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)
rhw 5/99
C-peptide level within normal range
At diagnosis One year
Two years
0-15
20%
10%
<5%
15-34
60%
55%
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
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 specificity
of autoantibodies for Type 1 diabetes
Autoantigen
rhw12/98
Sensitivity
Specificity
Insulin
40-70%
99%
GAD65
70-80%
99%
IA-2
50-70%
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
R
CONTROLS: MATCHED FOR AGE AND GENDER
n=702
R
HLA, INS VNTR AND CTLA-4
R
GAD65A, IA-2A, IAA AND ICA
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
622
673
673
591
591
686
686
652
652
708
708
613
613
826
826
898
898
853
853
1306
1 306
0 .0
0,0
2 .5
5 .0
7 .5
1 0 .0
1 2 .5
0.00
2,5
5,0
7,5
10,0
12,5
0,0
IL -2 co n cen tratio n (U /m l)
IL-2 concentration(U/ml)
0.25
0 .50
0.7 5
1.00
0,25
0,5
0,75
1,0
G A D 6 5 a n tib o d y in d e x
GAD65 antibody index
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
• STEN-A. IVARSSON
• CORRADO CILIO
• JINKO GRAHAM
• NORMAN BRESLOW
• HELENA REIJONEN
• GERALD T NEPOM
• SWEDISH DIABETES
REGISTRIES FOR
CHILDREN AND
ADULTS