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

Abstract

Purpose of ReviewHyperexpression 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 FindingsEvidence 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.SummaryNon-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.

HLA-G 14-bp insertion/deletion polymorphism and risk of coronavirus disease 2019 (COVID-19) among Iraqi patients

“…It has been suggested that during clot formation an amount of sHLA-G is trapped and/or consumed [47] . In addition, there are other causes that can affect sHLA-G level in relation to HLA-G 14-bp Ins/Del polymorphism including therapies and co-morbidities (for instance diabetes and cardiovascular disease), which were not identified in the current study, as it was observed that sHLA-G level may be affected by them [11] , [14] , [17] , [23] , [48] .…”

“…They are involved in presenting viral epitopes to T cells and inducing activation, differentiation and proliferation of these cells to become effective antiviral cells [10] . Whereas, non-classical HLA-class I molecules appear mostly to have immunosuppressive functions [11] .…”

Immunomodulatory Potential of Non-Classical HLA-G in Infections including COVID-19 and Parasitic Diseases

“…The classical molecules show high polymorphism and are characterized by unique patterns of transcription, protein structure, and immunological function. Non-classical MHC-I molecules exert functions in both the innate and adaptive immune system and, compared to classical MHC-I, appear to have mostly inhibitory effects on immune cells via interaction with inhibitory receptors [ 1 ].…”

Making Insulin and Staying Out of Autoimmune Trouble: The Beta-Cell Conundrum

“…Protective factors at play in alpha cells may include their lower biosynthetic rate, the narrower dynamic range of their secretory response ( 34 ), their lower susceptibility to ER stress-induced apoptosis ( 35 ), and their higher expression of non-classical, inhibitory MHC-I molecules, i.e. human leukocyte antigen (HLA)-E ( 36 ). Moreover, autophagy seems less important for the maintenance of alpha-cell metabolism ( 37 ) than it is for beta cells ( 38 ), possibly making autophagy-related APP pathways less active.…”