Transcript Autoimmunity and Type 1 Diabetes Mellitus

Autoimmunity and Type 1
Diabetes Mellitus
Prof Nigel Crowther, NHLS,
Department of Chemical Pathology,
University of Witwatersrand Medical
School.
Diagnosis of type 1 diabetes
• Clinical features: polyuria, polydipsia,
weight loss
• Biochemical features: fasting glucose
greater than 7 mM; random glucose
greater than 11.1 mM; glycosuria,
ketonuria
• Presents during childhood, but also in
adults (latent autoimmune diabetes of
adulthood or LADA)
Diabetes types
• Type 1: insulin requiring, childhood (aka
IDDM). Two types:
– 1A: autoimmune
– 1B: unknown origin (idiopathic)
• Type 1.5: insulin requiring, autoimmune,
adults (aka LADA)
• Type 2: non-insulin requiring, adults,
insulin resistance, beta cell dysfunction,
non-autoimmune (aka NIDDM)
Diabetes types (continued)
• Other types: due to gene defects (eg
MODY), induced by toxins, damage
to exocrine pancreas etc....
• Gestational diabetes: occurs only
during pregnancy. Risk for later
development of type 2 diabetes.
Aetiology of type 1 diabetes
Genetic predisposition
+
Environmental factor
Autoimmune destruction of beta cells
Genetics of type 1 diabetes
• Evidence for genetic input
– Family history (complex)
– Animal models e.g. NOD mouse and BB rat
– Linkage with HLA (IDDM1): accounts for
45% of genetic susceptibility
– Linkage with insulin gene (IDDM2): 10% of
genetic susceptibility
– At least 14 other genetic loci have been
associated with type 1 diabetes
Lifelong risks of type 1 diabetes
Group
Normal subject
Non-diabetic relatives of
patients with diabetes:
Parent
Offspring:
with affected father
with affected mother
Sibling
identical twin
HLA-identical sibling
Risk (%)
0.4
3.0
8.0
3.0
5.0
33.0
15.0
HLA and type 1 diabetes
• HLA (or MHC) region on short arm of chr 6 (3500
kbs in size)
• Are 3 groups of genes
– HLA class 1 molecules: exist on all nucleated
cells. Present antigen to cytotoxic T cells
– HLA class 2 molecules: exist on cells of immune
system. Present antigens to helper T cells
– HLA class 3 molecules: various functions e.g
TNF
• The HLA genotype affects ability and degree to
which subject responds to an antigen
Class 2 HLA molecules
• Polymorphisms in class 2 region are
closely linked with type 1 diabetes
• Are 3 class 2 molecules called HLA-DQ,
HLA-DP and HLA-DR
• Each molecule comprises an alpha and a
beta subunit that associate together to
form a transmembrane receptor
• Subjects with Asp at position 57 of the
HLA-DQ beta chain are protected
against type 1 diabetes
T cell
T cell
receptor
HLA-DQ
molecule
A chain
Antigen
Amino acid 57
B chain
Macrophage
Environmental factors
• Viruses
• Nitrosamine-containing compounds e.g.
– rat poison (Vacor)
– meats cured with nitrates - popular in
Iceland
– nitrate in drinking water: reduced to
nitrite and aminated in stomach to
nitrosamine
Incidence of type 1 diabetes
Country
Finland
Sardinia
UK
USA
Algeria
Japan
Mauritius
China
Pakistan
Peru
Incidence (per 100,000/yr)
36.5
36.8
15.3 - 24.0
11.7 - 17.8
5.7
1.4 - 2.2
1.4
0.1 - 3.8
0.7
0.4
Numbers
Seasonal variation in diagnosis
Viruses and type 1 diabetes
• Congenital rubella syndrome: infection in
utero and 5-20 years later 20% develop
type 1 diabetes
• Cytomegalovirus (CMV): one study
showed 15% of newly diagnosed type 1’s
have CMV genome in lymphocytes and
islet cell antibodies in serum
• Coxsackie B viruses are most often
associated with type 1 diabetes
Coxsackie B and diabetes
• serum level of autoantibodies against
beta cell antigens are raised in presence
of coxsackie infection
• insulitis is often seen in conjunction with
coxsackie infection
• IgM against coxsackie virus found in
serum of newly diagnosed type 1
diabetics
• virus isolated from human pancreas
caused diabetes in mice
Hygiene hypothesis
• Age at which virus exposure occurs may affect
disease progression
• Neonatal or prenatal exposure increases risk of
diabetes
• Exposure later in childhood reduces risk of
disease
• Children who attend pre-school day care have
lower incidence of diabetes
• Inverse relation between population density
and incidence of diabetes
• Frequency of diabetes increased in rodents
raised in pathogen-free environment
Incidence and population density
120
Incidence ratio
110
100
90
80
70
60
<18
18-90
Children per km2
>90
Autoimmunity and type 1 diabetes
• Type 1 diabetes can occur in conjunction
with other autoimmune disorders e.g.
Graves’ disease, Addison’s disease,
coeliac disease
• Infiltration of islets with cytotoxic- and
helper T cells, B lymphocytes,
macrophages (insulitis)
• In presence of insulitis islet cells display
high expression of HLA class 1 and 2
molecules
Autoimmunity (continued)
• NOD mouse and BB rat both display
autoimmune destruction of beta cells
• Only beta cells destroyed i.e targeted
attack characteristic of immune response
• Presence of autoantibodies and T cells in
serum from diabetics that react with islet
antigens e.g. glutamic acid decarboxylase
(GAD), insulin
GAD and type 1 diabetes
• GAD synthesizes gamma-aminobutyric
acid (GABA) in islets - paracrine control
of glucagon secretion?
• 50-80% of newly diagnosed type 1
diabetics have antibodies to GAD,
compared to 2% of general population
• Can prevent diabetes in NOD mouse by
injecting GAD
• Autoantibodies can be used to predict
subjects who will develop disease
Molecular mimicry and type 1
diabetes
• A region of coxsackie coat protein has
amino acid sequence similarity to a
region found on GAD molecule
• Hypothesis: coxsackie infection results in
development of T cell clones that react
with beta cell protein that has similar
structure to coxsackie protein
GAD and Coxsackie virus:
molecular mimicry
GAD a m m i a r f k m f p e v k e k g m a a l p r l
Virus f i e w l k v k i l p e v k e k h e f - l s r l
Solid lines enclose identical amino acids, dotted lines
enclose residues with similar charge, polarity or
hydrophobicity.
Death of the beta cell
• Beta cells destroyed by cytotoxic T cells
• Death may be due to cytokines secreted
by activated T cells
• Interleukin 1 causes production of free
radicals in beta cell
• Beta cell is hypersensitive to free radicals
due to low level of expression of enzymes
that destroy free radicals
• Free radicals cause DNA and protein
damage
Summary
• Type 1 diabetes is a result of complex
environment-gene interactions
• Viruses play a complex role in disease
aetiology
• Polymorphisms in HLA region contribute
significantly to disease process
• Disease is characterised by presence of
autoantibodies to islet cell antigens
• Autoimmune response is responsible for
beta cell death