Tobacco and multiple sclerosis susceptibility
Author: Hedström, Anna Karin
Date: 2016-02-19
Location: Blå Hallen, Nobels väg 13, Karolinska Institutet, Solna
Time: 10.00
Department: Institutet för miljömedicin / Institute of Environmental Medicine
Abstract
Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system (CNS) that arises from a combination of a complex genetic predisposition and environmental factors. For northern Europeans, the lifetime risk of MS is 1:400, making it the most common non-traumatic cause of disability in young adults. The strongest genetic associations with MS are located within the human leukocyte antigen (HLA) complex and in recent years, a large number of non-HLA risk loci that influence disease susceptibility have been identified. The contribution of lifestyle and environmental factors is more difficult to study. However, it is important to identify these factors since they are potentially preventable and may also lead to hypotheses on critical pathogenic events.
This thesis focuses on the impact of tobacco on MS risk. We replicated the finding of an association between smoking and MS risk and demonstrated that the risk of developing the disease increases with cumulative dose of smoking. However, snuff use, which leads to exposure to high doses of nicotine, was associated with decreased MS risk (paper I). In paper II, we showed an inverse dose-response correlation between cumulative dose of snuff use and disease risk. Nicotine has been shown to be protective in several models of inflammatory diseases, and may thus exert anti-inflammatory and immune-modulating effects in a way that reduces the risk of developing MS.
In paper IV, we investigated the association between smoking and MS in more detail. Both duration and intensity of smoking contribute independently to the risk of developing the disease. Smoking affects MS risk regardless of age at exposure, in contrast to many other environmental risk factors which seem to act mainly during adolescence. The detrimental effect of smoking slowly abates after smoking cessation regardless of the timing of smoking and regardless of the cumulative dose of smoking.
In paper III, we demonstrated that exposure to passive smoking among never smokers is associated with increased risk of MS. Tobacco smoke, but not tobacco consumption in the form of moist snuff, increases MS risk, suggesting that the critical effects of smoking may be caused by irritation in the lungs. Smoking increases pro-inflammatory cell activation and induces post-translational modifications of proteins in the lungs. In paper V, an interaction was demonstrated between carriage of HLA-DRB1*15, absence of HLA A*02, and smoking in the development of MS. We hypothesize that smoke-induced lung irritation, in the context of MS risk HLA genes, may generate post-translationally modified peptides which are cross-reactive with CNS antigens, promoting a CNS-directed autoaggressive immunity that results in MS. Further studies would be valuable in order to investigate whether other forms of lung irritation contribute to the triggering of MS.
Apart from generating data of importance for preventive measures, our finding of an interaction between smoking and HLA genotype emphasizes the need to include data on environmental exposures in genetic analyses of complex diseases and vice versa.
This thesis focuses on the impact of tobacco on MS risk. We replicated the finding of an association between smoking and MS risk and demonstrated that the risk of developing the disease increases with cumulative dose of smoking. However, snuff use, which leads to exposure to high doses of nicotine, was associated with decreased MS risk (paper I). In paper II, we showed an inverse dose-response correlation between cumulative dose of snuff use and disease risk. Nicotine has been shown to be protective in several models of inflammatory diseases, and may thus exert anti-inflammatory and immune-modulating effects in a way that reduces the risk of developing MS.
In paper IV, we investigated the association between smoking and MS in more detail. Both duration and intensity of smoking contribute independently to the risk of developing the disease. Smoking affects MS risk regardless of age at exposure, in contrast to many other environmental risk factors which seem to act mainly during adolescence. The detrimental effect of smoking slowly abates after smoking cessation regardless of the timing of smoking and regardless of the cumulative dose of smoking.
In paper III, we demonstrated that exposure to passive smoking among never smokers is associated with increased risk of MS. Tobacco smoke, but not tobacco consumption in the form of moist snuff, increases MS risk, suggesting that the critical effects of smoking may be caused by irritation in the lungs. Smoking increases pro-inflammatory cell activation and induces post-translational modifications of proteins in the lungs. In paper V, an interaction was demonstrated between carriage of HLA-DRB1*15, absence of HLA A*02, and smoking in the development of MS. We hypothesize that smoke-induced lung irritation, in the context of MS risk HLA genes, may generate post-translationally modified peptides which are cross-reactive with CNS antigens, promoting a CNS-directed autoaggressive immunity that results in MS. Further studies would be valuable in order to investigate whether other forms of lung irritation contribute to the triggering of MS.
Apart from generating data of importance for preventive measures, our finding of an interaction between smoking and HLA genotype emphasizes the need to include data on environmental exposures in genetic analyses of complex diseases and vice versa.
List of papers:
I. Tobacco smoking, but not Swedish snuff use, increases the risk of multiple sclerosis. Hedström AK, Bäärnhielm M, Olsson T, Alfredsson L. Neurology 2009;73:696-701.
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II. Nicotine might have a protective effect in the etiology of multiple sclerosis. Hedström AK, Hillert J, Olsson T, Alfredsson L. Multiple Sclerosis 2013;19:1009-1013.
Fulltext (DOI)
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III. Exposure to environmental tobacco smoke is associated with increased risk for multiple sclerosis. Hedström AK, Bäärnhielm M, Olsson T, Alfredsson L. Multiple Sclerosis 2011;17:788-793.
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IV. Smoking and MS susceptibility. Hedström AK, Hillert J, Olsson T, Alfredsson L. Eur J Epidemiol 2013;28:867-874.
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V. Smoking and two human leukocyte antigen genes interact to increase the risk for multiple sclerosis. Hedström AK, Sundqvist E, Bäärnhielm M, Nordin N, Hillert J, Kockum I, Olsson T, Alfredsson L. Brain 2011;134:653-664.
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I. Tobacco smoking, but not Swedish snuff use, increases the risk of multiple sclerosis. Hedström AK, Bäärnhielm M, Olsson T, Alfredsson L. Neurology 2009;73:696-701.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Nicotine might have a protective effect in the etiology of multiple sclerosis. Hedström AK, Hillert J, Olsson T, Alfredsson L. Multiple Sclerosis 2013;19:1009-1013.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Exposure to environmental tobacco smoke is associated with increased risk for multiple sclerosis. Hedström AK, Bäärnhielm M, Olsson T, Alfredsson L. Multiple Sclerosis 2011;17:788-793.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Smoking and MS susceptibility. Hedström AK, Hillert J, Olsson T, Alfredsson L. Eur J Epidemiol 2013;28:867-874.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Smoking and two human leukocyte antigen genes interact to increase the risk for multiple sclerosis. Hedström AK, Sundqvist E, Bäärnhielm M, Nordin N, Hillert J, Kockum I, Olsson T, Alfredsson L. Brain 2011;134:653-664.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Alfredsson, Lars
Issue date: 2016-01-28
Rights:
Publication year: 2016
ISBN: 97891-7676-148-9
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