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Cell Death During Progression to Diabetes insight review articles b-Cell death during progression to diabetes Diane Mathis, Luis Vence & Christophe Benoist Section on Immunology and Immunogenetics, Joslin Diabetes Centre; Department of Medicine, Brigham and Women’s Hospital; Harvard Medical School, One Joslin Place, Boston, Massachusetts 02215, USA (e-mail: [email protected]) The hallmark of type 1 diabetes is specific destruction of pancreatic islet b-cells. Apoptosis of b-cells may be crucial at several points during disease progression, initiating leukocyte invasion of the islets and terminating the production of insulin in islet cells. b-Cell apoptosis may also be involved in the occasional evolution of type 2 into type 1 diabetes. ype 1 diabetes is an autoimmune disease sis of autoimmune diabetes. We do not know what triggers resulting from specific destruction of the it, have little understanding of the genetic and environmen- insulin-producing b-cells of the islets of tal factors regulating its progression, and have a confused Langerhans of the pancreas1. It has two distinct view of the final effector mechanism(s). Consequently, we phases: insulitis, when a mixed population of still do not know how to prevent or reverse type 1 diabetes in Tleukocytes invades the islets; and diabetes, when most a sufficiently innocuous manner to be therapeutically b-cells have been killed off, and there is no longer useful. Faced with the difficulties of addressing these issues sufficient insulin production to regulate blood glucose in humans, many investigators have turned to small-animal levels, resulting in hyperglycaemia. Individuals can have models of diabetes, in particular the non-obese diabetic covert insulitis for a long time (years in humans, months (NOD) mouse and transgenic derivatives of it (Box 1). in rodent models) before it finally progresses to overt Here we focus on the crux of autoimmune diabetes — diabetes, and sometimes it never does. b-cell death. We explore the possibility that physiological Type 1 diabetes is an old disorder — descriptions of it destruction of b-cells is a crucial event at disease outset, appear in ancient Egyptian and Greek writings. It is also a initiating autoimmunity. We also evaluate what is common disease, currently affecting about 0.5% of the known about the mechanism(s) of b-cell death in the population in developed countries and increasing in terminal phases of the autoimmune attack, and weigh the incidence. In addition, there is mounting evidence that a contention that destruction of b-cells can convert type 2 fraction (variously estimated at 5–15%) of people originally into type 1 diabetes. diagnosed as type 2 diabetic may actually have a slowly progressing and less severe form of type 1 termed ‘latent Death as the initiator autoimmune diabetes of adults’. It is surprising, then, that Type 1 diabetes is primarily a T-lymphocyte-mediated we remain so ignorant about the aetiology and pathogene- disease1,2. Immunohistological analyses show that most Figure 1 Proposed scheme for the Islet initiation of type 1 diabetes. Naive T β-cell cells (purple spheres) circulate through mass Antigen- β-cell the blood and lymphoid organs, presenting cell Antigens including the pancreatic lymph nodes (PLNs). In the nodes, they encounter APCs (probably mature DCs) displaying on their surface MHC molecules carrying antigens in the form of peptide fragments. In this case, the antigens PLN derive from proteins synthesized by Activated pancreatic islet b-cells, picked up (in T cell soluble form, as cell bits or as apoptotic cells) when the APCs (probably DCs in immature state) resided in the islets. A minute fraction of the naive T cells can recognize MHC molecule/b-cell antigen complexes, become activated (red Naive asterisks), and then access tissues T cells including the pancreas, where they re- encounter cognate antigen, and are reactivated and retained. 792 © 2001 Macmillan Magazines Ltd NATURE | VOL 414 | 13 DECEMBER 2001 | www.nature.com insight review articles leukocytes in the islet infiltrate are T cells. Disease does not develop in Box 1 NOD mice that are genetically athymic or T lymphopenic, or were The NOD mouse and simpler murine models thymectomized at birth; likewise, it is dampened or even abrogated by reagents that interfere with T-cell function. Finally, diabetes can be transferred by injecting T cells from diseased donors into healthy Discovered in the late 1970s, the non-obese diabetic (NOD) mouse NOD recipients — the purest demonstration being inoculation of a has become the most commonly used animal model of autoimmune single T-cell clone into a lymphocyte-deficient NOD mouse. diabetes2. Disease develops spontaneously in this strain, sharing Although most of these data derive from rodent diabetes models, several crucial features with the human disorder — for example, a there is ample indication that the human disease is also mediated by protracted course of pathology, disease that is primarily mediated by T lymphocytes, and has a similar islet histology and positive response T lymphocytes, and disease that is under complex polygenic to treatment with T-cell inhibitors. control, by far the most important contributor being the MHC. The T cells with diabetogenic properties fall into both the CD4+ helper NOD mouse has permitted many of the outstanding issues in the and the CD8+ killer classes, although both may be required for diabetes field to be addressed by direct experimentation, and results optimum disease activity1,2. They respond to several antigens that are from this animal have heavily coloured our view of the pathogenesis specifically, but perhaps not uniquely, synthesized by pancreatic islet of diabetes. But, because of the asynchrony and complexity of the b-cells, including peptides derived from insulin, glutamic acid disease in this model, vital issues have remained unresolved. Thus, decarboxylase and the tyrosine phosphatases 1A-2 and 1A-2b diverse strategies have been taken to simplify the NOD disease in (phogrin). For CD4+ T cells, the antigens are peptides presented by order to highlight particular features by ablation or exaggeration. major histocompatibility complex (MHC) class II molecules found One strategy has been the generation of T-cell receptor (TCR) primarily on specialized antigen-presenting cells (APCs); for CD8+ transgenic mice to focus on the role of T lymphocytes. Because of T cells, they are peptides displayed by MHC class I molecules present allelic exclusion, mice carrying already rearranged TCR transgenes on most cell types. have a T-cell repertoire highly skewed for the transgene-encoded specificity — even monoclonal when mutations blocking Where and when the autoimmune response is initiated rearrangement of endogenous TCR genes (SCID, RAG0/0) are Where do naive, potentially diabetogenic T cells first encounter their introduced. Such a skewed repertoire has proved useful for b-cell-derived antigens? The most likely possibilities are in the islets synchronizing disease unfolding and for monitoring the behaviour of themselves; in the lymph nodes draining the islets (the pancreatic pathogenic T cells. There are now several examples of TCR lymph nodes; PLNs); or at some distant site (although in this case the transgenic mice with repertoires enriched for a diabetogenic original stimulus would not be the b-cell antigen itself, but rather a specificity98,99 — either MHC class-I-restricted CD8+ or class-II- molecular mimic of it introduced by infection or diet). Data from restricted CD4+ T cells, and T cells recognizing either a natural two transgenic mouse models of diabetes3,4 support the second antigen or a genetically engineered neo-antigen synthesized explanation, suggesting a scheme (Fig. 1) that is highly analogous specifically by b-cells. to that established for T-cell responses to antigens introduced Another strategy has been to direct expression of molecules of through the skin. interest specifically to islet b-cells under the dictates of the insulin Like all naive T lymphocytes, naive b-cell-reactive, potentially promoter, permitting assessment of the effects of expression at diabetogenic T cells do not usually access the tissues (including the enhanced levels, ectopically, locally or in isolation. Examples include pancreas), but circulate freely through the blood and lymphoid mice expressing MHC molecules, cytokines, co-stimulatory organs. At some point, b-cell-derived antigens are taken up by APCs molecules and neo-antigens99,100. (probably dendritic cells; DCs) in the islets, inducing maturation of Thus, there now exists a set of powerful murine models of the APCs and their migration to the immediately draining PLNs. diabetes, each one with its inherent interests and disadvantages. Here, they display the b-cell-derived antigens to naive b-cell-reactive We do not know, however, which model most faithfully mimics which T cells in circulation and activate them. As part of the activation variant of human diabetes. Given the heterogeneous symptoms, process, the T cells acquire the ability to migrate through the tissues; courses and genetics exhibited by affected individuals, it may well in the islets, they re-encounter cognate antigen, become reactivated be that human diabetes is really a multiplicity of diseases. It seems and are retained, thereby initiating insulitis. An unknown fraction of that an open-minded view is called for at this point. the activated and/or re-activated T cells may re-enter the circulation. Much evidence suggests that a similar sequence of events unfolds to initiate insulitis in standard NOD mice3. This scheme raises the issue of when b-cell antigens are first made 14–17 days after birth7–10. Significant death at this age was first postu- available for uptake by islet-resident APCs. An answer has come lated on the basis of mathematical modelling studies, taking into from a T-cell receptor (TCR) transgenic mouse model of diabetes3. account the kinetics of b-cell division, changes in cell volume, and the Insulitis begins abruptly and highly synchronously in these animals evolution of cell mass7.
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