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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

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.


  • 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


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


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

  • I Genetic Susceptibility

  • II Triggering

  • III Active Autoimmunity

  • IV Progressive Metabolic Abnormalities

  • V Overt Diabetes

  • VI Insulin Dependence


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


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


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


DQB1*0402

 -chain

Leu56

-chain

Asp57

BDC

BDC


BDC


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


InheritedSusceptibility Loci

LOCUS CHROMOSOME CANDIDATE GENES or MICROSATELLITES

IDDM16p21HLA-DQ\DR

IDDM211p15INS VNTR

IDDM315q26D15s107

IDDM411q13MDU1, ZFM1, RT6,FADD/MORT1, LRP5

IDDM56q24-27ESR,MnSOD

IDDM618q12-q21D18s487, D18s64, JK (Kidd locus)

IDDM72q31D2s152, IL-1,NEUROD, GALNT3

IDDM86q25-27D6s264, D6s446, D6s281

IDDM93q21-25D3s1303

IDDM1010p11-q11D10s193, D10s208, D10s588

IDDM1114q24.3-q31D14s67

IDDM122q33CTLA-4, CD28

IDDM132q34D2s137, D2s164, IGFBP2, IGFBP5

IDDM14?NCBI # 3413

IDDM156q21D6s283, D6s434, D6s1580

IDDM16?NCBI # 3415

IDDM1710q25D10s1750-D10s1773

OTHERS


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


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.


General Paradigm

  • Identify Genetic Susceptibility

  • Detect Initial Autoantibodies

  • Monitor Metabolic Decompensation

  • Treat Overt Disease Prior to Morbidity/Mortality

  • Basic/Clinical Research to Allow Prevention


Associated Autoimmune Illnesses


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

  • 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

  • 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

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


Major DR/DQ Associations

  • 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


Known Initiators


Mediator/Autoantigen(s)


Celiac Disease

  • 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


Prevalence of TGA by HLA-DR amongst patients with type 1 DM, relatives of DM patients and general population

Prevalence

HLA-DR

BDC


Stages Type IA Diabetes

  • I Genetic Susceptibility

  • II Triggering

  • III Active Autoimmunity

  • IV Progressive Metabolic Abnormalities

  • V Overt Diabetes

  • VI Insulin Dependence


Environment

  • Congenital Rubella

  • Controversy re Enteroviruses/ other virus

  • Controversy re bovine milk

  • Hygiene Hypothesis

  • 2 JAMA papers re early cereal


BabyDiab and DAISY

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


Stages Type IA Diabetes

  • I Genetic Susceptibility

  • II Triggering

  • III Active Autoimmunity

  • IV Progressive Metabolic Abnormalities

  • V Overt Diabetes

  • VI Insulin Dependence


Insulin Autoantibodies:

A Chain L13

Receptor

Binding

Region


Experimental Autoimmune Diabetes

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


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


PNAS 2003,18:10376


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


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


Autoantibodies

  • Insulin

  • Glutamic Acid Decarboxylase

  • ICA512 (IA-2)


IAA assay


10000

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


The Levels of mIAA in Prediabetic Children

DM

DM

DM

DM

DM

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

BDC


Progression to Diabetes vs Number of Autoantibodies

(GAD, ICA512, Insulin)

Percent not Diabetic

Years of Follow-up

3 Ab n = 4117 8 1

2 Abs n = 442715 421

1 Abs n = 932314106 4


Stages Type IA Diabetes

  • 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.

We cannot now prevent type 1 diabetes.


What are we missing?

Assay for Pathogenic T cells.

? TETRAMER

? ELISPOT


% tetramer+ CD8+ cells

% 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


Multiple Trials New Onset Planned/ Underway

  • Anti-CD3 Monoclonal

  • Anti-IL2 Receptor + MMF

  • Altered Peptide Ligand B:9-23 insulin

  • HSP 60, p277 Peptide (LADA Pts)

  • GAD65 (LADA patients)


Changes from Study Entry to 12 Months in the Total

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.


Large NIH Prevention Initiatives

  • Immune Tolerance Network

  • DPT-1 ===> TrialNet

  • Autoimmunity Centers Excellence

  • Autoimmunity Prevention Centers

Rewers-BDC


IDS Guidelines for Intervention TrialsGreenbaum 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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