Type 1A Diabetes Immunology and Polyglandular Syndromes Textbook on web with Teaching Slides

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)

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

“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

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

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

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

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

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

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

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

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

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

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

Yu et al, JCEM, 1999

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

Transglutaminase Autoantibodies and Marsh score (Disease Severity) tTG titer 0123 Marsh score Spearman correlation, r = p < Hoffenberg, J. Peds 137:

Stage II: Precipitating Event

Diabetes Autoimmunity Study in the Young Sibling/offspring cohort General population cohort enrolled = 293 high risk moderate risk average - low risk 401 1,069 All 693 relatives 1,491 1,007 screened = 21,713

Stage III: Autoimmunity

Cytoplasmic ICA kindly provided by the discoverer Franco Bottazzo

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

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

Stage IV: Progressive Loss Function Stage V: Overt Diabetes

A

Barker et al, Diabetes Care 27: 1399, 2004

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

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.

TRIALNET 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

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