Defective expression and tyrosine phosphorylation of the T cell receptor zeta chain in peripheral blood T cells from systemic lupus erythematosus patients

Pang, Mao; Setoyama, Yumiko; Tsuzaka, Kensei; Yoshimoto, Keiko; Amano, Kouichi; Abe, Tomoatsu; Takeuchi, Tsutomu

doi:10.1046/j.1365-2249.2002.01833.x

Cited by 44 publications

(41 citation statements)

References 61 publications

(62 reference statements)

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“…In line with this, defects in CD3z expression/ function were suggested to have implications for the development of human autoimmune phenotypes (24,35,36). Thus, several groups reported altered expression and function of CD3z in patients with SLE (19,20) or rheumatoid arthritis (21,22). Moreover, familybased association studies of SLE showed that polymorphisms in the CD3z 39-untranslated region are associated with defective CD3z expression in SLE patients (37).…”

Section: Discussionmentioning

confidence: 92%

“…Ras is a GTPase upstream of the MAPK cascade pathway, and its activity is dependent on phosphorylation of CD3z and ZAP-70. In humans, a defective expression of the CD3z-chain has been associated with autoimmune diseases, including systemic lupus erythematosus (SLE) (19,20) and rheumatoid arthritis (21,22), with T cells from these patients displaying a functional impairment. Together, these data suggest that downregulation of CD3z has functional consequences in systemic autoimmunity (23,24).…”

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confidence: 99%

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Variation in the Cd3ζ (Cd247) Gene Correlates with Altered T Cell Activation and Is Associated with Autoimmune Diabetes

Lundholm

Mayans

Motta

et al. 2010

The Journal of Immunology

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Section: Discussionmentioning

confidence: 92%

mentioning

confidence: 99%

Variation in the Cd3ζ (Cd247) Gene Correlates with Altered T Cell Activation and Is Associated with Autoimmune Diabetes

Lundholm

Mayans

Motta

et al. 2010

The Journal of Immunology

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“…In T cells obtained from peripheral blood of subjects with the autoimmune disease systemic lupus erythematosus, defective expression and tyrosine phosphorylation of the TCR chain has been reported (35)(36)(37). The molecular mechanisms of expression and phosphorylation defects in the TCR chain may involve distinct DNA sequences in the 3Ј UTR of the CD247 gene encoding TCR .…”

Section: Discussionmentioning

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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“…Cells were lysed with the lysis buffer and disrupted by sonication according to a previously described method (19). After centrifuging at 10,000 ϫ g for 5 min, the supernatant was loaded on a 12.5% SDS-PAGE gel by a reducing method.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…The flow cytometric analysis procedure has been described previously (19). Briefly, the MA5.8 mutants were stained with an FITC-conjugated Armenian hamster anti-mouse CD3⑀ mAb (145-2C11; Coulter Immunology), an FITC-conjugated mouse anti-human mAb (TIA-2; Coulter Immunology), or a PE-conjugated rat anti-mouse Sdc1 mAb (281-2; BD Biosciences).…”

Section: Flow Cytometric Analysismentioning

confidence: 99%

DNA Microarray Gene Expression Profile of T Cells with the Splice Variants of TCRζ mRNA Observed in Systemic Lupus Erythematosus

Tsuzaka

Nozaki

Kumazawa

et al. 2006

The Journal of Immunology

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We have reported that the TCRζ mRNA with alternatively spliced 3′ UTR (ζ mRNA/as-3′-untranslated region (UTR)) and ζ mRNA lacking exon 7 (ζ mRNA/exon 7−) observed in systemic lupus erythematosus patient T cells can lead to down-regulation of both ζ and TCR/CD3 complexes. To determine whether these T cells expressing decreased ζ exhibit differential transcription patterns, we transfected retrovirus vectors containing wild-type ζ cDNA, ζ cDNA/as-3′ UTR, and ζ cDNA/exon 7− into murine T cell hybridoma MA5.8 cells which lack ζ expression to construct the MA5.8 mutants WT, AS3′ UTR, and EX7−, respectively. FACS analyses demonstrated reduced cell surface expression of ζ and TCR/CD3 complexes on the AS3′ UTR mutant and the EX7− mutant in comparison to that on the WT mutant. Total RNA was collected after stimulating the MA5.8 mutants with anti-CD3 Ab. Reverse-transcribed cDNA was applied to the mouse cDNA microarray containing 8691 genes, and the results were confirmed by real-time PCR. The results showed that 36 genes encoding cytokines and chemokines, including IL-2, IL-15, IL-18, and TGF-β2, were down-regulated in both the AS3′ UTR mutant and the EX7− mutant. Another 16 genes were up-regulated in both, and included genes associated with membranous proteins and cell damage granules, including the genes encoding poliovirus receptor-related 2, syndecan-1, and granzyme A. Increased protein expression of these genes was confirmed by Western blot and FACS analyses. Identification of these responsive genes in T cells in which the ζ and TCR/CD3 complexes were down-regulated may help to better understand the pathogenesis of systemic lupus erythematosus.

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Defective expression and tyrosine phosphorylation of the T cell receptor zeta chain in peripheral blood T cells from systemic lupus erythematosus patients

Cited by 44 publications

References 61 publications

Variation in the Cd3ζ (Cd247) Gene Correlates with Altered T Cell Activation and Is Associated with Autoimmune Diabetes

Variation in the Cd3ζ (Cd247) Gene Correlates with Altered T Cell Activation and Is Associated with Autoimmune Diabetes

Allelic variant inCTLA4alters T cell phosphorylation patterns

DNA Microarray Gene Expression Profile of T Cells with the Splice Variants of TCRζ mRNA Observed in Systemic Lupus Erythematosus

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