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Keystone Diabetes in Youth

Keystone Diabetes in Youth. Snowmass: Jan 23, 2008 Clinical diabetes and Endocrinology. Book on Immunology Diabetes www.barbaradaviscenter.org_ With teaching slides. “Monogenic” Type 1 Diabetes. IPEX (Immune Dysfunction/ Polyendocrinopathy/ Enteropathy/ X-Linked) APS-1

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Keystone Diabetes in Youth

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  1. KeystoneDiabetes in Youth Snowmass: Jan 23, 2008 Clinical diabetes and Endocrinology Book on Immunology Diabetes www.barbaradaviscenter.org_ With teaching slides

  2. “Monogenic” Type 1 Diabetes • IPEX (Immune Dysfunction/ Polyendocrinopathy/ Enteropathy/ X-Linked) • APS-1 • Insulin Folding Mutations

  3. Awaiting Bone Marrow Transplant for child with IPEX syndrome 9 Months

  4. IPEX: Immune Dysfunction, Polyendocrinopathy, Enteropathy, X-linked • Scurfin gene (Foxp3/JM2)- Controls Regulatory T Cells! • Approximately 80% of children with syndrome develop diabetes! • Bone marrow transplant can reverse BDC

  5. Onset Infancy SiblingsAIRE gene mutated Not HLA Associated ImmunodeficiencyAsplenismMucocutaneous Candidiasis 18% Type 1 DM 100% anti-interferon Abs Older Onset Multiple Generations DR3/4 Associated No Defined Immunodeficiency 20% Type 1 DM Comparison APS-I and APS-IIAPS-IAPS-II

  6. APS-I Loss Thymic Tolerance to “Peripheral” Antigens • Knockout of the AIRE gene abrogates expression of many “peripheral antigens” within the thymus such as insulin • IDDM2 locus is insulin gene and Pugliese (Miami) and Polychronakos (Montreal) have shown, protective allele associated with greater thymic insulin messenger RNA.

  7. 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

  8. Europium-ELISA completely differentiated APS1 patients from non-APS1 patients, AD and T1D patients.

  9. Check List APS-I Visit

  10. Eisenbarth GS, Gottlieb PA. New Engl J Med 2004;350:2068-79

  11. Eisenbarth GS, Gottlieb PA. New Engl J Med 2004;350:2068-79

  12. Development of 21-hydroxylase Autoantibodies in Patients with Type 1A Diabetes

  13. Premature Mortality in Patients with Addison’s Disease: A Population-Based StudyJ clin endocrinol Metab 91:4859, 2006 Percent Dying 6.7 yr follow-up; mean start age 52.8 N=507 deaths of 1675 patients N=199 deaths

  14. PALM ELBOW

  15. Transglutaminase Deamidation of Gliadin Peptides increases affinity for DQ2!

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

  17. DQB1*0402  -chain Leu56 -chain Asp57 BDC BDC

  18. HLA-defined IDDM risk groupsDenver population, n=9,338

  19. MHC Haplotype Sharing Increases DR3/4 Sibling Risk Haplotype Determination:

  20. ODDS RATIO Modified from Todd et al. Robust Associations of four new chromosome regions from genome-wide anlayses of type 1 diabetes Nature Genetics June 6 2007

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