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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.

Author:
  • CO Jonson
  • Åke Lernmark
  • J Ludvigsson
  • EA Rutledge
  • A Hinkkanen
  • M Faresjö
Publishing year: 2007
Language: English
Pages: 185-192
Publication/Series: Pediatr Diabetes
Volume: 8
Issue: 4
Document type: Journal article

Abstract english

Type 1 diabetes (T1D) is an autoimmune disease associated with the destruction of pancreatic β cells and genetically linked to human leukocyte antigen (HLA) class II DR3-DQ2 and DR4-DQ8 haplotypes. The +49A/G polymorphism of the immunoregulatory cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene is also associated with T1D. Genetic and environmental risk factors precede the onset of T1D, which is characterized by a T helper 1 cell-dominating cytokine response to diabetes-related autoantigens. Aim:



To investigate immunological differences between healthy children with and without CTLA-4 +49A/G and HLA genetic susceptibility for T1D. Study design:



Young, 7-15 years of age, healthy subjects (n = 58) were investigated to test whether CTLA-4 +49A/G genotype was associated with enzyme-linked immunospot assay T-cell responses to T1D-related autoantigens. Because T1D is primarily HLA-DQ associated, we stratified the healthy subjects by HLA genotypes associated with the disease. Results:



Peptide of heat shock protein 60 induced a higher interferon-γ (IFN-γ) response in subjects with risk-associated CTLA-4 polymorphism (GG genotype) (p = 0.02) while glutamic acid decarboxylase 65-induced interleukin-4 (IL-4) secretion was lower in GG genotype subjects (p = 0.02). Conclusion:



The increased IFN-γ 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.

Keywords

  • Endocrinology and Diabetes
  • CTLA-4
  • cytokines
  • HLA
  • SNP
  • type 1 diabetes mellitus

Other

Published
  • Diabetes and Celiac Unit
E-mail: ake [dot] lernmark [at] med [dot] lu [dot] se

Principal investigator

Diabetes and Celiac Unit

+46 40 39 19 01

+46 70 616 47 79

60:11:015

Jan Waldenströms gata 35, Malmö

33

Lund University Diabetes Centre, CRC, SUS Malmö, Jan Waldenströms gata 35, House 91:12. SE-214 28 Malmö. Telephone: +46 40 39 10 00