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CTLA4 Gene Variants in Autoimmunity and Cancer: a Comparative Review

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Author(s): Abbas Ghaderi

Journal: Iranian Journal of Immunology
ISSN 1735-1383

Volume: 8;
Issue: 3;
Start page: 127;
Date: 2011;
Original page

Keywords: Autoimmunity | Cancer | CTLA4 | Immune Balance | Polymorphism

ABSTRACT
Gene association studies are less appealing in cancer compared to autoimmune diseases.Complexity, heterogeneity, variation in histological types, age at onset, short survival,and acute versus chronic conditions are cancer related factors which are different froman organ specific autoimmune disease, such as Grave’s disease, on which a large bodyof multicentre data is accumulated. For years the focus of attention was on diversity andpolymorphism of major histocompatibility complex in respect to human diseasesspecially the autoimmune diseases, but in recent years, access to other human genesequences prompted investigators to focus on genes encoding the immune regulatoryproteins such as the co-stimulatory, adhesion molecules, cytokines and chemokines andtheir receptors. Among them, CTLA4 (CD152) has been in the centre of attention for itspivotal role in autoimmunity and cancer. Although not fully understood, CTLA4 withno doubt plays an important role in the maintenance of the immune response by itsexpression on activated and regulatory T cells. CTLA4 (Gene ID:1493, MIMnumber:123890) has many variants and polymorphic forms, some present in regulatorypositions, some in 3' UTR and the most important one in the leader sequence (+49 A/G).As a pivotal regulatory element of the immune responses magnitude, CTLA4 could beconsidered as a two-blade knife, for which only the optimal expression ensures aneffective, but at the same time, safe immune response. It can accordingly be speculatedthat CTLA4 alleles associated with extraordinary expression could make a person moresusceptible to tumor growth and/or progression. On the other hand, alleles associatedwith a compromised CTLA4 expression/function may accelerate the formation and/ormanifestation of inflammatory autoimmune disorder. I hypothesized a spectrum of thefunctional dichotomy of CTLA4 SNPs diverging from autoimmunity to cancer. Toexamine these hypotheses, results from previously published investigations on CTLA4polymorphisms together with the work done by our own group are discussed in details.Because the most published data are about the polymorphism at position +49, Iconcentrated on this position; however the data regarding other SNPs are also includedfor comparison. To support the significance of CTLA4 gene variation in these twomajor human diseases evidences from organ transplantation are also included. As population perspective support the hypothesis that individuals inheriting a GG genotypeat position +49, for which lower CTLA4 expression has been extensively suggested, aremore susceptible for developing autoimmune disorders and those with AA genotype,with an existence of a state of self-tolerance, may have a higher chance of developingcancer. CTLA4 SNPs may accordingly be considered as a crucial element, along withother known or yet unknown mechanisms, in keeping the immune balance inpredisposed individuals to cancer and autoimmunity. Although an spectrum line can bedrawn between autoimmunity and cancer by considering published data regardingCTLA4 +49 polymorphism, the extreme functional dichotomy of this SNP appears to bemore complex and difficult to understand, but there is no doubt that the futureinvestigations will resolve most ambiguities.
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