Type 1A Diabetes (Immune Mediated)

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  • Lists the loci linked to diabetes, will mention green loci
  • Type 1A Diabetes (Immune Mediated)

    1. 1. 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.
    2. 2. <ul><li>WWW.BARBARADAVISCENTER.ORG : Book: Immunology Type 1 Diabetes </li></ul><ul><li>Teaching slides are Powerpoint slide sets that can be downloaded. </li></ul><ul><li>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, </li></ul><ul><li>Allan E. Karlsen, Jørn Nerup, Flemming Pociot and Thomas Mandrup-Poulsen. Steno Diabetes </li></ul><ul><li>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 </li></ul>
    3. 3. 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)
    4. 4. 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
    5. 5. Stages Type IA Diabetes <ul><li>I Genetic Susceptibility </li></ul><ul><li>II Triggering </li></ul><ul><li>III Active Autoimmunity </li></ul><ul><li>IV Progressive Metabolic Abnormalities </li></ul><ul><li>V Overt Diabetes </li></ul><ul><li>VI Insulin Dependence </li></ul>
    6. 6. Type 1A Diabetes <ul><li>Monogenic: Single gene defect. APS-I: AIRE autosomal recessive XPID: Scurfy Gene X-linked </li></ul><ul><li>Polygenic: Summation of small effects of multiple genes creating diabetes susceptibility (e.g. NOD mouse) </li></ul><ul><li>Oligogenic: MHC+few major genes Genetic heterogeneity with different major non-MHC genes for different families (e.g. BB rat) </li></ul>BDC
    7. 7. 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
    8. 9. 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
    9. 10. DQB1*0402 Asp57  Leu56   -chain  -chain BDC BDC
    10. 11. BDC
    11. 12. 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
    12. 13. 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
    13. 14. Autoimmune Polyendocrine Syndromes <ul><li>APS-II (Autoimm Polyendocrine) </li></ul><ul><li>APS-I (AIRE mutation) </li></ul><ul><li>XPID: (Scurfy Mutation) </li></ul><ul><li>Anti-insulin Receptor Abs + “Lupus” </li></ul><ul><li>Hirata (Anti-insulin Autoantibodies) </li></ul><ul><li>POEMS (Plasmacytoma,..) </li></ul><ul><li>Thymic Tumors + Autoimmunity </li></ul><ul><li>Congenital Rubella + DM +Thyroid </li></ul>
    14. 15. APS-Syndromes Betterle et al. Endocrine Reviews 23:327-364 Neufeld and Blizzard: 1980, Pinchera, in Symposium Autoimmune Endocrine Aspects of Endocrine Disorders <ul><li>APS-I:>=2 of Candidiasis, Hypopara,Addison’s </li></ul><ul><li>APS-II:Addison’s + Autoimmune Thyroid and/or Type 1 Diabetes </li></ul><ul><li>APS-III: Thyroid Autoimmune + other autoimmune [not above] </li></ul><ul><li>APS-IV: Two or more organ-specific autoimmune, not I,II, or III. </li></ul>
    15. 16. General Paradigm <ul><li>Identify Genetic Susceptibility </li></ul><ul><li>Detect Initial Autoantibodies </li></ul><ul><li>Monitor Metabolic Decompensation </li></ul><ul><li>Treat Overt Disease Prior to Morbidity/Mortality </li></ul><ul><li>Basic/Clinical Research to Allow Prevention </li></ul>
    16. 17. Associated Autoimmune Illnesses
    17. 18. Comparison APS-I and APS-II APS-I APS-II <ul><li>Onset Infancy </li></ul><ul><li>Siblings AIRE gene mutated </li></ul><ul><li>Not HLA Associated </li></ul><ul><li>Immunodeficiency Asplenism Mucocutaneous Candidiasis </li></ul><ul><li>18% Type 1 DM </li></ul><ul><li>Older Onset </li></ul><ul><li>Multiple Generations </li></ul><ul><li>DR3/4 Associated </li></ul><ul><li>No Defined Immunodeficiency </li></ul><ul><li>20% Type 1 DM </li></ul>BDC
    18. 19. APS-I <ul><li>Autoimmune Polyendocrine Syndrome Type 1 </li></ul><ul><li>Autosomal Recessive mutations AIRE (Autoimmune Regulator) gene </li></ul><ul><li>Mucocutaneous Candidiasis/Addison’s Disease/Hypoparathyroidism </li></ul><ul><li>18% Type 1 Diabetes </li></ul><ul><li>“ Transcription Factor” in Thymus </li></ul>BDC
    19. 20. XPID: X-linked polyendocrinopathy, immune dysfunction and diarrhea <ul><li>Other Names IPEX : Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked XLAAD : X-Linked Autoimmunity Allergic Dysregulation </li></ul><ul><li>Foxp3 Gene Mutation </li></ul><ul><li>Loss of Regulatory T Lymphocytes Bone Marrow Transplant with Chimera “Cures” Scurfy Mouse and Man </li></ul>BDC
    20. 21. 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
    21. 22. Major DR/DQ Associations <ul><li>Type 1 Diabetes DR3: DRB1*0301/DQA1*0501/DQB1*0201 DR4: DRB1*0401/DQA1*0301/DQb1*0302 </li></ul><ul><li>Celiac Disease The same as Type 1 DM plus DR5/DR7 = DQA1*0501/DQB1*0201 in trans </li></ul><ul><li>Addison’s Disease The same as Type 1 DM but DRB1*0404 preference (Yu, JCEM 84:328,1999) </li></ul>BDC
    22. 23. Known Initiators
    23. 24. Mediator/Autoantigen(s)
    24. 25. Celiac Disease <ul><li>Intestinal Autoimmune Disorder </li></ul><ul><li>Anti-Transglutaminase (EMA) </li></ul><ul><li>1/200 General Population U.S./Europe 1/20 Patients with Type 1 DM 1/6 Patients Type 1 DM who are DR3/DR3 </li></ul><ul><li>Gliadin Induction </li></ul><ul><li>Hypothesis: transglutaminase+gliadin </li></ul>
    25. 26. Prevalence of TGA by HLA-DR amongst patients with type 1 DM, relatives of DM patients and general population Prevalence HLA-DR BDC
    26. 27. Stages Type IA Diabetes <ul><li>I Genetic Susceptibility </li></ul><ul><li>II Triggering </li></ul><ul><li>III Active Autoimmunity </li></ul><ul><li>IV Progressive Metabolic Abnormalities </li></ul><ul><li>V Overt Diabetes </li></ul><ul><li>VI Insulin Dependence </li></ul>
    27. 28. Environment <ul><li>Congenital Rubella </li></ul><ul><li>Controversy re Enteroviruses/ other virus </li></ul><ul><li>Controversy re bovine milk </li></ul><ul><li>Hygiene Hypothesis </li></ul><ul><li>2 JAMA papers re early cereal </li></ul>
    28. 29. BabyDiab and DAISY Age introduction gluten (Ziegler) or cereal (Norris) greatly increases development of anti-islet autoantibodies in infants followed from birth.
    29. 30. Stages Type IA Diabetes <ul><li>I Genetic Susceptibility </li></ul><ul><li>II Triggering </li></ul><ul><li>III Active Autoimmunity </li></ul><ul><li>IV Progressive Metabolic Abnormalities </li></ul><ul><li>V Overt Diabetes </li></ul><ul><li>VI Insulin Dependence </li></ul>
    30. 31. <ul><li>Insulin Autoantibodies: </li></ul><ul><li>A Chain L13 </li></ul>Receptor Binding Region
    31. 32. 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
    32. 33. 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
    33. 34. PNAS 2003,18:10376
    34. 35. 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
    35. 36. HLA-defined IDDM risk groups Denver population, n=9,338
    36. 37. Autoantibodies <ul><li>Insulin </li></ul><ul><li>Glutamic Acid Decarboxylase </li></ul><ul><li>ICA512 (IA-2) </li></ul>
    37. 38. IAA assay
    38. 39. 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)
    39. 40. <ul><li>The Levels of mIAA in Prediabetic Children </li></ul>DM DM DM DM DM Yu et al. PNAS: 97:1701-1706, 2,000 BDC
    40. 42. 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
    41. 43. Stages Type IA Diabetes <ul><li>I Genetic Susceptibility </li></ul><ul><li>II Triggering </li></ul><ul><li>III Active Autoimmunity </li></ul><ul><li>IV Progressive Metabolic Abnormalities </li></ul><ul><li>V Overt Diabetes </li></ul><ul><li>VI Insulin Dependence </li></ul>
    42. 44. We can now predict type 1 diabetes. We cannot now prevent type 1 diabetes.
    43. 45. What are we missing? Assay for Pathogenic T cells. ? TETRAMER ? ELISPOT
    44. 47. 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
    45. 48. Multiple Trials New Onset Planned/ Underway <ul><li>Anti-CD3 Monoclonal </li></ul><ul><li>Anti-IL2 Receptor + MMF </li></ul><ul><li>Altered Peptide Ligand B:9-23 insulin </li></ul><ul><li>HSP 60, p277 Peptide (LADA Pts) </li></ul><ul><li>GAD65 (LADA patients) </li></ul>
    46. 49. 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
    47. 50. Large NIH Prevention Initiatives <ul><li>Immune Tolerance Network </li></ul><ul><li>DPT-1 ===> TrialNet </li></ul><ul><li>Autoimmunity Centers Excellence </li></ul><ul><li>Autoimmunity Prevention Centers </li></ul>Rewers-BDC
    48. 51. IDS Guidelines for Intervention Trials Greenbaum and Harrison:Diabetes 52:1059, 2003 <ul><li>Diagnosis ADA criteria </li></ul><ul><li>Document: age,sex,pubertal, family history,glucose, bicarb,ketoacidosis, weight loss, symptoms,HbA1c,islet autoab, insulin Rx, HLA </li></ul><ul><li>Phase I >=18 </li></ul><ul><li>GAD, IA-2, IAA(<2 wks), and if DM ICA C-peptide>=.2 nmol/L, early = <12 weeks from diagnosis </li></ul><ul><li>>=2 year trials </li></ul><ul><li>Randomize, blind, mask, safety review, tight control, and continue insulin </li></ul><ul><li>2 hr. AUC C-Peptide with meal tolerance test, no AM insulin except pump basal, fasting glucose 4-11.1 mmol/l </li></ul><ul><li>Measure islet autoAb other immune with HLA </li></ul>

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