Autoantibodies to protein tyrosine phosphatase-like proteins in type I diabetes. Overlapping specificities to phogrin and ICA512/IA-2.
An insulin granule membrane protein, phogrin (phosphatase homologue of granules from rat insulinoma), with homology to islet cell antigen (ICA) 512/IA-2 has recently been cloned from an insulinoma cDNA expression library with antigranule membrane sera. We have developed a radioimmunoassay for detecting antiphogrin autoantibodies using in vitro transcribed and translated phogrin and have established the sensitivity and specificity of this assay. Thirty-two of 57 (56%) new-onset patients with type I diabetes and 26 of 44 (59%) first-degree relatives followed to diabetes had anti-phogrin antibody levels exceeding the 99th percentile of 108 normal control subjects. Levels of antiphogrin autoantibodies correlated with ICA512/IA-2 autoantibodies (r = 0.82, P < 0.0001), but minimally with insulin autoantibodies (r = 0.20, P = 0.05) and not with GAD65 autoantibodies (r = 0.16, P = 0.12). Ninety-eight percent (57 of 58) of patients positive for anti-phogrin autoantibodies were also positive for autoantibodies against ICA512/IA-2. Nine percent (9 of 101) of new-onset patients and relatives followed to diabetes were ICA512/IA-2 autoantibody-positive but anti-phogrin autoantibody-negative. Preincubation of sera with recombinant ICA512/IA-2 protein completely for the majority and partially for a minority inhibited binding to in vitro translated phogrin. In three relatives in which ICA512/IA-2 autoantibodies converted to positivity with sequential follow-up, anti-phogrin autoantibodies developed at the same time. These results suggest that anti-phogrin and ICA512/IA-2 autoantibodies are related subsets of anti-islet autoantibodies.
Kawasaki
E
E
Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver 80262, USA.
Eisenbarth
G S
GS
Wasmeier
C
C
Hutton
J C
JC
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000818:Animals; D000918:Antibody Specificity; D001323:Autoantibodies / Q000097:blood*; D001324:Autoantigens; D002648:Child; D002675:Child, Preschool; D018076:DNA, Complementary; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000235:genetics / Q000276:immunology*; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology; D006801:Humans; D007223:Infant; D007340:Insulinoma; D007515:Islets of Langerhans / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000276:immunology*; D009679:Nuclear Family; D010190:Pancreatic Neoplasms; D011236:Prediabetic State / Q000097:blood / Q000235:genetics / Q000276:immunology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000276:immunology*; D051381:Rats; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D011994:Recombinant Proteins / Q000276:immunology; D012016:Reference Values; D012680:Sensitivity and Specificity
D001323:Autoantibodies; D001324:Autoantigens; D018076:DNA, Complementary; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; C516862:PTPRN protein, human; C102889:PTPRN2 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516864:Ptprn protein, rat; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase