type 1 diabetes
Thursday 25 September 2003
Type 1 diabetes (T1D) results from autoimmune-mediated loss of insulin-producing beta-cells.
Type 1 diabetes (T1D) results from a severe lack of insulin caused by an immunologically mediated destruction of β cells. Type 1 diabetes most commonly develops in childhood, becomes manifest at puberty, and progresses with age.
Since the disease can develop at any age, including late adulthood, the appellation "juvenile diabetes" is now considered obsolete. Similarly, the older moniker "insulin-dependent diabetes mellitus" (IDDM) has been excluded from the recent classification of diabetes to reflect the emphasis on pathogenic mechanisms rather than mode of therapy.
Nevertheless, most patients depend on insulin for survival; without insulin, they develop serious metabolic complications such as acute ketoacidosis and coma. A rare form of "idiopathic" type 1 diabetes has been described in which the evidence for autoimmunity is not definitive. Here we will focus on the typical immune-mediated type 1 diabetes.
Type 1 diabetes is an autoimmune disease in which islet destruction is caused primarily by T lymphocytes reacting against as yet poorly defined β-cell antigens. As in all autoimmune diseases, genetic susceptibility and environmental factors play important roles in the pathogenesis.
Mechanisms of β Cell Destruction
Although the clinical onset of type 1 diabetes is abrupt, this disease in fact results from a chronic autoimmune attack on β cells that usually starts many years before the disease becomes evident. The classic manifestations of the disease (hyperglycemia and ketosis) occur late in its course, after more than 90% of the β cells have been destroyed.
Several mechanisms contribute to β cell destruction
T lymphocytes react against β-cell antigens and cause cell damage. These T cells include (1) CD4+ T cells of the TH1 subset, which cause tissue injury by activating macrophages, and (2) CD8+ cytotoxic T lymphocytes, which directly kill β cells and also secrete cytokines that activate macrophages.
This lesion is called insulitis. The infiltrates consist of both CD4+ and CD8+ T cells. Surviving β cells often express class II MHC molecules, probably an effect of local production of the cytokine IFN-γ by the T cells. The specificity of these T cells is largely unknown.
Various studies have implicated a β-cell enzyme, glutamic acid decarboxylase (GAD), and insulin itself as autoantigens, but the evidence supporting their importance is mainly circumstantial or based on mouse models of the disease. Also, the key question of why tolerance to these self-antigens breaks down has not been answered.
Locally produced cytokines damage β cells. Among the cytokines implicated in the cell injury are IFN-γ, produced by T cells, and TNF and IL-1, produced by macrophages that are activated during the immune reaction.
All these cytokines have been shown to induce β-cell apoptosis in culture; in mouse models of the disease, β-cell destruction can be reduced by treatment with antagonists against these cytokines.
Autoantibodies against islet cells and insulin are also detected in the blood of 70% to 80% of patients. The autoantibodies are reactive with a variety of β-cell antigens, including GAD.
These antibodies may participate in causing the disease or may be a result of T cell-mediated cell injury and release of normally sequestered antigens.
It is likely that many of these immune mechanisms work together to produce progressive destruction of β cells, resulting in clinical diabetes. The factors that predispose to autoimmunity are discussed next.
Type 1 diabetes has a complex pattern of genetic associations, and putative susceptibility genes have been mapped to at least 20 loci.72 Many of these associations are with chromosomal regions, and the particular genes involved are not known yet.
Of the multiple loci that are associated with the disease, by far the most important is the class II MHC (HLA) locus; according to some estimates, the MHC contributes about half the genetic susceptibility, and all the other genes combined
The MHC Locus. The principal susceptibility locus for type 1 diabetes resides in the region that encodes the class II molecules of the MHC on chromosome 6p21 (HLA-D).
Linkage to the HLA locus has also been demonstrated in other autoimmune diseases. Ninety per cent to 95% of Caucasians with type 1 diabetes have HLA-DR3, DR4, or both, in contrast to about 40% of normal subjects; and 40% to 50% of patients are DR3/DR4 heterozygotes, in contrast to 5% of normal subjects.
Thus, the DQB1*0302 allele is considered the primary determinant of susceptibility for the HLA-DR4 haplotype; in contrast, the HLA-DQB1*0602 allele is considered "protective" against diabetes.
Sequencing of DQ molecules associated with diabetes, both in humans and in the nonobese diabetic (NOD) mouse strain, suggests that an asparagine at position 57 in the DQβ chain protects against type 1 diabetes and that its absence increases susceptibility.
Although there are many exceptions to this finding, a general hypothesis is that development of type 1 diabetes is influenced by the structure of the entire DQ peptide-binding cleft, with residue 57 playing a significant but not exclusive role. Despite the high relative risk of type 1 diabetes in individuals with particular class II alleles, most individuals who inherit these alleles do not develop the disease. We still do not know precisely how the MHC contributes to autoimmunity in this or in any other autoimmune disease (Chapter 6). Since MHC molecules normally function to display peptides to T cells, these associations clearly point to an important role of T cells in the disease.
Non-MHC Genes. The first disease-associated non-MHC gene to be identified was insulin, with tandem repeats in the promoter region being associated with disease susceptibility. The mechanism of this association is unknown.
It may be that the disease-associated polymorphism makes the protein less functional or stable and thus compromises the functional reserve.
Alternatively, these polymorphisms may influence the level of expression of insulin in the thymus, thus altering the negative selection of insulin-reactive T cells.
Recently, another gene has been shown to be associated with the disease, encoding the T-cell inhibitory receptor CTLA-4.
Patients with type 1 diabetes show increased frequency of a splice variant that may abrogate the normal ability of this receptor to keep self-reactive T lymphocytes under control.
There is evidence that environmental factors, especially infections, are involved in triggering autoimmunity in type 1 diabetes and other autoimmune diseases.
Epidemiologic studies suggest a role of viruses. Seasonal trends that often correspond to the prevalence of common viral infections have long been noted in the diagnosis of new cases, as has the association between coxsackieviruses of group B and pancreatic diseases, including diabetes. Other implicated viral infections include mumps, measles, cytomegalovirus, rubella, and infectious mononucleosis.
In all these cases, the viruses are not thought to cause diabetes by directly damaging β cells. Rather, as was discussed in Chapter 6, two mechanisms, which are not mutually exclusive, have been proposed to explain how infections can trigger autoimmunity.
One is that the infections induce tissue damage and inflammation, leading to the release of β-cell antigens and the recruitment and activation of lymphocytes and other inflammatory leukocytes in the tissue. The other possibility is that the viruses produce proteins that mimic self-antigens and the immune response to the viral protein cross-reacts with the self tissue.
Although there is experimental evidence in support of both possibilities, neither has been established as being actually involved. It should also be pointed out that recent epidemiologic studies have shown that in the United States, the incidence of type 1 diabetes in children under 15 years of age has tripled since the 1960s.
Similar trends are seen in Western Europe. These findings are often interpreted as suggesting that infections may actually be protective in this disease and the increased incidence reflects the reduction in common infections. Consistent with this possibility, infections also prevent disease development in the nonobese diabetic mouse model.
Events controlling T1D development are not only immunological, but also neuronal in nature.
In the non-obese diabetic (NOD) mouse model of T1D, a mutant sensory neuron channel, TRPV1, initiates chronic, progressive beta-cell stress, inducing islet cell inflammation.
This novel mechanism of organ-specific damage requires a permissive, autoimmune-prone host, but ascribes tissue specificity to the local secretory dysfunction of sensory afferent neurons.
In NOD mice, normalizing this neuronal function by administration of the neurotransmitter substance P clears islet cell inflammation, reduces insulin resistance and restores normoglycemia.
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