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The heterogeneous pathogenesis of type 1 diabetes mellitus

Abstract

Type 1 diabetes mellitus (T1DM) results from the destruction of pancreatic β-cells that is mediated by the immune system. Multiple genetic and environmental factors found in variable combinations in individual patients are involved in the development of T1DM. Genetic risk is defined by the presence of particular allele combinations, which in the major susceptibility locus (the HLA region) affect T cell recognition and tolerance to foreign and autologous molecules. Multiple other loci also regulate and affect features of specific immune responses and modify the vulnerability of β-cells to inflammatory mediators. Compared with the genetic factors, environmental factors that affect the development of T1DM are less well characterized but contact with particular microorganisms is emerging as an important factor. Certain infections might affect immune regulation, and the role of commensal microorganisms, such as the gut microbiota, are important in the education of the developing immune system. Some evidence also suggests that nutritional factors are important. Multiple islet-specific autoantibodies are found in the circulation from a few weeks to up to 20 years before the onset of clinical disease and this prediabetic phase provides a potential opportunity to manipulate the islet-specific immune response to prevent or postpone β-cell loss. The latest developments in understanding the heterogeneity of T1DM and characterization of major disease subtypes might help in the development of preventive treatments.

Key points

  • The incidence of type 1 diabetes mellitus in childhood has increased, and the age at diagnosis has decreased due to environmental changes during the last half of the twentieth century.

  • Inherited defects in central and peripheral immune tolerance allow the generation of autoimmune responses directed against pancreatic islets.

  • Environmental factors that modify the immune system, such as microbiota composition, microbial infections and nutrition, affect the development and course of the autoimmune response.

  • Type 1 diabetes mellitus is a heterogeneous disease with multiple different features, but two major pathways can be discerned with either insulin autoantibodies or glutamic acid decarboxylase autoantibodies as the first autoantibody indicating initiation of the autoimmune process.

  • Multiple trials aiming to prevent development of the disease in different phases of the autoimmune process are ongoing or being planned.

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Fig. 1: Suggested key points in the β-cell targeted autoimmune process and pathways in type 1 diabetes mellitus.
Fig. 2: Estimated proportion of genetic (blue) and environmental (red) components in children with type 1 diabetes mellitus.

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Correspondence to Jorma Ilonen.

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Glossary

Class II HLA region

The gene region where class II HLA genes encoding HLA-DR, HLA-DQ and HLA-DP molecules that present antigen epitopes to T cells are located.

Autoantibodies

Antibodies that recognize and bind an individual’s own proteins or tissue constituents.

Antigenic cross-reaction

Antibodies or T cells that recognize two different molecules by their antigen-specific receptor.

Molecular mimicry

Two different molecules have an antigenic structure resembling each other enough to allow antigenic cross-reaction.

Seroconversion

The time period when a specific antibody develops and becomes detectable.

Complement components

A number of small proteins that circulate in the blood as inactive components; after activation, they cause bacterial opsonization and lysis and attract inflammatory cells.

Linkage disequilibrium

Allelic association, nonrandom association of alleles at two or more gene loci in the general population.

Ectopic expression

An abnormal expression of a gene in a tissue where it is not usually expressed.

Thymic education

T cells go through positive and negative selection where most of the T cell precursors that recognize autologous structures too weakly or too strongly are deleted.

Humoral immunity

Antibody-mediated immunity.

Macromolecular crowding

This phenomenon alters the properties of molecules in a solution when high concentrations of macromolecules such as proteins are present.

Complement cascade

The process where complement components interact with each other in a specific sequence called a complement pathway to achieve cell lysis and an inflammatory response.

Overload hypothesis

The assumption that increased insulin demand caused by multiple mechanisms might stress β-cells and sensitize them to immune damage and apoptosis.

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Ilonen, J., Lempainen, J. & Veijola, R. The heterogeneous pathogenesis of type 1 diabetes mellitus. Nat Rev Endocrinol 15, 635–650 (2019). https://doi.org/10.1038/s41574-019-0254-y

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