Pathogenic mechanisms in type 1 diabetes: the islet is both target and driver of disease

Abstract

Recent advances in our understanding of the pathogenesis of type 1 diabetes have occurred in all steps of the disease. This review outlines the pathogenic mechanisms utilized by the immune system to mediate destruction of the pancreatic beta-cells. The autoimmune response against beta-cells appears to begin in the pancreatic lymph node where T cells, which have escaped negative selection in the thymus, first meet beta-cell antigens presented by dendritic cells. Proinsulin is an important antigen in early diabetes. T cells migrate to the islets via the circulation and establish insulitis initially around the islets. T cells within insulitis are specific for islet antigens rather than bystanders. Pathogenic CD4⁺ T cells may recognize peptides from proinsulin which are produced locally within the islet. CD8⁺ T cells differentiate into effector T cells in islets and then kill beta-cells, primarily via the perforin-granzyme pathway. Cytokines do not appear to be important cytotoxic molecules in vivo. Maturation of the immune response within the islet is now understood to contribute to diabetes, and highlights the islet as both driver and target of the disease. The majority of our knowledge of these pathogenic processes is derived from the NOD mouse model, although some processes are mirrored in the human disease. However, more work is required to translate the data from the NOD mouse to our understanding of human diabetes pathogenesis. New technology, especially MHC tetramers and modern imaging, will enhance our understanding of the pathogenic mechanisms.

Figure 1. Activation, migration, entry, and infiltration of immune cells into islets during spontaneous diabetes

A-C: Dendritic cells loaded with beta-cell antigens migrate from islets to pancreatic lymph nodes and present antigen to naïve autoreactive CD4⁺ and CD8⁺ T cells. These T cells undergo initial activation and migrate towards the pancreas via the circulation. D: Entry for CD4⁺ T cells and CD8⁺ T cells into islets and presentation (CD8⁺ T cells). Once arrested, T cells roll and extravasate via integrins and adhesion molecules. E: Insulitis development in islets. Initial macrophage infiltration occurs, followed by T cell infiltration, and the formation of peri-islet insulitis. The islet basement membrane breaks down and invasive insultis with concurrent beta-cell destruction occurs.

Figure 2. Effector cells and their actions in mediating beta-cell destruction

Cytotoxic T lymphocytes are the main mediators of beta-cell death through the production of perforin and granzymes. Fas-FasL interactions have a minor role in beta-cell destruction. CD4⁺ T cells do not directly kill beta-cells, instead they are proposed to activate macrophages to kill beta-cell cells via NO and reactive oxygen species. Pro-inflammatory cytokines are produced by CD4⁺, CTLs, and macrophages, and act to regulate the immune response. The presence of NK cells within the islets is proposed to promote effector CD4⁺ T cell function. Intra-islet DCs present antigen to CD4⁺ T cells and may present antigen to CTLs. B cells are also present in the islet and secrete autoantibodies and promote CD4⁺ T cell function through antigen presentation (not shown). Figure is prepared from descriptions within mouse models.

Figure 3. How the islet environment modifies the pathogenesis of diabetes

A: Immune regulatory mechanisms fail within the islet as diabetes progresses. Tregs present in the islet initially control the immune response. However, declining concentrations of IL-2 and increasing concentration of IL-21 result in decreased Treg number and function and increases in effector CD4+ T cells. The high concentration of IL-21 also promotes CTL and B cell function in the islet. Increasing concentrations of IL-7 results in downregulation of PD-1 expression on Tregs and effector CD4+ T cells, which promotes beta-cell destruction through failure of the PD-1/PDL-1 pathway. B: Islet environment promotes CTL function. Beta-cell antigen presentation promotes local proliferation of CTLs within the islet, increasing insulitis development. CTLs also respond to cytokines present in the islet, and this may increase the expression of cytotoxic markers, including granzymeB and IFNγ, and CTL function. CTLs within the islet are also stimulated to form an effector memory CTL pool.