PMID- 37867531
OWN - NLM
STAT- MEDLINE
DCOM- 20231031
LR  - 20240311
IS  - 1664-2392 (Print)
IS  - 1664-2392 (Electronic)
IS  - 1664-2392 (Linking)
VI  - 14
DP  - 2023
TI  - The role of the interferon/JAK-STAT axis in driving islet HLA-I hyperexpression 
      in type 1 diabetes.
PG  - 1270325
LID - 10.3389/fendo.2023.1270325 [doi]
LID - 1270325
AB  - 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.
CI  - Copyright (c) 2023 Russell, Richardson and Morgan.
FAU - Russell, Mark A
AU  - Russell MA
AD  - Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, 
      United Kingdom.
FAU - Richardson, Sarah J
AU  - Richardson SJ
AD  - Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, 
      United Kingdom.
FAU - Morgan, Noel G
AU  - Morgan NG
AD  - Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, 
      United Kingdom.
LA  - eng
GR  - DH_/Department of Health/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20231006
PL  - Switzerland
TA  - Front Endocrinol (Lausanne)
JT  - Frontiers in endocrinology
JID - 101555782
RN  - 9008-11-1 (Interferons)
RN  - 0 (Janus Kinase Inhibitors)
RN  - EC 2.7.10.2 (Janus Kinases)
SB  - IM
CIN - Front Endocrinol (Lausanne). 2024 Feb 06;15:1367245. PMID: 38379865
MH  - Animals
MH  - Mice
MH  - Humans
MH  - Interferons
MH  - *Diabetes Mellitus, Type 1/pathology
MH  - *Janus Kinase Inhibitors
MH  - Janus Kinases/metabolism
MH  - Disease Progression
PMC - PMC10588626
OTO - NOTNLM
OT  - HLA-I
OT  - STAT1
OT  - STAT2
OT  - pancreatic islet
OT  - type 1 diabetes
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2023/10/23 06:48
MHDA- 2023/10/31 06:42
PMCR- 2023/01/01
CRDT- 2023/10/23 04:25
PHST- 2023/07/31 00:00 [received]
PHST- 2023/09/06 00:00 [accepted]
PHST- 2023/10/31 06:42 [medline]
PHST- 2023/10/23 06:48 [pubmed]
PHST- 2023/10/23 04:25 [entrez]
PHST- 2023/01/01 00:00 [pmc-release]
AID - 10.3389/fendo.2023.1270325 [doi]
PST - epublish
SO  - Front Endocrinol (Lausanne). 2023 Oct 6;14:1270325. doi: 
      10.3389/fendo.2023.1270325. eCollection 2023.