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Classification of diabetic syndromes

Classification of diabetic syndromes. • Type 1A: Immune-mediated Type 1B: Insulin deficient, no autoantibodies • Type 2: No autoantibodies, can initially be treated without insulin • Other specific forms of diabetes • Gestational diabetes. Type 1 diabetes mellitus.

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Classification of diabetic syndromes

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  1. Classification of diabetic syndromes • Type 1A: Immune-mediated Type 1B: Insulin deficient, no autoantibodies • Type 2: No autoantibodies, can initially be treated without insulin • Other specific forms of diabetes • Gestational diabetes

  2. Type 1 diabetes mellitus • Acute presentation: hyperglycemia, tiredness, weight loss, polyuria, thirst, nausea, vomiting, signal of impending ketoacidosis • Patients need insulin replacement to live • Honeymoon period: temporary remission in some patients • In long-standing patients: micro + macro vascular complications • Mortality increased 4-7 fold (nephropathy, card/vx disease) • Some patients survive without major complications

  3. Type 1 diabetes mellitus • Organ specific, autoimmune disease targeting pancreatic b cells • Complex interaction between environmental and genetic factors • Preceded by inflammation of pancreatic islets: insulitis • Circulating antibodies specific for islet cell antigens • Mediated by autoreactive CD4+ and CD8+ T cells • Laboratory animal models available

  4. PUTATIVE ENVIRONMENTAL TRIGGER HUMORAL AUTOANTIBODIES (ICA, IAA, Anti-GAD65, IA2Ab, etc) BETA CELL MASS GENETIC PREDISPOSI TION INSULITIS BETA CELL INJURY CLINICAL ONSET DIABETES TIME Natural History of Type 1 Diabetes CELLULAR (T CELL) AUTOIMMUNITY LOSS OF FIRST PHASE INSULIN RESPONSE (IVGTT) GLUCOSE INTOLERANCE (OGTT) “PRE”- DIABETES DIABETES

  5. Type 1 diabetes mellitus • Organ specific, autoimmune disease targeting pancreatic b cells • Complex interaction between environmental and genetic factors • Preceded by inflammation of pancreatic islets: insulitis • Circulating antibodies specific for islet cell antigens • Mediated by autoreactive CD4+ and CD8+ T cells • Laboratory animal models available

  6. Type 1 Diabetes and Environmental Factors • The incidence of childhood type 1 diabetes varies with geographic location, age, sex, ethnicity and time period. • Increase in Type 1 incidence worldwide • Concordance rate in monozygotic twins:50-80% • Estimated contribution of environmental factors to familial clustering of type 1 diabetes ~ 20%

  7. Incidence Type 1 Diabetesper 100,000 per year Children ≤14

  8. Type 1 diabetes in Finland Incidence /100,000 children age 0-14

  9. Remarks Reason(s) for the increasing T1D incidence are unknown A rapid change in incidence within genetically stable populations implies an etiological role for environmental factors Little evidence that Ags novel to the 2nd half of the 20th century explain these epidemiological trends Alternative view is the ‘hygiene hypothesis’: human populations selected to survive endemic infections in the past, now mount inappropriate autoimmune responses when Ag exposure is reduced by good hygiene in developed countries “Childhood Type 1 diabetes was in the past a partly preventable condition, and could become so again” Edwin Gale, 2002

  10. Type 1 diabetes mellitus • Organ specific, autoimmune disease targeting pancreatic b cells • Complex interaction between environmental and genetic factors • Preceded by inflammation of pancreatic islets: insulitis • Circulating antibodies specific for islet cell antigens • Mediated by autoreactive CD4+ and CD8+ T cells • Laboratory animal models available

  11. TIME COURSE OF INSULITIS IN NOD MICE

  12. Type 1 diabetes mellitus • Organ specific, autoimmune disease targeting pancreatic b cells • Complex interaction between environmental and genetic factors • Preceded by inflammation of pancreatic islets: insulitis • Circulating antibodies specific for islet cell antigens • Mediated by autoreactive CD4+ and CD8+ T cells • Laboratory animal models available

  13. Cytoplasmic ICA kindly provided by the discoverer GF Bottazzo

  14. Autoantibody specificities in type 1 diabetes • Insulin • Glutamic acid decarboxylase • ICA512 (IA-2) • Carboxypeptidase H, ICA 69…. • The target Ag(s) of diabetogenic T cells has not been identified in humans

  15. Autoantibodies in type 1 diabetes • No pathogenic role in human diabetics (e.g. no diabetes in infants born to autoAb+ mothers) • Mostly used as serologic markers to detect people at risk for type 1 diabetes (the risk is proportional to the number of specificities, the titer, and, for some, the affinity, and epitope specificity of Abs)

  16. Type 1 diabetes mellitus • Organ specific, autoimmune disease targeting pancreatic b cells • Complex interaction between environmental and genetic factors • Preceded by inflammation of pancreatic islets: insulitis • Circulating antibodies specific for islet cell antigens • Mediated by autoreactive CD4+ and CD8+ T cells • Laboratory animal models available

  17. Type 1 diabetes is a T-cell mediated disease The disease is prevented by neonatal thymectomy, antibody-mediated T-cell depletion of NOD mice and BB rats The disease does not develop in nude, SCID, RAG-/- NOD mice nor in nude BB rats Susceptibility to the disease is MHC-linked

  18. Effect of B and T cells in the transfer of diabetes in the NOD mouse Effect of CD4+ and CD8+ T cells in the transfer of diabetes Miller et al. (1988) J. Immunol. 140:52 Type 1 diabetes is mediated by autoreactive CD4+ and CD8+ T cells

  19. Genetic Susceptibility of Type 1 Diabetes • - non-Mendelian inheritance, under the control of allelic variations at multiple loci • - Recent GWA studies have revealed many T1D genes, a few with relatively large effect (MHC, INS, PTPN22), many with small effect, perhaps acting in subgroups of cases • - These results show that T1D is a disease of thymic selection & immune homeostasis • - Major pathways: - HLA class II & I antigen (insulin) recognition • - Tyrosine dephosphorylation in signalling • - Interleukin-2 pathway • - Shared genes/regions with autoimmune thyroid disease, Crohn’s disease, celiac disease and multiple sclerosis = common “autoimmune” pathways

  20. 19 T1D susceptibility loci (~ P<10-7) Locus, chr Risk allele (freq) Effect size P value Reference HLA-DRB1 – DQB1, 6p21 DR3/DR4 (28%) RR=3 for DR3 or DR4 RR=11 for DR3/4 <10-200 Herr et al., 2000 INS, 11p15 23HphI (A,80%) RR=4.5 for A/A 5 x 10-8 Barratt et al., 2004 CTLA4, 2q33 JO30 (G,51%) RR=1.18 for G 8 x 10-11 Ueda et al., 2003 PTPN22, 1p13 Arg620Trp (T, 10%) RR=1.67 for T 10-40 Smyth et al., 2004 IL2RA (CD25), 10p15-14 ss5258010 rs11594656 OR=1.30 for T/G, 1.84 for T/T 6 x 10-8 Vella et al., 2005 IFIH1, 2q24.3 A946T (A,60%) RR 1.17 for A 2 x 10-11 Todd et al., 2007 KIAA0350, 16p13 rs2903692 (G, 62%) OR=1.33 for G 7 x 10-11 Hokanarson; WTCCC; Todd 2007 C12orf30, 12q24 rs17696736, (G, 42%) OR 1.22 6 x 10-18 WTCCC; Todd 2007 ERBB3, 12q13 rs2292239 (C, 34%) OR 1.28 2 x 10-20 WTCCC;Todd 2007 PTPN2, 18p11 rs2542151 (C, 16%) OR 1.30 1 x 10-14 WTCCC;Todd 2007 NRP1, 10p11 rs2666236 (A, 41%) OR 1.76 7 x 10-8 WTCCC;Todd 2007 HLA-A, 6p21 HLA-A24 (8%) OR 1.54 2x10-10 Nejentsev 2007 HLA-B, 6p21 HLA-B39 (3%) OR 1.92 4x10-7 Nejentsev 2007 CD226, 18q22 rs763361 (46%) OR 1.16 1 x 10-8 Todd et al., 2007

  21. 19 T1D susceptibility loci (~ P<10-7) Locus, chr Risk allele (freq) Effect size P value Reference IL-2/IL-21, 4q27 G>A (30.8% and 30.1%) RR=1.26 and 1.17 1.9x10-8 Cooper et al, 2008 BACH2, 6q15 C>G (46.5%) RR=1.13 5 x 10-12 Cooper et al, 2008 PRKCQ, 10p15 A>G (18.7%) RR=0.91 4 x 10-9 Cooper et al, 2008 CTSH, 15q24 T>C (31.8%) RR=0.86 3 x 10-15 Cooper et al, 2008 CT1QTNF6, 22q13 C>T (42.7%) OR=1.04 2 x 10-8 Cooper et al, 2008

  22. 19 T1D susceptibility loci (~ P<10-7) Locus, chr Risk allele (freq) Effect size P value Other disease HLA-DRB1 – DQB1, 6p21 DR3/DR4 (28%) RR=3 for DR3 or DR4 RR=11 for DR3/4 <10-200 Celiac disease INS, 11p15 23HphI (A,80%) RR=4.5 for A/A 5 x 10-8 CTLA4, 2q33 JO30 (G,51%) RR=1.18 for G 8 x 10-11 Celiac disease PTPN22, 1p13 Arg620Trp (T, 10%) RR=1.67 for T 10-40 Grave’s, RA, LEAD IL2RA (CD25), 10p15-14 ss5258010 rs11594656 OR=1.30 for T/G, 1.84 for T/T 6 x 10-8 Grave’s disease, RA IFIH1, 2q24.3 A946T (A,60%) RR 1.17 for A 2 x 10-11 KIAA0350, 16p13 rs2903692 (G, 62%) OR=1.33 for G 7 x 10-11 C12orf30, 12q24 rs17696736, (G, 42%) OR 1.22 6 x 10-18 Crohn’s, RA, CD ERBB3, 12q13 rs2292239 (C, 34%) OR 1.28 2 x 10-20 PTPN2, 18p11 rs2542151 (C, 16%) OR 1.30 1 x 10-14 Crohn’s, Grave’s NRP1, 10p11 rs2666236 (A, 41%) OR 1.76 7 x 10-8 HLA-A, 6p21 HLA-A24 (8%) OR 1.54 2 x 10-10 HLA-B, 6p21 HLA-B39 (3%) OR 1.92 4 x 10-7 CD226, 18q22 rs763361 (46%) OR 1.16 1 x 10-8 Grave’s disease

  23. 19 T1D susceptibility loci (~ P<10-7) Locus, chr Risk allele (freq) Effect size P value Other disease IL-2/IL-21, 4q27 G>A (30.8% and 30.1%) RR=1.26 and 1.17 1.9x10-8 BACH2, 6q15 C>G (46.5%) RR=1.13 5 x 10-12 PRKCQ, 10p15 A>G (18.7%) RR=0.91 4 x 10-9 Celiac disease CTSH, 15q24 T>C (31.8%) RR=0.86 3 x 10-15 CT1QTNF6, 22q13 C>T (42.7%) OR=1.04 2 x 10-8

  24. GWA Meta-analysis Nov 2008 HLA class II INS CD25 (IL2Ra) KIAA0350 16p13 CD25 (IL2Ra) IL2-IL21 4q27 BACH2 6q15 C1QTNF6 22q13 ERBB3 12q13 PTPN22 PTPN11 12q24 PTPN2 18p11 CTLA4 IFIH1 CTSH 15q24 PRKCQ 10p15 Odds ratios for the susceptibility allele for independent T1D-associated genes or regions 7 6.5 6 2.5 2 1.5 1 Odds ratio for the T1D susceptibility allele

  25. MHC class II association with type 1 diabetes

  26. MHC class II-linked susceptibility and resistance to IDDM - Inherited as dominant traits with incomplete penetrance - In humans, MHC association predominantly determined by polymorphism at the HLA DQB1 locus(highest risk haplotypic combination DRB1*04-DQB1*302/DRB1*03- DQB1*0201 carries a ~5% absolute risk of T1D) - Alleles encoding DQb chains with Ser, Ala, or Val at position 57 provide susceptibility, while those with Asp provide resistance

  27. IDDM2/INS HUMTHO1 INS IGF2 VNTR Chr 11p15 region Promoter Exon 1 Exon 2 Exon 3 UTR IDDM2: QTL resulting from allelic variation and complex parental and epigenetic effects at the VNTR locus Class I alleles: 30-60 repeats; homozygosity associated low intrathymic expression and increased IDDM risk (Vafiadis et al.; Pugliese et al.) Class III alleles: 120-170 repeats; homozygosity associated high intrathymic expression and decreased IDDM risk

  28. Association of CTLA4 with susceptibility to autoimmune diseases Polymorphisms of CTLA4 associated with Grave’s disease, autoimmune hypothyroidism, type 1 diabetes in humans (IDDM12) and NOD mice (idd5.1) In humans, disease susceptibility maps to a non-coding region and is associated with lower transcript levels of soluble CTLA4 In mice, disease susceptibility maps to an exon 2 SNP and is associated with decreased levels of a ligand independent isoform of CTLA4

  29. proline-rich region phosphatase domain N C PTPN22 P1 P2 PTPN22 • - non receptor protein-tyrosine phosphatase expressed in hematopoietic cells • - negative regulator of T cell activation • - interacts through its proline-rich sequence termed P1 with the SH3 domain of p50csk • - PTPN22/p50csk cooperation inhibits Ag-receptor-mediated • signal transduction in T cells

  30. PTPN22 and human autoimmune diseases A functional variant of PTPN22 is associated with T1D, RA, SLE, thyroid autoimmunity but not with MS, IBD. This functional variant has a 90% decreased affinity for p50csk This altered interaction of PTPN22 with p50csk could decrease the activation threshold of autoreactive T cells but initial functional analyses do not support this model

  31. IL-2 signaling pathway and T1D Allelic variation of the IL-2 gene is associated with T1D in the spontaneously diabetic NOD mouse Allelic variation of the IL-2 R alpha chain is associated with human T1D Null mutations of murine IL-2 and CD25 are associated with multi-organ inflammation due to impaired postthymic homeostasis of Tregs Allelic variation of the IL-2 gene in NOD mice contributes to T1D pathogenesis through altered development and function of Tregs Whether allelic variation of CD25 contributes to human T1D through altered function/development of Tregs remains to be determined

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