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Posttranslational modification of HLA-DQ binding islet autoantigens in type 1 diabetes.
van Lummel, Menno; Duinkerken, Gaby; van Veelen, Peter A; de Ru, Arnoud; Cordfunke, Robert; Zaldumbide, Arnaud; Gomez-Touriño, Iria; Arif, Sefina; Peakman, Mark; Drijfhout, Jan W; Roep, Bart O.
Afiliação
  • van Lummel M; Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
Diabetes ; 63(1): 237-47, 2014 Jan.
Article em En | MEDLINE | ID: mdl-24089515
Posttranslational modification (PTM) of islet autoantigens can cause lack of central tolerance in type 1 diabetes (T1D). Tissue transglutaminase (tTG), involved in PTM of gluten antigens in celiac disease, creates negatively charged peptides favored by T1D-predisposing HLA-DQ molecules, offering an attractive candidate modifying islet autoantigens in T1D. The highly predisposing HLA-DQ8cis/trans molecules share preferences for negatively charged peptides, as well as distinct peptide-binding characteristics that distinguish their peptide-binding repertoire. We screened islet autoantigens with the tTG substrate motif for candidate-modified epitopes binding to HLA-DQ8cis/trans and identified 31 candidate islet epitopes. Deamidation was confirmed for 28 peptides (90%). Two of these epitopes preferentially bound to HLA-DQ8cis and six to HLA-DQ8trans upon deamidation, whereas all other peptides bound equally to HLA-DQ8cis/trans. HLA-DQ8cis-restricted T cells from a new-onset T1D patient could only be generated against a deamidated proinsulin peptide, but cross-reacted with native proinsulin peptide upon restimulation. The rate of T-cell autoreactivity in recent-onset T1D patients extended from 42% to native insulin to 68% adding responses to modified proinsulin, versus 20% and 37% respectively, in healthy donors. Most patients responded by interferon-γ, whereas most healthy donors produced interleukin-10 only. Thus, T-cell autoreactivity exists to modified islet epitopes that differs in quality and quantity between patients and healthy donors.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Autoantígenos / Linfócitos T / Antígenos HLA-DQ / Processamento de Proteína Pós-Traducional / Diabetes Mellitus Tipo 1 Tipo de estudo: Prognostic_studies Limite: Child / Female / Humans Idioma: En Revista: Diabetes Ano de publicação: 2014 Tipo de documento: Article País de afiliação: Holanda

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Autoantígenos / Linfócitos T / Antígenos HLA-DQ / Processamento de Proteína Pós-Traducional / Diabetes Mellitus Tipo 1 Tipo de estudo: Prognostic_studies Limite: Child / Female / Humans Idioma: En Revista: Diabetes Ano de publicação: 2014 Tipo de documento: Article País de afiliação: Holanda