Age dependent type 1 diabetes pathogenesis
Ake Lernmark
From Joerg Ermann & C. Garrison Fathman Nature Immunology 2, 759 - 761 (2001)
Insulitis
Residual -cell function in new onset Type 1 diabetes
Age (years) 0-15 15-34
rhw 5/99
C-peptide level within normal range At diagnosis One year Two years 20% 60% 10% 55% <5% 46%
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. v The risk of DQ2/8 heterozygotes decreases with increasing age. v The protection of DQ6.2 is attenuated by increasing age and is lost at about 35 years of age. v Class I - INS VNTR -short tandem repeats - increase the risk by about 2-5 %.
v CTLA-4 - long AT-repeats at the 5’ end UTR - increase the risk by about 2-3%.
ENVIRONMENTAL FACTORS
* MONOZYGOTIC TWINS 20-30% CONCORDANCE. ** ONLY 10-15% OF NEW PATIENTS HAVE A PARENT OR SIBLING WITH THE DISEASE. VIRUS: MUMPS,COXSACKIE, RUBELLA, ECHO, ROTA, LJUNGAN AND OTHERS. FOOD ITEMS: NITROSAMINES, MILK PROTEINS
GESTATIONAL INFECTIONS AND ABO INCOMPATIBILITY
VIRUS AND TYPE 1 DIABETES
Coxsackie Rubella Mumps Cytomegalovirus Rotavirus Human, mice (Yoon) Human, hamster Human Human 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 hyperbilirubinemia
Autoantibody Controls ABO immunization Hyperbilirubinemia IA-2Ab GAD65Ab ICA 1,4% (4/288) 1,6% (5/320) 0,6% (2/320) 6,6% (10/151)* 2,6% (4/151) 4,0% (6/151)** 1,6% (5/311) 1,3% (4/311) 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 specificity of autoantibodies for Type 1 diabetes
Autoantigen Insulin GAD65 IA-2
rhw12/98
Sensitivity 40-70% 70-80% 50-70%
Specificity 99% 99% 99%
GENETIC EFFECTS ON AGE-DEPENDENT ONSET AND ISLET CELL ANTIBODIES IN TYPE 1 DIABETES.
R
PATIENTS: INCIDENT, 0-34 YEARS OF AGE n=971 CONTROLS: MATCHED FOR AGE AND GENDER n=702 HLA, INS VNTR AND CTLA-4 GAD65A, IA-2A, IAA AND ICA
R
R R
R
LOGISTIC REGRESSION TO MODEL THE NATURAL LOGARITHM OF THE ODDS
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
RISK FOR TYPE 1 DIABETES AS FUNCTION OF AGE, GENDER, HLA, AND IA-2Ab.
THE ODDS FOR TYPE 1 DIABETES WITH IA-2Ab AT 5 YEARS OF AGE IS 11 TIMES THAT AT 34 YEARS OF AGE. THE ODDS FOR EACH ADDITIONAL DQ8: 1.5 TIMES FOR ONE DQ8 3.0 TIMES FOR TWO DQ8 THE ODDS OF EACH ADDITIONAL DQ2: DECREASES 0.27 TIMES FOR ONE DQ2 0.6 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 IAA AT 5 YEARS OF AGE IS 10 TIMES THAT AT 34 YEARS OF AGE. THE ODDS FOR EACH ADDITIONAL DQ8: 1.4 TIMES FOR ONE DQ8 2.1 TIMES FOR TWO DQ8 THE ODDS OF EACH ADDITIONAL INS VNTR CLASS I ALLELE: 1.5 TIMES FOR ONE CLASS I 2.2 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 ON GAD65Ab IAA - INS VNTR CONTRIBUTES IA-2Ab
* USEFUL INFORMATION FOR PREDICTION?
COMBINATIONS OF ISLET CELL AUTOANTIBODIES PREDICT TYPE 1 DIABETES
Click for larger picture
WHAT ABOUT CHILDREN AND TEENAGERS?
* WASHINGTON PREDICTION STUDY:
> 4 500 14 year olds were screened Follow 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 antibodies DIPP (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
Reijonen et al Diabetes 2001
• GAD65Ab positive sera from new onset children at various end-point titers
GAD65Ab ENHANCE ANTIGEN PRESENTATION
622 673 591 686 652 708 613 826 898 853 1306
622 673 591 686 652 708 613 826 898 853 1 306
0 .0 0,0
IL-2 concentration(U/ml)
2 .5 5 .0 1 2 .5 0.00 2,5 -2 co5,0 tratio7n.5(U /m10,0 12,5 0,0 7,5 l) 1 0 .0 IL n cen
GAD65 antibody index
0.25 1.00 0,25 G A D 06.50a n tib0,75d e x 1,0 0,5 o d0.7 5in 5 y
1.2 5 1,25
ANTIBODY-MEDIATED POTENTIATION OF ANTIGEN-PRESENTATION.
• GAD65Ab mediated • Preservation of potentiation of conformation antigen presentation dependent GAD65Ab may explain: after diagnosis when beta cells are gone. • Preservation of conformation • Acceleration of beta dependent GAD65Ab cell destruction by before diagnosis. 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 ON GAD65Ab IAA INS VNTR CONTRIBUTE IA-2Ab. * CHRONIC BETA-CELL AUTOIMMUNITY MAY BE MAINTAINED BY AUTOANTIBODY-FACILITATED T CELL RESPONSES.
Acknowledgement
• • • • CHRISTIANE HAMPE LUO DONG TERRI DANIELS LISA HAMMERLE
• JINKO GRAHAM • NORMAN BRESLOW • HELENA REIJONEN • GERALD T NEPOM • SWEDISH DIABETES REGISTRIES FOR CHILDREN AND ADULTS
• STEN-A. IVARSSON • CORRADO CILIO