Human islets and dendritic cells generate post‐translationally modified islet autoantigens

Summary The initiation of type 1 diabetes (T1D) requires a break in peripheral tolerance. New insights into neoepitope formation indicate that post‐translational modification of islet autoantigens, for example via deamidation, may be an important component of disease initiation or exacerbation. Inde...

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Bibliographic Details
Published in:Clinical and experimental immunology 2016-08, Vol.185 (2), p.133-140
Main Authors: McLaughlin, R. J., de Haan, A., Zaldumbide, A., de Koning, E. J., de Ru, A. H., van Veelen, P. A., van Lummel, M., Roep, B. O.
Format: Article
Language:English
Subjects:
Amides - chemistry
Autoantigens - biosynthesis
Autoantigens - genetics
Autoantigens - immunology
Autoantigens - metabolism
C-Peptide - immunology
Dendritic cells
Dendritic Cells - immunology
Dendritic Cells - physiology
Diabetes Mellitus, Type 1 - immunology
Enzymes
HLA
HLA-DQ Antigens - immunology
HLA-DR3 Antigen - immunology
Humans
Immune Tolerance
Inflammation - immunology
islets
Islets of Langerhans - cytology
Islets of Langerhans - immunology
Islets of Langerhans - physiology
Original
post‐translational modification
Protein Processing, Post-Translational
Proteome
T cell receptors
T-Lymphocytes - immunology
Transglutaminases - metabolism
type 1 diabetes
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Summary:Summary The initiation of type 1 diabetes (T1D) requires a break in peripheral tolerance. New insights into neoepitope formation indicate that post‐translational modification of islet autoantigens, for example via deamidation, may be an important component of disease initiation or exacerbation. Indeed, deamidation of islet autoantigens increases their binding affinity to the T1D highest‐risk human leucocyte antigen (HLA) haplotypes HLA‐DR3/DQ2 and ‐DR4/DQ8, increasing the chance that T cells reactive to deamidated autoantigens 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 autoantigens 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 autoantigens could present naturally processed deamidated neoepitopes. 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 autoantigens and implicates inflammatory activation of tissue transglutaminase as a potential mechanism for islet and DC deamidation.
ISSN:0009-9104
1365-2249
DOI:10.1111/cei.12775