A type 1 diabetes subgroup with a female bias is characterised by failure in tolerance to thyroid peroxidase at an early age and a strong association with the cytotoxic T-lymphocyte-associated antigen-4 gene

Howson, Joanna M.M.; Dunger, David B.; Nutland, Sarah; Stevens, Helen; Wicker, Linda S.; Todd, John A.

doi:10.1007/s00125-007-0603-6

Cited by 69 publications

(69 citation statements)

References 38 publications

(85 reference statements)

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“…Idd5 is located on mouse chromosome 1 and has been shown by congenic strain analysis to consist of at least two loci, Idd5.1 and Idd5.2, positioned at the proximal and distal ends, respectively, of an ϳ15 Mb interval (3). Idd5.1 was defined as a 2.0 Mb B10-derived resistance interval containing four genes including the candidate genes Ctla4 and Icos (3,4), a remarkable finding since human T1D is associated with CTLA4 (5,6). In addition to the human T1D association with CTLA4, functional studies support the candidacy of Ctla4 as the diabetes gene in the Idd5.1 interval because the B10 allele of Ctla4 produces more of the "ligand-independent" splice form of CTLA-4 (liCTLA-4) than does the NOD allele (6).…”

Section: G Enes Termed Insulin-dependent Diabetes (Idd)mentioning

confidence: 99%

“…For the sets of susceptibility genes in humans that can give rise to isolated T1D, not complicated with AITD disease or related autoantibodies, the CTLA4 SNPs are not associated, or only very weakly, with this subclass of T1D, and we proposed that this is due to the presence and function of human genes similar to Idd5.3 and Idd5.2/Nramp1 that can mask the effect of variation in the CTLA-4 gene. In the minor subgroup of T1D that is complicated with AITD or AITD autoantibodies, ϳ10 -15% of T1D cases, CTLA-4 genetic variation has a strong effect, presumably via its role in regulation of peripheral tolerance, in which the disease-associated CTLA4 haplotype is predisposing to a failure in tolerance to multiple organs or tissues (5). Our current results highlight the complexities of studying autoimmunity genes even in a well-controlled experimental model, and promote further caution in the design, execution, and interpretation of susceptibility gene mapping in humans.…”

Section: Human Gene Discovery and Disease Subclassificationmentioning

confidence: 99%

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Interactions between Idd5.1/Ctla4 and Other Type 1 Diabetes Genes

Hunter

Rainbow

Plagnol

et al. 2007

The Journal of Immunology

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Two loci, Idd5.1 and Idd5.2, that determine susceptibility to type 1 diabetes (T1D) in the NOD mouse are on chromosome 1. Idd5.1 is likely accounted for by a synonymous single nucleotide polymorphism in exon 2 of Ctla4: the B10-derived T1D-resistant allele increases the expression of the ligand-independent isoform of CTLA-4 (liCTLA-4), a molecule that mediates negative signaling in T cells. Idd5.2 is probably Nramp1 (Slc11a1), which encodes a phagosomal membrane protein that is a metal efflux pump and is important for host defense and Ag presentation. In this study, two additional loci, Idd5.3 and Idd5.4, have been defined to 3.553 and 78 Mb regions, respectively, on linked regions of chromosome 1. The most striking findings, however, concern the evidence we have obtained for strong interactions between these four disease loci that help explain the association of human CTLA4 with T1D. In the presence of a susceptibility allele at Idd5.4, the CTLA-4 resistance allele causes an 80% reduction in T1D, whereas in the presence of a protective allele at Idd5.4, the effects of the resistance allele at Ctla4 are modest or, as in the case in which resistance alleles at Idd5.2 and Idd5.3 are present, completely masked. This masking of CTLA-4 alleles by different genetic backgrounds provides an explanation for our observation that the human CTLA-4 gene is only associated with T1D in the subgroup of human T1D patients with anti-thyroid autoimmunity.

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Section: G Enes Termed Insulin-dependent Diabetes (Idd)mentioning

confidence: 99%

Section: Human Gene Discovery and Disease Subclassificationmentioning

confidence: 99%

Interactions between Idd5.1/Ctla4 and Other Type 1 Diabetes Genes

Hunter

Rainbow

Plagnol

et al. 2007

The Journal of Immunology

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“…One well validated region associated with susceptibility to autoimmune disease harbors the CTLA4 gene on chromosome 2q33. An associated allele in this susceptibility region is the G allele of the SNP CT60 (rs3087243; A/G) in the CTLA4 gene region, which has been associated with risk to type 1 diabetes, Graves disease, autoimmune hypothyroidism, systemic lupus erythematosus, and Addison's disease (6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

Allelic variant inCTLA4alters T cell phosphorylation patterns

Maier

Anderson

Jager

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Little is known regarding the functional effects of common autoimmune susceptibility variants on human immune cells. The SNP CT60 (rs3087243; A/G) located in the 3 UTR of the CTLA4 gene has been associated with autoimmune diseases. We examined a cohort of healthy individuals stratified by genotypes at CTLA4 to gain insight into the functional effects of allelic variation on T cell signaling. Using phospho-site-specific mAbs, we tested the hypothesis that the CT60 genotype at CTLA4 is associated with altered T cell antigen receptor (TCR) signaling in naive and/or memory T cells. By normalizing for the extent of the initial TCR signaling event at CD3 , we observed that the relative responsiveness to TCR stimulation as assessed by phosphorylation levels of downstream signaling molecules was altered in naive (CD4 ؉ CD45RA high ) and memory (CD4 ؉ CD45RA low ) T cells obtained from individuals with the disease-susceptibility allele at CTLA4. Thus, allelic variation associated with autoimmune disease can alter the signaling threshold of CD4 ؉ T cells. These experiments provide a rational approach for the dissection of T cell-susceptibility genes in autoimmune diseases.genotype ͉ human ͉ T cell antigen receptor signaling ͉ CTLA4 ͉ autoimmunity T he recent successful completion of several genome-wide association scans, together with the rapid advancement in highthroughput genotyping technologies, have resulted in the discovery of an ever-increasing number of genetic variants associated with susceptibility to human autoimmune diseases (1-5). However, because of the small genetic effects of these variants, compared with the strong genetic effects seen in Mendelian diseases, the study of genotypic variation in relation to phenotypes has been a substantial challenge. One well validated region associated with susceptibility to autoimmune disease harbors the CTLA4 gene on chromosome 2q33. An associated allele in this susceptibility region is the G allele of the SNP CT60 (rs3087243; A/G) in the CTLA4 gene region, which has been associated with risk to type 1 diabetes, Graves disease, autoimmune hypothyroidism, systemic lupus erythematosus, and Addison's disease (6-10).The expression of mRNA isoforms of CTLA4 has been investigated in relation to CTLA4 genotype in healthy controls. Moreover, the genotype-dependent difference in the expression of soluble CTLA4 transcripts appears to be T cell-specific (6, 10). In the nonobese diabetic (NOD) mouse, the orthologous CTLA4 region also is associated with autoimmune diabetes, and, similar to humans, an allelic variant causes the increased expression of a major splice isoform. In the NOD model, the isoform is ligandindependent CTLA-4 (11) and results in strongly inhibited T cell responses, as well as increased susceptibility to disease (12). Together these investigations in both the experimental model and in humans suggest that genetic variation in the CTLA4 gene region may have an important effect on T cell function because of altered T cell signaling.Although CTLA4 is important in aut...

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“…The most widely accepted is the autoimmune genetic hypothesis, assuming involvement of genes associated with immune regulation [17]. Numerous observations have confirmed that genetic susceptibility is shared among autoimmune diseases, with the strongest association seen between T1DM and autoimmune thyroid disease (AITD) [11,12,[18][19][20][21].…”

Section: Discussionmentioning

confidence: 99%

Przypadek pokrzywki autoimmunologicznej współistniejącej z autoimmunologicznym zespołem wielogruczołowym typu III związanym z chorobą Hashimoto, cukrzycą typu 1 i bielactwem

Kasznicki¹,

Drzewoski²

2014

Endokrynologia Polska

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We present a case of autoimmune polyglandular syndrome type III (APS III) associated with Hashimoto's disease, type 1 diabetes mellitus, vitiligo and autoimmune urticaria. This rare genetic disorder occurs with unknown frequency in the Polish population. It is characterised by endocrine tissue destruction resulting in the malfunction of multiple organs. Several cases of APS III associated with organ-specific autoimmune diseases such as coeliac disease, hypogonadism and myasthenia gravis, as well as organ-nonspecific or systemic autoimmune diseases such as sarcoidosis, Sjögren syndrome, and rheumatoid arthritis have been described. To the best of our knowledge, we here describe the first case of APS III associated with autoimmune thyroiditis, type 1 diabetes mellitus, vitiligo and autoimmune urticaria in an adult patient.

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A type 1 diabetes subgroup with a female bias is characterised by failure in tolerance to thyroid peroxidase at an early age and a strong association with the cytotoxic T-lymphocyte-associated antigen-4 gene

Cited by 69 publications

References 38 publications

Interactions between Idd5.1/Ctla4 and Other Type 1 Diabetes Genes

Interactions between Idd5.1/Ctla4 and Other Type 1 Diabetes Genes

Allelic variant inCTLA4alters T cell phosphorylation patterns

Przypadek pokrzywki autoimmunologicznej współistniejącej z autoimmunologicznym zespołem wielogruczołowym typu III związanym z chorobą Hashimoto, cukrzycą typu 1 i bielactwem

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