Human islets and dendritic cells generate post-translationally modified islet auto-antigens

Rene J McLaughlin, Anne de Haan, Arnaud Zaldumbide, Eelco J de Koning, Arnoud H de Ru, Peter A van Veelen, Menno van Lummel, Bart O Roep

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgaveArtikelWetenschappelijkpeer review

Samenvatting

Initiation of type 1 diabetes (T1D) requires a break in peripheral tolerance. New insights into neo-epitope formation indicate that post-translational modification of islet auto-antigens, for example via deamidation, may be an important component of disease initiation or exacerbation. Indeed, deamidation of islet auto-antigens increases their binding affinity to the T1D highest-risk HLA haplotypes HLA-DR3/DQ2 and -DR4/DQ8, increasing the chance that T-cells reactive to deamidated auto-antigens can be activated upon T-cell receptor ligation. Here we investigated human pancreatic islets and inflammatory and tolerogenic human dendritic cells (DC and tolDC) as potential sources of deamidated islet auto-antigens and examined whether deamidation is altered in an inflammatory environment. Islets, DC and tolDC contained tissue transglutaminase, the key enzyme responsible for peptide deamidation, and enzyme activity increased following an inflammatory insult. Islets treated with inflammatory cytokines were found to contain deamidated insulin C-peptide. DC, heterozygous for the T1D highest-risk DQ2/8, pulsed with native islet auto-antigens could present naturally processed deamidated neo-epitopes. HLA-DQ2 or -DQ8 homozygous DC did not present deamidated islet peptides. This study identifies both human islets and DC as sources of deamidated islet auto-antigens and implicates inflammatory activation of tissue transglutaminase as a potential mechanism for islet and DC deamidation. This article is protected by copyright. All rights reserved.

Originele taal-2Engels
TijdschriftClinical & Experimental Immunology
DOI's
StatusGepubliceerd - 09 feb 2016

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