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Stages of type 1 diabetes
570
From the 4th International Congress of Autoimmunity Budapest 3–8 November 2004
Stages of type 1 diabetes George S. Eisenbarth Barbara Davis Center for Childhood Diabetes, United States Available online 23 August 2004
Type 1A or immune mediated diabetes has become one of the first immunologic disorders where it is possible to predict the development of overt disease. This has led to large collaborative studies of prediction both among relatives of patients with type 1 diabetes and in the general population, as well as prospective follow up of infants HLA typed at birth for alleles associated with disease risk. In addition, in animal studies, investigators are attempting to develop T-cell-based predictive techniques that will be applicable in man (e.g. sampling blood rather than internal lymphoid organs). In parallel with the development of ability to predict disease, efforts are directed at understanding the pathophysiology of the multiple stages preceding type 1 diabetes, and alternative hypotheses have been proposed relative to disease course. Given the ability to predict, we believe it is likely that the disease is a chronic autoimmune disorder with evidence of islet beta cell destruction/ loss function long before the development of hyperglycemia. One formulation divides the development of type 1 diabetes into five stages beginning with genetic susceptibility and ending with essentially complete loss of islet beta cells and insulin dependence. Over the past two decades, there is an expanding wealth of information concerning each of the stages and we will emphasize predictive parameters and pathophysiology with autoimmunity to insulin as a central component. I.
The dominant known determinant of type 1A diabetes is the alleles of genes within the major histocompatibility complex, and in particular alleles of DR and DQ. The highest risk genotype for type 1A diabetes consists of the heterozygous pairing of DR3/4, DQ2/8 haplotypes. In a study of more than 30,000 cord blood samples from newborns in Colorado (DAISY study led by M. Rewers), 2.4% of newborns have this genotype
and approximately 50% of children developing anti-islet autoimmunity before age 5. Expression of specific anti-islet autoantibodies is used to detect the initial signs of anti-islet autoimmunity. Insulin autoantibodies are usually the first to appear and can precede development of diabetes by years. The insulin locus perhaps by influencing expression of insulin within the thymus determines approximately 10% of the familial aggregation of type 1A diabetes, and rare AIRE mutations may act on a similar pathway. It is likely that there are additional polymorphisms outside of DR and DQ influences diabetes risk. II. At present there is not consensus in terms of environmental factors that either decrease or increase development of diabetes, but a marker increase in the incidence of the disease (worldwide) provides strong evidence for environmental determinants. Two recent reports suggest that early introduction of cereal/gluten increases development of anti-islet autoimmunity. III. At present the typical autoantibodies measured react with GAD65, ICA512 and insulin. Assays are usually performed in fluid phase as ELISA assays have lacked sensitivity/specificity. Presence of z2 of the above autoantibodies indicates a risk of type 1A diabetes exceeding 90% in studies such as DAISY and large prevention trials such as DPT-1. T-cell assays with specific antigens to date in man have had difficulty in matching sensitivity and specificity of the autoantibody assays. A tetramer analysis of T cells reacting with IGRP (Tan and coworkers) found almost 1% of CD8 T cells positive in prediabetic but not non-progressing NOD mice. IGRP is a beta cell specific molecule, and the other beta cell specific target of islet autoimmunity in the NOD mouse is insulin. Wegmann and coworkers described the dominance in this model of T cells reacting with insulin B chain
From the 4th International Congress of Autoimmunity Budapest 3–8 November 2004
peptide B:9–23. This peptide can be utilized to induce diabetes in an experimental autoimmune diabetes model (1). In addition, knocking out the insulin 1 gene prevents diabetes, while knockouts of the insulin 2 gene accelerate the development of diabetes (2). We hypothesize that insulin is a primary autoantigenic target of the NOD mouse. IV. Prior to the development of diabetes for both the NOD mouse and man. there is evidence of progressive loss of islet beta cells (mouse) and in man loss of insulin secretion and impaired glucose tolerance. Abnormalities in man can precede the development of diabetes by years. We lack pathogology in man for prediabetic individuals, but a recent program headed by Roberto Gianani is evaluating pancreas from cadaveric pancreatic donors for anti-islet autoantibodies, and should allow detection of insulitis in bat riskQ individuals. V. At onset of type 1 diabetes, significant beta cell insulin secretion remains and a series of trials are planned or underway to preserve such secretion. The IDS has developed an outline for conducting
571
such trials and C-peptide secretion is an important marker of retained beta cell function. VI. With complete loss of C-peptide secretion, an individual is dependent upon insulin therapy for survival, and maintenance of reasonable glycemia in the absence of hypoglycemia is much more difficult compared to stage V when some residual insulin secretion remains.
Further reading Abiru N, Maniatis AK, Yu L, Miao D, Moriyama H, Wegmann D, et al. Peptide and MHC specific breaking of humoral tolerance to native insulin with the B:9–23 peptide in diabetes prone and normal mice. Diab 2001;50:1274–81. Moriyama H, Abiru N, Paronen J, Sikora K, Liu E, Miao D, et al. Evidence for a primary islet autoantigen (preproinsulin 1) for insulitis and diabetes in the NOD mouse. Proc Natl Acad Sci U S A 2003;100(18):10376–81.
doi:10.1016/j.autrev.2004.07.017
GRAIL, an E3 ubiquitin ligase, is necessary for anergy induction in CD4+ T cells L. Soares, C.M. Seroogy, C. Garrison Fathman Stanford University Medical School Avaiable online 23 August 2004
Anergy has been used as a descriptive term for many decades to describe the state of induced antigenspecific unresponsiveness of CD4+ T cells in vitro, seen following antigen rechallenge assays. Although there is the possibility that defects in T cell anergy may underlie certain autoimmune diseases states, to date, there has been no convincing demonstration that the anergy phenotype is even demonstrable in vivo, let alone involved in autoimmune disease. My lab set out to understand the molecular nature of anergy in order to begin to answer these questions and to identify potential new targets for therapeutic intervention. Acquisition of the anergy phenotype in T cells has been blocked by inhibitors of protein synthesis and
calcineurin activity, suggesting that anergy induction in T cells may involve a unique genetic program. By taking advantage of various models of anergy induction in vitro, we were able to identify a unique genetic program seemingly controlled by the protein product of a gene we named GRAIL (1). In order to demonstrate potential functional relevance of GRAIL expression in induction of the anergy phenotype in vivo, we analyzed GRAIL expression in CD4+ T cells following anergy induction strategies. These studies demonstrated the presence of GRAIL mRNA and protein in CD4+ T cells that had been anergized, but not in CD4+ T cells that had been activated in vivo. As a further demonstration of the requirement of GRAIL expression in the
From the 4th International Congress of Autoimmunity Budapest 3–8 November 2004
Stages of type 1 diabetes George S. Eisenbarth Barbara Davis Center for Childhood Diabetes, United States Available online 23 August 2004
Type 1A or immune mediated diabetes has become one of the first immunologic disorders where it is possible to predict the development of overt disease. This has led to large collaborative studies of prediction both among relatives of patients with type 1 diabetes and in the general population, as well as prospective follow up of infants HLA typed at birth for alleles associated with disease risk. In addition, in animal studies, investigators are attempting to develop T-cell-based predictive techniques that will be applicable in man (e.g. sampling blood rather than internal lymphoid organs). In parallel with the development of ability to predict disease, efforts are directed at understanding the pathophysiology of the multiple stages preceding type 1 diabetes, and alternative hypotheses have been proposed relative to disease course. Given the ability to predict, we believe it is likely that the disease is a chronic autoimmune disorder with evidence of islet beta cell destruction/ loss function long before the development of hyperglycemia. One formulation divides the development of type 1 diabetes into five stages beginning with genetic susceptibility and ending with essentially complete loss of islet beta cells and insulin dependence. Over the past two decades, there is an expanding wealth of information concerning each of the stages and we will emphasize predictive parameters and pathophysiology with autoimmunity to insulin as a central component. I.
The dominant known determinant of type 1A diabetes is the alleles of genes within the major histocompatibility complex, and in particular alleles of DR and DQ. The highest risk genotype for type 1A diabetes consists of the heterozygous pairing of DR3/4, DQ2/8 haplotypes. In a study of more than 30,000 cord blood samples from newborns in Colorado (DAISY study led by M. Rewers), 2.4% of newborns have this genotype
and approximately 50% of children developing anti-islet autoimmunity before age 5. Expression of specific anti-islet autoantibodies is used to detect the initial signs of anti-islet autoimmunity. Insulin autoantibodies are usually the first to appear and can precede development of diabetes by years. The insulin locus perhaps by influencing expression of insulin within the thymus determines approximately 10% of the familial aggregation of type 1A diabetes, and rare AIRE mutations may act on a similar pathway. It is likely that there are additional polymorphisms outside of DR and DQ influences diabetes risk. II. At present there is not consensus in terms of environmental factors that either decrease or increase development of diabetes, but a marker increase in the incidence of the disease (worldwide) provides strong evidence for environmental determinants. Two recent reports suggest that early introduction of cereal/gluten increases development of anti-islet autoimmunity. III. At present the typical autoantibodies measured react with GAD65, ICA512 and insulin. Assays are usually performed in fluid phase as ELISA assays have lacked sensitivity/specificity. Presence of z2 of the above autoantibodies indicates a risk of type 1A diabetes exceeding 90% in studies such as DAISY and large prevention trials such as DPT-1. T-cell assays with specific antigens to date in man have had difficulty in matching sensitivity and specificity of the autoantibody assays. A tetramer analysis of T cells reacting with IGRP (Tan and coworkers) found almost 1% of CD8 T cells positive in prediabetic but not non-progressing NOD mice. IGRP is a beta cell specific molecule, and the other beta cell specific target of islet autoimmunity in the NOD mouse is insulin. Wegmann and coworkers described the dominance in this model of T cells reacting with insulin B chain
From the 4th International Congress of Autoimmunity Budapest 3–8 November 2004
peptide B:9–23. This peptide can be utilized to induce diabetes in an experimental autoimmune diabetes model (1). In addition, knocking out the insulin 1 gene prevents diabetes, while knockouts of the insulin 2 gene accelerate the development of diabetes (2). We hypothesize that insulin is a primary autoantigenic target of the NOD mouse. IV. Prior to the development of diabetes for both the NOD mouse and man. there is evidence of progressive loss of islet beta cells (mouse) and in man loss of insulin secretion and impaired glucose tolerance. Abnormalities in man can precede the development of diabetes by years. We lack pathogology in man for prediabetic individuals, but a recent program headed by Roberto Gianani is evaluating pancreas from cadaveric pancreatic donors for anti-islet autoantibodies, and should allow detection of insulitis in bat riskQ individuals. V. At onset of type 1 diabetes, significant beta cell insulin secretion remains and a series of trials are planned or underway to preserve such secretion. The IDS has developed an outline for conducting
571
such trials and C-peptide secretion is an important marker of retained beta cell function. VI. With complete loss of C-peptide secretion, an individual is dependent upon insulin therapy for survival, and maintenance of reasonable glycemia in the absence of hypoglycemia is much more difficult compared to stage V when some residual insulin secretion remains.
Further reading Abiru N, Maniatis AK, Yu L, Miao D, Moriyama H, Wegmann D, et al. Peptide and MHC specific breaking of humoral tolerance to native insulin with the B:9–23 peptide in diabetes prone and normal mice. Diab 2001;50:1274–81. Moriyama H, Abiru N, Paronen J, Sikora K, Liu E, Miao D, et al. Evidence for a primary islet autoantigen (preproinsulin 1) for insulitis and diabetes in the NOD mouse. Proc Natl Acad Sci U S A 2003;100(18):10376–81.
doi:10.1016/j.autrev.2004.07.017
GRAIL, an E3 ubiquitin ligase, is necessary for anergy induction in CD4+ T cells L. Soares, C.M. Seroogy, C. Garrison Fathman Stanford University Medical School Avaiable online 23 August 2004
Anergy has been used as a descriptive term for many decades to describe the state of induced antigenspecific unresponsiveness of CD4+ T cells in vitro, seen following antigen rechallenge assays. Although there is the possibility that defects in T cell anergy may underlie certain autoimmune diseases states, to date, there has been no convincing demonstration that the anergy phenotype is even demonstrable in vivo, let alone involved in autoimmune disease. My lab set out to understand the molecular nature of anergy in order to begin to answer these questions and to identify potential new targets for therapeutic intervention. Acquisition of the anergy phenotype in T cells has been blocked by inhibitors of protein synthesis and
calcineurin activity, suggesting that anergy induction in T cells may involve a unique genetic program. By taking advantage of various models of anergy induction in vitro, we were able to identify a unique genetic program seemingly controlled by the protein product of a gene we named GRAIL (1). In order to demonstrate potential functional relevance of GRAIL expression in induction of the anergy phenotype in vivo, we analyzed GRAIL expression in CD4+ T cells following anergy induction strategies. These studies demonstrated the presence of GRAIL mRNA and protein in CD4+ T cells that had been anergized, but not in CD4+ T cells that had been activated in vivo. As a further demonstration of the requirement of GRAIL expression in the