BDC Keystone Genetics Type 1 Diabetes. Immunology of diabetes book with Teaching Slides

Transcription

1 BDC Keystone Genetics Type 1 Diabetes Immunology of diabetes book with Teaching Slides

2 PRACTICAL Trailnet screens relatives and new onset patients for autoantibodies and HLA when appropriate for free halt-dm1 GAD Dynal commercial laboratory excellent assay re sensitivity BDC has laboratory re outside samples: (only ZnT8 at present and anti-interferon and HLA re DM) Book Immunology diabetes with slides

3 893 newly diagnosed diabetic subjects (Age: 0.92 to yrs) AutoAb to GAD65, ICA512bdc,insulin (IA-2ic, ICA, ZnT8) #4: ZnT8 antibodies: Beta Cell Zinc Transporter* 753 patients, >= 1 autoantibodies (84.3%) 140 patients, negative for all autoantibodies (15.7%) *ZnT8 Patent BDC

4 AB positive DM C-peptide (pg/ml) Diabetes duration (years)

5 AB negative DM C-peptide (pg/ml) , , patient sister Duration of diabetes (years)

6 JDRF npod 37 yo 20 yrs DM Ab- C-peptide=.2 Atkinson PI

7 Islets with Beta Cells

8 Pseudoatrophic islets

9 Monogenic IPEX syndrome Autoimmune Polyendocrine Type 1 Polygenic Autoimmune Polyendocrine Type 2 Type 1A diabetes

10 9 Months of Age

11 Mutation of FoxP3 gene - Controls regulatory T cells Approximately 80% of children with syndrome develop diabetes Bone marrow transplant can reverse

12 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

13 Eisenbarth GS, Gottlieb PA. NEJM 350:

14 RISK OF TYPE 1 DM Proband with DM % Diabetes % Autoantibody+ General Population 0.3% 4% >=1 Antibody Offspring 1% 4.1% Sibling 6% 7.4% Dizygotic Twin 6% 10% Mother 2% 5% Father 4.6% 6.5% Both Parents 10%?? Monozygotic Twin 60% 70-80%

15

16

17 % Diabetes Proband Diabetes Non-Proband Antibodies Non-Proband Diabetes Age N = % Antibody Positive Redondo, Jeffrey, Fain, Eisenbarth, Orban NEJM 359:

18 HLA Insulin production & metabolism Locus Immunity β cell apoptosis protection Unknown function

19 The IDDM2 Locus Predisposing IDDM2 Class I VNTR repeats 21 alleles Insulin Gene (INS) Protective IDDM2 Class III VNTR repeats 15 alleles Insulin Gene (INS) VNTR = Variable Number of Tandem Repeats

20 Antigen Endocytosis APC MHC II CD4 + T cell T Cell Receptor Trimolecular Complex

21 The Major Histocompatibility Complex Human Chromosome 6 Class II Class III Class I DP DQ DR B C A Antigen Processing Genes Complement Proteins Cytokines Class I-like genes and pseduogenes Mouse Chromosome 17 Class III Class II Class I Class I K I-A I-E D L

22 Human Chromosome 6 Class II Class III Class I DP DQ DR B C A Allele: Haplotype: DRB1*0401 DRB1*0401 DQB1*0302 Genotype: DRB1*0401 DQB1*0302 DRB1*0301 DQB1*0201 Type 1 Diabetes: Molecular, Cellular and Clinical immunology

23 HBDI Series: Transmission from Parents with second haplotype not DQ2 or DQ N= 406/333/33/ 79/ 72/ 55/ 55/ 44/ 42/ 38/ 29/ 37/ 4 DQ8 DQ2 0401/ / / / / / / / / / /0503(1401)

24 NEwborn Cohort (NEC) General population cohort (SOC) Sibling/Offspring Cohort screened = 33,096 Enrolled 391 high risk (2.4 %) 456 moderate risk 384 average-low risk 1,231 offspring siblings Total enrolled 2,270

25 Haplotype Sharing Siblings Share Both Haplotypes Family A Haplotypes A B Siblings Share One Haplotype Family B Siblings Share No Haplotypes Family C C D A B C D A B C D HLA-A HLA-DRB Father Mother Father Mother Father Mother Diabetic Proband DAISY Sibling Diabetic Proband DAISY Sibling Diabetic Proband DAISY Sibling HLA-A HLA-DRB A C A C A C A D A C B D

26 % Autoantibody Positive 100 Siblings at high risk 90 (Share 2) Siblings at low risk 80 (Share 0 or 1) N = N = Age (y) % With Diabetes Age (y) Aly et al. PNAS 103:

27 Autoantibody Positive (%) 30 High Risk 25 (no protective alleles) Low Risk (DRB1* or DPB1*0402) Diabetes (%) Age (years) 30 High Risk 25 (no protective alleles) Low Risk (DRB1* or DPB1*0402) Age (years) Baschal et al. Diabetes 56:

28 Transglutaminase autoantibodies (5% celiac disease) 21-Hydroxylase autoantibodies (1% positive: predictive Addison s disease) Sensitive TSH assay (hypothyroidism very common)

29 Spontaneous Animal Models BB rat Homozygosity Lymphopenia (Ch4;Ian) RT1-U U class II (Ch 20) Additional Loci (Ch2,18,X) NOD mouse Polygenic: class II + class I loci + IL-2 linked polymorphism + >12 iddm loci Long-EvansTokushima Rat RT1-U U MHC Homozygosity Chr 11-Cblb gene BDC

30 TCR MHC PEPTIDE INS B:9-23

31 AA Peptide Side Chains I-A g7 Peptide

32 H S L V 9 13 E A L 16 A Y L V C 23 G R E G Barbara Davis Center

33 % of Diabetes Free ins1+, ins2- (n=24) B16:A Insulin ins1-, ins2- (n=31, P<0.0001) Weeks Nakayama et al. Nature 435:

34 ARG(22) GLU GLY CYS VAL LEU TYR LEU ALA(14)

35 TCR MHC PEPTIDE INS B:9-23

36 Antigen Presenting Cell Peptide V V D J J Chr. 14 Chr. 6

37 THOUGHTS IMMUNE MEDIATED DIABETES HAS A NUMBER OF GENETIC CAUSES DEFINING NON-AUTOIMMUNE IMPORTANT HLA ALLELES MAJOR DETERMINANT IN TERMS OF DIAGNOSIS AND PREDICTION TRIALS IN EXTREME RISK PATIENTS PLANNED/UNDERWAY