The Genetic Epidemiology of Resistance
The Genetic Epidemiology of Resistance
Purpose of Review: An inverse relationship between resistance to certain parasitic diseases and measures of atopy and asthma has long been observed. A possible explanation is that genetic determinants which confer protection against detrimental worm burdens are the same determinants involved in atopic asthma. The focus of this review is to consider the potential candidate genes that have been elucidated as part of molecular, genomic and genetic studies of parasite biology, host-parasite interactions and classic genetic epidemiology studies on parasitic disease and allergic asthma.
Recent Findings: Comparative studies of the Plasmodium and Schistosoma spp. genomes have revealed a number of proteins that are homologous to humans. A number of linkage and association studies on susceptibility/resistance to parasitic diseases, including malaria and schistosomiasis, overlap with associations that have been identified for susceptibility to atopy and asthma.
Summary: In response to parasitic approaches in maintaining survival, the human host has evolved genetic adaptations that minimize severe manifestations of disease, which conversely appear to contribute to allergic disease. A clearer understanding of this process will elucidate the complex pathways and mechanisms involved in these traits.
Atopic asthma is a disease of chronic inflammation of the airways, for which there is a strong genetic basis. The most probable source of the inflammation is a specific immunoglobulin E (IgE)-mediated reaction initiated by chronic exposure to innocuous environmental allergens, such as those associated with house dust. It has long been observed that in regions endemic for extracellular parasitic (helminthic) diseases, such as schistosomiasis, there is a lower prevalence of atopy overall and, among asthmatics, a less severe form of disease, even in settings where exposure to domestic allergens (such as house dust mite) is comparable to that which atopic asthmatics are exposed to in non-endemic regions. Interestingly, it has also been noted that individuals with a history of atopy appear to be 'protected' from helminthic parasites to the extent that they mount a stronger IgE-mediated response to worm antigen and demonstrate a lower intensity of parasitic infection than non-atopic individuals with the same exposure.
Why is this? One possibility is that genetic determinants which confer protection against detrimental worm burdens are the same determinants involved in atopic asthma. A potential relationship between intracellular parasitic infection (a primarily Th1-driven phenomenon) and asthma/atopy is less clear, just as, currently, there is intense discussion and debate regarding the Th1/Th2 paradigm and the development and progression of atopic asthma. Importantly, there is a growing body of literature suggesting a protective role of IgE subsequent to clinical malaria as well as interest in the impact of co-infection with malaria and extracellular parasitic diseases on the development of acquired immunity associated with the susceptibility or resistance to disease.
Characterization of parasite genomes and subsequent genomic comparison of parasites to more complex species such as mammalian hosts have contributed to our understanding of the mechanisms of parasite evolution and have provided compelling evidence for the role of host-parasite interaction in genetic adaptation. An understanding of that genetic adaptation has elucidated candidates which may drive susceptibility to other diseases of the immune system, including atopy and asthma. In consideration of the practical division of parasites into intracellular (or 'microparasites'), which comprise bacteria, viruses and protozoa, compared with the extracellular (or 'macroparasites'), and which include but are not limited to helminths, the primary focus of this review is on the protozoa and helminths models for dissecting host-parasite interactions as they relate to human evolution, particularly in the context of allergic disease, and their overall impact on the human immune system. Germaine to the discussion is a brief review of the extent to which human molecular adaptations in the form of genetic variation as a response to parasitic infection have potentially mediated our response to seemingly innocuous antigens and whether or not these variants are similarly contributing to susceptibility to allergic asthma.
Purpose of Review: An inverse relationship between resistance to certain parasitic diseases and measures of atopy and asthma has long been observed. A possible explanation is that genetic determinants which confer protection against detrimental worm burdens are the same determinants involved in atopic asthma. The focus of this review is to consider the potential candidate genes that have been elucidated as part of molecular, genomic and genetic studies of parasite biology, host-parasite interactions and classic genetic epidemiology studies on parasitic disease and allergic asthma.
Recent Findings: Comparative studies of the Plasmodium and Schistosoma spp. genomes have revealed a number of proteins that are homologous to humans. A number of linkage and association studies on susceptibility/resistance to parasitic diseases, including malaria and schistosomiasis, overlap with associations that have been identified for susceptibility to atopy and asthma.
Summary: In response to parasitic approaches in maintaining survival, the human host has evolved genetic adaptations that minimize severe manifestations of disease, which conversely appear to contribute to allergic disease. A clearer understanding of this process will elucidate the complex pathways and mechanisms involved in these traits.
Atopic asthma is a disease of chronic inflammation of the airways, for which there is a strong genetic basis. The most probable source of the inflammation is a specific immunoglobulin E (IgE)-mediated reaction initiated by chronic exposure to innocuous environmental allergens, such as those associated with house dust. It has long been observed that in regions endemic for extracellular parasitic (helminthic) diseases, such as schistosomiasis, there is a lower prevalence of atopy overall and, among asthmatics, a less severe form of disease, even in settings where exposure to domestic allergens (such as house dust mite) is comparable to that which atopic asthmatics are exposed to in non-endemic regions. Interestingly, it has also been noted that individuals with a history of atopy appear to be 'protected' from helminthic parasites to the extent that they mount a stronger IgE-mediated response to worm antigen and demonstrate a lower intensity of parasitic infection than non-atopic individuals with the same exposure.
Why is this? One possibility is that genetic determinants which confer protection against detrimental worm burdens are the same determinants involved in atopic asthma. A potential relationship between intracellular parasitic infection (a primarily Th1-driven phenomenon) and asthma/atopy is less clear, just as, currently, there is intense discussion and debate regarding the Th1/Th2 paradigm and the development and progression of atopic asthma. Importantly, there is a growing body of literature suggesting a protective role of IgE subsequent to clinical malaria as well as interest in the impact of co-infection with malaria and extracellular parasitic diseases on the development of acquired immunity associated with the susceptibility or resistance to disease.
Characterization of parasite genomes and subsequent genomic comparison of parasites to more complex species such as mammalian hosts have contributed to our understanding of the mechanisms of parasite evolution and have provided compelling evidence for the role of host-parasite interaction in genetic adaptation. An understanding of that genetic adaptation has elucidated candidates which may drive susceptibility to other diseases of the immune system, including atopy and asthma. In consideration of the practical division of parasites into intracellular (or 'microparasites'), which comprise bacteria, viruses and protozoa, compared with the extracellular (or 'macroparasites'), and which include but are not limited to helminths, the primary focus of this review is on the protozoa and helminths models for dissecting host-parasite interactions as they relate to human evolution, particularly in the context of allergic disease, and their overall impact on the human immune system. Germaine to the discussion is a brief review of the extent to which human molecular adaptations in the form of genetic variation as a response to parasitic infection have potentially mediated our response to seemingly innocuous antigens and whether or not these variants are similarly contributing to susceptibility to allergic asthma.
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