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).
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 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.
Share
Citation/Export: |
|
Social Networking: |
|
Details
Item Type: |
Article
|
Status: |
Published |
Creators/Authors: |
Creators | Email | Pitt Username | ORCID |
---|
Bon, J | | | | Kahloon, R | | | | Zhang, Y | zhang3@pitt.edu | ZHANG3 | | Xue, J | jix28@pitt.edu | JIX28 | | Fuhrman, CR | fuhrman1@pitt.edu | FUHRMAN1 | | Tan, J | jit16@pitt.edu | JIT16 | | Burger, M | | | | Kass, DJ | djk61@pitt.edu | DJK61 | | Csizmadia, E | | | | Otterbein, L | | | | Chandra, D | dic15@pitt.edu | DIC15 | | Bhargava, A | | | | Pilewski, JM | pilewski@pitt.edu | PILEWSKI | | Roodman, GD | | | | Sciurba, FC | fcs@pitt.edu | FCS | | Duncan, SR | | | |
|
Contributors: |
Contribution | Contributors Name | Email | Pitt Username | ORCID |
---|
Editor | Pershouse, Mark A | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED |
|
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 |
URI: |
http://d-scholarship.pitt.edu/id/eprint/24016 |
Metrics
Monthly Views for the past 3 years
Plum Analytics
Altmetric.com
Actions (login required)
|
View Item |