The importance of CTLA-4 polymorphism and human leukocyte antigen genotype for the induction of diabetes-associated cytokine response in healthy school children

Jonson, Carl‐Oscar; Lernmark, Åke; Ludvigsson, Johnny; Rutledge, Elizabeth A.; Hinkkanen, Ari; Faresjö, Maria

doi:10.1111/j.1399-5448.2007.00245.x

Cited by 7 publications

(4 citation statements)

References 42 publications

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“…In combination with previous reports, the role of CTLA-4 in T1D with increasing age can be understood as partly due to the fact that different environmental factors can trigger autoimmune processes in different age groups. The role of CTLA-4 gene has been evident from a clinical perspective in several studies in association with early diagnosis, differential cytokines profile, and recently with differences between fulminant T1D and so-called classic T1D [36,37]. This information is concordant with our data about similar associations in T1D in Chilean children.…”

Section: Discussionsupporting

confidence: 94%

Association of CTLA-4 polymorphisms and clinical-immunologic characteristics at onset of type 1 diabetes mellitus in children

et al. 2009

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Section: Discussionsupporting

confidence: 94%

Association of CTLA-4 polymorphisms and clinical-immunologic characteristics at onset of type 1 diabetes mellitus in children

et al. 2009

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“…Peptides with overlapping sequence from HSP60, were detected in DQ8, DQ2-8, and DQ8-2 samples. These peptide sequences, as well as an additional HSP60 peptide eluted from DQ2-8 and three IA-2 peptide sequences eluted from DQ8, DQ2-8, and DQ8-2 samples have been previously reported as positive stimulators in autoreactive CD4 + T-cell activation assays (Table 1) [39][40][41][42][43][44][45][46][47][48][49][50][51][52]. We also confirmed that the ZnT8 peptide binds T1D-susceptible DQ molecules with relatively higher binding affinity than the pan-DQ binding peptide, CLIP1 (Fig.…”

Section: Direct Analysis Of Dq-bound Clip and T1d-associated Autoantimentioning

confidence: 96%

Type 1 diabetes associated HLA‐DQ2 and DQ8 molecules are relatively resistant to HLA‐DM mediated release of invariant chain‐derived CLIP peptides

et al. 2016

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Summary HLA-DM is essential for editing peptides bound to MHC class II, thus influencing the repertoire of peptides mediating selection and activation of CD4+ T cells. Individuals expressing HLA-DQ2 or DQ8, and DQ2/8 trans-dimers, have elevated risk for type 1 diabetes (T1D). Cells co-expressing DM with these DQ molecules were observed to express elevated levels of CLIP (Class II associated invariant chain peptide). Relative resistance to DM-mediated editing of CLIP was further confirmed by HPLC-MS/MS analysis of eluted peptides, which also demonstrated peptides from known T1D-associated autoantigens, including a shared epitope from ZnT8 that is presented by all four major T1D-susceptible DQ molecules. Assays with purified recombinant soluble proteins confirmed that DQ2-CLIP complexes are highly resistant to DM editing, whereas DQ8-CLIP is partially sensitive to DM, but with an apparent reduction in catalytic potency. DM sensitivity was enhanced in mutant DQ8 molecules with disruption of hydrogen bonds that stabilize DQ8 near the DM-binding region. Our findings show that T1D-susceptible DQ2 and DQ8 share significant resistance to DM editing, compared with control DQ molecules. The relative resistance of the T1D-susceptible DQ molecules to DM editing and preferential presentation of T1D-associated autoantigenic peptides may contribute to the pathogenesis of T1D.

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“…Interestingly, our results further indicated that +49 G/A affected CTLA-4 expression in FoxP3 hi , but not CD25 hi Foxp3 + activated Treg subsets. Several studies also indicated that PHA or peptide of heat shock protein 60 induced a higher IFN-γ response, while GAD65 induced a lower IL-4 secretion in subjects with risk GG genotype of +49 G/A 29 , 30 , one of the interpretations might be individuals with G allele had lower CTLA-4 expression in Treg subsets and reduced suppressive function. It should be noted that CTLA-4 also expressed by diverse cell types, including activated CD4+ conventional T (Tconv) cells, activated B cells, and CD8 T cells 31 – 33 .…”

Section: Discussionmentioning

confidence: 99%

CTLA-4 +49 G/A, a functional T1D risk SNP, affects CTLA-4 level in Treg subsets and IA-2A positivity, but not beta-cell function

Yang

Chen

et al. 2018

Sci Rep

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To investigate whether CTLA-4 +49 G/A (rs231775), a tagSNP in Asian, is a functional T1D SNP, we genotyped this SNP with 1035 T1D patients and 2575 controls in Chinese Han population. And 1280 controls measured insulin release and sensitivity based on an oral glucose tolerance test; 283 newly diagnosed T1D patients assayed C-peptide level based on a mixed-meal tolerance test. 31 controls were analyzed for different T cell subsets by multi-color flow cytometry. Under additive model, we found that CTLA-4 +49 G/A was significantly associated with T1D (P = 2.82E-04, OR = 1.25, 95% CI: 1.12–1.41), which was further confirmed by meta-analysis (P = 1.19E-08, OR = 1.65, 95% CI: 1.38–1.96) in Chinese Han population. Although we did not find any association between this SNP and beta-cell function in either healthy individuals or newly diagnosed T1D patients, healthy individuals carrying GG/GA genotypes had lower CTLA-4 expression in naïve or activated CD4 Treg subsets (P = 0.0046 and 0.0317 respectively). A higher positive rate of IA-2A was observed among T1D patients with GG genotype compared with AA (OR = 0.51, 95% CI: 0.30–0.84, p = 0.008). Collectively, CTLA-4 +49 G/A reached a GWAS significant association with T1D risk in Chinese Han population, affects CTLA-4 expression in Treg subsets and subsequently humoral immunity in T1D patients.

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The importance of CTLA-4 polymorphism and human leukocyte antigen genotype for the induction of diabetes-associated cytokine response in healthy school children

Abstract: The increased IFN-gamma response and lower IL-4 response toward diabetes-related autoantigens shown in CTLA-4 +49 GG risk subjects show a possible mechanism for the association between CTLA-4 and T1D.

Cited by 7 publications

References 42 publications

Association of CTLA-4 polymorphisms and clinical-immunologic characteristics at onset of type 1 diabetes mellitus in children

Association of CTLA-4 polymorphisms and clinical-immunologic characteristics at onset of type 1 diabetes mellitus in children

Type 1 diabetes associated HLA‐DQ2 and DQ8 molecules are relatively resistant to HLA‐DM mediated release of invariant chain‐derived CLIP peptides

CTLA-4 +49 G/A, a functional T1D risk SNP, affects CTLA-4 level in Treg subsets and IA-2A positivity, but not beta-cell function

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