Autoreactivity to Glucose Regulated Protein 78 Links Emphysema and Osteoporosis in Smokers

Abstract

RationaleEmphysema 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.ObjectivesTo discover an antigen-specific autoimmune response associated with both emphysema and osteoporosis among smokers.MethodsReplicate 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 ResultsCirculating 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).ConclusionsHumoral 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.

Biologics for Chronic Obstructive Pulmonary Disease: Present and Future

“…Autoimmune responses have also been implicated in COPD-associated emphysema, and identification of specific autoantibodies associated with emphysema offers potential novel therapeutic targets (e.g., anti-glucose-regulated protein 78 and anti-elastin) 44 .…”

“…COPD patients with a history of ≥2 exacerbations in the previous year were randomized to 600-mg intravenous dose on day 1 (loading dose), followed by 300 mg subcutaneous (two 150-mg injections) every 4 weeks (Q4W) for a total of 14 doses (MED18968, n = 160; placebo, n = 164) 46 . The primary endpoint was a reduction in the annualized rate of moderate to severe COPD exacerbations 44 . MED18968 was well-tolerated but had no effect on the rate of moderate or severe exacerbations or health-related quality of life (HRQOL).…”

“…CLEC5A is expressed on alveolar macrophages in mice exposed longterm to cigarette smoke and is required for the development of inflammation and proinflammatory cytokine expression 65 . The autoantibodies to anti-glucose-regulated protein 78 are associated with emphysema 44 . IL-33 is a type 2 cytokine that is upregulated by cigarette smoke, released in response to viral infection, and associated with driving Th 1 celllike inflammatory response to viral infection 65 .…”

The clinical relevance of the emphysema-hyperinflated phenotype in COPD

“…Finally, there is increasing data supporting the association of COPD and osteoporosis. The causative mechanisms underlying this association are still being investigated, but are likely modulated by gender, clinical phenotype (with a significant relationship to the severity of emphysema) and genetic predisposition [82][83][84][85].…”

Comment on Rondas et al. Citrullinated Glucose-Regulated Protein 78 Is an Autoantigen in Type 1 Diabetes. Diabetes 2015;64:573–586

“…The article by Lu et al (2) manifested that anti-citrullinated protein antibodies activated nuclear factor-kB and tumor necrosis factor-a through binding to citrullinated GRP78 via activated extracellular signal-related kinase 1/2 and Jun NH 2 -terminal kinase in rheumatic arthritis. The article by Bon et al (3) indicated that GRP78 autoimmune responses in smokers were associated with emphysema and osteoporosis. Furthermore, the article by Wang et al (4) suggested that GRP78 was the drug target of isoliquiritigenin to enhance breast cancer stem cell chemosensitivity.…”