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Age dependent type 1 diabetes pathogenesis
Ake Lernmark
FromJoerg Ermann &
C. Garrison Fathman Nature Immunology
2, 759 - 761 (2001)
Insulitis
Residual -cell function in newonset Type 1 diabetes
Age C-peptide level within normal range
(years) At diagnosis One year Two years
0-15 20% 10% <5%
15-34 60% 55% 46%
rhw 5/99
Type 1 diabetes genes
v HLA DQ2, DQ8, or both, represents almost 90% of all type 1 diabetes patients younger than 20 years of age. The risk of DQ2/8 heterozygotes decreases with increasing age.The protection of DQ6.2 is attenuated by increasing age and is lost at about 35 years of age.
vClass I - INS VNTR -short tandem repeats - increase the risk by about 2-5 %.
v CTLA-4 - long AT-repeats at the 5’ end UTR - increasethe risk by about 2-3%.
v
v
ENVIRONMENTAL FACTORS
VIRUS: MUMPS,COXSACKIE, RUBELLA, ECHO,ROTA, LJUNGAN AND OTHERS.
FOOD ITEMS: NITROSAMINES, MILK PROTEINS
* MONOZYGOTIC TWINS 20-30% CONCORDANCE.** ONLY 10-15% OF NEW PATIENTS HAVE A
PARENT OR SIBLING WITH THE DISEASE.
GESTATIONAL INFECTIONS AND ABO INCOMPATIBILITY
VIRUS AND TYPE 1 DIABETES
Coxsackie Human, mice (Yoon)Rubella Human, hamsterMumps HumanCytomegalovirus HumanRotavirus Human
CBV4 T cell activation (Vbeta analysis): T1DM=controls (Varela-Calvino et al. 2001)
CBV4 T cell proliferation: T1DM > controls (Juhela et al 2000)CBV4-specific T-cell epitopes: T1DM = controls
(Martilla et al. 2001)No or little cross reactivity between molecular mimicry regions
(Several authors)
ABO and hyperbilirubinemiaAutoantibody Controls ABO immunization Hyperbilirubinemia
IA-2Ab 1,4% (4/288) 6,6% (10/151)* 1,6% (5/311)
GAD65Ab 1,6% (5/320) 2,6% (4/151) 1,3% (4/311)
ICA 0,6% (2/320) 4,0% (6/151)** 4,2% (13/311)***
Difference compared to controls: * p=0.007; ** p=0.015; *** p=0.003.
All samples are cord blood.
Diagnostic sensitivity and specificityof autoantibodies for Type 1 diabetes
Autoantigen Sensitivity Specificity
Insulin 40-70% 99%
GAD65 70-80% 99%
IA-2 50-70% 99%
rhw12/98
GENETIC EFFECTS ON AGE-DEPENDENT ONSET AND ISLET CELL ANTIBODIES IN TYPE 1 DIABETES.
R
R
R
R
R
PATIENTS: INCIDENT, 0-34 YEARS OF AGE n=971
CONTROLS: MATCHED FOR AGE AND GENDERn=702
HLA, INS VNTR AND CTLA-4
GAD65A, IA-2A, IAA AND ICA
LOGISTIC REGRESSION TO MODEL THE NATURALLOGARITHM OF THE ODDS
0 10 20 30
B0 DQ8, Males
0.8
0.6
0.4
0.2
0 10 20 30
A0 DQ8, Females
0 DQ2
0 DQ2
Age at clinical onset (years)
0 10 20 30
B0 DQ8, Males
0.8
0.6
0.4
0.2
0 10 20 30
A0 DQ8, Females
0 DQ2
1 DQ2
0 DQ2
1 DQ2
Age at clinical onset (years)
0 10 20 30
B0 DQ8, Males
0.8
0.6
0.4
0.2
0 10 20 30
A0 DQ8, Females
0 DQ2
1 DQ2
2 DQ2
0 DQ2
1 DQ2
2 DQ2
Age at clinical onset (years)
RISK FOR TYPE 1 DIABETES AS FUNCTION
OF AGE, GENDER, HLA AND GAD65A. THE ODDS TO DEVELOP TYPE 1 DIABETES:
A FEMALE WITH GAD65Ab HAS 3 TIMES THE RISK OF A MALE.
COMPARED TO A FIVE YEAR OLD WITH GAD65Ab BUT NO DQ2: 3 TIMES HIGHER RISK WITH ONE DQ2 8 TIMES HIGHER RISK WITH TWO DQ2
DQ2 DOES NOT AFFECT THE RISK FOR A GAD65AB POSITIVE 34 YEAR OLD
0.8
0.6
0.4
0.2
0.00 10 20 30 0 10 20 30
A B0 DQ8, Females
0 DQ2 0 DQ2
0 DQ8, Males
Age at clinical onset (years)
0.8
0.6
0.4
0.2
0.00 10 20 30 0 10 20 30
A B0 DQ8, Females
0 DQ2
1
0 DQ2
1
0 DQ8, Males
Age at clinical onset (years)
0.8
0.6
0.4
0.2
0.00 10 20 30 0 10 20 30
A B0 DQ8, Females
0 DQ2
1
2
0 DQ2
1
2
0 DQ8, Males
Age at clinical onset (years)
RISK FOR TYPE 1 DIABETES AS FUNCTION OF AGE, GENDER, HLA, AND IA-2Ab.
THE ODDS FOR TYPE 1 DIABETES WITH IA-2AbAT 5 YEARS OF AGE IS 11 TIMES THAT AT34 YEARS OF AGE.
THE ODDS FOR EACH ADDITIONAL DQ8:1.5 TIMES FOR ONE DQ83.0 TIMES FOR TWO DQ8
THE ODDS OF EACH ADDITIONAL DQ2:DECREASES0.27 TIMES FOR ONE DQ20.6 TIMES FOR TWO DQ2
Insulin autoantibodies are associated with a combination of HLA-DQ8 and INS VNTR.
Click for larger picture
RISK FOR TYPE 1 DIABETES AS FUNCTION OF AGE, GENDER, HLA, INS VNTR AND IAA.
THE ODDS FOR TYPE 1 DIABETES WITH IAAAT 5 YEARS OF AGE IS 10 TIMES THAT AT34 YEARS OF AGE.
THE ODDS FOR EACH ADDITIONAL DQ8:1.4 TIMES FOR ONE DQ82.1 TIMES FOR TWO DQ8
THE ODDS OF EACH ADDITIONAL INS VNTRCLASS I ALLELE:
1.5 TIMES FOR ONE CLASS I2.2 TIMES FOR TWO CLASS I
SUMMARY, SO FAR……...
* MULTIPLE ENVIRONMENTAL FACTORS. *GESTATIONAL EFFECTS.
* HLA HAS THE MAJOR GENETIC EFFECT - INS VNTR AND OTHER GENETIC FACTORS CONTRIBUTE.
* AGE-DEPENDENT EFFECTS OF HLA AND ONGAD65AbIAA - INS VNTR CONTRIBUTESIA-2Ab
* USEFUL INFORMATION FOR PREDICTION?
COMBINATIONS OF ISLET CELL
AUTO-ANTIBODIES
PREDICT
TYPE 1 DIABETES
0
20
40
60
80
100
0 2 4 6 8 10
Years of follow-up
Three autoantibodies
Two autoantibodies
One autoantibody
Click for larger picture
WHAT ABOUT CHILDREN AND TEENAGERS?
* WASHINGTON PREDICTION STUDY:> 4 500 14 year olds were screenedFollow up 9 years.All 15 children developing diabetes were predicted. No false negatives.
No false positives. Hagopian et al. Diabetes Care 2002
* SCREENING NEWBORNS: HLA and antibodiesDIPP (Finland), TRIGR (international), DAISY (Denver, CO), PANDA (Gainesville, FL),ABIS (South East Sweden), DiPiS (South Sweden)MELBOURNE NEWBORN STUDY
TYPE 1 DIABETES IS A T-CELL MEDIATED DISEASE
* Poor antigen quality has hampered novel technologies to detect T-cells reactive with GAD65, proinsulin (PI), and IA-2.
* The second T cell IDS workshop reported GAD65 (Diamyd Medical) generated in insect cells that stimulate relevant clones and
does not inhibit third-party antigens.
* A PI preparation generated in bacteria was free of effects on proliferation to third-party antigens and low in endotoxin.
* These preparations should be useful to develop robust and sensitive assays of autoantigen-specific T cells that predict diseases.
* Peakman et al. Report of phase II of the Second International Immunology of Diabetes Society Workshop for Standardization of T-cell assays. Diabetes 50:1749-54, 2001.
GAD65Ab modulate GAD65 antigen presentation.
• T-cell hybridomas• DRB1*0401
restricted• GAD65 peptide
274-286 dependent• APC from
DRB1*0401 subjects• IL-2 release response
• GAD65Ab positive sera from new onset children at various end-point titers
Reijonen et al Diabetes 2001
GAD65Ab ENHANCE ANTIGENPRESENTATION
0 .0 2 .5 5 .0 7 .5 10 .0 12 .5
1306
853
898
826
613
708
652
686
591
673
622
IL -2 concentration (U /m l)
0.00 0.25 0 .50 0.75 1.00 1.25
1306
853
898
826
613
708
652
686
591
673
622
G A D 65 antibod y indexGAD65 antibody index
1,251,00,750,50,250,0IL-2 concentration(U/ml)
0,0 2,5 5,0 7,5 10,0 12,5
ANTIBODY-MEDIATED POTENTIATION OF ANTIGEN-PRESENTATION.
• GAD65Ab mediated potentiation of antigen presentation may explain:
• Preservation of conformation dependent GAD65Ab before diagnosis.
• Preservation of conformation dependent GAD65Ab after diagnosis when beta cells are gone.
• Acceleration of beta cell destruction by recruiting new CD4 and CD8 T cells.
SUMMARY AND CONCLUSIONS
* HLA HAS THE MAJOR EFFECT - OTHER GENETIC FACTORS SUCH AS INS VNTR AND CTLA-4 CONTRIBUTE.
* MULTIPLE ENVIRONMENTAL FACTORS. *GESTATIONAL EFFECTS.
*EARLY T CELL RESPONSES ARE KEY TO INITIATION OF BETA CELL AUTOIMMUNITY.
* AGE-DEPENDENT EFFECTS OF HLA AND ONGAD65AbIAA INS VNTR CONTRIBUTEIA-2Ab.
* CHRONIC BETA-CELL AUTOIMMUNITY MAY BE MAINTAINED BY AUTOANTIBODY-FACILITATED T CELL RESPONSES.
Acknowledgement
• CHRISTIANE HAMPE• LUO DONG• TERRI DANIELS• LISA HAMMERLE
• STEN-A. IVARSSON• CORRADO CILIO
• JINKO GRAHAM• NORMAN BRESLOW
• HELENA REIJONEN• GERALD T NEPOM
• SWEDISH DIABETES REGISTRIES FOR CHILDREN AND ADULTS