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.
Highlights
Emphysema, defined as radiologic and/or histological evidence of lung parenchymal destruction, accounts for enormous worldwide morbidity and mortality [1]
Anti-glucose regulated protein 78 (GRP78) autoantibodies were singularly prevalent among subjects with radiographic emphysema
Emphysema among tobacco smokers often occurs in association with chronic obstructive pulmonary disease (COPD), a complex syndrome typified by airway narrowing and inflammation, and diagnosed by the presence of expiratory airflow obstruction on spirometric testing [1,2,3,4]
Summary
Emphysema, defined as radiologic and/or histological evidence of lung parenchymal destruction, accounts for enormous worldwide morbidity and mortality [1]. Emphysema among tobacco smokers often occurs in association with chronic obstructive pulmonary disease (COPD), a complex syndrome typified by airway narrowing and inflammation, and diagnosed by the presence of expiratory airflow obstruction on spirometric testing [1,2,3,4]. Emphysema and COPD are by no means invariably concordant, and many patients severely afflicted by one of these lung abnormalities may have little or no evidence of the other [2,3,4]. The abnormal and often pathological bone demineralization that occurs in smokers is notable for being highly related to the presence and severity of emphysema, and is independent of the co-existence or magnitude of COPD per se [8]. The pathophysiological processes that cause or promote emphysema and its co-morbidities remain enigmatic, systemic immunological responses, including the actions of activated monocyte-lineage phagocytes, have been implicated in these disorders [11,12]
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