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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