Type 1A Diabetes (Immune Mediated)
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Type 1A Diabetes (Immune Mediated)

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  • Lists the loci linked to diabetes, will mention green loci

Type 1A Diabetes (Immune Mediated) Type 1A Diabetes (Immune Mediated) Presentation Transcript

  • 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 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. Eisenbarth 2A. Cell Therapy of Diabetes (Updated - 3/02) Jan Nygaard Jensen and Jan Jensen 2B. Proprotein Processing and Pancreatic Islet Function (Updated - 3/02) John Hutton, Tina Wasmeier, Rodabe Amaria, Nicholas Bright and John Creemers 2C. 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 Bellgrau 4. The Role of T Cells in Beta Cell Damage in NOD Mice and Humans (Updated - 3/02) Katalin Kelemen 5. 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, Denmark 6. The Immunobiology of Pancreatic Islet Transplantation (Updated - 11/01) Marilyne Coulombe and Ronald G. Gill 7. Type I Diabetes Mellitus of Man: Genetic Susceptibility and Resistance (Updated - 4/02) A. Pugliese and G. S. Eisenbarth 8. Autoimmune Polyendocrine Syndromes (Updated - 10/03) J.M. Barker and G. S. Eisenbarth 9. Epidemiology of Type I Diabetes (Updated - 4/02) Marian Rewers, Jill Norris and Dana Dabelea 10. Humoral Autoimmunity (Updated - 9/02) L. Yu and G.S. Eisenbarth 11. Prediction of Type I Diabetes: The Natural History of the Prediabetic Period (Updated - 11/03) George S. Eisenbarth 12. 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 Genetic Predisposition Beta cell mass (?Precipitating Event) Overt immunologic abnormalities Normal insulin release Progressive loss insulin release Glucose normal Overt diabetes C-peptide present No C-peptide Age (years)
  • Peak insulin response to intravenous glucose (1+3 min) immunoreactive insulin ( μ U/ml) ANTIBODY NEGATIVE * ** ANTIBODY POSITIVE * DM Srikanta S. et al, New Engl J Med 308:322-325, 1983 Triplets Serial Intravenous Glucose Tolerance Tests 0 50 100 150 200 250 300 350 '66 '67 '68 '69 '70 '71 '72 '73 '74 '75 '66 '68 '70 '72 '74 '76 '78 '80 '82
  • 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)
    BDC
  • HLA H uman L eukocyte A ntigen 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 DRB1*02 DQB1*0302 DRB1*0401 DRB1*0401 DRB1*0301 DQB1*0302 DRB1*0401 DQB1*02(DQ2) Allele: Haplotype: Genotype J. Noble DR4 DR3 DR4 DR4 DQ2 DQ8 DQ8
  • DQB1*0402 Asp57  Leu56   -chain  -chain BDC BDC
  • BDC
  • Insulin Gene (INS) Class I VNTR 26-63 repeats 21 alleles Predisposing IDDM2 Insulin Gene (INS) Class III VNTR 140-200 repeats 15 alleles IDDM2 Protective The IDDM2 Locus VNTR = Variable Number of Tandem Repeats
  • Inherited Susceptibility Loci LOCUS CHROMOSOME CANDIDATE GENES or MICROSATELLITES IDDM1 6p21 HLA-DQDR IDDM2 11p15 INS VNTR IDDM3 15q26 D15s107 IDDM4 11q13 MDU1 , ZFM1 , RT6 , FADD/MORT1 , LRP5 IDDM5 6q24-27 ESR , MnSOD IDDM6 18q12-q21 D18s487 , D18s64, JK (Kidd locus) IDDM7 2q31 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 IDDM12 2q33 CTLA -4, CD28 IDDM13 2q34 D2s137, D2s164, IGFBP2, IGFBP5 IDDM14 ? NCBI # 3413 IDDM15 6q21 D6s283, D6s434, D6s1580 IDDM16 ? NCBI # 3415 IDDM17 10q25 D10s1750-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-Syndromes Betterle et al. Endocrine Reviews 23:327-364 Neufeld 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
  • Comparison APS-I and APS-II APS-I APS-II
    • Onset Infancy
    • Siblings AIRE gene mutated
    • Not HLA Associated
    • Immunodeficiency Asplenism Mucocutaneous Candidiasis
    • 18% Type 1 DM
    • Older Onset
    • Multiple Generations
    • DR3/4 Associated
    • No Defined Immunodeficiency
    • 20% Type 1 DM
    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 Names IPEX : Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked XLAAD : X-Linked Autoimmunity Allergic Dysregulation
    • Foxp3 Gene Mutation
    • Loss of Regulatory T Lymphocytes Bone Marrow Transplant with Chimera “Cures” Scurfy Mouse and Man
    BDC
  • Mutations for XPID Syndrome Scurfy/Foxp3/JM2 Gene Fork Head Homology Zn Zip X X Scurfy D ORF XLAAD-100 XLAAD-200 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 Diabetes DR3: DRB1*0301/DQA1*0501/DQB1*0201 DR4: DRB1*0401/DQA1*0301/DQb1*0302
    • Celiac Disease The same as Type 1 DM plus DR5/DR7 = DQA1*0501/DQB1*0201 in trans
    • Addison’s Disease The 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./Europe 1/20 Patients with Type 1 DM 1/6 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
  • B Chain 1: FVKQHLCG P HLVEALYLVCGERGFFYTP K S 2 B Chain 2: FVKQHLCG S HLVEALYLVCGERGFFYTP M S Difference of Amino acid sequence between preproinsulin 1 and 2 B:9-23 Leader 1: MAL LYH FLPL LALL A LWE PK PTQA 6 Leader 2: MAL WMR FLPL LALL F LWE SH PTQA A Chain 1: GIVDQCCTSI CSLYQLENYC N 0 A Chain 2: GIVDQCCTSI CSLYQLENYC N C-Peptide 1: EVEDPQV E QLELGG S PGDLQTLALEVA R Q 5 C-Peptide 2: EVEDPQV A QLELGG G PG AG DLQTLALEVA Q Q
  • PNAS 2003,18:10376
  • Diabetes Autoimmunity Study in the Young Sibling/offspring cohort General population cohort enrolled = 293 high risk 72 429 moderate risk 220 347 average - low risk 401 1,069 All 693 relatives 1,491 1,007 screened = 21,713
  • HLA-defined IDDM risk groups Denver population, n=9,338
  • Autoantibodies
    • Insulin
    • Glutamic Acid Decarboxylase
    • ICA512 (IA-2)
  • IAA assay
  • Insulin Autoantibodies Versus Age of Diabetes Onset Diabetes Care 11:736-739, 1988 1 10 100 1000 10000 5 10 15 20 25 30 35 Age (years) Anti-insulin autoantibodies (nU/ml)
    • 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 = 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 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
  •  
  • Female NOD Mice Peripheral Blood Avidin K d NRP-V7 Peptide (KYNKANVFL ) K d K d K d Tetramer Analysis Diabetes No Diabetes Trudeau,Santamaria,Tan: JCI 2003 IGRP-2 nd Beta Cell Specific Ag Age (weeks) % tetramer+ CD8+ cells Age (weeks) % tetramer+ CD8+ cells
  • 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 Herold K. et al., N Engl J Med 2002; 346:1692-8. Total Area under the C-Peptide Response Curve (nmol/l/4 hr) Monoclonal-Antibody Group Total Area under the C-Peptide Response Curve (nmol/l/4 hr) Control Group
  • 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
    • 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