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Autoimmunity and Diabetes

Department of Pediatrics, Weill Medical College, Cornell University, New York, New York 10021

Address correspondence and requests for reprints to: Noel K. Maclaren, Department of Pediatrics, Room LC604, Cornell University, Weill Medical College, 1300 York Avenue, New York, New York 10021. E-mail: nkmaclaren{at}aol.com

	Abstract

Top Abstract Introduction The Genetics of IMD... Pathogenesis of IMD Role of APC in... Polarized Th1 and Th2... CD1d-Restricted NK-T Cells and... The Inductive Event Future Directions References

 
The face of immune-mediated (type 1) diabetes is changing. No longer considered a disease confined to childhood, the incidence rate in Western countries is clearly rising and affecting younger children. Such a secular trend can only be explained on the basis of increased contacts with adverse environmental factors acting on a background of complex genetics. Multiple defects in immunological tolerance to "self" predispose to immune-mediated (type 1) diabetes. Initiation of immune responses involves the cytokine rich natural killer T cells. Such cells appear deficient in both humans and the rodent models of the disease. Furthermore, the regulatory abilities of T cells in general seem to be compromised. Effector mechanisms probably are dominated by cell-mediated ß cell destruction through apoptosis induction. Surprisingly, the essential antigen-presenting cells in the autoimmune processes involved appear to be B lymphocytes. The improved understanding of the ß cell autoantigens involved has led to better disease prediction. The long prodromal phase now readily identifiable through autoantibodies is spawning hopes of disease prevention, notably through antigen-based interventions or diabetes "vaccines."

	Introduction

Top Abstract Introduction The Genetics of IMD... Pathogenesis of IMD Role of APC in... Polarized Th1 and Th2... CD1d-Restricted NK-T Cells and... The Inductive Event Future Directions References

 
IT IS CRITICAL that an individual be able to elicit strong immune responses to foreign antigens, yet not to react to a "self" antigen. This lack of an immune response to self when responses to environmental antigens are retained is due to immunological tolerance. Tolerance has been one of the most controversial areas of immunology and remains a phenomenon that must be explained in any theories of immunity. The role of tolerance, or lack of tolerance, is important to the understanding of autoimmune diseases and transplantation immunobiology. A loss of natural tolerance (to self) underlies all autoimmune diseases. Many more individuals develop autoimmune phenomena than autoimmune diseases. Diseases associated with autoimmune phenomena tend to distribute themselves within a spectrum. At one pole are the organ-specific autoimmunities typified by Hashimoto’s thyroiditis or autoimmune Addison’s disease, in which autoantibodies and invasive chronic inflammatory cells destructive lesions are directed against a single organ in the body. At the other end of the spectrum are the nonorgan-specific autoimmunities typified by systemic lupus erythematosus, where autoantibodies are directed to antigens that are distributed throughout the body, resulting in immune complex-mediated lesions that are also widely disseminated. Common target organs affected in organ-specific diseases include the pancreatic islets, thyroid, adrenal, gonads, anterior pituitary, skin, liver, and stomach, whereas the nonorgan-specific diseases include rheumatological disorders involving skin, blood vessels, kidney, joints, and muscles. There is remarkable disease clustering at each end of this disease spectrum, also. In organ-specific autoimmunity these clusters comprise the autoimmune polyglandular syndromes.

Immune-mediated (type 1) diabetes (IMD) results from an organ-specific autoimmune-mediated loss of insulin-secreting ß cells (Fig. 1). This chronic destructive process involves both cellular and humoral components detectable in the peripheral blood, months or even years, before the onset of clinical diabetes. Throughout this long prediabetic period, metabolic changes, including reduced insulin secretion with eventual glucose tolerance, develop at quite variable rates toward full-blown diabetes. Whereas, IMD is predominantly the diabetes of children and young adults, it is common to all age groups. IMD is principally a disease of Caucasians. The worldwide incidence rates of IMD vary greatly among different racial groups, with Finland and Sardinia showing the greatest incidence rates and Chinese/Japanese and negroid populations showing the lowest incidence rates. IMD is diagnosed more frequently in winter months in both hemispheres. The major genetic susceptibility to IMD is linked to the histocompatibility leucocyte antigen (HLA) complex on chromosome 6p, but many other genes contribute. These genetic backgrounds interact with the environmental factors (probably certain viruses and exposure to bacteria/parasites) to initiate the immune-mediated process that culminates in ß-cell destruction. Despite significant progress in our understanding of the genetic susceptibility factors and the natural history of islet autoimmunity preceding the clinical onset of type 1 diabetes, there are considerable gaps in our knowledge. The etiology of IMD remains unclear. We speculate that multiple environmental factors may initiate ß cell autoimmunity, which once begun then proceeds by common pathogenic pathways. Whereas some advance to clinical IMD rapidly, others do not. Furthermore, we believe that progression may be irregular, with an accelerated destructive phase occurring commonly, just prior to the clinical diagnosis.

View larger version (41K): [in this window] [in a new window]   Figure 1. Pathogenesis of IMD. Genetic and environmental factors are the key contributors to the susceptibility of the disease. A susceptible person develops insulitis and eventually the disease by an autoimmune response thought to be mediated by T lymphocytes that are reactive to islet ß-cell autoantigens. These CD4+/CD8+ T lymphocytes directly cause ß cell damage or through indirect mechanisms, such as by producing cytokines and free radicals and inducing ß cell-programmed cell death or apoptosis.

	The Genetics of IMD (Type 1)

Top Abstract Introduction The Genetics of IMD... Pathogenesis of IMD Role of APC in... Polarized Th1 and Th2... CD1d-Restricted NK-T Cells and... The Inductive Event Future Directions References

The major genetic component in the HLA class II region on chromosome 6p21.3 was discovered to be associated with the disease about 20 yr ago (IMD1) (1, 2). This HLA gene region plays a role in antigen presentation and initiation of immune responses. There seems to be multiple loci in this region contributing to susceptibility haplotypes HLA-DRB1, DQB1, DQA1, DPB1, and, perhaps, others. In human IMD, there is a hierarchy of genetic associations, of which HLA-DRB1*04/DQA1*0301/DQB1*0302 is the predominant HLA haplotype associated with susceptibility in IMD. When in heterozygous association with DRB1*03/DQA1*0501/DQB1*0201, the absolute risk in HLA identical siblings of an affected proband is 1 in 4 but is as high as 1 in 12 even in the general population. Some 3–4% of Caucasians are such heterozygotes. HLA-DRB1*15/DQA1*0102/DQB1*0602 are the predominant HLA class II alleles associated with protection, even in individuals who also carry the susceptible HLA-DQA1*0301/DQB1*0302 (3). Alleles without an aspartic acid at B chain residue 57 or having an arginine at position 52 of the DQA1 chain are susceptible (4). Analysis of the DRB1*04-subtype (5) is particularly informative because it encodes a risk of IMD that is greatly variable depending on the population studied. DRB1*0401 and 0404 have been shown to be associated with IMD in the United States and Norway (5), as are DRB1*0402 and 0405 in French and in Mexican Americans (6), and DRB1*0401 and 0402 in Australians (7). DRB1*0405 confers a strong risk in Sardinians, Spaniards, North Africans, blacks, and Japanese (8). Conversely, strong protection from the disease is provided by DRB1*0403 in Sardinians, Belgians, and Chinese (9, 10); DRB1*0404 in French (11); and DRB1*0403, 0408, and 0411 in Mexican Americans (6); and DRB1*0406 in Orientals (11). A recent study showed that DRB1*0401 subtypes represent almost 74% of all DR4 alleles and confer a significant risk to IMD when combined to DQB1*0302 (12). Among the various DRB-DQB allelic combinations, a single dose of protective DR or DQ allele, such as DRB1*0403, is sufficient to provide dominant protection.

Another locus (IMD2) located near the insulin gene on chromosome 11p15 was identified about 10 yr ago by association analysis (13). IMD2 has been identified as the variable number of tandem repeats region immediately 5' to the insulin gene, which seems to play a role in the level of gene transcript expression (14) in the thymus presumably by eliminating insulin-autoreactive T cells from escaping into the circulation. IMD is some 15 times more common for siblings of an affected proband than it is in the general population. This product that genetic contribution must explain is termed s. IMD1 and IMD2 have been estimated to contribute 42% and 10%, respectively, to the s, whereas many other IMD susceptibility genes have been described accounting for additional small genetic contributions of only a few additional percent. The recent reports of at least five additional genomic intervals influencing IMD predisposition (IMD3, IMD4, IMD5, IMD7, and IMD8) represent significant advances in our understanding of the genetic complexity of this disorder. IMD3 was localized to chromosome 15q26 (15), IMD4 to the 11q13 region (16), IMD5 to near ESR in the chromosome 6q25 (16), and IMD7 to chromosome 2q31-q33 (17). Lately, another locus on chromosome 6 near the marker D6S264, distal to IMD5, has been reported and designated as IMD8 (18). But the genes responsible for the increased susceptibility to IMD in these intervals have not been identified. These genes could alter immunological responsiveness in general, such as via the inducible polymorphism of the immunoglobulin constant region (Fc) receptors and the associated cytotoxic T-lymphocyte adhesion ligand (CTLA-4) (19). Various studies have provided evidence of linkage and associations of a polymorphic marker in the CTLA-4 gene with IMD in Italian and Spanish families (19), but not in patients of Northern European descent or the United States. This T cell accessory molecule is induced during normal immune responses, leading to apoptosis in the activated T cells and, thus, limiting the response. It is, thus, easy to see that a defect in this gene could lead to poorly controlled immune responses or to autoimmunity. In addition, it has been postulated that increased susceptibility of islet cells to the induction of apoptosis by cytotoxic T cells may also be responsible for facilitated death of islet ß cells (20). IMD12 is one of the confirmed susceptibility loci located on chromosome 2q33.

	Pathogenesis of IMD

Top Abstract Introduction The Genetics of IMD... Pathogenesis of IMD Role of APC in... Polarized Th1 and Th2... CD1d-Restricted NK-T Cells and... The Inductive Event Future Directions References

 
The availability of Biobreeding (BB) rats and nonobese diabetic (NOD) mice, the rodent models of IMD, have greatly enhanced our understanding of the possible pathogenic mechanisms involved in human IMD. Furthermore, epidemiological studies have allowed for a developing picture of the natural history to emerge. The process of destruction of ß cells is chronic in nature, often beginning during infancy and continuing over the many months or years that follow. At the time of clinical diagnosis of IMD, about +80% of the ß cells have been destroyed, whereas the islets are infiltrated with chronic inflammatory mononuclear cells (insulitis), including CD8⁺ cytotoxic T cells. Long before a person develops diabetes, however, autoantibodies to ß cells and their antigens called islet cell antibody (ICA) are detectable. The nature, intensity, and antigenic spreading of the reactivities of these autoantibodies distinguish individuals who develop diabetes from those who do not. These autoantibodies have been found to be reactive to islet cell, insulin, and their constituent enzymes glutamic acid decarboxylase (GAD₆₅) and the insulinoma-associated antigen-2 (IA-2) and a homologous antigen, IA-2ß. GAD₆₅, IA-2, and IA-2ß, but not insulin, have all been shown to be antigenic components of the islet cell antibody reaction. IA-2 and IA-2ß are structurally related transmembrane proteins of the tyrosine phosphatase family of enzymes, which are 70% homologous in their antigenic intracellular regions. Autoantibodies recognize internal domain epitopes that are specific to each protein, as well as epitopes that are shared by both IA-2 and IA-2ß. GAD and the IA-2 are highly present in the brain as well as the islets, however, the blood brain barrier prevents ingress of pathogenic antigen-specific T cells, thus preventing brain disease. The antibodies react to undenatured, native molecules by their conformational epitopes, whereas autoreactive T cells reactive to their peptides are recognizable in the peripheral blood of patients in low numbers.

Once islet cell autoimmunity has begun, progression to islet cell destruction is quite variable, with some patients rapidly progressing to clinical diabetes, while others remain in a nonprogressive state. Antigenic/epitope spreading of the autoantibody responses is one important marker of impending progression because those with but a single autoantibody progress slowly, whereas those with autoantibodies to multiple antigens most often progress rapidly. First discovered with respect to ICA plus insulin autoantibodies (21), the principle extends to all antibody markers. Diabetes risk and time to diabetes in relatives of patients, thus, directly correlates with the number of different autoantibodies present. The pathogenesis of IMD has been extensively studied, but the exact mechanism involved in the initiation and progression of ß cell destruction is still unclear (Table 1) (22). The presentation of ß cell-specific autoantigens by antigen-presenting cells (APC) [macrophages or dendritic cells (DC)] to CD4⁺ helper T cells in association with MHC class II molecules is considered to be the first step in the initiation of the disease process (Fig. 2). Macrophages secrete interleukin (IL)-12 stimulating CD4⁺ T cells, to secrete interferon (IFN)- and IL-2. IFN- stimulates other resting macrophages to release, in turn, other cytokines such as IL-1ß, tumor necrosis factor (TNF)-, and free radicals, which are toxic to pancreatic ß cells. During this process, cytokines induce the migration of ß-cell autoantigen specific CD8⁺ cytotoxic T cells. On recognizing specific autoantigen on ß-cells in association with class I molecules, these CD8⁺ cytotoxic T cells cause ß-cell damage by releasing perforin and granzyme and by Fas-mediated apoptosis of the ß cells. Continued destruction of ß cells eventually results in the onset of diabetes.

View larger version (42K): [in this window] [in a new window]   Figure 2. A schematic description of the roles of various subsets of T cells and their cytokines in ß cell destruction, leading to diabetes. Islet cell proteins are presented by APC (dendritic cells or macrophages or B cells) to naïve Th0 type cells in association with MHC class II molecules and other costimulatory molecules (B7) to CD28 on T cells. These APC in turn secrete IL-12, promoting the differentiation of Th0 cells to Th1 type cells. Th1 cells secrete IL-2 and IFN- that further stimulate macrophages or specific cytotoxic CD8+ T cells to release free radicals (superoxides) or perforin/granzymes, leading to ß cell apoptosis and eventually diabetes. CD4+ or CD8+ T cells further mediate death of ß cells by Fas mediated mechanisms. NK1.1+ T cells or NK-T cells, on the other hand can prevent ß cell destruction by secreting IL-4 early during the differentiation of Th0 cells, favoring a benign Th2 type response and down-regulating Th1 cells. IL-4 and IL-10 secreted by CD4+ Th2 type cells and reduced IL-2 and IFN- secretion prevents ß cell destruction and diabetes. However, at times, Th2 cells may also become disease producing (data not shown).

	Role of APC in IMD

Top Abstract Introduction The Genetics of IMD... Pathogenesis of IMD Role of APC in... Polarized Th1 and Th2... CD1d-Restricted NK-T Cells and... The Inductive Event Future Directions References

B lymphocytes represent another essential subpopulation of APC for generating MHC class II-restricted T cell responses to certain antigens. Recent studies in NOD mice suggest that B cells play an important role as APC for self antigens in their progression to diabetes. This diabetogenic role of B lymphocytes in NOD mice could be as APC, which present certain ß-cell antigens to autoreactive T cells, permitted to be generated as a result of inherent tolerogenic defects. Alternatively B cells secrete the autoantibodies that bind to pancreatic ß cell antigens and may thereby subsequently trigger autoreactive T cells through an antibody-dependent cell-mediated cytotoxicity response. A study by Serreze et al. (26) in NOD mice showed that the initiation of GAD-reactive T cell responses in NOD mice require only B lymphocytes as APC. Once such GAD-reactive T cells have been initially activated in NOD mice, however, the responses may be maintainable by APC other than B lymphocytes.

Macrophages may also be involved in the pathogenesis of IMD early on because inactivation of macrophages results in the near complete prevention of diabetes in NOD mice as well as BB rats (22). This could be because T cells in a macrophage-depleted environment lose their ability to differentiate into ß cell-reactive cytotoxic T cells. On studying the islet antigen-specific immune response and T cell activation in macrophage-depleted NOD mice, it was found that there was a decrease in usually pathogenic Th1 and an increase in Th2-type responses due to reduced expression of macrophage-derived cytokine, IL-12 (27).

	Polarized Th1 and Th2 Subsets and Cytokines in IMD

Top Abstract Introduction The Genetics of IMD... Pathogenesis of IMD Role of APC in... Polarized Th1 and Th2... CD1d-Restricted NK-T Cells and... The Inductive Event Future Directions References

 
The cross-regulatory, polarized roles of Th1 and Th2 cells in the induction and regulation of Th-dependent immune responses is now well established both in mice and humans. Th cells are differentiable by their chemokine receptors and the cytokines they secrete. Cytokines themselves are important and efficient regulators for the development of naïve Th0 cells toward Th1 or Th2 cells. IL-12 and IFN- together promote the differentiation of Th1 cells, whereas IL-4 itself has the important role in Th2 differentiation. Locally secreted IL-4 strongly suppresses Th1-inducing capacity of IL-12 and IFN-. Thus, IL-4 is a potent inducer of Th2 cells and, simultaneously, a powerful inhibitor of Th1 development. The Janus Kinase STAT pathway is important in cytokine-induced signal transduction, which directly transfers signals from the cell surface cytokine receptors to the nucleus (28). IL-12 and IL-4 act through STAT4 and STAT6, respectively, to deliver specific differentiating, transduction stimuli.

Cytokines are important to the outcome of an autoimmune disease. A variety of approaches have been used to study the roles of cytokines in the pathogenesis of IMD for past 15 years. Most of the studies have been carried out in NOD mice and BB rats. These studies largely support the concept that ß-cell destructive insulitis is associated with increased expression of proinflammatory cytokines (IL-1, TNF-, and IFN-) and Th1 cytokines (IFN-, TNF-ß, IL-2, and IL-12), whereas nondestructive (benign) insulitis is associated with increased expression of Th2 cytokines (IL-4 and IL-10). However, cytotoxic T cell clones of both Th1 and Th2 lineages can be used to transmit diabetes in NOD mice, suggesting that the Th1/Th2 paradigm represents a pathogenic bias that is far from absolute. Oral insulin or GAD protects against diabetes through the generation of regulatory Th2/Th3 cells characterized by their TGF-ß secretion. Cytokines render ß cells susceptible to destruction either by direct cytotoxic effect or by T cells infiltrating the islets (e.g. MHC class I-restricted CD8⁺ T cells) because IFN- up-regulates MHC class I expression on rodent and human ß cells. Another mechanism whereby cytokines may render ß cells susceptible to T cell-mediated killing is via induction of Fas (CD95) receptors on their surfaces. Ligation of Fas receptors on ß cells by FasL (CD95L) on CD4⁺ and/or CD8⁺ T cells has been postulated to be a mechanism of ß-cell death by apoptosis in IMD.

	CD1d-Restricted NK-T Cells and IMD

Top Abstract Introduction The Genetics of IMD... Pathogenesis of IMD Role of APC in... Polarized Th1 and Th2... CD1d-Restricted NK-T Cells and... The Inductive Event Future Directions References

 
Until recently, antigen presentation to T cells was defined only by class I and II proteins encoded within the MHC. However, the human cluster of differentiation 1 (CD1) family of proteins has now been well characterized as non-MHC, antigen-presenting molecules. The MHC class I-like structure of CD1 proteins and their prominent expression on specialized APC has led to the hypothesis that these proteins represent a third distinct lineage of antigen-presenting molecules. CD1 proteins are class I MHC like heterodimers that consist of an approximately 45-kDa chain that is associated with ß2-microglobulin (ß2m). Five CD1 genes have been identified in humans; namely CD1 a, b, c, d, and e. The pocket of antigen binding groove of CD1 is entirely made up of hydrophobic residues, suggesting that CD1 binds to highly hydrophobic ligands such as lipids. Thus, the most surprising finding of the CD1 antigen-presenting system is that the antigens presented by CD1 are not peptides, but rather lipid and glycolipid in nature.

One of the properties shared by mouse CD1 and human CD1 molecules is their ability to be recognized by natural killer T (NK-T) cells (29). Recently, much interest has been focused on NK-T cells because of their ability to rapidly produce large amounts of cytokines, suggesting that these cells play a role in regulating the speed and type of immune responses. The majority of mouse NK-T cells express receptors, biased to variable Vß8.2, Vß7, or Vß2 chains paired in an invariant V14J281 chain rearrangement (30). The human counterpart, also expresses a limited repertoire of restricted V chain paired opposite to Vß chain, i.e. an invariant V24 rearrangement paired with Vß11, the human homologue of mouse Vß8 (31). NK-T cells in both species can be autoreactive in vitro for CD1 molecules in the absence of exogenous antigens. NK-T cells of both species resemble each other in several additional ways, including expression of intermediate T-cell receptor (TCR) levels, expression of CD4 without CD8 or the absence of both CD4 and CD8, expression of cell surface proteins characteristic of memory or activated T cells (32), and the presence of NK receptors, NK1.1 (CD161) in mice (33) and NKRP1 in humans (32). Recent studies have suggested the importance of NK-T cells as effector cells in tumor rejection, in IL-4 production, and as regulatory cells in autoimmune diseases.

A major element driving the development of Th2 cells is the presence of IL-4 at the site of the immune response. These NK-T cells have been recognized as a major source of IL-4 on primary antigenic stimulation. Thus, an important immunoregulatory role has been attributed to this discrete T cell subset, whereas recent evidence provides a strong link between CD1d-restricted T cells and autoimmunity. Several mouse models of autoreactivity are characterized by decreased V14⁺ T cells, the subset of T cells that are CD1d-restricted (34). Furthermore, lupus-prone mice injected with V14 antibodies show an earlier onset of disease and increased titers of antidouble-stranded DNA antibodies. NOD mice have been shown to be deficient in NK-T cells by 3 weeks of age. Furthermore, these cells lack the ability to produce IL-4 at this age, suggesting that a very early defect in NK-T cells could lead to the genesis of autoimmunity through a deficiency in Th2 cell function (35). One study in humans showed that T cells from diabetic patients bearing V24 TCR preferentially produced Th1 cytokines, whereas their healthy siblings did not (36). They proposed a model in which Th1-cell-mediated damage is initially regulated by V24JQ⁺ T cells producing both IFN- and IL-4 cytokines, whereas their loss of ability to specifically secrete IL-4 could be correlated with IMD. They further suggested a strong link between V24JQ⁺ T cells and IMD, indicating that these cells may be functionally related to this autoimmune disease in humans. Our own unpublished studies document deficiencies in NK-T cells in both human and murine IMD and suggest this area should be immediately fruitful for investigations.

	The Inductive Event

Top Abstract Introduction The Genetics of IMD... Pathogenesis of IMD Role of APC in... Polarized Th1 and Th2... CD1d-Restricted NK-T Cells and... The Inductive Event Future Directions References

 
Molecular mimicry has long been proposed as a pathogenic mechanism for autoimmune diseases (Table 1). Antigenic molecular mimicry is defined by cross-reactive immune responses, arising because of antigenically significant, structural homologies shared by molecules encoded by dissimilar genes or by antigens of exogenous and endogenous origins. The incidence of type 1 diabetes is well documented over the last 3 decades in Europe, and the preferential seasonal onset of IMD emphasizes the probable role of environmental factors in the disease process. It has long been suggested that IMD in humans is caused by viral infections. Several studies have reported a viral etiology associated with IMD (37, 38), of which congenital rubella is clinically established. Immune responses against a determinant shared by host cells and a viral protein could cause a tissue-specific immune response by generation of cross-reactive, cytotoxic effector lymphocytes or antibodies that recognize self-proteins located on the target ß cells. Monoclonal antibodies against viruses have been observed to be capable of cross-reacting with host determinants (39).

Although numerous sequence similarities between viral proteins and ß-cell autoantigens are plausible, the relationship between Coxsackie B virus infection and GAD₆₅ autoimmunity has recently received the most attention. The finding by Kauffman et al. (40), of a striking sequence homology of 18 amino acid peptide between human GAD₆₅ and the Coxsackie virus p2-C protein, provides the best evidence of a specific molecular mimicry model. The sequence of this region of GAD₆₅ (amino acid 250–273) is significantly similar to the p2-C protein of Coxsackie B virus. However, not all published studies have demonstrated a linkage between immunity to GAD₆₅ and Coxsackie virus. For example, one study identified a non-Coxsackie-homologous region of GAD₆₅ as a predominant cellular immune epitope while studying the polyclonal human T cell responses (41), but of peripheral blood T cells, not pancreatic.

The tyrosine phosphatase IA-2 is another molecular target of pancreatic islet autoimmunity in IMD, as discussed above. In one of the recent studies, the epitope spanning 805–820 amino acid elicited maximum T-cell responses in all at-risk relatives out of a total of 68 overlapping, synthetic peptides encompassing the intracytoplasmic domain of IA-2 (42). This epitope was found to have 56% identity and 100% similarity over 9 amino acid with a sequence in VP7, a major immunogenic protein of human rotavirus. This dominant epitope also has 45–75% identity and 64–88% similarity over 8–14 amino acid to sequences in Dengue, cytomegalovirus, measles, hepatitis C, and canine distemper viruses and the bacterium Haemophilus influenzae. Furthermore, three other IA-2 epitope peptides have 71–100% similarity over a 7–12 amino acid stretch to herpes, rhino-, hanta-, and flaviviruses. Two other peptides have 80–82% similarity with dietary proteins of milk, wheat, and bean proteins. These molecular mimicries could lead to either triggering or exacerbation of ß-cell autoimmunity. Besides molecular mimicry, retroviral expression of env protein superantigens (Sags) may be able to activate clonal expansion of autoreactive T cell clones. Superantigens have been implicated in the pathogenesis of the various autoimmune diseases (43). Superantigens are the microbial proteins able to mediate interactions between MHC class II and polyclonal T cells, resulting in their reciprocal activation. The presence of MHC class II molecules on the surface of APC and the expression of one or more defined variable (V)ß TCR chains on T cells, are the only two absolute requirements for the superantigens. Conrad et al. (44) isolated a novel mouse mammary tumor virus-related human endogenous retrovirus (HERV), in patients suffering from acute onset type 1 diabetes termed as HERV IDDMK_1,222 subtype. They further reported that selective expansion of Vß7⁺ T cells in the islet cell infiltrates from two patients with recent onset IMD was associated with extensive junctional diversity of Vß7⁺ T cell clones. These investigators demonstrated that islet cell membrane preparations preferentially expanded Vß7⁺ T cells from nondiabetic peripheral blood mononuclear cells (45). We, among others, were, however, unable to confirm any IMD specificity of the IDDMK_1,2 22 because it was equally recoverable as viraemia from controls as well as patients (46), whereas this HERV was a minor variant of the HERVK-10 family of viruses. Furthermore, both patients and controls in our studies made antibodies to HERV-K env proteins. The Sag effect they reported also needs confirmation.

	Future Directions

Top Abstract Introduction The Genetics of IMD... Pathogenesis of IMD Role of APC in... Polarized Th1 and Th2... CD1d-Restricted NK-T Cells and... The Inductive Event Future Directions References

 
Sixteen million people in United States have diabetes mellitus, and about 800,000 new cases are diagnosed each year. Probably as many as 1 million patients have type 1 diabetes, with some additional 50,000 newly diagnosed patients appearing each year. In both human and economic terms, diabetes is one of the most costly diseases of the United States. It is incurable, and the number of people afflicted by diabetes continues to increase at an alarming rate. At present, there is no method proven to prevent or cure diabetes, whereas available insulin replacement treatments have only limited success in controlling its devastating consequences. Current therapy is limited to replacement of insulin by daily injections, rather than blockade of the immune response to prevent destruction of ß cells to preserve insulin secretion. Affected patients, therefore, remain at a high risk for the development of long-term complications of the disease. Over the past few decades, a solid foundation had been laid to understand various aspects of IMD, i.e. genetic susceptibility, cell biology, and basic immunology. The most important long-term goal of the research on IMD, perhaps, is to gain an understanding of the genetics and immunopathological basis of the disease. The explosion of new genetic technologies provides us with an extraordinary opportunity to uncover the cause of the disease. Two new technologies that will help us to diagnose and treat IMD are rapid accumulation of genetic sequence information and the application of the micro-array technology to measure changes in messenger RNA expressions of patient T cells and pancreatic ß cells. Furthermore, through human studies and the use of NOD mouse models, important target antigens for T cells that attack the islets of Langerhans in type 1 diabetes have already been identified, while more will be discovered. These findings led to the NIH-supported clinical trial for prevention of type 1 diabetes called Diabetes Prevention Trial-1. Until the results are in, extensive research should be carried out in the animal models to identify novel immunotherapies over the next 3–4 yr, which can be assessed initially in newly diagnosed patients. The fundamental research efforts described should help identify the optimal antigens/cytokines for immunotherapy and the appropriate markers to detect early autoimmune response of type 1 diabetes in general population. Table 2 lists some of the most promising approaches, of which we believe immunization with the insulin B chain 8–24 peptide as a vaccine appear the most exciting. This antigen could be given with a suitable Th2-promoting adjuvant or in combination with soluble class II MHC that would promote tolerance.

Received August 16, 1999.

Accepted September 22, 1999.

	References

Top Abstract Introduction The Genetics of IMD... Pathogenesis of IMD Role of APC in... Polarized Th1 and Th2... CD1d-Restricted NK-T Cells and... The Inductive Event Future Directions References

 

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