What the HLA-I!—Classical and Non-classical HLA Class I and Their Potential Roles in Type 1 Diabetes

• Published in: Current diabetes reports 2019-12, Vol.19 (12), p.159-11, Article 159
• Main Authors: Wyatt, Rebecca C., Lanzoni, Giacomo, Russell, Mark A., Gerling, Ivan, Richardson, Sarah J.
• Format: Article
• Language: English
• Subjects: B-Lymphocytes - immunology; CD8 Antigens - immunology; Diabetes; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - physiopathology; Histocompatibility Antigens Class I - biosynthesis; Histocompatibility Antigens Class I - immunology; HLA-E Antigens; HLA-G Antigens - biosynthesis; Humans; Inflammation - immunology; Insulin-Secreting Cells - immunology; Islets of Langerhans - immunology; Islets of Langerhans - physiopathology; Killer Cells, Natural - immunology; Medicine; Medicine & Public Health; Pathogenesis of Type 1 Diabetes (A Pugliese and SJ Richardson; Pathogenesis of Type 1 Diabetes (A Pugliese and SJ Richardson, Section Editors); Proteins; Section Editors; T-Lymphocytes - immunology; Topical Collection on Pathogenesis of Type 1 Diabetes; Up-Regulation
• ISSN: 1534-4827; 1539-0829
• DOI: 10.1007/s11892-019-1245-z

Purpose of Review Hyperexpression of classical HLA class I (HLA-I) molecules in insulin-containing islets has become a widely accepted hallmark of type 1 diabetes pathology. In comparison, relatively little is known about the expression, function and role of non-classical subtypes of HLA-I. This review focuses on the current understanding of the non-classical HLA-I subtypes: HLA-E, HLA-F and HLA-G, within and outside the field of type 1 diabetes, and considers the possible impacts of these molecules on disease etiology. Recent Findings Evidence is growing to suggest that non-classical HLA-I proteins are upregulated, both at the RNA and protein levels in the pancreas of individuals with recent-onset type 1 diabetes. Moreover, associations between non-classical HLA-I genotypes and age at onset of type 1 diabetes have been reported in some studies. As with classical HLA-I, it is likely that hyperexpression of non-classical HLA-I is driven by the release of diffusible interferons by stressed β cells (potentially driven by viral infection) and exacerbated by release of cytokines from infiltrating immune cells. Summary Non-classical HLA-I proteins predominantly (but not exclusively) transduce negative signals to immune cells infiltrating at the site of injury/inflammation. We propose a model in which the islet endocrine cells, through expression of non-classical HLA-I are fighting back against the infiltrating immune cells. By inhibiting the activity and function on NK, B and select T cells, the non-classical HLA-I, proteins will reduce the non-specific bystander effects of inflammation, while at the same time still allowing the targeted destruction of β cells by specific islet-reactive CD8+ T cells.