Keystone Diabetes in Youth Snowmass: Jan 23, 2008 Clinical diabetes and Endocrinology Book on Immunology Diabetes With teaching slides

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

Awaiting Bone Marrow Transplant for child with IPEX syndrome 9 Months

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

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 100% anti-interferon Abs Older Onset Multiple Generations DR3/4 Associated No Defined Immunodeficiency 20% Type 1 DM

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.

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

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

Check List APS-I Visit New Symptoms History New Signs Physical Oral Candidiasis New Antibodies ( 21-OH, GAD, IA-2 ) Ca, Pi, Mg Na, K ALT ACTH, TSH, (LH, FSH) HbA1c Blood Smear (Howell-Jolly) Platelet Count Other

Eisenbarth GS, Gottlieb PA. New Engl J Med 2004;350:

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

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

PALM ELBOW

Transglutam inase Deamidation of Gliadin Peptides increases affinity for DQ2!

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

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

HLA-defined IDDM risk groups Denver population, n=9,338

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

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