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

Autor: E. J. P. de Koning, A.H. de Ru, P.A. van Veelen, A de Haan, Bart O. Roep, Rene J. Mclaughlin, M van Lummel, Arnaud Zaldumbide
Přispěvatelé: Hubrecht Institute for Developmental Biology and Stem Cell Research
Rok vydání: 2016
Předmět:
0301 basic medicine
endocrine system
Proteome
endocrine system diseases
type 1 diabetes
Tissue transglutaminase
T-Lymphocytes
Immunology
030209 endocrinology & metabolism
Autoantigens
DC
Proinflammatory cytokine
Immune tolerance
Islets of Langerhans
03 medical and health sciences
HLA-DR3 Antigen
0302 clinical medicine
HLA-DQ Antigens
Immune Tolerance
medicine
Humans
Immunology and Allergy
Deamidation
Inflammation
islets
geography
Transglutaminases
geography.geographical_feature_category
C-Peptide
biology
Pancreatic islets
T-cell receptor
nutritional and metabolic diseases
Peripheral tolerance
Dendritic Cells
Original Articles
Islet
Amides
HLA
Diabetes Mellitus
Type 1
030104 developmental biology
medicine.anatomical_structure
post-translational modification
biology.protein
Protein Processing
Post-Translational
Zdroj: Clinical and Experimental Immunology, 185(2), 133-140
Clinical & Experimental Immunology. Wiley-Blackwell
ISSN: 1365-2249
0009-9104
DOI: 10.1111/cei.12775
Popis: 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.
Databáze: OpenAIRE
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