KeystoneDiabetes in YouthSnowmass: Jan 23, 2008

Clinical diabetes and Endocrinology

Book on Immunology Diabetes

www.barbaradaviscenter.org_

With teaching slides

“Monogenic” Type 1 Diabetes

• IPEX (Immune Dysfunction/ Polyendocrinopathy/ Enteropathy/ X-Linked)

• APS-1

• Insulin Folding Mutations

Awaiting Bone Marrow Transplant for child with IPEX syndrome

9 Months

IPEX: Immune Dysfunction, Polyendocrinopathy, Enteropathy, X-linked

• Scurfin gene (Foxp3/JM2)- Controls Regulatory T Cells!

• Approximately 80% of children with syndrome develop diabetes!

• Bone marrow transplant can reverse BDC

Comparison APS-I and APS-II APS-I APS-II

• Onset Infancy• Siblings

AIRE gene mutated• Not HLA Associated• Immunodeficiency

AsplenismMucocutaneous Candidiasis

• 18% Type 1 DM• 100% anti-interferon Abs

• Older Onset• Multiple Generations• DR3/4 Associated• No Defined

Immunodeficiency• 20% Type 1 DM

APS-I Loss Thymic Tolerance to

“Peripheral” Antigens

• Knockout of the AIRE gene abrogates expression of many “peripheral antigens” within the thymus such as insulin

• IDDM2 locus is insulin gene and Pugliese (Miami) and Polychronakos (Montreal) have shown, protective allele associated with greater thymic insulin messenger RNA.

TCR

MHC + Peptide

Autoreactive thymocyte

Self-peptides from "peripheral"

antigens

Tolerization of autoreactive thymocyte

MODEL AIRE Role in Preventing Autoimmunity

Thymic MedullaryEpithelial Cells

AIRE

Mathis/Benoist

Europium-ELISA completely differentiated APS1 patients from non-APS1 patients, AD and T1D patients.

APS1 non-APS1 Normal Ctrl AD T1D-0.25

0.00

0.25

0.50

0.75

1.00

1.25

1.50

Ind

ex o

f h

IFN

a A

b

Check List APS-I Visit

New Symptoms History

New Signs Physical

Oral Candidiasis

New Antibodies (21-OH, GAD, IA-2)

Ca, Pi, Mg

Na, K

ALT

ACTH, TSH, (LH, FSH)

HbA1c

Blood Smear (Howell-Jolly)

Platelet Count

Other

Eisenbarth GS, Gottlieb PA. New Engl J Med 2004;350:2068-79

Eisenbarth GS, Gottlieb PA. New Engl J Med 2004;350:2068-79

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

0 5 10 15 20 25 30 35 40 45

AGE

21-y

drox

ylas

e A

utoA

bDevelopment of 21-hydroxylase Autoantibodies in Patients with

Type 1A Diabetes

Proportion AD free by MICA (21OH+ follow-up group)

0.0 2.5 5.0 7.5 10.0 12.50.00

0.25

0.50

0.75

1.005.1/5.1not

p=0.001

Follow-up time

Fra

ctio

n s

urv

ival

Premature Mortality in Patients with Addison’s Disease: A Population-Based Study

J clin endocrinol Metab 91:4859, 2006

0

5

10

15

20

25

30

Addison's Expected

Percent Dying 6.7 yr follow-up; mean start age 52.8

N=507 deaths of 1675 patients N=199 deaths

21-Hydroxylase Autoantibody Positive Patients

0

10

20

30

40

50

1 10 100 1000 10000ACTH (pg/ml

Peak

Cor

tisol

(u

g/dl

)

PALM

ELBOW

Transglutaminase Deamidation of Gliadin Peptides increases affinity for DQ2!

Figure 1. MZT Twins: Survival analysis of progression to diabetesby age in probands and non-probands

0 10 20 30 40 50 60 70 800

10

20

30

40

50

60

70

80

90

100

P<0.0001

Non-proband

Proband

Probands n= 83 51 16 8 1Non-probands n= 83 73 45 28 19 9 3 1

Age

Per

cen

t N

ot

Dia

bet

ic

Figure 4. Survival analysis of progression to Ab+ or diabetesby age in MZ twin mates

0 10 20 30 40 50 60 70 800

10

20

30

40

50

60

70

80

90

100

Non-proband n= 83 70 38 26 15 5 2Age first positive Ab+ and/or diabetes

Per

cen

t n

eith

er A

b+

no

r d

iab

etic

Figure 2. Correlation between the age of onset of diabetesin MZT proband and his/her twin mate

(for those twin mates who developed diabetes)

0 10 20 30 40 50 600

10

20

30

40

50

60

p< 0.0001r2= 0.7083

L i n e o

f I d

e n t i t y

Age of Onset in Proband Twin

Ag

e o

f O

nse

t in

In

itia

lly

Dis

cord

ant

Tw

in

TERMINOLOGY

DRB1*02

DQB1*0302DRB1*0401

DRB1*0401

DRB1*0301

DQB1*0302

DRB1*0401

DQB1*02

Allele:

Haplotype:

Genotype

J. Noble

DQB1*0402

Asp57

Leu56

-chain

-chain

BDC BDC

Sibling/offspring cohortGeneral population cohort

Enrolled 387 high risk 51 (7.6%) 53 (14%)

456 moderate risk 111 (17%) 65 (17%)

384 average-low risk 509 254

1,227 All 671 372

screened = 31,881 offspring siblings

DAISY Study Population

HLA-defined IDDM risk groupsDenver population, n=9,338

IDDM risk by age 20 HLA-DR DQB1 Frequency %

High 1:15 3/4 0201/0302 2.4 Moderate 4/x 0302/ 12.7 1:60-1:200 4/4 0302/ 3.0 3/3 0201/0201 1.4

Average 1:300 3/x 0201/ 12.5 3/4 0201/not 0302 1.0

Lower than 1:300 4/x, 4/4 /not 0302 6.6 others 60.4

DAISY 7/96

0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 1 50

1 02 03 04 05 06 07 08 09 0

1 0 0

H ig h r is k s ib l in g

H ig h r is k o ffs p r in g

% A u t o a n t i b o d y P o s i t i v e

Mo d r is k s ib l in gMo d r is k o ffs p r in gL o w r is k s ib l in gL o w r is k o ffs p r in g

A g e ( y )

Au

toan

tib

od

y p

osi

tive

(%)

H igh risk s ib : 49 43 40 33 26 22 20 14 11 10 8 7 6 4 2 0M od risk s ib : 62 60 50 45 39 34 30 28 23 19 16 10 8 3 2 0L ow risk sib : 221 216 198 181 160 139 109 88 66 55 44 34 27 24 19 0H igh risk o ffsp : 51 49 44 40 33 28 21 19 15 10 8 6 3 1 0 0 M od risk o ffsp : 11 0 106 92 83 69 58 49 41 33 27 20 14 12 12 8 0L ow risk o ffsp : 506 477 430 378 324 271 228 191 153 128 109 89 72 52 38 0

0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 1 50

1 02 03 04 05 06 07 08 09 0

1 0 0

H ig h r i s k

M o d r i s k

% A u t o a n t i b o d y P o s i t i v e

L o w r i s k

A g e ( y )

Au

toa

nti

bo

dy

po

sit

ive

(%)

High risk: 380 345 295 236 192 169 138 103 75 35 17Mod risk: 441 388 267 186 137 115 100 92 76 59 26 Low risk: 383 326 272 237 211 185 171 154 128 88 55

MHC Haplotype Sharing Increases DR3/4 Sibling RiskHaplotype Determination:

0.0 2.5 5.0 7.5 10.0 12.5 15.00

102030405060708090

100 Share 2

Share 0 or 1

% Autoantibody Positive

Age (y)0.0 2.5 5.0 7.5 10.0 12.5 15.0

0102030405060708090

100 Share 2

Share 0 or 1

% Diabetic

Age (y)

1

2

3

4

5

6

7ODDS RATIO

Modified from Todd et al. Robust Associations of four new chromosome regions from genome-wide anlayses of type 1 diabetes Nature Genetics June 6 2007