HLA class I hyper-expression unmasks beta cells but not alpha cells to the immune system in pre-diabetes

Human leukocyte antigens of class-I (HLA-I) molecules are hyper-expressed in insulin-containing islets (ICI) of type 1 diabetic (T1D) donors. This study investigated the HLA-I expression in autoantibody positive (AAB+) donors and defined its intra-islet and intracellular localization as well as prox...

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Veröffentlicht in:Journal of autoimmunity Jg. 119; S. 102628
Hauptverfasser: Benkahla, Mehdi A., Sabouri, Somayeh, Kiosses, William B., Rajendran, Sakthi, Quesada-Masachs, Estefania, von Herrath, Matthias G.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England Elsevier Ltd 01.05.2021
Schlagworte:
Alpha cells
Autoantibodies - immunology
Autoantigens - immunology
Autoimmunity
Beta cells
Biomarkers
Diabetes Mellitus, Type 1 - etiology
Diabetes Mellitus, Type 1 - metabolism
Disease Susceptibility - immunology
Fluorescent Antibody Technique
Gene Expression
Glucagon-Secreting Cells - metabolism
Histocompatibility Antigens Class I - genetics
Histocompatibility Antigens Class I - immunology
HLA class I
Humans
Insulin-Secreting Cells - immunology
Insulin-Secreting Cells - metabolism
Islets of Langerhans - immunology
Islets of Langerhans - metabolism
Islets of Langerhans - pathology
nPOD
Prediabetic State - etiology
Prediabetic State - immunology
Protein Transport
T-Lymphocyte Subsets - immunology
T-Lymphocyte Subsets - metabolism
Type 1 diabetes
Beta cells
HLA class I
nPOD
Type 1 diabetes
Alpha cells
ISSN:0896-8411, 1095-9157, 1095-9157
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Zusammenfassung:Human leukocyte antigens of class-I (HLA-I) molecules are hyper-expressed in insulin-containing islets (ICI) of type 1 diabetic (T1D) donors. This study investigated the HLA-I expression in autoantibody positive (AAB+) donors and defined its intra-islet and intracellular localization as well as proximity to infiltrating CD8 T cells with high-resolution confocal microscopy. We found HLA-I hyper-expression had already occurred prior to clinical diagnosis of T1D in islets of AAB+ donors. Interestingly, throughout all stages of disease, HLA-I was mostly expressed by alpha cells. Hyper-expression in AAB+ and T1D donors was associated with intra-cellular accumulation in the Golgi. Proximity analysis showed a moderate but significant correlation between HLA-I and infiltrating CD8 T cells only in ICI of T1D donors, but not in AAB+ donors. These observations not only demonstrate a very early, islet-intrinsic immune-independent increase of HLA-I during diabetes pathogenesis, but also point towards a role for alpha cells in T1D. •HLA-I was hyperexpressed in autoantibody positive (AAB+) patients prior to clinical diagnosis of T1D.•HLA-I was mostly expressed by alpha cells irrespective of disease status.•In islets of AAB+ and T1D donors, HLA-I accumulates in the Golgi compartment.•A significant correlation between HLA-I and infiltrating CD8 T cells in insulin-containing islets of T1D donors.
Bibliographie:ObjectType-Article-1
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Current address: Sanofi, Translational Medicine & Early development, 1 Mountain Road, Farmingham, MA, 01701, USA
Author contributions: MAB: Data curation, formal analysis, Writing - original draft, Writing - review & editing. SS: Data curation, Writing - review & editing. WBK: Data curation, Formal analysis, Software, Writing - review & editing. SR: Formal analysis, Writing - review & editing. EQM: Formal analysis, Writing - review & editing. MGvH: Funding acquisition, supervision, formal analysis, writing - review & editing.
ISSN:0896-8411
1095-9157
1095-9157
DOI:10.1016/j.jaut.2021.102628