Transcript Type 1A Diabetes Immunology and Polyglandular Syndromes

Type 1A Diabetes
Immunology and
Polyglandular Syndromes
Textbook on web with Teaching Slides
www.barbaradaviscenter.org
Develop Insulin 1 and insulin 2 Knockouts with B16
alanine-insulin 2
Insulin 1 - B Chain : FVKQHLCGPHLVEALYLVCGERGFFYTPKS
Insulin 2 - B Chain : FVKQHLCGSHLVEALYLVCGERGFFYTPMS
Tyrosine (TAC)
Alanine (GCC)
X
Insulin 1-KO
X
Insulin 2-KO
B:16ala-tg
Insulin 1 (-)
Insulin 2 (-)
B:16ala-insulin 2 (+)
Nakayama et al. Prime role for an insulin epitope in the development of
type 1 diabetes in NOD mice. Nature 435:220, 2005
“Stages” in Development of Type1 Diabetes
(?Precipitating Event)
Beta cell mass
Genetic
Predisposition
Overt
immunologic
abnormalities
Normal insulin
release
Progressive
loss insulin
release
Glucose
normal
Overt
diabetes
C-peptide
present
Age (years)
No
C-peptide
Stage I: Genetics
• Polygenic-common
HLA DR+DQ+ other MHC
Insulin gene
PTPN22-lyp
?CTLA-4
• “Monogenic”-rare
APS-I: AIRE mutation
IPEX syndrome: FoxP3 mutation
The Major Histocompatibility Complex
HLA: Human Leukocyte Antigens
LMP7
DPA1
DPB1
LMP2
C4A
TAP2
DRA
MHC Class II Region
0 base pairs
CYP
21B
TAP1
DQA1
DRB1
DQB1
1 million
MICA
HSP70
B
C
E
A
TNF
1 million Class III Region
Class I Region
4 million
J. Noble
HLA
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
J. Noble
TERMINOLOGY
Allele:
Haplotype:
Genotype
DRB1*0401
DRB1*0401
DQB1*0302
DRB1*0401
DQB1*0302
DRB1*0301
DRB1*02
DQB1*02
Autoimmune Polyendocrine Syndromes
•
•
•
•
•
•
•
•
APS-II (Autoimmune Polyendocrine)
APS-I (AIRE mutation)
IPEX (XPID): (Scurfy Mutation)
Anti-insulin Receptor Abs + “Lupus”
Hirata (Anti-insulin Autoantibodies)
POEMS (Plasmacytoma,..)
Thymic Tumors + Autoimmunity
Congenital Rubella + DM +Thyroid
IPEX: Immunodysregulation,
Polyendocrinopathy, Enteropathy, X-linked
• Other Names
XPID: X-linked polyendocrinopathy, immune
dysfunction and diarrhea
XLAAD: X-Linked Autoimmunity Allergic
Dysregulation
• Foxp3 Gene Mutation
• Loss of Regulatory T Lymphocytes
• Bone Marrow Transplant with Chimera “Cures”
BDC
APS-I
• Autoimmune Polyendocrine Syndrome
Type 1
• Autosomal Recessive mutations AIRE
(Autoimmune Regulator) gene
• Mucocutaneous Candidiasis/Addison’s
Disease/Hypoparathyroidism
• 18% Type 1 Diabetes
• “Transcription Factor” in Thymus
BDC
MODEL AIRE Role in Preventing
Autoimmunity
Autoreactive
thymocyte
Tolerization of
autoreactive thymocyte
TCR
MHC + Peptide
Thymic Medullary
Epithelial Cells
AIRE
Self-peptides from
"peripheral" antigens
Mathis/Benoist
Comparison APS-I and APS-II
APS-I
APS-II
• Onset Infancy
• Siblings
AIRE gene mutated
• Not HLA Associated
• Immunodeficiency
Asplenism
•
•
•
•
Older Onset
Multiple Generations
DR3/4 Associated
No Defined
Immunodeficiency
• 20% Type 1 DM
Mucocutaneous Candidiasis
• 18% Type 1 DM
BDC
A family of diseases occurring in
families
Type 1A Diabetes
Celiac Disease
Addison’s Disease
Thyroid Autoimmunity
BDC
21-Hydroxylase Autoantibodies
Levels of autoantibodies
2
1.5
1
0.5
n= 241
Known
Healthy
Controls
Addison's
Yu et al, JCEM, 1999
n= 817
n= 13
Negatives
Positives
Type I Diabetics
Figure 2
Prevalence of TGA by HLA-DR amongst patients
with type 1 DM, relatives of DM patients and
general population
25%
IDDM
Relatives
Population
Prevalence
20%
15%
10%
5%
0%
DR3+
DR3-
HLA-DR
BDC
Transglutaminase Autoantibodies and
Marsh score (Disease Severity)
Spearman correlation, r =
2.5 0.569
p < 0.003
2.0
1.5
tTG titer
1.0
.5
0.0
0
1
2
Marsh score
Hoffenberg, J. Peds 137:356 2000
3
Stage II: Precipitating Event
Diabetes Autoimmunity Study in the Young
General population cohort
Sibling/offspring cohort
screened = 21,713
enrolled =
293
high risk
429
moderate risk
220
347
average - low risk
401
1,069
relatives
1,491
All
72
693
1,007
Stage III: Autoimmunity
Cytoplasmic ICA kindly provided by the discoverer Franco Bottazzo
Major Autoantibody Targets
• GAD65 (glutamic acid decarboxylase)
• IA-2 (ICA512): Insulinoma Associated
Protein
• Insulin
Insulin Autoantibodies
• Usually the first autoantibody to appear
• Highest levels in youngest children
developing type 1A diabetes
• Mature high-affinity immune responses to
(pro)insulin anticipate the autoimmune
cascade that leads to type 1 diabetes.
Achenbach et al, J.Clin Invest 2004,
114:589
Stage IV:
Progressive Loss Function
Stage V: Overt Diabetes
HbA1c (%)
A
7
7
6
6
7
5
5
6
4
4
3
3
5
HbA1c (%)
0
HbA1c (%)
2
4
6
8
10
12
14
4
3
0
2
4
6
8
10
12
14
7
7
7
6
6
6
5
5
5
4
4
4
3
3
0
2
4
6
8
10
12
14
2
4
6
8
10
12
14
7
7
6
6
6
5
5
5
4
4
4
3
3
2
4
6
8
10
12
14
7
6
5
0
2
4
6
8
10
12
14
0
2
4
6
8
10
12
14
0
2
4
6
8
10
12
14
0
2
4
6
8
10
12
14
0
2
4
6
8
10
12
14
3
0
7
0
HbA1c (%)
8
3
0
2
4
6
8
10
12
14
7
7
6
6
5
5
4
4
4
3
3
0
2
4
6
8
10
12
3
0
14
2
4
6
8
10
12
14
HbA1c (%)
Age (years)
7
7
7
6
6
6
5
5
5
4
4
4
3
3
0
2
4
6
8
Age (years)
10
12
14
3
0
2
4
6
8
Age (years)
10
12
14
Age (years)
Blood glucose, md/dL
Blood glucose values in
Control vs. Daisy children
1400
1200
1000
800
600
400
200
0
DAISY
Control-FH
Control no FH
Barker et al, Diabetes Care 27: 1399, 2004
We can predict Type 1
diabetes.
We can prevent the disorder
in animal models.
We cannot yet safely prevent
in man.
NEXT
1. Improved T Cell Assays
2. Trials of antigen-specific therapies prior to
autoantibodies.
3. Immunomodulator/Immunosuppressive Trials
post-onset and with islet transplantation.
TRIALNET
1-800-HALT-DM1
• Dalizumab+ MMF – New Onset Trial
• Oral Insulin Trial – Post Autoantibodies –
Relative Screening
• With ITN: Anti-CD3 Trial Multiple course
• JDRF: Oral Insulin Prior to Anti-islet
Autoantibodies being planned
Diabetes Autoimmunity Study in the Young (DAISY)
Also: Lars Stene, Patricia Graves, Heather Stanley, Jaime Keen, Peter Chase
Carolyn Fronczak, Jennifer Barker, Akane Ide, Andrea Steck