Pathogenesis of Type 1 Diabetes: Established Facts and New Insights
Abstract
:1. Introduction
2. Pathology of β-Cells
3. Genetic Predisposition
4. Environmental Risk Factors in Connection to Genetic Predisposition
4.1. Viral Infections
4.2. Endogenized Viral Elements in the Genome
4.3. Gut Biome
5. Epigenetic Factors in T1D Pathology
6. Extracellular Vesicles and Non-Coding RNAs
7. Conclusions and Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Gene Name | Gene Function(s) | References |
---|---|---|
BACH2 | Regulating proinflammatory cytokine-induced apoptotic pathways in pancreatic β-cells (crosstalk with PTPN2) | [46] |
C1QTNF6 | Participating in the BCR signalling pathway/cytotoxicity | [50] |
CCR5 | Th cell development/chemokine-induced signalling | [50] |
CD226 | Modulating thymic T cell selection Impact on peripheral memory/effector CD8+ T cell activation and function Reducing regulatory functions of Foxp3+ Tregs | [51,52] |
CD69 | Participating in early lymphocyte activation Limiting the inflammatory response Influencing the signalling of NK cells | [53] |
CLEC16A | Regulating the mitophagy for mitochondrial quality control Possible involvement in β-cell fragility | [54] |
COL6A6 | / | [55] |
CTLA4 | Controlling the proliferation of Tregs in the periphery Regulating pancreas autoimmunity | [56] |
CTSH | Regulating cytokines inside β-cells for proapoptotic signal transduction | [49] |
ERBB3 | Modulating antigen presentation Modulating cytokine-induced β-cell apoptosis | [53] |
GLIS3 | Implication in the generation of β-cells, insulin expression Maintaining β-cell functions and mass Exerting antiapoptotic effects | [46,50,57] |
HIP14 | Regulating β-cell apoptosis and insulin secretion | [50] |
IFIH1 | Mediating the innate immune system’s interferon response to certain viruses Participating in β-cell response to viral dsRNA | [46,49] |
IKZF1 | Regulating immune cell development | [50] |
IL2/IL21 | Influencing T(h) cell differentiation and inflammatory response | [50] |
IL27 | Modulating T cell subsets and regulating inflammatory response | [53] |
IL2RA | Variants causing abnormalities in sensitivity to IL2, which is critical to T-regulatory cell function Potential altering of the balance between Tregs and Teffs | [46] |
IL7R | Involvement in antigen binding, Ig production, and cytotoxicity | [50] |
MRPS21-PRPF3 | / | [55] |
NRIR | Negative regulator of interferon response | [55] |
PRKCQ | Influencing T cell function/apoptosis/innate immune response | [50] |
PTPN2 | Inducing β-cell apoptosis after interaction with increased local levels of interferon Influencing β-cell response to viral dsRNA | [46,49] |
PTPN22 | Participating in T cell receptor signalling pathway | [53] |
SH2B3 | Participating in growth factor and cytokine signalling | [50] |
STX4 | Associated with insulin secretion Downregulating the expression of chemokine genes associated with inflammation and the apoptosis of pancreatic islets Decreasing the translocation and activation of NF-kB, thus decreasing the apoptosis | [50] |
TASP1 | Cleaving the MLL protein, which is required for proper HOX gene expression | [55] |
TNFAIP3 | Downregulating the intrinsic apoptotic pathway Regulating the expression levels of ZnT8 Essential for insulin production and secretion | [50] |
TYK2 | Regulating the effects of cytokines inside β-cells for proapoptotic signal transduction Mediating interferon response in connection to resistance to various infections Mediating Th1- and Th17-type immune reactions | [50,58,59] |
UBASH3A | Downregulating the NF-kB signalling pathway upon T cell receptor stimulation, thus reducing the IL2 expression | [46,60] |
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Zajec, A.; Trebušak Podkrajšek, K.; Tesovnik, T.; Šket, R.; Čugalj Kern, B.; Jenko Bizjan, B.; Šmigoc Schweiger, D.; Battelino, T.; Kovač, J. Pathogenesis of Type 1 Diabetes: Established Facts and New Insights. Genes 2022, 13, 706. https://doi.org/10.3390/genes13040706
Zajec A, Trebušak Podkrajšek K, Tesovnik T, Šket R, Čugalj Kern B, Jenko Bizjan B, Šmigoc Schweiger D, Battelino T, Kovač J. Pathogenesis of Type 1 Diabetes: Established Facts and New Insights. Genes. 2022; 13(4):706. https://doi.org/10.3390/genes13040706
Chicago/Turabian StyleZajec, Ana, Katarina Trebušak Podkrajšek, Tine Tesovnik, Robert Šket, Barbara Čugalj Kern, Barbara Jenko Bizjan, Darja Šmigoc Schweiger, Tadej Battelino, and Jernej Kovač. 2022. "Pathogenesis of Type 1 Diabetes: Established Facts and New Insights" Genes 13, no. 4: 706. https://doi.org/10.3390/genes13040706