1. Type 1A Diabetes Immunology and Polyglandular Syndromes Textbook on web with Teaching Slides www.barbaradaviscenter.org

4. Develop Insulin 1 and insulin 2 Knockouts with B16 alanine-insulin 2 Insulin 1-KO Insulin 2-KO B:16ala-tg XX Insulin 1 - B Chain : FVKQHLCGPHLVEALYLVCGERGFFYTPKS Insulin 2 - B Chain : FVKQHLCGSHLVEAL Y LVCGERGFFYTPMS Insulin 1 (-) Insulin 2 (-) B:16ala-insulin 2 (+) Tyrosine (TAC) Alanine (GCC)

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

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

7. Stage I: Genetics Polygenic-common HLA DR+DQ+ other MHC Insulin gene PTPN22-lyp ?CTLA-4 “Monogenic”-rare APS-I: AIRE mutation IPEX syndrome: FoxP3 mutation

8. The Major Histocompatibility Complex HLA: Human Leukocyte Antigens 0 base pairs1 million 4 million DPB1 DPA1 LMP2 TAP1 LMP7 TAP2 DQB1 DQA1 DRB1 DRA CYP 21B C4AHSP70 TNF BCE A MICA Class I Region MHC Class II Region Class III Region

9. Human Leukocyte Antigen 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 HLA J. Noble

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

11. 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

12. IPEX: Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked Other Names XPID: 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

13. 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

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

15. 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

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

17. Yu et al, JCEM, 1999

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

19. Transglutaminase Autoantibodies and Marsh score (Disease Severity) 0.0.5 1.0 1.5 2.0 2.5 tTG titer 0123 Marsh score Spearman correlation, r = 0.569 p < 0.003 Hoffenberg, J. Peds 137:356 2000

20. Stage II: Precipitating Event

21. 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

22. Stage III: Autoimmunity

23. Cytoplasmic ICA kindly provided by the discoverer Franco Bottazzo

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

25. 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

26. Stage IV: Progressive Loss Function Stage V: Overt Diabetes

27. A

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

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

30. NEXT 1.Improved T Cell Assays 2.Trials of antigen-specific therapies prior to autoantibodies. 3.Immunomodulator/Immunosuppressive Trials post-onset and with islet transplantation.

31. TRIALNET 1-800-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

32. 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