Type 1 diabetes

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Age dependent type 1 diabetes pathogenesis
Ake Lernmark
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From Joerg Ermann C. Garrison Fathman Nature
Immunology 2, 759 - 761 (2001)
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Insulitis
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Type 1 diabetes genes
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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.
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Class I - INS VNTR -short tandem repeats -
increase the risk by about 2-5 .
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CTLA-4 - long AT-repeats at the 5 end UTR -
increase the risk by about 2-3.
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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
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VIRUS AND TYPE 1 DIABETES
Coxsackie Human, mice (Yoon) Rubella Human,
hamster Mumps Human Cytomegalovirus Human Ro
tavirus Human CBV4 T cell activation (Vbeta
analysis) T1DMcontrols
(Varela-Calvino et al. 2001) CBV4 T cell
proliferation T1DM gt 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)
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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 p0.007 p0.015
p0.003. All samples are cord blood.
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GENETIC EFFECTS ON AGE-DEPENDENT ONSET AND ISLET
CELL ANTIBODIES IN TYPE 1 DIABETES.
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PATIENTS INCIDENT, 0-34 YEARS OF AGE
n971
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CONTROLS MATCHED FOR AGE AND GENDER n702
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HLA, INS VNTR AND CTLA-4
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GAD65A, IA-2A, IAA AND ICA
LOGISTIC REGRESSION TO MODEL THE
NATURAL LOGARITHM OF THE ODDS
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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
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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 0.2
7 TIMES FOR ONE DQ2 0.6 TIMES FOR TWO DQ2
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Insulin autoantibodies are associated with a
combination of HLA-DQ8 and INS VNTR.
Click for larger picture
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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
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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?
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COMBINATIONS OF ISLET CELL AUTO-ANTIBODIESPREDICT
TYPE 1 DIABETES
Click for larger picture
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WHAT ABOUT CHILDREN AND TEENAGERS?
WASHINGTON PREDICTION STUDY gt 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
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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 501749-54, 2001.
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GAD65Ab modulate GAD65 antigen presentation.

• T-cell hybridomas
• DRB10401 restricted
• GAD65 peptide 274-286 dependent
• APC from DRB10401 subjects
• IL-2 release response

• GAD65Ab positive sera from new onset children at
  various end-point titers

Reijonen et al Diabetes 2001
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1,25
1,0
0,75
0,5
0,25
0,0
0,0
2,5
5,0
7,5
10,0
12,5
GAD65 antibody index
IL-2 concentration(U/ml)
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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.

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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.
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Acknowledgement

• JINKO GRAHAM
• NORMAN BRESLOW
• HELENA REIJONEN
• GERALD T NEPOM
• SWEDISH DIABETES REGISTRIES FOR CHILDREN AND
  ADULTS

• CHRISTIANE HAMPE
• LUO DONG
• TERRI DANIELS
• LISA HAMMERLE
• STEN-A. IVARSSON
• CORRADO CILIO