The incidence of type 1 diabetes is increasing, particularly in young children. Multicenter studies across Europe have shown a 5.4% annual rise in type 1 diabetes in children under the age of 5 years (1), increasing the burden on health care resources worldwide. Better understanding of the causes of this increase is required for new therapies or lifestyle changes to reverse this trend. The study by Leete et al. (2) in this issue of Diabetes demonstrates striking differences in the cellular composition of islet inflammation causing type 1 diabetes between children diagnosed before the age of 6 years and those developing disease at an older age that may help define mechanisms underlying accelerated progression to diabetes. The distinguishing feature of islet inflammation in very young children is a high proportion of infiltrating B lymphocytes.
B-cell responses to islet autoantigens are characteristic of type 1 diabetes, and autoantibodies provide important predictive markers of disease. Studies in families of patients with diabetes have shown that autoantibodies first appear in the first 5 years of life, most commonly with specificity for insulin (3), which may then be followed by the progressive appearance of autoantibodies to other major islet cell antigens including glutamate decarboxylase (GAD), IA-2, and the zinc transporter ZnT8 (4). Diversification of the immune response appears critical for disease progression: few individuals persistently positive for autoantibodies to only a single islet cell antigen develop disease (5). Furthermore, the rising incidence of disease is associated with accelerated diversification of the autoantibody response. In studies following relatives of patients with type 1 diabetes from birth, the age at which insulin autoantibodies are first detected did not change over the period studied, despite increasing prevalence of diabetes (6). In contrast, antibodies to GAD and IA-2, which usually develop after insulin antibodies, appeared earlier over time (6). Furthermore, a study of islet autoantibodies in patients with diabetes showed increasing prevalence of IA-2 and ZnT8 antibodies over a 17-year period, whereas antibodies to insulin did not change (7). Both studies point to a link between rising diabetes incidence and a more diverse B-cell response to islet autoantigens.
A crucial question is how these observations in the periphery relate to the destructive inflammation in the pancreas. Because of difficulties in accessing tissue, there are few descriptions of the characteristics of islet inflammation in disease. Leete et al. carefully quantified immune-cell subsets and residual endocrine cells within islets on sections of pancreas from patients with type 1 diabetes and, by combining the results from three different sources of tissue, provide evidence of distinct profiles of islet inflammation defined by numbers of infiltrating B cells. Children diagnosed with diabetes up to 6 years of age were found to have markedly higher numbers of B cells in the infiltration than older patients. All inflamed islets examined within an individual pancreas showed similar characteristics, although analyses were necessarily restricted to small regions of each pancreas that were available for study. B-cell infiltration was associated with higher numbers of CD8+ cytotoxic T cells, which have been implicated as direct mediators of pancreatic β-cell destruction, and with very low numbers of residual insulin-containing islets. B-cell infiltration of islets may therefore be linked to a particularly aggressive inflammation that leads to an accelerated loss of insulin-secreting β-cells and an earlier appearance of disease. Immunotherapy aimed at depleting or inactivating those B cells relevant to disease may be particularly effective in this group of patients.
How might B cells promote such destructive inflammation? It is generally accepted that neither autoreactive B cells nor their secreted antibodies are directly involved in β-cell killing; rather B cells are thought to act as highly efficient antigen-presenting cells that promote T cell–mediated β-cell destruction (8). B cells are capable of efficient uptake of antigens through high-affinity cell surface receptors, processing the antigen to peptide fragments for presentation and activation of T cells (Fig. 1). B cells present processed peptides on MHC class II molecules (including products of HLA genes conferring susceptibility to disease) to CD4+ T cells, which then provide “help” in the form of secreted cytokines to maintain B-cell responses or activate CD8+ cytotoxic T cells. B cells also accelerate diabetes in animal models by cross-presentation of antigens to CD8+ T cells on MHC class I molecules (9). The processing and presentation of antigens by B cells is important for diversification of immune responses (10,11), a crucial factor in disease progression as described above. B-cell responses to islet antigens are broadly detected in type 1 diabetes and may occur in pancreatic lymph nodes and elsewhere in the periphery. The observations of Leete et al. suggest that it is the recruitment of B cells to the islets themselves, or an increased expansion of the B cells within islets, that accelerates β-cell destruction potentially through highly efficient presentation of islet autoantigens released into the local environment to T cells.
It is often assumed that B-cell and T-cell responses detected in blood reflect those at the site of disease, but detailed studies on the nature of the immune response within the diabetic islet are only now emerging. The antigen specificity of islet-infiltrating CD8+ T cells has been demonstrated by labeling frozen sections of type 1 diabetic pancreas using HLA-A2 tetramers carrying peptides representing major T-cell epitopes on islet autoantigens (12). Both single and multiple autoantigen reactivity of infiltrating CD8+ T cells were detected within individual islets. Resources such as the Network for Pancreatic Organ Donors with Diabetes (nPOD) should permit similar investigations of antigen specificity of infiltrating B cells using labeled islet autoantigens for section staining to establish links with the diversity of circulating autoantibodies associated with rapid disease progression. Also important is the definition of how profiles of islet inflammation relate to different phenotypes of islet antigen–specific T cells in blood that also show heterogeneity in disease (13). The availability of accessible markers of different patterns of immunopathology described by Leete et al. will be crucial for the administration of appropriate immunotherapies to prevent disease.
See accompanying article, p. 1362.
Funding. Research in the author’s laboratory is funded by Diabetes UK (grant 14/0004970).
Duality of Interest. No potential conflicts of interest relevant to this article were reported.