1 / 29

Age dependent type 1 diabetes pathogenesis

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.

thimba
Download Presentation

Age dependent type 1 diabetes pathogenesis

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Age dependent type 1 diabetes pathogenesis Ake Lernmark

  2. From Joerg Ermann & C. Garrison Fathman Nature Immunology 2, 759 - 761 (2001)

  3. Insulitis

  4. 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%.

  5. 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

  6. 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)

  7. 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.

  8. 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

  9. 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

  10. 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

  11. Insulin autoantibodies are associated with a combination of HLA-DQ8 and INS VNTR. Click for larger picture

  12. 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

  13. 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?

  14. COMBINATIONS OF ISLET CELL AUTO-ANTIBODIESPREDICTTYPE 1 DIABETES Click for larger picture

  15. 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

  16. 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.

  17. 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 GAD65Ab modulate GAD65 antigen presentation. Reijonen et al Diabetes 2001

  18. 0,0 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

  19. 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.

  20. 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.

  21. 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

More Related