Abnormal expression of CTLA-4 by T cells from patients with myasthenia gravis: effect of an AT-rich gene sequence

Wang, Xiongbiao; Kakoulidou, Maria; Giscombe, Ricardo; Qiu, Qianhui; Huang, DeRen; Pirskanen, Ritva; Lefvert, Ann Kari

doi:10.1016/s0165-5728(02)00228-x

Cited by 132 publications

(124 citation statements)

References 45 publications

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Section: Sctla-4 and Autoimmune Diseasesmentioning

confidence: 90%

“…A sCTLA-4, namely a functional molecule with specific CD80 and CD86 binding ability, generated by alternatively spliced mRNA has been described [10,13,20,[49][50][51][52][53]. The mRNA encoding sCTLA-4 consists of three exons: exon 1 encoding the leader peptide, exon 2 the ligand-binding domain, and exon 4 the cytoplasmic tail, but it lacks exon 3 encoding the transmembrane domain [10,20,53].…”

Section: Soluble Form Of Ctla-4mentioning

confidence: 99%

“…Increased serum levels of sCTLA-4 have been reported in patients with several autoimmune diseases significantly more often than in healthy individuals [20, 33, 49-51, 60, 62]. Patients with GD [20,33,49], HT [20,49], MG [50], systemic lupus erythematosus [55], systemic sclerosis (SSc) [54], CD [51], autoimmune pancreatitis (AIP) [62] and spondyloarthropathies and RA [60] have been investigated. The first studies on sCTLA-4 serum levels in autoimmune disease were performed 10 years ago [20] in 17 patients with GD and 3 patients with HT.…”

Section: Sctla-4 and Autoimmune Diseasesmentioning

confidence: 99%

“…Patients with MG also show increased serum levels of sCTLA-4 [50]. The median sCTLA-4 level in a group of 96 patients with MG was 6.8 ng/ml (range 0-1,200 ng/ml), while in the control group it was 3.0 ng/ml (range 0-600 ng/ml; p<0.001) [50]. The serum levels of sCTLA-4 have been found to be positively correlated with the serum concentration of antibodies against the acetylcholine receptor (r=0.396, p<0.01) [50].…”

Section: Sctla-4 and Autoimmune Diseasesmentioning

confidence: 99%

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The soluble CTLA-4 receptor and its role in autoimmune diseases: an update

Saverino

Simone

Bagnasco

et al. 2010

Autoimmun Highlights

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CTLA-4, initially described as a membranebound molecule, is a costimulatory receptor transducing a potent inhibitory signal. Increasing evidence shows the CTLA-4 gene to be an important susceptibility locus for autoimmune endocrinopathies and other autoimmune disorders. A soluble form of cytotoxic T-lymphocyte-associated antigen-4 (sCTLA-4) has been established and shown to possess CD80/CD86 binding activity and in vitro immunoregulatory functions. sCTLA-4 is generated by alternatively spliced mRNA. Whereas low levels of sCTLA-4 are detected in normal human serum, increased serum levels are observed in several autoimmune diseases (e.g. Graves’ disease, myasthenia gravis, systemic lupus erythematosus, type 1 diabetes, systemic sclerosis, coeliac disease, autoimmune pancreatitis and primary biliary cirrhosis). The biological significance of increased sCTLA-4 serum levels is not fully clarified yet. On the one hand, it can be envisaged that sCTLA-4 specifically inhibits early T-cell activation by blocking the interaction of CD80/CD86 with the costimulatory receptor CD28. On the other hand, higher levels of sCTLA-4 could compete for the binding of the membrane form of CTLA-4 with CD80/CD86 in the later phases of T-lymphocyte activation, causing a reduction in inhibitory signalling. This double-edged nature of sCTLA-4 to block the binding of CD28 to CD80/CD86 may result in different outcomes during the clinical course of an autoimmune disease.

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Section: Sctla-4 and Autoimmune Diseasesmentioning

confidence: 90%

Section: Soluble Form Of Ctla-4mentioning

confidence: 99%

Section: Sctla-4 and Autoimmune Diseasesmentioning

confidence: 99%

Section: Sctla-4 and Autoimmune Diseasesmentioning

confidence: 99%

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The soluble CTLA-4 receptor and its role in autoimmune diseases: an update

Saverino

Simone

Bagnasco

et al. 2010

Autoimmun Highlights

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“…Indeed, preliminary data in myasthenia gravis showed that the (AT)n microsatellite at the 3 0 UTR of the CTLA-4 gene influenced the half-life of the CTLA-4 mRNA, 48,49 and contributed to decreased mRNA stability. 50 This could provide an attractive explanation for the association between the short alleles of the (AT)n microsatellite and AITD, as well as other autoimmune diseases. Other studies have reported that individuals carrying thymidine at position -318 of the CTLA-4 promoter showed significantly increased expression both of cell-surface CTLA-4 after cellular stimulation and CTLA-4 mRNA in nonstimulated cells.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the CTLA-4, CD28, and inducible costimulator (ICOS) genes in autoimmune thyroid disease

et al. 2003

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The cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene on 2q33 is associated with autoimmune thyroid diseases (AITDs). Our earlier study in 56 families showed linkage of 2q33 to the presence of thyroid antibodies (TAbs). The goals of this study were to confirm the linkage of the 2q33 region to TAbs, to fine map this region, and study the ICOS gene. We performed a linkage study in an expanded data set of 99 multiplex AITD-TAb families (529 individuals). The highest two-point LOD score of 2.9 was obtained for marker D2S325 on 2q33. To fine map this locus, we genotyped 238 Caucasian AITD patients and 137 controls for five additional markers in the linked locus, which contained the CTLA-4, CD28, and ICOS genes. The A/G singlenucleotide polymorphism at position 49 of CTLA-4 was associated with AITD (P¼0.01, OR¼1.5), while markers inside CD28 and ICOS were not. Functional studies have shown that the G allele was associated with reduced inhibition of T-cell proliferation by CTLA-4. We concluded that: (1) the AITD gene in the 2q33 locus is the CTLA-4 gene and not the CD28 or ICOS genes; and (2) the G allele is associated with decreased function of CTLA-4.

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New Insights Into the Genetics of Autoimmune Myasthenia Gravis

Lisak

Barcellos

2015

JAMA Neurol

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Abnormal expression of CTLA-4 by T cells from patients with myasthenia gravis: effect of an AT-rich gene sequence

Cited by 132 publications

References 45 publications

The soluble CTLA-4 receptor and its role in autoimmune diseases: an update

The soluble CTLA-4 receptor and its role in autoimmune diseases: an update

Analysis of the CTLA-4, CD28, and inducible costimulator (ICOS) genes in autoimmune thyroid disease

New Insights Into the Genetics of Autoimmune Myasthenia Gravis

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