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Why does the immune system destroy pancreatic β-cells but not α-cells in type 1 diabetes?

Nature Reviews Endocrinology volume 19, pages 425–434 (2023)Cite this article

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Abstract

A perplexing feature of type 1 diabetes (T1D) is that the immune system destroys pancreatic β-cells but not neighbouring α-cells, even though both β-cells and α-cells are dysfunctional. Dysfunction, however, progresses to death only for β-cells. Recent findings indicate important differences between these two cell types. First, expression of BCL2L1, a key antiapoptotic gene, is higher in α-cells than in β-cells. Second, endoplasmic reticulum (ER) stress-related genes are differentially expressed, with higher expression levels of pro-apoptotic CHOP in β-cells than in α-cells and higher expression levels of HSPA5 (which encodes the protective chaperone BiP) in α-cells than in β-cells. Third, expression of viral recognition and innate immune response genes is higher in α-cells than in β-cells, contributing to the enhanced resistance of α-cells to coxsackievirus infection. Fourth, expression of the immune-inhibitory HLA-E molecule is higher in α-cells than in β-cells. Of note, α-cells are less immunogenic than β-cells, and the CD8+ T cells invading the islets in T1D are reactive to pre-proinsulin but not to glucagon. We suggest that this finding is a result of the enhanced capacity of the α-cell to endure viral infections and ER stress, which enables them to better survive early stressors that can cause cell death and consequently amplify antigen presentation to the immune system. Moreover, the processing of the pre-proglucagon precursor in enteroendocrine cells might favour immune tolerance towards this potential self-antigen compared to pre-proinsulin.

Key points

  • Pancreatic β-cells and α-cells are both dysfunctional in type 1 diabetes (T1D) but, while β-cells are killed, α-cells survive.

  • Exposure of islet cells to interferon-α (IFNα), a cytokine that is induced early in T1D pathogenesis, induces expression of both similar genes (such as HLA-related genes) and different genes (such as BCL2L1, endoplasmic reticulum (ER) stress-related genes, innate immune response genes and antiviral response genes) in β-cells and α-cells.

  • Expression of candidate genes for T1D shows major differences between β-cells and α-cells.

  • The antigen presentation capacity seems similar in β-cells and α-cells, but either α-cells are less antigenic than β-cells (perhaps owing to higher HLA-E expression) or their capacity to better endure viral infections and ER stress increases their survival when facing diabetogenic stressors and thus decreases antigen presentation.

  • Pre-proglucagon processing in enteroendocrine cells might favour immune tolerance towards glucagon and further limit α-cell immunogenicity.

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Fig. 1: Immunofluorescence imaging of islets in individuals with T1D and with normoglycaemia.
Fig. 2: Different basal and IFNα-induced gene expression in α-like and β-like cells.
Fig. 3: Points of increased resistance of α-cells to different stressors and to autoimmunity as compared to β-cells.

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Data availability

The data used to create Fig. 2 are available in ref. 33.

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Acknowledgements

D.L.E. acknowledges the support of grants from the Welbio-FNRS (Fonds National de la Recherche Scientifique) (WELBIO-CR-2019C-04), Belgium; the Dutch Diabetes Research Foundation (Innovate2CureType1), Netherlands; the JDRF (3-SRA-2022-1201-S-B); the National Institutes of Health Human Islet Research Network Consortium on Beta Cell Death & Survival from Pancreatic β-Cell Gene Networks to Therapy (HIRN-CBDS) (grant U01 DK127786). D.L.E. and R.M. acknowledge support from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreements 115797 (INNODIA) and 945268 (INNODIA HARVEST). These joint undertakings receive support from the European Union’s Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA), JDRF, and The Leona M. and Harry B. Helmsley Charitable Trust. F.S. is supported by a Research Fellow (Aspirant) fellowship from the Fonds National de la Recherche Scientifique (FNRS, Belgium). R.M. acknowledges the support of grants from Agence Nationale de la Recherche (ANR-19-CE15-0014-01), Fondation pour la Recherche Medicale (EQU20193007831), and from The Leona M. and Harry B. Helmsley Charitable Trust to INSERM.

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Authors and Affiliations

  1. Université Libre de Bruxelles (ULB) Center for Diabetes Research and Welbio, Medical Faculty, Brussels, Belgium

    Decio L. Eizirik & Florian Szymczak

  2. Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France

    Roberto Mallone

  3. Assistance Publique Hôpitaux de Paris, Service de Diabétologie et Immunologie Clinique, Cochin Hospital, Paris, France

    Roberto Mallone

Authors
  1. Decio L. Eizirik
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  2. Florian Szymczak
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  3. Roberto Mallone
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Contributions

All authors researched data for the article, contributed substantially to discussion of the content, wrote sections of the article and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Decio L. Eizirik.

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Competing interests

D.L.E. received grant support from Eli Lilly, Indianapolis, IN, for research on new approaches to protect pancreatic β-cells in T1D (not directly related to the present study). The other authors declare no competing interests.

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Nature Reviews Endocrinology thanks Maureen Gannon, Jason Collier and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Review criteria

Relevant publications were identified by searching the PubMed database (1 January 2005 to September 2022) using combinations of the following terms: ‘pancreatic beta cells’, ‘pancreatic alpha cells’, ‘pancreatic β-cells’, ‘pancreatic α-cells’, ‘pancreatic islets’, ‘insulin release’, ‘insulin secretion’, ‘glucagon release’, ‘glucagon secretion’, ‘diabetes’, ‘type 1 diabetes’, ‘type 2 diabetes’, ‘pathogenesis’, ‘histology’, ‘transcriptome’, ‘genetics’, ‘candidate genes’, ‘islet gene regulation’, ‘islet epigenomics’, ‘viral infection’, ‘endoplasmic reticulum stress’ and ‘apoptosis’. We preferentially selected publications from the past 5 years, plus earlier key publications for citation (of note, the literature on α-cells in T1D is rather limited). Some references cited in these papers or in relevant articles related to the fate of pancreatic β-cells and α-cells in diabetes were also searched manually. All selected papers were full-text articles in English. Review articles are often cited to provide the readers with additional references.

Glossary

Antigens

Molecular structures (proteins, peptides, polysaccharides, lipids or nucleic acids) that can bind to an antigen receptor (for example, antibodies for B cells and T cell receptors for T cells) and trigger an immune response. Antigens can originate from within the body (self-antigens or autoantigens) or from the external environment (foreign antigens).

Candidate genes

Genes related to particular traits that either increase or decrease the risk of disease, either as a result of their protein product or their position on a chromosome.

Epitopes

The specific parts of the antigen (most commonly peptides) to which antigen receptors bind.

Gene set enrichment analysis

Computational method to determine whether an a priori defined set of genes shows statistically significant differences between two biological states (for example, phenotypes).

Immune tolerance

The state of unresponsiveness of the immune system to antigens that have the potential to induce an immune response. Immune tolerance to self-antigens is achieved through both central tolerance and peripheral tolerance mechanisms in the thymus and in the periphery, respectively.

Insulitis

Inflammation of the islets of Langerhans, characterized by infiltration of immune cells within and at the periphery of islets.

Leading edges

Subsets of genes in a gene set that contribute the most to the enrichment or depletion in a gene set enrichment analysis.

Neoantigens

Peptide sequences not templated in the genome that can be preferentially recognized as non-self and trigger autoimmunity. Neoantigens can be generated by mis-initiated mRNA transcription, alternative mRNA splicing and post-translational modifications (that is, the addition of chemical groups to amino acid residues or the fusion of non-contiguous fragments from the same protein (cis-splicing) or of two fragments from different proteins (trans-splicing, generating so-called hybrid peptides)).

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Eizirik, D.L., Szymczak, F. & Mallone, R. Why does the immune system destroy pancreatic β-cells but not α-cells in type 1 diabetes?. Nat Rev Endocrinol 19, 425–434 (2023). https://doi.org/10.1038/s41574-023-00826-3

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