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Type 1 Diabetes
Figure 1: The Trimolecular Complex
the TCR have led to the hypothesis that this V-alpha segment is
important in enhancing diabetes susceptibility.
19–21
The final component
in the trimolecular complex in the NOD mouse is I-Ag7, homologous to
TCR
the DQ8 HLA class II molecule in humans. HLA class II molecules play a
major role in the development of autoimmunity (see below). Human
DR3–DQ2 and DR4–DQ8 haplotypes, which are closely associated with
type 1 diabetes risk, have similar polymorphisms to I-Ag7.
22,23
These
polymorphisms alter the peptides bound and presented to TCRs, and
thus alter self-antigen recognition as described above.
Although in the NOD mouse model there are convincing data
g7
MHC/I-A
supporting the hypothesis that insulin is the primary autoantigen,
studies in humans are not definitive. In particular, although insulin
autoimmunity is prominent and polymorphisms of the insulin gene
Peptide
influence diabetes risk, there are multiple islet autoantigens targeted in
humans. Autoantibodies to IA-2, glutamic acid decarboxylase (GAD),
MHC = major histocompatibility complex; TCR = T-cell receptor.
and the newly discovered autoantigen ZnT8 (discussed in more detail
below) are important markers of disease risk. Furthermore, loss of
epithelium (via major histocompatibility [MHC] class I and II molecules), tolerance and development of autoimmunity clearly depend on more
the TCR binds to it. In the absence of any TCR engagement in the than the trimolecular complex recognition of insulin. Environmental
thymus, T cells will die by ‘neglect.’ If recognition in the developing factors and polymorphisms of non-MHC genes involving maintenance
thymus is modest (due to weak binding related to variations in the of tolerance can play a distinct role in disease development (see
presenting molecule, the antigenic peptide, and the TCR binding below). Inability to maintain tolerance is a key aspect of the NOD mouse
sequence), T-cells fail to be ‘deleted.’ They then leave the thymus and model and humans.
enter the peripheral circulation. A subset of autoreactive T-cells fail to be
deleted in the thymus and can react with self-antigens in the periphery. Disease Prediction in Type 1 Diabetes
Self-antigen reactivity can occur by several mechanisms, including Genetic Markers
modification of self-molecules in the periphery but not the thymus (e.g. Approximately one in 300 individuals in the general population in the US
citrinylated peptides), failure of the thymus to express certain peripheral develop type 1 diabetes, while approximately one in 20 first-degree
antigens in concentrations that are sufficient to delete all self-reactive relatives of patients with type 1 diabetes (offspring or sibling) develop
T cells, and innate immune activation of self-reactive T-cells in the diabetes.
24,25
More than 60% of monozygotic twins with a twin-mate
periphery. These peripherally activated, autoreactive T cells can then having type 1 diabetes will develop diabetes and more than 70%
trigger a cascade of events leading to a large-scale immune response develop anti-islet antibodies.
26
Dizygotic twin risk is much lower and
that ultimately ends in tissue destruction. similar to that of siblings (again, one in 20 or 5%).
27
Insulin peptide sequences are now thought to be central to the Environmental factors play a role in the development of type 1 diabetes.
development of autoimmunity in the NOD mouse.
6–14
The insulin B:9–23 This is evident by the lack of 100% concordance in twin studies, the
peptide sequence may be of particular importance in loss of tolerance increasing incidence of type 1 diabetes worldwide (at a rate too fast
leading to diabetes.
9,14
In the mouse there are two insulin genes (insulin to be explained by genetic changes alone), potential disease links to
1 and 2) that form nearly identical preproinsulin molecules. Insulin 1 and medications, temporal associations with environmental factors (e.g. diet
2 are both expressed in pancreatic islet beta cells, but only insulin 2 is and viral infections), and variability of disease penetrance in mouse
expressed in the thymus. Ideally, insulin-reactive T cells would be models with different environmental exposures.
28–34
One recent study
deleted in the thymus. Knocking out insulin 2 accelerates the followed monozygotic and dizygotic twins for 10 years and reported that
development of type 1 diabetes, while knocking out insulin 1 prevents 88% of phenotypic variance was due to genetics, while 12% could be
the majority of type 1 diabetes development.
15
Thus, it is likely that attributed to the environment.
35
More research is warranted in this field,
attenuated expression of insulin 2 in the thymus of knockout mice and studies such as The Environmental Determinates of Diabetes in the
enhances autoimmunity by decreasing negative selection in the thymus, Young (TEDDY) are under way to help explore these issues.
while eliminating Insulin 1 in the periphery may remove an important
islet target peptide. Of note, knocking out both insulin genes and Regarding genetic susceptibility to diabetes, there are well-known
providing mice with a single mutated insulin gene (replacing beta-chain single-gene causes of autoimmune diabetes. They include autoimmune
16 tyrosine with alanine) prevents all diabetes of NOD mice.
13,16–18
polyendocrine syndrome type 1 (APS1) caused by mutations in the
AIRE gene and immunodysregulation, polyendocrinopathy, enteropathy,
A specific V alpha segment of the TCR, TRAV5D-4*04, appears to play a X-linked (IPEX) syndrome caused by mutations in the FOXP3 gene. Both
unique role in targeting the B:9–23 sequence of the insulin molecule. of these syndromes are well studied and have contributed to current
Experiments involving variation of this specific alpha chain sequence understanding of diabetes pathophysiology. The FOXP3 gene in
but conservation of other elements in the beta and alpha construct of particular is essential for the development of regulatory T cells, and
80 US ENDOCRINOLOGY
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