Tidm etiopathogenesis

45
ETIOPATHOGENESIS OF TYPE 1 DIABETES DR. SYED MOHD RAZI

Transcript of Tidm etiopathogenesis

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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

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60

80

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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

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Age (years)

Isle

t au

toim

mu

nit

y, %

<=3 mo.

>6 mo.

>3 to6 mo.

DR3/4 DQ8: Norris JAMA 290:1713

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Age (years)

Isle

t A

uto

imm

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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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THANKS