Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease

  title={Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease},
  author={Hironori Ueda and Joanna M. M. Howson and Laura Esposito and Joanne M. Heward and Snook and Giselle Chamberlain and Daniel B. Rainbow and Kara M D Hunter and Annabel N. Smith and Gianfranco di Genova and Mathias Herr and Ingrid Dahlman and Felicity Payne and Deborah J. Smyth and Christopher E Lowe and Rebecca C. J. Twells and Sarah K. Howlett and Barry C. Healy and Sarah Nutland and Helen E. Rance and Vincent H. Everett and Luc J. Smink and Alex C. Lam and Heather J. Cordell and Neil M. Walker and Cristina Bordin and John S Hulme and Costantino Motzo and Francesco Cucca and John F. Hess and M. L. Metzker and Jane Rogers and Simon G. Gregory and Amit Allahabadia and Ratnasingam Nithiyananthan and Eva Tuomilehto-Wolf and Jaakko Tuomilehto and Polly J. Bingley and Kathleen M. Gillespie and Dag Erik Undlien and Kjersti S R{\o}nningen and Cristian Guja and Constantin Ionescu-Tirgoviste and David A. Savage and Alexander P. Maxwell and Dennis J. Carson and Christopher C. Patterson and Jayne A. Franklyn and David Clayton and Laurence B. Peterson and Linda S. Wicker and John A. Todd and Stephen C. L. Gough},
Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)—which encodes a vital negative regulatory molecule of the immune system—as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was… 

HLA , CTLA-4 and PTPN22 : the shared genetic master-key to autoimmunity?

This review summarises recent developments and current understanding of the way in which molecules encoded by these susceptibility loci contribute to T-cell activation, and hypothesises how aberrant function of these molecules might trigger autoimmunity.

Polymorphisms in the cytotoxic T lymphocyte antigen-4 gene region confer susceptibility to Addison's disease.

This finding suggests that polymorphisms in CTLA4 confer general risk to develop autoimmunity and identifies a potential therapeutic target in the prevention of autoimmune endocrine disorders.

PDCD1: a tissue-specific susceptibility locus for inherited inflammatory disorders

PDCD1 is identified as a second immunomodulatory gene with pleiotropic effects in human disease, a number of which show significant associations with the specific immunoglobulin E response to grass allergens in atopic individuals.

Genetic polymorphisms in cytotoxic T-lymphocyte antigen 4 and cancer: the dialectical nature of subtle human immune dysregulation.

Findings indicate an important role of the dialectical nature of T-cell immune dysregulation in human disorders, such as autoimmune disease and cancer, as well as susceptibility to cancer and response to targeted therapy.

CBLB variants in type 1 diabetes and their genetic interaction with CTLA4

Gene‐gene interactions probably play substantial roles in T1D susceptibility, and evidence for a genetic interaction between the CTLA4 and CBLB genes, involved in the same biological pathway of T cell receptor signaling, was observed.

CTLA4 gene variants in autoimmunity and cancer: a comparative review.

  • A. Ghaderi
  • Biology
    Iranian journal of immunology : IJI
  • 2011
The hypothesis that individuals inheriting a GG genotype at position +49, for which lower CTLA4 expression has been extensively suggested, are more 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 developing cancer is supported.

Cytotoxic T-lymphocyte antigen 4 gene polymorphisms are associated with latent autoimmune diabetes in adults.

Autoimmunity risk alleles in costimulation pathways

The unbiased genome‐wide association scans suggest that indeed immune related genes underlie the pathogenesis of human autoimmune disease with common involvement of costimulatory pathways.

Coeliac disease: investigation of proposed causal variants in the CTLA4 gene region.

  • A. KingS. Moodie P. Ciclitira
  • Biology, Medicine
    European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics
  • 2003
No association was detected with either SNP using both the transmission disequilibrium test (TDT) and case-control methods, and this study appears to have good power to detect moderate genetic effects, but possibly these SNPs exert too weak an effect on risk of CD to have been detected in the authors' sample.

CTLA4 is differentially associated with autoimmune diseases in the Dutch population

The association of the CTLA4 haplotype 2 with the high-risk HLA genotype in T1D and CD, which share DQ2 as the one of high- risk alleles, might provide a clue to understanding the common genetic background of AID.



The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry.

Susceptibility to autoimmune insulin-dependent (type 1) diabetes mellitus is determined by a combination of environmental and genetic factors, which include variation in MHC genes on chromosome 6p21

Apoptosis resistance of nonobese diabetic peripheral lymphocytes linked to the Idd5 diabetes susceptibility region.

Interestingly, it is found that the CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) and the CD28 costimulatory molecules are defectively expressed in NOD mice, suggesting that one or both of these molecules may be involved in the control of apoptosis resistance and, in turn, in diabetes susceptibility.

A polymorphism in the human cytotoxic T-lymphocyte antigen 4 (CTLA4) gene (exon 1 +49) alters T-cell activation

The results suggest that the G allele at position +49 of exon 1 affects the CTLA4-driven down-regulation of T-cell activation and may be an important factor in the pathogenesis of autoimmune diseases.

Cutting Edge: A Soluble Form of CTLA-4 in Patients with Autoimmune Thyroid Disease

It is concluded that a native soluble form of CTLA-4 is derived from an alternate transcript of the CTLA -4 gene, and its level in plasma is elevated among a population of patients with ATD.

Fine mapping of an IgE-controlling gene on chromosome 2q: Analysis of CTLA4 and CD28.

Fine- mapping the chromosome 2q33 region and data suggest that the costimulatory pathway, specifically CTLA4, is important in the development of atopy and asthma.

A CD45 Polymorphism Associated with Multiple Sclerosis Disrupts an Exonic Splicing Silencer*

Proper functioning of the immune system is dependent on a complex interplay of regulatory activities that mediate the appropriate splicing of CD45 exon 4, which is disrupted by a single nucleotide polymorphism.

MHC class II region, CTLA4 gene, and ophthalmopathy in patients with Graves' disease

The CTLA-4 gene is expressed in placental fibroblasts.

It is demonstrated that CTLA-4 mRNA and protein are indeed expressed in fetal tissues at the maternal-fetal interface throughout gestation.

Further mapping of the Idd5.1 locus for autoimmune diabetes in NOD mice.

The Idd5.1 locus protected against both spontaneous and cyclophosphamide-induced diabetes, but it did not prevent inflammatory infiltration of the islets of Langerhans, and diabetogenic precursor spleen cells from prediabetic NOD and Idd4.scid/scid recipient mice were equally capable of transferring diabetes to immunodeficient NOD.