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Type 1A Diabetes (Immune Mediated) Clinical Immunology Society. George S. Eisenbarth Barbara Davis Center for Childhood Diabetes Slides Chosen From Teaching Slides of: Type 1 Diabetes: Molecular, Cellular, Clinical Immunology -www.barbaradaviscenter.org.

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Type 1a diabetes immune mediated clinical immunology society l.jpg

Type 1A Diabetes(Immune Mediated)Clinical Immunology Society

George S. Eisenbarth

Barbara Davis Center for Childhood DiabetesSlides Chosen From Teaching Slides of:

Type 1 Diabetes: Molecular, Cellular, Clinical Immunology-www.barbaradaviscenter.org

Made possible through an unrestricted educational grant from KRONUS.


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  • WWW.BARBARADAVISCENTER.ORG: Book: Immunology Type 1 Diabetes

  • Teaching slides are Powerpoint slide sets that can be downloaded.

  • Primer Immunology and Autoimmunity(Updated - 12/03) Stephanie C. Eisenbarth2A. Cell Therapy of Diabetes(Updated - 3/02)Jan Nygaard Jensen and Jan Jensen2B. Proprotein Processing and Pancreatic Islet Function(Updated - 3/02)John Hutton, Tina Wasmeier, Rodabe Amaria, Nicholas Bright and John Creemers2C. Stimulus-Secretion Coupling in the Pancreatic Beta-Cell (Updated - 3/02)Kirstine Juhl and John Hutton 3. Animal Models of Type 1 Diabetes: Genetics and Immunological Function(Updated - 8/02)Julie Lang and Donald Bellgrau4. The Role of T Cells in Beta Cell Damage in NOD Mice and Humans (Updated - 3/02)Katalin Kelemen5. Type 1 Diabetes Mellitus: An Inflammatory Disease Of The Islet(Updated - 12/03)Regine Bergholdt, Peter Heding, Karin Nielsen, Runa Nolsøe, Thomas Sparre, Joachim Størling,

  • Allan E. Karlsen, Jørn Nerup, Flemming Pociot and Thomas Mandrup-Poulsen. Steno Diabetes

  • Center, Gentofte, Denmark6. The Immunobiology of Pancreatic Islet Transplantation (Updated - 11/01)Marilyne Coulombe and Ronald G. Gill7. Type I Diabetes Mellitus of Man: Genetic Susceptibility and Resistance (Updated - 4/02) A. Pugliese and G. S. Eisenbarth8. Autoimmune Polyendocrine Syndromes(Updated - 10/03)J.M. Barker and G. S. Eisenbarth9. Epidemiology of Type I Diabetes(Updated - 4/02)Marian Rewers, Jill Norris and Dana Dabelea10. Humoral Autoimmunity(Updated - 9/02) L. Yu and G.S. Eisenbarth11. Prediction of Type I Diabetes: The Natural History of the Prediabetic Period(Updated - 11/03)George S. Eisenbarth12. Clinical Trials for the Prevention of Type I Diabetes(Updated - 9/03)H. Peter Chase, Anthony R. Hayward & G. S. Eisenbarth


1986 nejm stages in development of type1diabetes l.jpg

Age (years)

1986 NEJM “Stages” in Development of Type1Diabetes

(?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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350

300

250

200

150

100

50

'66

'68

'70

'72

'74

'76

'78

'80

'82

'66

'67

'68

'69

'70

'71

'72

'73

'74

'75

0

Triplets Serial Intravenous Glucose Tolerance Tests

ANTIBODY POSITIVE

ANTIBODY NEGATIVE

*

**

Peak insulin response to intravenous glucose (1+3 min) immunoreactive insulin (μU/ml)

*

DM

Srikanta S. et al, New Engl J Med 308:322-325, 1983


Stages type ia diabetes l.jpg
Stages Type IA Diabetes

  • I Genetic Susceptibility

  • II Triggering

  • III Active Autoimmunity

  • IV Progressive Metabolic Abnormalities

  • V Overt Diabetes

  • VI Insulin Dependence


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Monogenic:Single gene defect. APS-I: AIRE autosomal recessive XPID: Scurfy Gene X-linked

Polygenic:Summation of small effects of multiple genes creating diabetes susceptibility (e.g. NOD mouse)

Oligogenic:MHC+few major genes Genetic heterogeneity with different major non-MHC genes for different families (e.g. BB rat)

Type 1A Diabetes

BDC


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J. Noble

HLA

Human Leukocyte Antigen

human MHC

cell-surface proteins

important in self vs. nonself distinction

present peptide antigens to T cells

CLASS II: DR,DQ,DP

CLASS I: A,B,C


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J. Noble

TERMINOLOGY

Allele:

DRB1*0401

DR4

Haplotype:

DRB1*0401

DQB1*0302

DR4

DQ8

DRB1*0401

DQB1*0302

Genotype

DR4

DQ8

DRB1*0301

DQB1*02(DQ2)

DRB1*02

DR3

DQ2


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DQB1*0402

 -chain

Leu56

-chain

Asp57

BDC

BDC



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The IDDM2 Locus

IDDM2

Insulin Gene (INS)

Predisposing

Class I VNTR

26-63 repeats

21 alleles

IDDM2

Insulin Gene (INS)

Protective

Class III VNTR

140-200 repeats

15 alleles

VNTR = Variable Number of Tandem Repeats


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InheritedSusceptibility Loci

LOCUS CHROMOSOME CANDIDATE GENES or MICROSATELLITES

IDDM1 6p21HLA-DQ\DR

IDDM211p15INS VNTR

IDDM3 15q26 D15s107

IDDM411q13MDU1, ZFM1, RT6,FADD/MORT1, LRP5

IDDM56q24-27 ESR,MnSOD

IDDM6 18q12-q21D18s487, D18s64, JK (Kidd locus)

IDDM72q31 D2s152, IL-1,NEUROD, GALNT3

IDDM8 6q25-27 D6s264, D6s446, D6s281

IDDM9 3q21-25 D3s1303

IDDM10 10p11-q11 D10s193, D10s208, D10s588

IDDM11 14q24.3-q31 D14s67

IDDM122q33CTLA-4, CD28

IDDM13 2q34 D2s137, D2s164, IGFBP2, IGFBP5

IDDM14 ?NCBI # 3413

IDDM15 6q21 D6s283, D6s434, D6s1580

IDDM16 ? NCBI # 3415

IDDM1710q25D10s1750-D10s1773

OTHERS


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Autoimmune Polyendocrine Syndromes

  • APS-II (Autoimm Polyendocrine)

  • APS-I (AIRE mutation)

  • 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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APS-SyndromesBetterle et al. Endocrine Reviews 23:327-364Neufeld and Blizzard: 1980, Pinchera, in Symposium Autoimmune Endocrine Aspects of Endocrine Disorders

  • APS-I:>=2 of Candidiasis, Hypopara,Addison’s

  • APS-II:Addison’s + Autoimmune Thyroid and/or Type 1 Diabetes

  • APS-III: Thyroid Autoimmune + other autoimmune [not above]

  • APS-IV: Two or more organ-specific autoimmune, not I,II, or III.


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General Paradigm

  • Identify Genetic Susceptibility

  • Detect Initial Autoantibodies

  • Monitor Metabolic Decompensation

  • Treat Overt Disease Prior to Morbidity/Mortality

  • Basic/Clinical Research to Allow Prevention



Comparison aps i and aps ii aps i aps ii l.jpg

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

Comparison APS-I and APS-IIAPS-IAPS-II

BDC


Aps i l.jpg
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


Xpid x linked polyendocrinopathy immune dysfunction and diarrhea l.jpg
XPID: X-linked polyendocrinopathy, immune dysfunction and diarrhea

  • Other NamesIPEX: Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linkedXLAAD: X-Linked Autoimmunity Allergic Dysregulation

  • Foxp3 Gene Mutation

  • Loss of Regulatory T LymphocytesBone Marrow Transplant with Chimera “Cures” Scurfy Mouse and Man

BDC


Mutations for xpid syndrome scurfy foxp3 jm2 gene l.jpg
Mutations for XPID Syndrome Scurfy/Foxp3/JM2 Gene diarrhea

Fork Head Homology

Zn

Zip

ORF

X

XLAAD-100

D

XLAAD-200

Scurfy

X

Zn = Zinc-finger domain, Zip = Zip Motif

ORF = Predicted Open Reading Frame

Modified from Review by Patel, JCI, 2000


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Major DR/DQ Associations diarrhea

  • Type 1 DiabetesDR3: DRB1*0301/DQA1*0501/DQB1*0201DR4: DRB1*0401/DQA1*0301/DQb1*0302

  • Celiac DiseaseThe same as Type 1 DM plusDR5/DR7 = DQA1*0501/DQB1*0201 in trans

  • Addison’s DiseaseThe same as Type 1 DM but DRB1*0404 preference (Yu, JCEM 84:328,1999)

BDC




Celiac disease l.jpg
Celiac Disease diarrhea

  • Intestinal Autoimmune Disorder

  • Anti-Transglutaminase (EMA)

  • 1/200 General Population U.S./Europe1/20 Patients with Type 1 DM1/6 Patients Type 1 DM who are DR3/DR3

  • Gliadin Induction

  • Hypothesis: transglutaminase+gliadin


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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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Stages Type IA Diabetes relatives of DM patients and general population

  • I Genetic Susceptibility

  • II Triggering

  • III Active Autoimmunity

  • IV Progressive Metabolic Abnormalities

  • V Overt Diabetes

  • VI Insulin Dependence


Environment l.jpg
Environment relatives of DM patients and general population

  • Congenital Rubella

  • Controversy re Enteroviruses/ other virus

  • Controversy re bovine milk

  • Hygiene Hypothesis

  • 2 JAMA papers re early cereal


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BabyDiab and DAISY relatives of DM patients and general population

Age introduction gluten (Ziegler) or cereal (Norris) greatly increases development of anti-islet autoantibodies in infants followed from birth.


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Stages Type IA Diabetes relatives of DM patients and general population

  • I Genetic Susceptibility

  • II Triggering

  • III Active Autoimmunity

  • IV Progressive Metabolic Abnormalities

  • V Overt Diabetes

  • VI Insulin Dependence


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Insulin Autoantibodies: relatives of DM patients and general population

A Chain L13

Receptor

Binding

Region


Experimental autoimmune diabetes l.jpg
Experimental Autoimmune Diabetes relatives of DM patients and general population

B:9-23 Peptide ----- Insulin Autoantibodies

B:9-23 Peptide + Poly-IC ------ Insulitis

B:9-23 Peptide + Poly-IC + B7.1 Islet -- Diabetes

Moriyama et al. PNAS 99: 5539-5544, 2002


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Difference of Amino acid sequence between preproinsulin 1 and 2

Leader 1: MALLYHFLPL LALLALWEPKPTQA 6

Leader 2: MALWMRFLPL LALLFLWESHPTQA

B:9-23

B Chain 1: FVKQHLCGPHLVEALYLVCGERGFFYTPKS 2

B Chain 2: FVKQHLCGSHLVEALYLVCGERGFFYTPMS

C-Peptide 1: EVEDPQVEQLELGGSPGDLQTLALEVARQ 5

C-Peptide 2: EVEDPQVAQLELGGGPGAGDLQTLALEVAQQ

A Chain 1: GIVDQCCTSI CSLYQLENYC N 0

A Chain 2: GIVDQCCTSI CSLYQLENYC N



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Diabetes Autoimmunity Study in the Young and 2

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


Hla defined iddm risk groups denver population n 9 338 l.jpg
HLA-defined IDDM risk groups and 2Denver population, n=9,338


Autoantibodies l.jpg
Autoantibodies and 2

  • Insulin

  • Glutamic Acid Decarboxylase

  • ICA512 (IA-2)


Slide38 l.jpg

IAA assay and 2


Slide39 l.jpg

10000 and 2

1000

Anti-insulin autoantibodies (nU/ml)

100

10

1

5

10

15

20

25

30

35

Age (years)

Insulin Autoantibodies Versus Age of Diabetes Onset

Diabetes Care 11:736-739, 1988


Slide40 l.jpg

The Levels of mIAA in Prediabetic Children and 2

DM

DM

DM

DM

DM

Yu et al. PNAS: 97:1701-1706, 2,000

BDC


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Progression to Diabetes vs Number of Autoantibodies and 2

(GAD, ICA512, Insulin)

Percent not Diabetic

Years of Follow-up

3 Ab n = 41 17 8 1

2 Abs n = 44 27 15 4 2 1

1 Abs n = 93 23 14 10 6 4


Stages type ia diabetes43 l.jpg
Stages Type IA Diabetes and 2

  • I Genetic Susceptibility

  • II Triggering

  • III Active Autoimmunity

  • IV Progressive Metabolic Abnormalities

  • V Overt Diabetes

  • VI Insulin Dependence


We can now predict type 1 diabetes l.jpg

We can now predict type 1 diabetes. and 2

We cannot now prevent type 1 diabetes.


What are we missing l.jpg

What are we missing? and 2

Assay for Pathogenic T cells.

? TETRAMER

? ELISPOT


Slide47 l.jpg

% tetramer+ CD8+ cells and 2

% tetramer+ CD8+ cells

Age (weeks)

Age (weeks)

Female NOD Mice Peripheral Blood

Kd

NRP-V7 Peptide (KYNKANVFL)

Tetramer Analysis

Avidin

Kd

Kd

IGRP-2nd Beta Cell Specific Ag

Kd

Diabetes

No Diabetes

Trudeau,Santamaria,Tan: JCI 2003


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Multiple Trials New Onset Planned/ Underway and 2

  • Anti-CD3 Monoclonal

  • Anti-IL2 Receptor + MMF

  • Altered Peptide Ligand B:9-23 insulin

  • HSP 60, p277 Peptide (LADA Pts)

  • GAD65 (LADA patients)


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Changes from Study Entry to 12 Months in the Total and 2

C-Peptide Response to Mixed-Meal Tolerance Testing

Monoclonal-Antibody Group

Control Group

Total Area under the C-Peptide Response Curve (nmol/l/4 hr)

Total Area under the C-Peptide Response Curve (nmol/l/4 hr)

Herold K. et al., N Engl J Med 2002; 346:1692-8.


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Large NIH Prevention Initiatives and 2

  • Immune Tolerance Network

  • DPT-1 ===> TrialNet

  • Autoimmunity Centers Excellence

  • Autoimmunity Prevention Centers

Rewers-BDC


Ids guidelines for intervention trials greenbaum and harrison diabetes 52 1059 2003 l.jpg
IDS Guidelines for Intervention Trials and 2Greenbaum and Harrison:Diabetes 52:1059, 2003

  • Diagnosis ADA criteria

  • Document: age,sex,pubertal, family history,glucose, bicarb,ketoacidosis, weight loss, symptoms,HbA1c,islet autoab, insulin Rx, HLA

  • Phase I >=18

  • GAD, IA-2, IAA(<2 wks), and if DM ICA C-peptide>=.2 nmol/L, early = <12 weeks from diagnosis

  • >=2 year trials

  • Randomize, blind, mask, safety review, tight control, and continue insulin

  • 2 hr. AUC C-Peptide with meal tolerance test, no AM insulin except pump basal, fasting glucose 4-11.1 mmol/l

  • Measure islet autoAb other immune with HLA


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