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Pleiotropic Effects of Immune Responses Explain Variation in the Prevalence of Fibroproliferative Diseases.

Russell SB, Smith JC, Huang M, Trupin JS, Williams SM - PLoS Genet. (2015)

Bottom Line: Selected genes may be pleiotropic, affecting multiple phenotypes and resulting in more than one disease or trait.Many studies on selection of Th2-related genes for host resistance to helminths have been reported, but the pleiotropic impact of this selection on the distribution of fibrotic disorders has not been explicitly investigated.We discuss the disproportionate occurrence of fibroproliferative diseases in individuals of African ancestry and provide evidence that adaptation of the immune system has shaped the genetic structure of these human populations in ways that alter the distribution of multiple fibroproliferative diseases.

View Article: PubMed Central - PubMed

Affiliation: Vanderbilt Genetics Institute, Division of Dermatology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America.

ABSTRACT
Many diseases are differentially distributed among human populations. Differential selection on genetic variants in ancestral environments that coincidentally predispose to disease can be an underlying cause of these unequal prevalence patterns. Selected genes may be pleiotropic, affecting multiple phenotypes and resulting in more than one disease or trait. Patterns of pleiotropy may be helpful in understanding the underlying causes of an array of conditions in a population. For example, several fibroproliferative diseases are more prevalent and severe in populations of sub-Saharan ancestry. We propose that this disparity is due to selection for an enhanced Th2 response that confers resistance to helminthic infections, and concurrently increases susceptibility to fibrosis due to the profibrotic action of Th2 cytokines. Many studies on selection of Th2-related genes for host resistance to helminths have been reported, but the pleiotropic impact of this selection on the distribution of fibrotic disorders has not been explicitly investigated. We discuss the disproportionate occurrence of fibroproliferative diseases in individuals of African ancestry and provide evidence that adaptation of the immune system has shaped the genetic structure of these human populations in ways that alter the distribution of multiple fibroproliferative diseases.

No MeSH data available.


Related in: MedlinePlus

Helminth exposure selects for a protective Th2 immune response that simultaneously increases risk for fibrosis.The high prevalence of helminths in Africa has selected for genotypes favoring an enhanced Th2 immune response characterized by increased levels of interleukin 4 (IL4), interleukin 13 (IL13), and interleukin 4 receptor (IL4R), and other Th2 factors. This selection also decreases Th1 factors, such as interferon gamma (IFNG) and interferon gamma receptor (IFNGR), and Th2 regulatory factors, such as IL10 and interleukin 13 receptor alpha 2 (IL13RA2). These genotypes increase resistance to helminthic infection and contribute to a subset of fibroproliferative diseases that are more common and/or more severe in individuals of African ancestry. Global distribution of helminth species in upper part of figure adapted from Lustigman et al. [168].
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pgen.1005568.g001: Helminth exposure selects for a protective Th2 immune response that simultaneously increases risk for fibrosis.The high prevalence of helminths in Africa has selected for genotypes favoring an enhanced Th2 immune response characterized by increased levels of interleukin 4 (IL4), interleukin 13 (IL13), and interleukin 4 receptor (IL4R), and other Th2 factors. This selection also decreases Th1 factors, such as interferon gamma (IFNG) and interferon gamma receptor (IFNGR), and Th2 regulatory factors, such as IL10 and interleukin 13 receptor alpha 2 (IL13RA2). These genotypes increase resistance to helminthic infection and contribute to a subset of fibroproliferative diseases that are more common and/or more severe in individuals of African ancestry. Global distribution of helminth species in upper part of figure adapted from Lustigman et al. [168].

Mentions: Helminths are parasitic worms that cause the most common infectious diseases of humans in developing countries. It is estimated that one billion people in developing areas of sub-Saharan Africa are infected with at least one helminth (Fig 1) [60]. These worms represent a highly diverse group of multicellular eukaryotic parasites, consisting of two phyla, Nematoda, and Platyhelminthes. Infection by any of these parasitic worms, including schistosomes, hookworms, and ascaris, induces a Th2 immune response [60,61]. This response includes the production of cytokines IL4, IL5, and IL13, antibody isotypes IgG1, IgG4, and IgE, and expanded populations of eosinophils, basophils, mast cells, and IL4- and IL13-activated (alternatively activated or M2) macrophages (Fig 1) [61,62]. The adaptive Th2 response mirrors a range of innate helper cell responses that occur upon parasite invasion of epithelium [62]. Interestingly, helminth diversity was observed to correlate with 3,478 gene variants in more than 800 genes in complex networks centered around Th2 cytokines [63]. Th2 immunity is enhanced in environments with a high prevalence of helminthic infection, and may have evolved to isolate and encapsulate the organism and resolve localized extracellular damage [64]. This process can result in tissue injury due to an excess deposition of extracellular matrix, i.e., fibrosis [62,64].


Pleiotropic Effects of Immune Responses Explain Variation in the Prevalence of Fibroproliferative Diseases.

Russell SB, Smith JC, Huang M, Trupin JS, Williams SM - PLoS Genet. (2015)

Helminth exposure selects for a protective Th2 immune response that simultaneously increases risk for fibrosis.The high prevalence of helminths in Africa has selected for genotypes favoring an enhanced Th2 immune response characterized by increased levels of interleukin 4 (IL4), interleukin 13 (IL13), and interleukin 4 receptor (IL4R), and other Th2 factors. This selection also decreases Th1 factors, such as interferon gamma (IFNG) and interferon gamma receptor (IFNGR), and Th2 regulatory factors, such as IL10 and interleukin 13 receptor alpha 2 (IL13RA2). These genotypes increase resistance to helminthic infection and contribute to a subset of fibroproliferative diseases that are more common and/or more severe in individuals of African ancestry. Global distribution of helminth species in upper part of figure adapted from Lustigman et al. [168].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4634921&req=5

pgen.1005568.g001: Helminth exposure selects for a protective Th2 immune response that simultaneously increases risk for fibrosis.The high prevalence of helminths in Africa has selected for genotypes favoring an enhanced Th2 immune response characterized by increased levels of interleukin 4 (IL4), interleukin 13 (IL13), and interleukin 4 receptor (IL4R), and other Th2 factors. This selection also decreases Th1 factors, such as interferon gamma (IFNG) and interferon gamma receptor (IFNGR), and Th2 regulatory factors, such as IL10 and interleukin 13 receptor alpha 2 (IL13RA2). These genotypes increase resistance to helminthic infection and contribute to a subset of fibroproliferative diseases that are more common and/or more severe in individuals of African ancestry. Global distribution of helminth species in upper part of figure adapted from Lustigman et al. [168].
Mentions: Helminths are parasitic worms that cause the most common infectious diseases of humans in developing countries. It is estimated that one billion people in developing areas of sub-Saharan Africa are infected with at least one helminth (Fig 1) [60]. These worms represent a highly diverse group of multicellular eukaryotic parasites, consisting of two phyla, Nematoda, and Platyhelminthes. Infection by any of these parasitic worms, including schistosomes, hookworms, and ascaris, induces a Th2 immune response [60,61]. This response includes the production of cytokines IL4, IL5, and IL13, antibody isotypes IgG1, IgG4, and IgE, and expanded populations of eosinophils, basophils, mast cells, and IL4- and IL13-activated (alternatively activated or M2) macrophages (Fig 1) [61,62]. The adaptive Th2 response mirrors a range of innate helper cell responses that occur upon parasite invasion of epithelium [62]. Interestingly, helminth diversity was observed to correlate with 3,478 gene variants in more than 800 genes in complex networks centered around Th2 cytokines [63]. Th2 immunity is enhanced in environments with a high prevalence of helminthic infection, and may have evolved to isolate and encapsulate the organism and resolve localized extracellular damage [64]. This process can result in tissue injury due to an excess deposition of extracellular matrix, i.e., fibrosis [62,64].

Bottom Line: Selected genes may be pleiotropic, affecting multiple phenotypes and resulting in more than one disease or trait.Many studies on selection of Th2-related genes for host resistance to helminths have been reported, but the pleiotropic impact of this selection on the distribution of fibrotic disorders has not been explicitly investigated.We discuss the disproportionate occurrence of fibroproliferative diseases in individuals of African ancestry and provide evidence that adaptation of the immune system has shaped the genetic structure of these human populations in ways that alter the distribution of multiple fibroproliferative diseases.

View Article: PubMed Central - PubMed

Affiliation: Vanderbilt Genetics Institute, Division of Dermatology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America.

ABSTRACT
Many diseases are differentially distributed among human populations. Differential selection on genetic variants in ancestral environments that coincidentally predispose to disease can be an underlying cause of these unequal prevalence patterns. Selected genes may be pleiotropic, affecting multiple phenotypes and resulting in more than one disease or trait. Patterns of pleiotropy may be helpful in understanding the underlying causes of an array of conditions in a population. For example, several fibroproliferative diseases are more prevalent and severe in populations of sub-Saharan ancestry. We propose that this disparity is due to selection for an enhanced Th2 response that confers resistance to helminthic infections, and concurrently increases susceptibility to fibrosis due to the profibrotic action of Th2 cytokines. Many studies on selection of Th2-related genes for host resistance to helminths have been reported, but the pleiotropic impact of this selection on the distribution of fibrotic disorders has not been explicitly investigated. We discuss the disproportionate occurrence of fibroproliferative diseases in individuals of African ancestry and provide evidence that adaptation of the immune system has shaped the genetic structure of these human populations in ways that alter the distribution of multiple fibroproliferative diseases.

No MeSH data available.


Related in: MedlinePlus