Autoreactivity to glucose regulated protein 78 links emphysema and osteoporosis in smokers

Jessica Bon, Rehan Kahloon, Yingze Zhang, Jianmin Xue, Carl R. Fuhrman, Jiangning Tan, Mathew Burger, Daniel J. Kass, Eva Csizmadia, Leo Otterbein, Divay Chandra, Arpit Bhargava, Joseph M. Pilewski, G. David Roodman, Frank C. Sciurba, Steven R. Duncan

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

RATIONALE: 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.

OBJECTIVES: 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.

MEASUREMENTS AND MAIN 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.

Original languageEnglish (US)
Article numbere105066
JournalPloS one
Volume9
Issue number9
DOIs
StatePublished - Sep 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Bon, J., Kahloon, R., Zhang, Y., Xue, J., Fuhrman, C. R., Tan, J., Burger, M., Kass, D. J., Csizmadia, E., Otterbein, L., Chandra, D., Bhargava, A., Pilewski, J. M., Roodman, G. D., Sciurba, F. C., & Duncan, S. R. (2014). Autoreactivity to glucose regulated protein 78 links emphysema and osteoporosis in smokers. PloS one, 9(9), [e105066]. https://doi.org/10.1371/journal.pone.0105066