The role of the interferon/JAK-STAT axis in driving islet HLA-I hyperexpression in type 1 diabetes
The hyperexpression of human leukocyte antigen class I (HLA-I) molecules on pancreatic beta-cells is widely accepted as a hallmark feature of type 1 diabetes pathogenesis. This response is important clinically since it may increase the visibility of beta-cells to autoreactive CD8+ T-cells, thereby a...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-10-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2023.1270325/full |
| _version_ | 1827798695285882880 |
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| author | Mark A. Russell Sarah J. Richardson Noel G. Morgan |
| author_facet | Mark A. Russell Sarah J. Richardson Noel G. Morgan |
| author_sort | Mark A. Russell |
| collection | DOAJ |
| description | The hyperexpression of human leukocyte antigen class I (HLA-I) molecules on pancreatic beta-cells is widely accepted as a hallmark feature of type 1 diabetes pathogenesis. This response is important clinically since it may increase the visibility of beta-cells to autoreactive CD8+ T-cells, thereby accelerating disease progression. In this review, key factors which drive HLA-I hyperexpression will be explored, and their clinical significance examined. It is established that the presence of residual beta-cells is essential for HLA-I hyperexpression by islet cells at all stages of the disease. We suggest that the most likely drivers of this process are interferons released from beta-cells (type I or III interferon; possibly in response to viral infection) or those elaborated from influent, autoreactive immune cells (type II interferon). In both cases, Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathways will be activated to induce the downstream expression of interferon stimulated genes. A variety of models have highlighted that HLA-I expression is enhanced in beta-cells in response to interferons, and that STAT1, STAT2 and interferon regulatory factor 9 (IRF9) play key roles in mediating these effects (depending on the species of interferon involved). Importantly, STAT1 expression is elevated in the beta-cells of donors with recent-onset type I diabetes, and this correlates with HLA-I hyperexpression on an islet-by-islet basis. These responses can be replicated in vitro, and we consider that chronically elevated STAT1 may have a role in maintaining HLA-I hyperexpression. However, other data have highlighted that STAT2-IRF9 may also be critical to this process. Thus, a better understanding of how these factors regulate HLA-I under chronically stimulated conditions needs to be gathered. Finally, JAK inhibitors can target interferon signaling pathways to diminish HLA-I expression in mouse models. It seems probable that these agents may also be effective in patients; diminishing HLA-I hyperexpression on islets, reducing the visibility of beta-cells to the immune system and ultimately slowing disease progression. The first clinical trials of selective JAK inhibitors are underway, and the outcomes should have important implications for type 1 diabetes clinical management. |
| first_indexed | 2024-03-11T19:40:21Z |
| format | Article |
| id | doaj.art-39124f7f4621470ea17eaec81a594aa8 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-03-11T19:40:21Z |
| publishDate | 2023-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-39124f7f4621470ea17eaec81a594aa82023-10-06T12:50:00ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922023-10-011410.3389/fendo.2023.12703251270325The role of the interferon/JAK-STAT axis in driving islet HLA-I hyperexpression in type 1 diabetesMark A. RussellSarah J. RichardsonNoel G. MorganThe hyperexpression of human leukocyte antigen class I (HLA-I) molecules on pancreatic beta-cells is widely accepted as a hallmark feature of type 1 diabetes pathogenesis. This response is important clinically since it may increase the visibility of beta-cells to autoreactive CD8+ T-cells, thereby accelerating disease progression. In this review, key factors which drive HLA-I hyperexpression will be explored, and their clinical significance examined. It is established that the presence of residual beta-cells is essential for HLA-I hyperexpression by islet cells at all stages of the disease. We suggest that the most likely drivers of this process are interferons released from beta-cells (type I or III interferon; possibly in response to viral infection) or those elaborated from influent, autoreactive immune cells (type II interferon). In both cases, Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathways will be activated to induce the downstream expression of interferon stimulated genes. A variety of models have highlighted that HLA-I expression is enhanced in beta-cells in response to interferons, and that STAT1, STAT2 and interferon regulatory factor 9 (IRF9) play key roles in mediating these effects (depending on the species of interferon involved). Importantly, STAT1 expression is elevated in the beta-cells of donors with recent-onset type I diabetes, and this correlates with HLA-I hyperexpression on an islet-by-islet basis. These responses can be replicated in vitro, and we consider that chronically elevated STAT1 may have a role in maintaining HLA-I hyperexpression. However, other data have highlighted that STAT2-IRF9 may also be critical to this process. Thus, a better understanding of how these factors regulate HLA-I under chronically stimulated conditions needs to be gathered. Finally, JAK inhibitors can target interferon signaling pathways to diminish HLA-I expression in mouse models. It seems probable that these agents may also be effective in patients; diminishing HLA-I hyperexpression on islets, reducing the visibility of beta-cells to the immune system and ultimately slowing disease progression. The first clinical trials of selective JAK inhibitors are underway, and the outcomes should have important implications for type 1 diabetes clinical management.https://www.frontiersin.org/articles/10.3389/fendo.2023.1270325/fullHLA-ISTAT1STAT2pancreatic islettype 1 diabetes |
| spellingShingle | Mark A. Russell Sarah J. Richardson Noel G. Morgan The role of the interferon/JAK-STAT axis in driving islet HLA-I hyperexpression in type 1 diabetes Frontiers in Endocrinology HLA-I STAT1 STAT2 pancreatic islet type 1 diabetes |
| title | The role of the interferon/JAK-STAT axis in driving islet HLA-I hyperexpression in type 1 diabetes |
| title_full | The role of the interferon/JAK-STAT axis in driving islet HLA-I hyperexpression in type 1 diabetes |
| title_fullStr | The role of the interferon/JAK-STAT axis in driving islet HLA-I hyperexpression in type 1 diabetes |
| title_full_unstemmed | The role of the interferon/JAK-STAT axis in driving islet HLA-I hyperexpression in type 1 diabetes |
| title_short | The role of the interferon/JAK-STAT axis in driving islet HLA-I hyperexpression in type 1 diabetes |
| title_sort | role of the interferon jak stat axis in driving islet hla i hyperexpression in type 1 diabetes |
| topic | HLA-I STAT1 STAT2 pancreatic islet type 1 diabetes |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2023.1270325/full |
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