Type I diabetes is primarily induced by an autoimmune process that destroys the pancreatic Beta cells. Genetic and environmental factors interplay to bring about an “insulitis”. Given that antibodies to GAD are detectable years before type I diabetes develops, there is a potential for treating and preventing the onset of this autoimmune process even before there is an irreversible pancreatic dysfunction.

1. Review Article
Immunology of type I diabetes: The journey from animal
models to human therapeutics
Sundeep Upadhyaya
Senior Consultant, Department of Rheumatology, Indraprastha Apollo Hospitals, New Delhi, India
a r t i c l e i n f o
Article history:
Received 11 May 2013
Accepted 15 May 2013
Available online 3 June 2013
Keywords:
Genetics
Immune therapies
Pathogenesis
Type I diabetes
a b s t r a c t
Type I diabetes is primarily induced by an autoimmune process that destroys the
pancreatic Beta cells. Genetic and environmental factors interplay to bring about an
“insulitis”. Given that antibodies to GAD are detectable years before type I diabetes
develops, there is a potential for treating and preventing the onset of this autoimmune
process even before there is an irreversible pancreatic dysfunction. NOD mice animal
models for type 1 diabetes have been studied extensively and have contributed to both
pathophysiologic insights and treatments (tolerance induction, T-cell based therapies, DC
vaccines).
Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
1. Introduction
The importance of type 1 diabetes is increasing with the
passage of time as the incidence of new cases is seeing record
numbers at-least in the developed world. From the initial days
of the insulin Discovery and the first insulin treatment of 1922,
to the gene therapies and dendritic-cell vaccines of the late
1990s, the science of the type 1 diabetes has been growing by
leaps and bounds, not only in its therapeutics but also in its
patho-genetics.1
Currently, based on the presence or absence
of anti-GAD antibodies and anti-insulin antibodies (which are
surrogate markers for an autoimmune pathology), type 1
diabetes is classified as either type 1 A (Immune mediated)
diabetes or type 1 B (non-Immune) diabetes.
There is incontrovertible evidence of autoimmune pa-
thology in 95% of type 1 diabetes patients but the other 5%
lack auto-immune markers, therefore are deemed “non auto-
immune”.2
Epidemiological studies indicate that the inci-
dence of type 1 diabetes in Finland, a developed European
country, is 40/100,000 per year and is only 0.1/100,000 per year
in a province (Zunyi) in China. Other epidemiological studies
(The EURODIAB collaborative study) indicate a 3e4 percent
annual increase in the incidence of type 1 diabetes.3
2. Genetics of type 1 diabetes
Human leukocyte antigen (HLA) association has been known
for several years4
and these are key players, responsible for
about 50% susceptibility to the disease. The HLAeDR4 and
HLAeDR3 was initially the association found, but these were
actually in linkage with HLAeDQ8 and HLAeDQ2 respectively.
Still later, the two haplotypes (combinations of genes)
HLAeDR4eDQ8 and HLAeDR3eDQ2 were found to be in as-
sociation with 90% of type 1 diabetes patients.5
HLAeDR15eDQ6 is found in less than 1 percent of type 1
diabetes patients as compared to being found in nearly 20% of
the general population and is probably protective.6
When the
two haplotypes DR4eDQ8/DR3eDQ2 combine, the risk for
E-mail address: sundeepupadhyaya@hotmail.com.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/apme
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 0 5 e1 0 7
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http://dx.doi.org/10.1016/j.apme.2013.05.008

2. diabetes is greatest and insulin dependent diabetes develops
very early in childhood.7
T-cell activation plays a crucial role in autoimmune insu-
litis. The CTLA-4 molecule, which is a negative regulator of T-
cell activation, has also been linked to the immunity of type 1
diabetes. The CTLA-4 gene is on the chromosome 2q33, and
this positively influences the immune response in type 1
diabetes: the soluble levels of CTLA-4 increase8
and this in
turn leads to higher levels of regulatory T-cell.9
Another suppressor of T-cell activation, the LYP protein
(PTPN22) variant is also associated with type 1 diabetes.10
The
genes coding for the intercellular adhesion molecule I (ICAM
I)11
and the vitamin D related signaling are the other factors.12
The insulin gene on the chromosome 11 is probably the sec-
ond most important genetic factor as it contributes almost
10% of the genetic susceptibility.13
Even within the insulin
gene, it is the number of tandem repeats that are associated
with the disease; longer tandem variants are protective.14
3. Environmental influences on the patho-
physiology of type 1 diabetes
Environmental pressures in the form of viruses like the rota-
viruses15
and the enteroviruses,16
are associated with an
increased risk of type 1 diabetes. Yet in countries with very
low viralewaterborne diseases like the Scandinavian coun-
tries, the incidence of type 1 diabetes is the highest. The
countries were viral infections and other hygiene related
factors predispose the general population (like Venezuela,
China, etc.), have the lowest incidence of type 1 diabetes. In
the developed world, the exposure to pathogens is minimal
and the infant’s developing immune system is spared the
antigen-pathogen onslaught. This according to the hygiene
hypothesis,17,18
promotes autoimmunity and atopy.18
4. Preclinical diabetes and the potential for
therapeutic intervention
Large population studies have now established that first de-
gree relatives of type 1 diabetic patients have a higher inci-
dence of diabetes related antibodies19
in the pre-diabetic
phase. Also, 90% of the children who ultimately developed
type 1 diabetes had antibodies in their serum, years before the
development of diabetes.20
Three of these antibodies can be
easily tested clinically and they are IA-2 (anti protein tyrosine
phosphatase like molecule),21
Isulin22
and GAD (glutamic acid
decarboxylase).23
The antibody to GAD, which persists for the
longest has the greatest utility in day to day practice since it
persists for the longest24
and since it is found most commonly
in children of 5 years or less, who are destined to develop type
1 diabetes. There is the potential to intervene therapeutically,
while the disease is “smouldering” because of the “autoim-
mune insulitis”. Several clinical trials have identified the “pre-
diabetes” condition in patients by the presence of at-least two
antibodies.
Even genetic testing in large population groups associates
HLA class II (DP, DQ) typing with higher incidence of anti-
bodies to GAD and insulin. One large population study the
DIPP (Type 1 Diabetes Prediction and Prevention)25
has tried
intranasal insulin as an immune-intervention in patients with
positive HLA- DP and DQ typing but absent GAD and insulin
antibodies. Similar to the intranasal immune- intervention
trial was the DPT-I or the diabetes prevention trial type I.26
The
DPT-I was largely a negative trial, failing to show a significant
effect in reducing onset of new type 1 diabetes with oral or
injectable insulin used as an immunogen.
5. T-cell directed therapies
Although cyclosporine was successfully used in the 1980s for
the treatment of type 1 diabetes, the toxicity of the medication
prevented it’s widespread use.27,28
Monoclonal antibody ther-
apies like the OKT3 (Anti CD3) monoclonals, have also been
successful. In one study the insulin requirements after anti
CD3 antibody treatment, were found to be reduced.29
Similarly
an earlier study on type 1 diabetes patients, with a different
anti CD3 monoclonal antibody (OKT3 gamma I AlaeAla),
resulted in better C-peptide responses and clinical parameters
over a two year period.30
6. Conclusion
The science of type 1 diabetes is on a rapid march. Immuno-
genetics and the monoclonal antibody revolution, promise
to make a paradigm shift to the management of type 1 dia-
betes. Indeed, gone are the days that studies on this very
important illness were based solely on animal models (the
NOD Mouse, etc). Large clinical trials are being conducted on
humans and the molecular pathogenesis of the disease is
unraveling at a pace that far out-paces our ability to come up
with treatment molecules suggested by these studies.
Conflicts of interest
The author has none to declare.
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