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Age dependent type 1 diabetes pathogenesis. Ake Lernmark. From Joerg Ermann & C. Garrison Fathman Nature Immunology 2, 759 - 761 (2001). Insulitis. 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.

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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)



Type 1 diabetes genes l.jpg
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.

v

v

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 l.jpg
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 l.jpg
VIRUS AND TYPE 1 DIABETES

Coxsackie Human, mice (Yoon)

Rubella Human, hamster

Mumps Human

Cytomegalovirus Human

Rotavirus 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 l.jpg
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.


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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

LOGISTIC REGRESSION TO MODEL THE NATURAL

LOGARITHM OF THE ODDS

R


Risk for type 1 diabetes as function of age gender hla and gad65a l.jpg
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 l.jpg
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


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Insulin autoantibodies are associated with a AND IA-2Ab.

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 l.jpg
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……... INS VNTR AND IAA.

* 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 auto antibodies predict type 1 diabetes l.jpg
COMBINATIONS OF ISLET CELL AUTO-ANTIBODIES INS VNTR AND IAA.PREDICTTYPE 1 DIABETES

Click for larger picture


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WHAT ABOUT CHILDREN AND TEENAGERS? INS VNTR AND IAA.

* 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


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TYPE 1 DIABETES IS A T-CELL MEDIATED DISEASE INS VNTR AND IAA.

* 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.


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T-cell hybridomas INS VNTR AND IAA.

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

GAD65Ab modulate GAD65 antigen presentation.

Reijonen et al Diabetes 2001


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0,0 INS VNTR AND IAA.

2,5

5,0

7,5

10,0

12,5

0,0

0,25

0,5

0,75

1,0

1,25

IL-2 concentration(U/ml)

GAD65 antibody index


Antibody mediated potentiation of antigen presentation l.jpg

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.

ANTIBODY-MEDIATED POTENTIATION OF ANTIGEN-PRESENTATION.


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SUMMARY AND CONCLUSIONS explain:

* 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 explain:

  • 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


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