tidm etiopathogenesis
TRANSCRIPT
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ETIOPATHOGENESIS OF
TYPE 1 DIABETESDR. SYED MOHD RAZI
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Juvenile onset diabetes.
Insulin dependent diabetes mellitus (IDDM).
“ Results from β cell destruction, ususally leading to absolute insulin deficiency.”
Diabetes Care, volume 36, supplement 1, January 2013
TYPE 1 DIABETES
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Multifactorial Etiologies :-
1. Genetics
2. Autoimmunity, autoantibodies & cellular immunity.
3. Environment. Cold Spring Harb Perspect Med 2012;2:a007641)
ETIOLOGY OF T1DM
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TYPE 1 DIABETES MELLITUS
MONOGENIC : Single gene defect.
APS-I: AIRE autosomal recessive
XPID: Scurfy Gene X-linked
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APS-SYNDROMES
APS-I:>=2 of Candidiasis, Hypopara,Addison’s
APS-II:Addison’s + Autoimmune Thyroid and/or Type 1 Diabetes.
APS-III: Thyroid Autoimmune + other autoimmune [not above].
APS-IV: Two or more organ-specific autoimmune, not I,II, or III.
Betterle et al. Endocrine Reviews 23:327-364Neufeld and Blizzard: 1980, Pinchera, in Symposium Autoimmune Endocrine Aspects of Endocrine Disorders
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XPID: X-linked polyendocrinopathy, immune dysfunction and diarrhea
Other Names
IPEX: Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked
XLAAD: X-Linked Autoimmunity Allergic Dysregulation
Foxp3 Gene Mutation
Loss of Regulatory T Lymphocytes
Bone Marrow Transplant with Chimera “Cures” Scurfy Mouse and Man
Greenspans b & c endocrinology 9th edition
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Summation of small effects of multiple genes creating
diabetes susceptibility (e.g. NOD mouse)
POLYGENIC
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Polygenic Spontaneous Animal Models : Nonobese Diabetic Mouse
Most intensively studied. Mutations causing absence of I-E ( similar to
DR) & unsually I-A ( similar to DQ). Inheritance polygenic & more Diabetic
females . T cell mediated destruction. Diabetes prevented by introduction of I-E or
I-A . William’s Textbook of Endocrinology, 12thEdition
ANIMAL MODELS OF T1DM
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MHC+few major genes
Genetic heterogeneity with different major non-MHC
genes for different families (e.g. BB rat)
OLIGOGENIC
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Oligogenic Animal Models : Biobreeding Rat 1st intensively studied rat model. Diabetes prone rat -> AR mutation & severe T cell
lymphopenia. Disease depends -> specific class II allele
mutations . Anti-inflammatory drugs prevent diabetes. Long-Evans Tokushima Lean Rat Cbl-b mutation altering T cell functioning.
William’s Textbook of Endocrinology, 12thEdition
ANIMAL MODELS OF T1DM
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T1DM--- Multifactorial disease. (Noble & Erlich 2012)
Risk of T1DM in general U.S. population- 1 in 300.
Risk in 1degree relatives of T1DM pt. -- 1 in 20.
Concordance rate in---- Monozygotic twins -30-50%. Dizygotic twins - 6-10%. Cold Spring Harb Perspect Med 2012;2:a007641)
GENETICS OF T1DM
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85% of cases occur -> pt. with no family H/O. (Hämälainen & Knip 2002).
Risk in children of T1DM: mother – 2% & with T1DM father- 7% ( Redondo et al. 2001).
> 50 loci identified. ( Cooper et al.2008)
No single locus : Necessary or sufficient. Cold Spring Harb Perspect Med 2012;2:a007641)
GENETICS OF T1DM Cont…
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Human Leukocyte Antigen
human MHC
cell-surface proteins
important in self vs. nonself distinction
present peptide antigens to T cells
CLASS I: A,B,C CLASS II: DR,DQ,DP
HLAJ. Noble
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HLA (Chr6p21) Greatest contribution (60%)
Strongest association HLA II genes (Redondo et al.2001)
MHC variability -> differences in β cell antigen presentation.
Cold Spring Harb Perspect Med 2012;2:a007641)
HUMAN LEUKOCYTE ANTIGEN(HLA)
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HLA is named as– Gene locus name-> Asterisk-> serologic specificity -> specific allele-> silent nucleotide polymorphism.
Highest risk genotype ---DRB1*0301,DQA1*0501,DQB1*0201,DRB1*0302, DQA1*0301,DQB1*0302.
Protective genotypes ----DQA1*0102,DQB1*0602. William’s Textbook of Endocrinology, 12thEdition
HUMAN LEUKOCYTE ANTIGEN(HLA)
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STRUCTURE OF HLA GENE
The Major Histocompatibility Complex
Human
Mouse
DP DQ DR B C A
K I-A I-E D L
Chromosome 6
Chromosome 17
Class II Class III Class I
Class IIClass III Class IClass I
Complement Proteins
Cytokines Class I-like genesand pseduogenes
Antigen Processing Genes
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HLA SUSCEPTIBILITY
0
1
2
3
4
5
Od
ds r
ati
o
0
20
40
60
80
Tra
ns
mis
sio
n f
req
ue
nc
y (
%) ******
**
* *
*p< 0.05 vs. control haplotype
High risk
ProtectiveModerate risk
461 389 40 51 182 82 99 20 121 55 124 27 135 34
HBDI Families: Odds Ratio
HBDI Families: Transmission from Heterozygous Parents
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IDDM2 : II nd highest impact on disease development. (OR 1.5)
locus located : VNTR region upstream insulin.
Shorter repeats confer higher risk & vice versa. ( Pugliese et al. 1997).
Other loci are – CTLA4 , PTPN22, CD25( Concannon et al.2008)
Cold Spring Harb Perspect Med 2012;2:a007641)
OTHER LOCI
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NON HLA LOCI IN T1DM
Cold Spring Harb Perspect Med 2012;2:a007641)
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Insulin Gene (INS)
Class I VNTR26-63 repeats
21 alleles
Predisposing
IDDM2
Insulin Gene (INS)
Class III VNTR140-200 repeats
15 alleles
IDDM2
Protective
The IDDM2 Locus
VNTR = Variable Number of Tandem Repeats
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Autoimmunity specific to β cells.( atkison et al.)
Specific mechanisms responsible Yet to be elucidated . ( La Torre 2010)
Cellular immune response Remains controversial.
( Roep 2003)
Cold Spring Harb Perspect Med 2012;2:a007641)
AUTOIMMUNITY , AUTOANTIBODIES & CELLULAR IMMUNITY
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1. Molecular mimicry. 2. Alteration of self antigens. 3.Defective MHC expression. 4. Breakdown of central tolerance. 5.Defective dendritic cell trafficking. 6.Sensitivity to free radicals & cytokines. 7.Ever elusive local viral infection. 8.Defects in peripheral tolerance. Cold Spring Harb Perspect Med 2012;2:a007641)
INDUCTION OF Βcell AUTOIMMUNITY
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Considered as surrogate marker of autoimmunity.
Present long before clinically evident disease.
(Ziegler 2010)
Autoantibodies “ smoke of fire” old view.
Crucial role of B cells & antibodies in pathogenesis.
( Marino et al. 2011)
AUTOANTIBODIES
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Autoantibodies 0.5% general population . 3-4% relatives of T1DM pt. 70-80% of newly diagnosed pt.
Autoantibodies titer & number independent predictors.
High titers, younger age, high risk HLA More accurate prediction.
Cold Spring Harb Perspect Med 2012;2:a007641)
AUTOANTIBODIES
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1
10
100
1000
10000
5 10 15 20 25 30 35
Age (years)
An
ti-i
nsu
lin
au
toan
tib
od
ies (
nU
/ml)
Insulin Autoantibodies Versus Age of Diabetes Onset
Diabetes Care 11:736-739, 1988
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Combination of antibodies Increased risk.
5 yr risk with 1 antibody 20-25% 2 antibodies 50-60%. 3 antibodies 70%. 4 antibodies 80%. (winter
2011 ,DPT 1)
Cold Spring Harb Perspect Med 2012;2:a007641)
AUTOANTIBODIES
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Progression to Diabetes vs Number of Autoantibodies (GAD, ICA512, Insulin)3 Ab n = 41 1 8 1
2 Abs n = 44 27 15 4 2 1
1 Abs n = 93 23 1410 6 4
0
20
40
60
80
100
0 2.5 5 7.5 10 12.5 15
3 Abs2 Abs1 Ab
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IAA Antibodies measured within a week of exogenous insulin. ( winter 2011).
IAA assays cumbersome. (Bonifacio 2010)
GAD antibodies Most predominant in LADA. (Leslie et al. 2008)
( Cold Spring Harb Perspect Med 2012;2:a007641)
AUTOANTIBODIES
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AUOTANTIBODIES Markers of the immune destruction of the β -cell
include
1 or more auto Ab are present in 85–90% of individuals the time of diagnosis
Greenspan’s b&c endorinology 9th ed
Ab Sensitivity Specficity
GAD 65 70-90 % 99 %
IAA 40-70 % 99 %
Tyrosine phosphatase
50-70 % 99 %
ZnT8 50-70 % 99 %
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T1DM RISK STRATIFICATIONCold Spring Harb Perspect Med 2012;2:a007641)
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Discordance in monozygotic twins.
Rise in global incidence.
Variance in geographical prevalence.
Assimilation of local incidence rate in migrants. (Atkinson 2001)
Cold Spring Harb Perspect Med 2012;2:a007641)
ENVIRONMENT
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Environmental stress Increase insulin demand
β cell overloading
Accelerating β cell damage (Fourlanos et al.2008)
Cold Spring Harb Perspect Med 2012;2:a007641)
ACCELERATOR & OVERLOAD THEORY
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“ Rising incidence of autoimmune diseases in general due to reduced or altered stimulation by environmental factor”.
(Cook 2009 )
Cold Spring Harb Perspect Med 2012;2:a007641)
HYGIENE HYPOTHSIS
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Microbial infection Other antigens react easily.
Auto- reactive T cells. (Von Herrath et al. 2003) Cold Spring Harb Perspect Med 2012;2:a007641)
FERTILE FIELD HYPOTHESIS
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“Normal GIT commensals implicate dietary exposure
as regulator of the immune system & self tolerance.”
(Vaarala et al. 2008) Cold Spring Harb Perspect Med 2012;2:a007641)
OLD FRIENDS HYPOTHESIS
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Mathematical model calculating risk of T1DM.
Contribution of genetics & environment as function of invariables subject to calculation. ( Wasserfall et al. 2011) Cold Spring Harb Perspect Med 2012;2:a007641)
THRESHOLD HYPOTHESIS
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Infectious agents
No direct evidence.
Rubella incorrectly cited evidence for this activity.
(Gale 2008)
Enteroviral association with the disease. ( Jaiden et al.2010)
ENVIRONMENTAL FACTORS
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Increased risk in early weaning & exposure to cow’s milk . ( TRIGR Study Group et al. )
Increased susceptibility associated with the timing of exposure to cereal & gluten. ( DIASY, BABY- DIAB)
Low Vit. D not only association but a cause of T1DM. ( North – South Gradient Hypothesis , Karvonen 2000)
ENVIRONMENTAL FACTORS
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Ziegler, JAMA 2003: 290:721
0
5
10
15
20
25
30
0 2 4 6 8
Age (years)
Isle
t au
toim
mu
nit
y, %
<=3 mo.
>6 mo.
>3 to6 mo.
DR3/4 DQ8: Norris JAMA 290:1713
0
5
10
15
20
25
0 2 4 6 8
Age (years)
Isle
t A
uto
imm
un
ity,
%
<=3 mo.
4 o 6 mo.
>=7 mo.
BabyDiab and DAISY
Age introduction gluten (Ziegler) or cereal (Norris) greatly increases development of anti-islet autoantibodies in infants followed from birth.
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Nitrosamine compounds T1DM ( Kostraba et al. 1992)
Maternal child blood group incompatibility.
Other obstretic factors pre-ecclampsia. Neonatal respiratory distress. Low birth weight. Caesarean section. Maternal age. Birth order. Gestational age. (Mc Kinney et al. 1997)
Cold Spring Harb Perspect Med 2012;2:a007641)
ENVIRONMENTAL FACTORS
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Stages:Type IA Diabetes
I Genetic Susceptibility
II Triggering
III Active Autoimmunity
IV Progressive Metabolic Abnormalities
V Overt Diabetes
VI Insulin Dependence
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1986 NEJM “Stages” in Development of T1Diabetes
Age (years)
Genetic Predisposition
Bet
a ce
ll m
ass
(?Precipitating Event)
Overtimmunologicabnormalities
Normal insulinrelease
Progressiveloss insulinreleaseGlucosenormal
Overtdiabetes
C-peptidepresent
NoC-peptide
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PATHOGENESIS & NATURAL HISTORY OF T1DM
Cold Spring Harb Perspect Med 2012;2:a007641)
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RELAPSING & REMITTING MODEL OF T1DM
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