: CR
authors.lastname: Fuhrman
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Jiangning
authors.initials: J
authors.lastname: Tan
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Mathew
authors.initials: M
authors.lastname: Burger
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Kass
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Eva
authors.initials: E
authors.lastname: Csizmadia
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Leo
authors.initials: L
authors.lastname: Otterbein
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Divay
authors.initials: D
authors.lastname: Chandra
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Arpit
authors.initials: A
authors.lastname: Bhargava
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Pilewski
authors.affiliation: Department of Medicine, Indiana School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: G David
authors.initials: GD
authors.lastname: Roodman
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Sciurba
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Duncan
mesh_terms: D000328:Adult; D000368:Aged; D000402:Airway Obstruction / Q000150:complications / Q000276:immunology / Q000503:physiopathology; D000906:Antibodies / Q000097:blood; D001323:Autoantibodies / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D015519:Bone Density; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D015331:Cohort Studies; D003710:Demography; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis / Q000150:complications* / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D011656:Pulmonary Emphysema / Q000150:complications* / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D012907:Smoking / Q000009:adverse effects*
chemical_list: D000906:Antibodies; D001323:Autoantibodies; D015415:Biomarkers; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins