Perspective: Clues, not conclusions

Duncan, Steven R.

doi:10.1038/489s15a

Cited by 5 publications

(11 citation statements)

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“…Autoimmunity is a frequent complication of numerous, varied, primary injury responses [15][16][17][18]. The microbiome within smokedamaged lungs is postulated to be highly immunogenic and, hence, a likely predisposition for the development of autoimmunity [13][14][15]. Neoantigens generated by reactive constituents within tobacco smoke can also provoke autoimmune responses [14].…”

Section: Discussionmentioning

confidence: 99%

“…The adaptive immune responses to GRP78 in smokers have several features of classical autoimmunity [15][16][17][18][19][20]. The biological plausibility of a particular autoimmune response is conditional on the presence of the corresponding autoantigen in the target organ(s), and GRP78 is highly expressed in lungs, especially in the disease specimens ( Figures 3A,3B).…”

Section: Discussionmentioning

confidence: 99%

“…The biologic validity of the putative autoimmunity could then be substantiated by demonstrating correlations between the presence of humoral autoreactivity to these self-proteins and disease prevalences. Additional evidence could be provided by finding concurrent T-cell autoreactivity, HLA bias, and discovering disease-relevant functional effects of the autoantibody(ies) [15][16][17][18][19][20][21].…”

Section: Autoantigen Discoverymentioning

confidence: 99%

“…Disease-associated autoantibody responses are also accompanied by concurrent T-cell responses to the autoantigen(s) [15,16,20,21]. Addition of heat-denatured rGRP78 protein to PBMNC cultures from smokers induced proliferations of their CD4 T-cells, unlike effects of denatured ESP ( Figure 5A).…”

Section: Cd4 T-cell Autoreactivitymentioning

confidence: 99%

“…Adaptive immune responses against a variety of autoantigens appear to be common among patients with lung disease attributable to smoking [13][14][15]. Unspecified autoantibodies from smokers have been shown to induce pulmonary epithelial cell cytotoxicity in vitro.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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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.

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