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

Bon, J and Kahloon, R and Zhang, Y and Xue, J and Fuhrman, CR and Tan, J and Burger, M and Kass, DJ and Csizmadia, E and Otterbein, L and Chandra, D and Bhargava, A and Pilewski, JM and Roodman, GD and Sciurba, FC and Duncan, SR (2014) Autoreactivity to glucose regulated protein 78 links emphysema and osteoporosis in smokers. PLoS ONE, 9 (9).

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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 proinflammatory 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.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Bon, J
Kahloon, R
Zhang, Yzhang3@pitt.eduZHANG3
Xue, Jjix28@pitt.eduJIX28
Fuhrman, CRfuhrman1@pitt.eduFUHRMAN1
Tan, Jjit16@pitt.eduJIT16
Burger, M
Kass, DJdjk61@pitt.eduDJK61
Csizmadia, E
Otterbein, L
Chandra, Ddic15@pitt.eduDIC15
Bhargava, A
Pilewski, JMpilewski@pitt.eduPILEWSKI
Roodman, GD
Sciurba, FCfcs@pitt.eduFCS
Duncan, SR
ContributionContributors NameEmailPitt UsernameORCID
Date: 1 September 2014
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 9
Number: 9
DOI or Unique Handle: 10.1371/journal.pone.0105066
Schools and Programs: School of Medicine > Medicine
School of Medicine > Radiology
Refereed: Yes
Other ID: NLM PMC4162538
PubMed Central ID: PMC4162538
PubMed ID: 25216103
Date Deposited: 05 May 2015 16:36
Last Modified: 30 Mar 2021 14:55


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