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Classification of diabetic syndromes. • Type 1A: Immune-mediated Type 1B: Insulin deficient, no autoantibodies • Type 2: No autoantibodies, can initially be treated without insulin • Other specific forms of diabetes • Gestational diabetes. Type 1 diabetes mellitus.

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Classification of diabetic syndromes
Classification of diabetic syndromes

• Type 1A: Immune-mediated

Type 1B: Insulin deficient, no autoantibodies

• Type 2: No autoantibodies, can initially be

treated without insulin

• Other specific forms of diabetes

• Gestational diabetes


Type 1 diabetes mellitus
Type 1 diabetes mellitus

• Acute presentation: hyperglycemia, tiredness, weight loss,

polyuria, thirst, nausea, vomiting, signal

of impending ketoacidosis

• Patients need insulin replacement to live

• Honeymoon period: temporary remission in some patients

• In long-standing patients: micro + macro vascular complications

• Mortality increased 4-7 fold (nephropathy, card/vx disease)

• Some patients survive without major complications


Type 1 diabetes mellitus1
Type 1 diabetes mellitus

• Organ specific, autoimmune disease targeting pancreatic b cells

• Complex interaction between environmental and genetic factors

• Preceded by inflammation of pancreatic islets: insulitis

• Circulating antibodies specific for islet cell antigens

• Mediated by autoreactive CD4+ and CD8+ T cells

• Laboratory animal models available


PUTATIVE

ENVIRONMENTAL

TRIGGER

HUMORAL AUTOANTIBODIES

(ICA, IAA, Anti-GAD65, IA2Ab, etc)

BETA CELL MASS

GENETIC PREDISPOSI

TION

INSULITIS

BETA CELL INJURY

CLINICAL

ONSET

DIABETES

TIME

Natural History of Type 1 Diabetes

CELLULAR (T CELL) AUTOIMMUNITY

LOSS OF FIRST PHASE

INSULIN RESPONSE

(IVGTT)

GLUCOSE INTOLERANCE

(OGTT)

“PRE”-

DIABETES

DIABETES


Type 1 diabetes mellitus2
Type 1 diabetes mellitus

• Organ specific, autoimmune disease targeting pancreatic b cells

• Complex interaction between environmental and genetic factors

• Preceded by inflammation of pancreatic islets: insulitis

• Circulating antibodies specific for islet cell antigens

• Mediated by autoreactive CD4+ and CD8+ T cells

• Laboratory animal models available


Type 1 diabetes and environmental factors
Type 1 Diabetes and Environmental Factors

  • The incidence of childhood type 1 diabetes varies with geographic location, age, sex, ethnicity and time period.

  • Increase in Type 1 incidence worldwide

  • Concordance rate in monozygotic twins:50-80%

  • Estimated contribution of environmental factors to familial clustering of type 1 diabetes ~ 20%


Incidence type 1 diabetes per 100 000 per year children 14
Incidence Type 1 Diabetesper 100,000 per year Children ≤14


Type 1 diabetes in finland
Type 1 diabetes in Finland

Incidence /100,000 children age 0-14


Remarks

Reason(s) for the increasing T1D incidence are unknown

A rapid change in incidence within genetically stable populations implies an etiological role for environmental factors

Little evidence that Ags novel to the 2nd half of the 20th century explain these epidemiological trends

Alternative view is the ‘hygiene hypothesis’: human populations

selected to survive endemic infections in the past, now mount inappropriate autoimmune responses when Ag exposure is reduced by good hygiene in developed countries

“Childhood Type 1 diabetes was in the past a partly

preventable condition, and could become so again”

Edwin Gale, 2002


Type 1 diabetes mellitus3
Type 1 diabetes mellitus

• Organ specific, autoimmune disease targeting pancreatic b cells

• Complex interaction between environmental and genetic factors

• Preceded by inflammation of pancreatic islets: insulitis

• Circulating antibodies specific for islet cell antigens

• Mediated by autoreactive CD4+ and CD8+ T cells

• Laboratory animal models available



Type 1 diabetes mellitus4
Type 1 diabetes mellitus

• Organ specific, autoimmune disease targeting pancreatic b cells

• Complex interaction between environmental and genetic factors

• Preceded by inflammation of pancreatic islets: insulitis

• Circulating antibodies specific for islet cell antigens

• Mediated by autoreactive CD4+ and CD8+ T cells

• Laboratory animal models available



Autoantibody specificities in type 1 diabetes
Autoantibody specificities in type 1 diabetes Bottazzo

• Insulin

• Glutamic acid decarboxylase

• ICA512 (IA-2)

• Carboxypeptidase H, ICA 69….

• The target Ag(s) of diabetogenic T cells

has not been identified in humans


Autoantibodies in type 1 diabetes
Autoantibodies in type 1 diabetes Bottazzo

• No pathogenic role in human diabetics (e.g.

no diabetes in infants born to autoAb+ mothers)

• Mostly used as serologic markers to detect people

at risk for type 1 diabetes (the risk is proportional to

the number of specificities, the titer, and, for some,

the affinity, and epitope specificity of Abs)


Type 1 diabetes mellitus5
Type 1 diabetes mellitus Bottazzo

• Organ specific, autoimmune disease targeting pancreatic b cells

• Complex interaction between environmental and genetic factors

• Preceded by inflammation of pancreatic islets: insulitis

• Circulating antibodies specific for islet cell antigens

• Mediated by autoreactive CD4+ and CD8+ T cells

• Laboratory animal models available


Type 1 diabetes is a T-cell mediated disease Bottazzo

The disease is prevented by neonatal thymectomy,

antibody-mediated T-cell depletion of NOD mice

and BB rats

The disease does not develop in nude, SCID, RAG-/-

NOD mice nor in nude BB rats

Susceptibility to the disease is MHC-linked


Effect of B and T cells in the transfer of diabetes in the NOD mouse

Effect of CD4+ and CD8+ T cells in the transfer of diabetes

Miller et al. (1988)

J. Immunol. 140:52

Type 1 diabetes is mediated by autoreactive

CD4+ and CD8+ T cells


Genetic susceptibility of type 1 diabetes
Genetic NOD mouseSusceptibility of Type 1 Diabetes

  • - non-Mendelian inheritance, under the control of allelic variations at multiple loci

  • - Recent GWA studies have revealed many T1D genes, a few with relatively large effect (MHC, INS, PTPN22), many with small effect, perhaps acting in subgroups of cases

  • - These results show that T1D is a disease of thymic selection & immune homeostasis

  • - Major pathways: - HLA class II & I antigen (insulin) recognition

  • - Tyrosine dephosphorylation in signalling

  • - Interleukin-2 pathway

  • - Shared genes/regions with autoimmune thyroid disease, Crohn’s disease, celiac disease and multiple sclerosis = common “autoimmune” pathways


19 t1d susceptibility loci p 10 7
19 T1D susceptibility loci (~ P<10 NOD mouse-7)

Locus, chr

Risk allele (freq)

Effect size

P value

Reference

HLA-DRB1 – DQB1, 6p21

DR3/DR4 (28%)

RR=3 for DR3 or DR4

RR=11 for DR3/4

<10-200

Herr et al., 2000

INS, 11p15

23HphI (A,80%)

RR=4.5 for A/A

5 x 10-8

Barratt et al., 2004

CTLA4, 2q33

JO30 (G,51%)

RR=1.18 for G

8 x 10-11

Ueda et al., 2003

PTPN22, 1p13

Arg620Trp (T, 10%)

RR=1.67 for T

10-40

Smyth et al., 2004

IL2RA (CD25), 10p15-14

ss5258010

rs11594656

OR=1.30 for T/G, 1.84 for T/T

6 x 10-8

Vella et al., 2005

IFIH1, 2q24.3

A946T (A,60%)

RR 1.17 for A

2 x 10-11

Todd et al., 2007

KIAA0350, 16p13

rs2903692 (G, 62%)

OR=1.33 for G

7 x 10-11

Hokanarson; WTCCC; Todd 2007

C12orf30, 12q24

rs17696736, (G, 42%)

OR 1.22

6 x 10-18

WTCCC; Todd 2007

ERBB3, 12q13

rs2292239 (C, 34%)

OR 1.28

2 x 10-20

WTCCC;Todd 2007

PTPN2, 18p11

rs2542151 (C, 16%)

OR 1.30

1 x 10-14

WTCCC;Todd 2007

NRP1, 10p11

rs2666236 (A, 41%)

OR 1.76

7 x 10-8

WTCCC;Todd 2007

HLA-A, 6p21

HLA-A24 (8%)

OR 1.54

2x10-10

Nejentsev 2007

HLA-B, 6p21

HLA-B39 (3%)

OR 1.92

4x10-7

Nejentsev 2007

CD226, 18q22

rs763361 (46%)

OR 1.16

1 x 10-8

Todd et al., 2007


19 t1d susceptibility loci p 10 71
19 T1D susceptibility loci (~ P<10 NOD mouse-7)

Locus, chr

Risk allele (freq)

Effect size

P value

Reference

IL-2/IL-21, 4q27

G>A (30.8% and 30.1%)

RR=1.26 and 1.17

1.9x10-8

Cooper et al, 2008

BACH2, 6q15

C>G (46.5%)

RR=1.13

5 x 10-12

Cooper et al, 2008

PRKCQ, 10p15

A>G (18.7%)

RR=0.91

4 x 10-9

Cooper et al, 2008

CTSH, 15q24

T>C (31.8%)

RR=0.86

3 x 10-15

Cooper et al, 2008

CT1QTNF6, 22q13

C>T (42.7%)

OR=1.04

2 x 10-8

Cooper et al, 2008


19 t1d susceptibility loci p 10 72
19 T1D susceptibility loci (~ P<10 NOD mouse-7)

Locus, chr

Risk allele (freq)

Effect size

P value

Other disease

HLA-DRB1 – DQB1, 6p21

DR3/DR4 (28%)

RR=3 for DR3 or DR4

RR=11 for DR3/4

<10-200

Celiac disease

INS, 11p15

23HphI (A,80%)

RR=4.5 for A/A

5 x 10-8

CTLA4, 2q33

JO30 (G,51%)

RR=1.18 for G

8 x 10-11

Celiac disease

PTPN22, 1p13

Arg620Trp (T, 10%)

RR=1.67 for T

10-40

Grave’s, RA, LEAD

IL2RA (CD25), 10p15-14

ss5258010

rs11594656

OR=1.30 for T/G, 1.84 for T/T

6 x 10-8

Grave’s disease, RA

IFIH1, 2q24.3

A946T (A,60%)

RR 1.17 for A

2 x 10-11

KIAA0350, 16p13

rs2903692 (G, 62%)

OR=1.33 for G

7 x 10-11

C12orf30, 12q24

rs17696736, (G, 42%)

OR 1.22

6 x 10-18

Crohn’s, RA, CD

ERBB3, 12q13

rs2292239 (C, 34%)

OR 1.28

2 x 10-20

PTPN2, 18p11

rs2542151 (C, 16%)

OR 1.30

1 x 10-14

Crohn’s, Grave’s

NRP1, 10p11

rs2666236 (A, 41%)

OR 1.76

7 x 10-8

HLA-A, 6p21

HLA-A24 (8%)

OR 1.54

2 x 10-10

HLA-B, 6p21

HLA-B39 (3%)

OR 1.92

4 x 10-7

CD226, 18q22

rs763361 (46%)

OR 1.16

1 x 10-8

Grave’s disease


19 t1d susceptibility loci p 10 73
19 T1D susceptibility loci (~ P<10 NOD mouse-7)

Locus, chr

Risk allele (freq)

Effect size

P value

Other disease

IL-2/IL-21, 4q27

G>A (30.8% and 30.1%)

RR=1.26 and 1.17

1.9x10-8

BACH2, 6q15

C>G (46.5%)

RR=1.13

5 x 10-12

PRKCQ, 10p15

A>G (18.7%)

RR=0.91

4 x 10-9

Celiac disease

CTSH, 15q24

T>C (31.8%)

RR=0.86

3 x 10-15

CT1QTNF6, 22q13

C>T (42.7%)

OR=1.04

2 x 10-8


GWA Meta-analysis NOD mouse

Nov 2008

HLA

class II

INS

CD25

(IL2Ra)

KIAA0350

16p13

CD25

(IL2Ra)

IL2-IL21

4q27

BACH2

6q15

C1QTNF6

22q13

ERBB3

12q13

PTPN22

PTPN11

12q24

PTPN2

18p11

CTLA4

IFIH1

CTSH

15q24

PRKCQ

10p15

Odds ratios for the susceptibility allele for independent

T1D-associated genes or regions

7

6.5

6

2.5

2

1.5

1

Odds ratio for the T1D susceptibility allele



Mhc class ii linked susceptibility and resistance to iddm
MHC class II-linked susceptibility and resistance to IDDM NOD mouse

- Inherited as dominant traits with incomplete penetrance

- In humans, MHC association predominantly determined

by polymorphism at the HLA DQB1 locus(highest risk

haplotypic combination DRB1*04-DQB1*302/DRB1*03-

DQB1*0201 carries a ~5% absolute risk of T1D)

- Alleles encoding DQb chains with Ser, Ala, or Val at

position 57 provide susceptibility, while those with Asp

provide resistance


Iddm2 ins
IDDM2/INS NOD mouse

HUMTHO1

INS

IGF2

VNTR

Chr 11p15 region

Promoter

Exon 1

Exon 2

Exon 3

UTR

IDDM2: QTL resulting from allelic variation and complex parental

and epigenetic effects at the VNTR locus

Class I alleles: 30-60 repeats; homozygosity associated low intrathymic

expression and increased IDDM risk (Vafiadis et al.; Pugliese et al.)

Class III alleles: 120-170 repeats; homozygosity associated high intrathymic

expression and decreased IDDM risk


Association of ctla4 with susceptibility to autoimmune diseases
Association of CTLA4 with susceptibility to autoimmune diseases

Polymorphisms of CTLA4 associated with Grave’s disease,

autoimmune hypothyroidism, type 1 diabetes in humans (IDDM12) and NOD mice (idd5.1)

In humans, disease susceptibility maps to a non-coding region

and is associated with lower transcript levels of soluble CTLA4

In mice, disease susceptibility maps to an exon 2 SNP and is

associated with decreased levels of a ligand independent isoform

of CTLA4


proline-rich diseases

region

phosphatase

domain

N

C

PTPN22

P1

P2

PTPN22

  • - non receptor protein-tyrosine phosphatase expressed in hematopoietic cells

  • - negative regulator of T cell activation

  • - interacts through its proline-rich sequence termed P1 with the SH3 domain of p50csk

  • - PTPN22/p50csk cooperation inhibits Ag-receptor-mediated

  • signal transduction in T cells


Ptpn22 and human autoimmune diseases
PTPN22 and human autoimmune diseases diseases

A functional variant of PTPN22 is associated with T1D, RA, SLE, thyroid autoimmunity but not with MS, IBD.

This functional variant has a 90% decreased affinity for p50csk

This altered interaction of PTPN22 with p50csk could decrease

the activation threshold of autoreactive T cells but initial functional analyses do not support this model


Il 2 signaling pathway and t1d
IL-2 signaling pathway and T1D diseases

Allelic variation of the IL-2 gene is associated with T1D in the spontaneously diabetic NOD mouse

Allelic variation of the IL-2 R alpha chain is associated with human T1D

Null mutations of murine IL-2 and CD25 are associated with multi-organ inflammation due to impaired postthymic homeostasis of Tregs

Allelic variation of the IL-2 gene in NOD mice contributes to T1D pathogenesis through altered development and function of Tregs

Whether allelic variation of CD25 contributes to human T1D through altered function/development of Tregs remains to be determined


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