Type 1A Diabetes Immunology and Polyglandular Syndromes

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Type 1A DiabetesImmunology and Polyglandular
Syndromes

• Textbook on web with Teaching Slideswww.barbarad
  aviscenter.org

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Develop Insulin 1 and insulin 2 Knockouts with
B16 alanine-insulin 2
Insulin 1 - B Chain FVKQHLCGPHLVEALYLVCGERGFFYTP
KS Insulin 2 - B Chain FVKQHLCGSHLVEALYLVCGERGFF
YTPMS
Tyrosine (TAC) Alanine (GCC)
X
X
Insulin 1-KO
Insulin 2-KO
B16ala-tg
Insulin 1 (-) Insulin 2 (-) B16ala-insulin 2 ()
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Nakayama et al. Prime role for an insulin epitope
in the development of type 1 diabetes in NOD
mice. Nature 435220, 2005
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Stages in Development of Type1 Diabetes
(?Precipitating Event)
Genetic Predisposition
Overt immunologic abnormalities
Progressive loss insulin release
Normal insulin release
Overt diabetes
Beta cell mass
Glucose normal
C-peptide present
No C-peptide
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Stage I Genetics

• Polygenic-commonHLA DRDQ other MHCInsulin
  gene PTPN22-lyp?CTLA-4
• Monogenic-rareAPS-I AIRE mutation
• IPEX syndrome FoxP3 mutation

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The Major Histocompatibility ComplexHLA Human
Leukocyte Antigens
LMP7
DQA1
DPA1
DRB1
DQB1
TAP1
DPB1
TAP2
DRA
LMP2
MHC Class II Region
0 base pairs
1 million
MICA
CYP 21B
B
C
E
A
C4A
HSP70
TNF
1 million
Class I Region
Class III Region
4 million
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HLA
J. Noble
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
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TERMINOLOGY
J. Noble
Allele
DRB10401
Haplotype
DQB10302
DRB10401
DRB10401
DQB10302
Genotype
DRB102
DRB10301
DQB102
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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

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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
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APS-I

• Autoimmune Polyendocrine Syndrome Type 1
• Autosomal Recessive mutations AIRE (Autoimmune
  Regulator) gene
• Mucocutaneous Candidiasis/Addisons
  Disease/Hypoparathyroidism
• 18 Type 1 Diabetes
• Transcription Factor in Thymus

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

• Onset Infancy
• SiblingsAIRE gene mutated
• Not HLA Associated
• ImmunodeficiencyAsplenismMucocutaneous
  Candidiasis
• 18 Type 1 DM

• Older Onset
• Multiple Generations
• DR3/4 Associated
• No Defined Immunodeficiency
• 20 Type 1 DM

BDC
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A family of diseases occurring in families

• Type 1A Diabetes
• Celiac Disease
• Addisons Disease
• Thyroid Autoimmunity

BDC
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Yu et al, JCEM, 1999
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Prevalence of TGA by HLA-DR amongst patients with
type 1 DM, relatives of DM patients and general
population
Prevalence
HLA-DR
BDC
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Transglutaminase Autoantibodies and Marsh score
(Disease Severity)
Spearman correlation, r 0.569 p lt 0.003
2.5
2.0
1.5
tTG titer
1.0
.5
0.0
0
1
2
3
Marsh score
Hoffenberg, J. Peds 137356 2000
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Stage II Precipitating Event
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Diabetes Autoimmunity Study in the Young
General population cohort
Sibling/offspring cohort
screened 21,713
enrolled 293 high risk
72
429 moderate risk
220 347 average
- low risk 401 1,069
All 693 relatives
1,491 1,007
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Stage III Autoimmunity
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Cytoplasmic ICA kindly provided by the discoverer
Franco Bottazzo
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Major Autoantibody Targets

• GAD65 (glutamic acid decarboxylase)
• IA-2 (ICA512) Insulinoma Associated Protein
• Insulin

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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, 114589

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Stage IV Progressive Loss FunctionStage V
Overt Diabetes
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A
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Barker et al, Diabetes Care 27 1399, 2004
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We can predict Type 1 diabetes.We can prevent
the disorder in animal models.We cannot yet
safely prevent in man.
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NEXT

• Improved T Cell Assays
• Trials of antigen-specific therapies prior to
  autoantibodies.
• Immunomodulator/Immunosuppressive Trials
  post-onset and with islet transplantation.

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TRIALNET1-800-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

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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