Tidm etiopathogenesis

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Tidm etiopathogenesis

  1. 1. ETIOPATHOGENESIS OF TYPE 1 DIABETES DR. SYED MOHD RAZI
  2. 2. TYPE 1 DIABETES Juvenile onset diabetes. Insulin dependent diabetes mellitus (IDDM). “ Results from β cell destruction, ususally leading to absolute insulin deficiency.”Diabetes Care, volume 36, supplement 1, January 2013
  3. 3. ETIOLOGY OF T1DMMultifactorial Etiologies :-1. Genetics2. Autoimmunity, autoantibodies & cellular immunity.3. Environment. Cold Spring Harb Perspect Med 2012;2:a007641)
  4. 4. TYPE 1 DIABETES MELLITUSMONOGENIC : Single gene defect. APS-I: AIRE autosomal recessive XPID: Scurfy Gene X-linked
  5. 5. APS-SYNDROMES APS-I:>=2 of Candidiasis, Hypopara,Addison’s APS-II:Addison’s + Autoimmune Thyroid and/or Type 1 Diabetes. APS-III: Thyroid Autoimmune + other autoimmune [not above]. APS-IV: Two or more organ-specific autoimmune, not I,II, or III. Betterle et al. Endocrine Reviews 23:327-364Neufeld and Blizzard: 1980, Pinchera, in Symposium Autoimmune Endocrine Aspects of EndocrineDisorders
  6. 6. XPID: X-linked polyendocrinopathy, immune dysfunction and diarrheaOther NamesIPEX: Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linkedXLAAD: X-Linked Autoimmunity Allergic DysregulationFoxp3 Gene MutationLoss of Regulatory T LymphocytesBone Marrow Transplant with Chimera “Cures” Scurfy Mouse and Man Greenspans b & c endocrinology 9th edition
  7. 7. POLYGENICSummation of small effects ofmultiple genes creating diabetes susceptibility (e.g. NOD mouse)
  8. 8. ANIMAL MODELS OF T1DMPolygenic Spontaneous Animal Models : NonobeseDiabetic MouseMost intensively studied.Mutations causing absence of I-E ( similar to DR) &unsually I-A ( similar to DQ).Inheritance polygenic & more Diabetic females .T cell mediated destruction.Diabetes prevented by introduction of I-E or I-A . William’s Textbook of Endocrinology, 12thEdition
  9. 9. OLIGOGENICMHC+few major genes Genetic heterogeneity with different major non-MHC genes for different families (e.g. BB rat)
  10. 10. ANIMAL MODELS OF T1DMOligogenic Animal Models : Biobreeding Rat1st intensively studied rat model.Diabetes prone rat -> AR mutation & severe T celllymphopenia.Disease depends -> specific class II allele mutations .Anti-inflammatory drugs prevent diabetes.Long-Evans Tokushima Lean RatCbl-b mutation altering T cell functioning. William’s Textbook of Endocrinology, 12thEdition
  11. 11. GENETICS OF T1DMT1DM--- Multifactorial disease. (Noble & Erlich 2012)Risk of T1DM in general U.S. population- 1 in 300.Risk in 1degree relatives of T1DM pt. -- 1 in 20.Concordance rate in---- Monozygotic twins -30-50%. Dizygotic twins - 6-10%. Cold Spring Harb Perspect Med 2012;2:a007641)
  12. 12. GENETICS OF T1DM Cont…85% of cases occur -> pt. with no family H/O.(Hämälainen & Knip 2002).Risk in children of T1DM: mother – 2% & with T1DM father- 7% ( Redondo et al. 2001).> 50 loci identified. ( Cooper et al.2008)No single locus : Necessary or sufficient. Cold Spring Harb Perspect Med 2012;2:a007641)
  13. 13. J. Noble HLA Human Leukocyte Antigen human MHC cell-surface proteins important in self vs. nonself distinction present peptide antigens to T cellsCLASS I: A,B,C CLASS II: DR,DQ,DP
  14. 14. HUMAN LEUKOCYTE ANTIGEN(HLA) HLA (Chr6p21)  Greatest contribution (60%) Strongest association HLA II genes (Redondo et al.2001) MHC variability -> differences in β cell antigen presentation. Cold Spring Harb Perspect Med 2012;2:a007641)
  15. 15. HUMAN LEUKOCYTE ANTIGEN(HLA) HLA is named as– Gene locus name-> Asterisk-> serologic specificity -> specific allele-> silent nucleotide polymorphism. Highest risk genotype --- DRB1*0301,DQA1*0501,DQB1*0201,DRB1*0302, DQA1*0301,DQB1*0302. Protective genotypes ----DQA1*0102,DQB1*0602. William’s Textbook of Endocrinology, 12thEdition
  16. 16. STRUCTURE OF HLA GENE The Major Histocompatibility Complex Class II Class III Class IHumanChromosome 6 DP DQ DR B C A Antigen Processing Complement Cytokines Class I-like genes Genes Proteins and pseduogenes Class III Class I Class I Class II MouseChromosome 17 K I-A I-E D L
  17. 17. HLA SUSCEPTIBILITYHBDI Families: Odds Ratio 5 * * 4 *p< 0.05 vs. control Odds ratio 3 haplotype 2 1 * * * * * * 0HBDI Families: Transmission from Heterozygous Parents * * 461 389 40 51 182 82 99 20 121 55 124 27 135 34 Transmission frequency (%) 80 60 High risk Moderate risk 40 Protective 20 0 02 1 02 1 02 2 03 1 03 4 01 3 05 02 3 01 2 01 1 02 02 01 503 01 2 02 3 03 2 01 50 01 40 30 60 05 60 30 01 50 01 30 04 /0 30 01 /0 3 6 /0 /0 /0 /0 /0 /0 /0 01 01 /0 /0 /0 /0 /0 03 01
  18. 18. OTHER LOCIIDDM2 : II nd highest impact on disease development.(OR 1.5)locus located : VNTR region upstream insulin.Shorter repeats confer higher risk & vice versa. ( Pugliese et al. 1997).Other loci are – CTLA4 , PTPN22, CD25( Concannon et al.2008) Cold Spring Harb Perspect Med 2012;2:a007641)
  19. 19. NON HLA LOCI IN T1DM Cold Spring Harb Perspect Med 2012;2:a007641)
  20. 20. The IDDM2 Locus IDDM2 Insulin Gene (INS)Predisposing Class I VNTR 26-63 repeats 21 alleles IDDM2 Insulin Gene (INS)Protective Class III VNTR 140-200 repeats 15 alleles VNTR = Variable Number of Tandem Repeats
  21. 21. AUTOIMMUNITY , AUTOANTIBODIES & CELLULAR IMMUNITY Autoimmunity specific to β cells.( atkison et al.) Specific mechanisms responsible  Yet to be elucidated . ( La Torre 2010) Cellular immune response Remains controversial. ( Roep 2003) Cold Spring Harb Perspect Med 2012;2:a007641)
  22. 22. INDUCTION OF Βcell AUTOIMMUNITY1. Molecular mimicry.2. Alteration of self antigens.3.Defective MHC expression.4. Breakdown of central tolerance.5.Defective dendritic cell trafficking.6.Sensitivity to free radicals & cytokines.7.Ever elusive local viral infection.8.Defects in peripheral tolerance. Cold Spring Harb Perspect Med 2012;2:a007641)
  23. 23. AUTOANTIBODIESConsidered as surrogate marker of autoimmunity.Present long before clinically evident disease. (Ziegler 2010)Autoantibodies  “ smoke of fire” old view.Crucial role of B cells & antibodies in pathogenesis. ( Marino et al. 2011)
  24. 24. AUTOANTIBODIESAutoantibodies  0.5% general population .  3-4% relatives of T1DM pt.  70-80% of newly diagnosed pt.Autoantibodies titer & number independentpredictors.High titers, younger age, high risk HLA  Moreaccurate prediction. Cold Spring Harb Perspect Med 2012;2:a007641)
  25. 25. 10000Anti-insulin autoantibodies (nU/ml) 1000 100 10 1 5 10 15 20 25 30 35 Age (years) Insulin Autoantibodies Versus Age of Diabetes Onset Diabetes Care 11:736-739, 1988
  26. 26. AUTOANTIBODIESCombination of antibodies  Increased risk.5 yr risk with  1 antibody 20-25%  2 antibodies 50-60%. 3 antibodies 70%. 4 antibodies 80%. (winter 2011 ,DPT 1) Cold Spring Harb Perspect Med 2012;2:a007641)
  27. 27. 100 Progression to Diabetes vs Number of80 Autoantibodies60 3 Abs (GAD, ICA512, Insulin) 2 Abs 3 Ab n = 41 1 8 140 1 Ab 2 Abs n = 44 27 1520 4 2 1 0 1 Abs n = 93 23 14 10 6 4 0 2.5 5 7.5 10 12.5 15
  28. 28. AUTOANTIBODIESIAA Antibodies  measured within a week ofexogenous insulin. ( winter 2011).IAA assays  cumbersome. (Bonifacio 2010)GAD antibodies  Most predominant in LADA. (Leslie et al. 2008) ( Cold Spring Harb Perspect Med 2012;2:a007641)
  29. 29. AUOTANTIBODIES Markers of the immune destruction of the β -cell includeAb Sensitivity SpecficityGAD 65 70-90 % 99 %IAA 40-70 % 99 %Tyrosine phosphatase 50-70 % 99 %ZnT8 more auto Ab50-70 present in 85–90% of individuals 1 or are % 99 % the time of diagnosis Greenspan’s b&c endorinology 9th ed
  30. 30. T1DM RISK STRATIFICATION Cold Spring Harb Perspect Med 2012;2:a007641)
  31. 31. ENVIRONMENTDiscordance in monozygotic twins.Rise in global incidence.Variance in geographical prevalence.Assimilation of local incidence rate in migrants. (Atkinson 2001) Cold Spring Harb Perspect Med 2012;2:a007641)
  32. 32. ACCELERATOR & OVERLOAD THEORY Environmental stress Increase insulin demand β cell overloading Accelerating β cell damage (Fourlanos et al.2008) Cold Spring Harb Perspect Med 2012;2:a007641)
  33. 33. HYGIENE HYPOTHSIS“ Rising incidence of autoimmune diseases in generaldue to reduced or altered stimulation byenvironmental factor”. (Cook 2009 ) Cold Spring Harb Perspect Med 2012;2:a007641)
  34. 34. FERTILE FIELD HYPOTHESIS Microbial infection Other antigens react easily. Auto- reactive T cells. (Von Herrath et al. 2003) Cold Spring Harb Perspect Med 2012;2:a007641)
  35. 35. OLD FRIENDS HYPOTHESIS“Normal GIT commensals implicate dietary exposureas regulator of the immune system & self tolerance.” (Vaarala et al. 2008) Cold Spring Harb Perspect Med 2012;2:a007641)
  36. 36. THRESHOLD HYPOTHESISMathematical model calculating risk of T1DM. Contribution of genetics & environment as function ofinvariables subject to calculation. ( Wasserfall et al. 2011) Cold Spring Harb Perspect Med 2012;2:a007641)
  37. 37. ENVIRONMENTAL FACTORSInfectious agentsNo direct evidence.Rubella incorrectly cited evidence for this activity. (Gale 2008)Enteroviral association with the disease. ( Jaiden et al.2010)
  38. 38. ENVIRONMENTAL FACTORSIncreased risk in early weaning & exposure to cow’smilk . ( TRIGR Study Group et al. )Increased susceptibility associated with the timing ofexposure to cereal & gluten. ( DIASY, BABY- DIAB)Low Vit. D  not only association but a cause ofT1DM. ( North – South Gradient Hypothesis , Karvonen 2000)
  39. 39. Ziegler, JAMA 2003: 290:721 BabyDiab and DAISY 30Islet autoimmunity, % 25 Age introduction 20 <=3 mo. 15 >6 mo. 10 >3 to6 mo. gluten (Ziegler) or 5 cereal (Norris) greatly 0 0 2 4 6 8 increases Age (years) development of anti- islet autoantibodies in DR3/4 DQ8: Norris JAMA 290:1713 infants followed from birth. 25 Islet Autoimmunity, % 20 15 <=3 mo. 4 o 6 mo. 10 >=7 mo. 5 0 0 2 4 6 8 Age (years)
  40. 40. ENVIRONMENTAL FACTORSNitrosamine compounds  T1DM ( Kostraba et al. 1992)Maternal child blood group incompatibility.Other obstretic factors pre-ecclampsia. Neonatal respiratory distress. Low birth weight. Caesarean section. Maternal age. Birth order. Gestational age. (Mc Kinney et al. 1997) Cold Spring Harb Perspect Med 2012;2:a007641)
  41. 41. Stages:Type IA DiabetesI Genetic SusceptibilityII TriggeringIII Active AutoimmunityIV Progressive Metabolic AbnormalitiesV Overt DiabetesVI Insulin Dependence
  42. 42. 1986 NEJM “Stages” in Development of T1Diabetes (?Precipitating Event) Genetic Overt Predisposition immunologic abnormalities Progressive loss insulinBeta cell mass release Normal insulin release Overt Glucose diabetes normal C-peptide present No C-peptide Age (years)
  43. 43. PATHOGENESIS & NATURAL HISTORY OF T1DM Cold Spring Harb Perspect Med 2012;2:a007641)
  44. 44. RELAPSING & REMITTING MODEL OF T1DM
  45. 45. THANKS

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