Abstract
Type 1 diabetes mellitus is believed to result from destruction of the insulin-producing β-cells in pancreatic islets that is mediated by autoimmune mechanisms. The classic view is that autoreactive T cells mistakenly destroy healthy (‘innocent’) β-cells. We propose an alternative view in which the β-cell is the key contributor to the disease. By their nature and function, β-cells are prone to biosynthetic stress with limited measures for self-defence. β-Cell stress provokes an immune attack that has considerable negative effects on the source of a vital hormone. This view would explain why immunotherapy at best delays progression of type 1 diabetes mellitus and points to opportunities to use therapies that revitalize β-cells, in combination with immune intervention strategies, to reverse the disease. We present the case that dysfunction occurs in both the immune system and β-cells, which provokes further dysfunction, and present the evidence leading to the consensus that islet autoimmunity is an essential component in the pathogenesis of type 1 diabetes mellitus. Next, we build the case for the β-cell as the trigger of an autoimmune response, supported by analogies in cancer and antitumour immunity. Finally, we synthesize a model (‘connecting the dots’) in which both β-cell stress and islet autoimmunity can be harnessed as targets for intervention strategies.
Key points
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Autoreactive T cells are part of the normal T cell repertoire.
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β-Cells are poorly equipped to survive an inflammatory milieu and participate in their own destruction.
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Metabolic activity drives β-cell dysfunction and destruction.
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Inflammation triggers profound metabolic, epigenetic and autoantigenic changes, which expose β-cells to the immune system.
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The immune response to distressed β-cells might be one with ‘good intentions’, as infected tissues or tumours provoke the immune system in similar ways.
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Immunotherapy might be insufficient to cure type 1 diabetes mellitus; β-cell therapy might contribute to reducing β-cell immunogenicity and islet autoimmunity.
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Acknowledgements
The authors are supported by grants from the Dutch Diabetes Research Foundation, Stichting DON, the European Commission, the Juvenile Diabetes Research Foundation and the Wanek Family Project for Type 1 Diabetes (directed by B.O.R.).
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Network for Pancreatic Organ Donors with Diabetes: www.jdrfnpod.org
Glossary
- Thymic education
-
The process that takes place in the thymus leading to the establishment of central immune tolerance to self-proteins and the potential for immune response against foreign proteins (such as viruses, bacteria, donor tissue and allergens).
- Self-proteins
-
Proteins normally produced by a particular organism.
- Thymic selection
-
The processes of positive and negative selection in the thymus through which T cells acquire the capacity to distinguish self-proteins from foreign proteins.
- Molecular fragility
-
The extreme sensitivity of β-cells to stress, inflammation and apoptosis.
- Translation infidelity
-
The ribosomal errors during the translation of mRNA into proteins that lead to changes in amino acid sequences of mRNA-encoded proteins (such as, alternative start site, frameshifts, readthrough of stop codons or premature termination of translation).
- Ligandome
-
The complete range of peptides presented by HLA molecules on the surface of β-cells.
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Roep, B.O., Thomaidou, S., van Tienhoven, R. et al. Type 1 diabetes mellitus as a disease of the β-cell (do not blame the immune system?). Nat Rev Endocrinol 17, 150–161 (2021). https://doi.org/10.1038/s41574-020-00443-4
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DOI: https://doi.org/10.1038/s41574-020-00443-4
