Value of antibodies to islet protein tyrosine phosphatase-like molecule in predicting type 1 diabetes.
Islet antigens associated with type 1 diabetes include a recently identified protein tyrosine phosphatase-like molecule IA-2, which contains the intracellular fragment IA-2ic. To determine whether combinations of antibodies including those to IA-2 characterize and predict type 1 diabetes, we studied antibodies to IA-2, IA-2ic, glutamic acid decarboxylase (GAD65), and islet cell antibodies (ICAs) in 1) 60 newly diagnosed type 1 diabetic patients followed for 1 year, 2) 31 monozygotic twin pairs discordant for type 1 diabetes followed up to 12 years (11 twins developed diabetes), 3) 18 dizygotic twin pairs discordant for type 1 diabetes, and 4) normal healthy control subjects. Newly diagnosed type 1 diabetic patients frequently had antibodies to IA-2 (62%), IA-2ic (67%), GAD65 (77%), and ICAs (85%). The intracellular fragment of IA-2 probably contains the immunodominant epitope as 137 of 143 samples with IA-2 antibodies from type 1 diabetic patients also had IA-2ic antibodies. Monozygotic twins were usually discordant for antibody specificities. Concordance was higher in monozygotic than matched dizygotic twins for both antibody combinations (33 vs. 6%, P < 0.05) and the development of diabetes (33 vs. 0%, P < 0.01). In monozygotic twins, all the antibodies were highly predictive of type 1 diabetes (positive predictive values all >87%), although antibodies were also detected in twins at low risk of disease. In summary, IA-2 emerges as a major antigen associated with type 1 diabetes and distinct from GAD65. Type 1 diabetes-associated autoimmunity, which is probably induced by environmental factors, does not necessarily herald progression to the disease. However, genetic factors may influence the development of combinations of disease-associated antibodies and the progression to type 1 diabetes.
Hawa
M
M
Department of Diabetes and Metabolism, St. Bartholomew's Hospital, London, U.K.
Rowe
R
R
Lan
M S
MS
Notkins
A L
AL
Pozzilli
P
P
Christie
M R
MR
Leslie
R D
RD
D000293:Adolescent; D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000032:analysis* / Q000276:immunology; D001324:Autoantigens / Q000032:analysis / Q000276:immunology*; D015415:Biomarkers / Q000097:blood; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D005500:Follow-Up Studies; D005968:Glutamate Decarboxylase / Q000032:analysis / Q000276:immunology; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000032:analysis / Q000276:immunology*; D008875:Middle Aged; D011237:Predictive Value of Tests; D011446:Prospective Studies; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000032:analysis / Q000276:immunology*; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D014429:Twins, Dizygotic; D014430:Twins, Monozygotic
D001323:Autoantibodies; D001324:Autoantigens; D015415:Biomarkers; D008565:Membrane Proteins; C516862:PTPRN protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase