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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

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.

slide2
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
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

slide4
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
Stages Type IA Diabetes
  • I Genetic Susceptibility
  • II Triggering
  • III Active Autoimmunity
  • IV Progressive Metabolic Abnormalities
  • V Overt Diabetes
  • VI Insulin Dependence
type 1a diabetes
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

slide7
J. NobleHLA

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

terminology
J. NobleTERMINOLOGY

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

slide10
DQB1*0402

 -chain

Leu56

-chain

Asp57

BDC

BDC

slide12
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

inherited susceptibility loci
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

autoimmune polyendocrine syndromes
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
slide15
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
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
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
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
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
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
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

celiac disease
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
slide26
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 diabetes27
Stages Type IA Diabetes
  • I Genetic Susceptibility
  • II Triggering
  • III Active Autoimmunity
  • IV Progressive Metabolic Abnormalities
  • V Overt Diabetes
  • VI Insulin Dependence
environment
Environment
  • Congenital Rubella
  • Controversy re Enteroviruses/ other virus
  • Controversy re bovine milk
  • Hygiene Hypothesis
  • 2 JAMA papers re early cereal
slide29
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 diabetes30
Stages Type IA Diabetes
  • I Genetic Susceptibility
  • II Triggering
  • III Active Autoimmunity
  • IV Progressive Metabolic Abnormalities
  • V Overt Diabetes
  • VI Insulin Dependence
slide31
Insulin Autoantibodies:

A Chain L13

Receptor

Binding

Region

experimental autoimmune diabetes
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

slide33
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

diabetes autoimmunity study in the young
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

autoantibodies
Autoantibodies
  • Insulin
  • Glutamic Acid Decarboxylase
  • ICA512 (IA-2)
slide39
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

slide40
The Levels of mIAA in Prediabetic Children

DM

DM

DM

DM

DM

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

BDC

slide42
Progression to Diabetes vs Number of Autoantibodies

(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
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 can now predict type 1 diabetes.

We cannot now prevent type 1 diabetes.

what are we missing

What are we missing?

Assay for Pathogenic T cells.

? TETRAMER

? ELISPOT

slide47
% 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
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)
slide49
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
Large NIH Prevention Initiatives
  • 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
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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