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Type 1A Diabetes Immunology and Polyglandular Syndromes

Type 1A Diabetes Immunology and Polyglandular Syndromes. Textbook on web with Teaching Slides www.barbaradaviscenter.org. Develop Insulin 1 and insulin 2 Knockouts with B16 alanine-insulin 2. Insulin 1 - B Chain : FVKQHLCG P HLVEALYLVCGERG FFYTP K S

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Type 1A Diabetes Immunology and Polyglandular Syndromes

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  1. Type 1A DiabetesImmunology and Polyglandular Syndromes Textbook on web with Teaching Slideswww.barbaradaviscenter.org

  2. Develop Insulin 1 and insulin 2 Knockouts with B16 alanine-insulin 2 Insulin 1 - B Chain : FVKQHLCGPHLVEALYLVCGERGFFYTPKS Insulin 2 - B Chain : FVKQHLCGSHLVEALYLVCGERGFFYTPMS Tyrosine (TAC) Alanine (GCC) X X Insulin 1-KO Insulin 2-KO B:16ala-tg Insulin 1 (-) Insulin 2 (-) B:16ala-insulin 2 (+)

  3. Nakayama et al. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 435:220, 2005

  4. Age (years) “Stages” in Development of Type1 Diabetes (?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

  5. Stage I: Genetics • Polygenic-commonHLA DR+DQ+ other MHCInsulin gene PTPN22-lyp?CTLA-4 • “Monogenic”-rareAPS-I: AIRE mutation IPEX syndrome: FoxP3 mutation

  6. The Major Histocompatibility ComplexHLA: Human Leukocyte Antigens LMP7 DQA1 DPA1 DRB1 DQB1 TAP1 DPB1 TAP2 DRA LMP2 MHC Class II Region 0 base pairs 1 million MICA CYP 21B B C E A C4A HSP70 TNF 1 million Class III Region Class I Region 4 million

  7. 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

  8. J. Noble TERMINOLOGY Allele: DRB1*0401 Haplotype: DRB1*0401 DQB1*0302 DRB1*0401 DQB1*0302 Genotype DRB1*0301 DQB1*02 DRB1*02

  9. Autoimmune Polyendocrine Syndromes • APS-II (Autoimmune Polyendocrine) • APS-I (AIRE mutation) • IPEX (XPID): (Scurfy Mutation) • Anti-insulin Receptor Abs + “Lupus” • Hirata (Anti-insulin Autoantibodies) • POEMS (Plasmacytoma,..) • Thymic Tumors + Autoimmunity • Congenital Rubella + DM +Thyroid

  10. IPEX: Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked • Other NamesXPID: X-linked polyendocrinopathy, immune dysfunction and diarrhea XLAAD: X-Linked Autoimmunity Allergic Dysregulation • Foxp3 Gene Mutation • Loss of Regulatory T Lymphocytes • Bone Marrow Transplant with Chimera “Cures” BDC

  11. 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

  12. MODEL AIRE Role in Preventing Autoimmunity Autoreactive thymocyte Tolerization of autoreactive thymocyte TCR MHC + Peptide Thymic Medullary Epithelial Cells AIRE Self-peptides from "peripheral" antigens Mathis/Benoist

  13. 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

  14. A family of diseases occurring in families Type 1A Diabetes Celiac Disease Addison’s Disease Thyroid Autoimmunity BDC

  15. Yu et al, JCEM, 1999

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

  17. Transglutaminase Autoantibodies and Marsh score (Disease Severity) Spearman correlation, r = 0.569 p < 0.003 2.5 2.0 1.5 tTG titer 1.0 .5 0.0 0 1 2 3 Marsh score Hoffenberg, J. Peds 137:356 2000

  18. Stage II: Precipitating Event

  19. 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

  20. Stage III: Autoimmunity

  21. Cytoplasmic ICA kindly provided by the discoverer Franco Bottazzo

  22. Major Autoantibody Targets • GAD65 (glutamic acid decarboxylase) • IA-2 (ICA512): Insulinoma Associated Protein • Insulin

  23. Insulin Autoantibodies • Usually the first autoantibody to appear • Highest levels in youngest children developing type 1A diabetes • Mature high-affinity immune responses to (pro)insulin anticipate the autoimmune cascade that leads to type 1 diabetes. Achenbach et al, J.Clin Invest 2004, 114:589

  24. Stage IV: Progressive Loss FunctionStage V: Overt Diabetes

  25. A

  26. Barker et al, Diabetes Care 27: 1399, 2004

  27. We can predict Type 1 diabetes.We can prevent the disorder in animal models.We cannot yet safely prevent in man.

  28. NEXT Improved T Cell Assays Trials of antigen-specific therapies prior to autoantibodies. Immunomodulator/Immunosuppressive Trials post-onset and with islet transplantation.

  29. TRIALNET1-800-HALT-DM1 • Dalizumab+ MMF – New Onset Trial • Oral Insulin Trial – Post Autoantibodies – Relative Screening • With ITN: Anti-CD3 Trial Multiple course • JDRF: Oral Insulin Prior to Anti-islet Autoantibodies being planned

  30. Diabetes Autoimmunity Study in the Young (DAISY) Also: Lars Stene, Patricia Graves, Heather Stanley, Jaime Keen, Peter Chase Carolyn Fronczak, Jennifer Barker, Akane Ide, Andrea Steck

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