Humoral and cellular immune responses to proinsulin in adults with newly diagnosed type 1 diabetes.
BACKGROUND
Type 1 diabetes (T1D) is an autoimmune disease characterized by immunity against pancreatic islet-derived proteins. The object of this study was to measure antibody and T-cell responses against proinsulin (PI), an islet-derived protein, and to map its dominant T-cell epitopes.


METHODS
Antibody responses to proinsulin, insulin, glutamic acid decarboxylase (GAD), protein tyrosine phosphatase IA-2 and islet-cell antigen were measured in 116 newly diagnosed diabetic subjects aged 16 to 40 years. T-cell proliferative responses to proinsulin and proinsulin peptides were measured in 33 of these diabetic subjects and in 21 healthy control subjects.


RESULTS
22% of diabetic subjects but no control subjects expressed antibodies to proinsulin. A strong correlation existed between antibody levels to proinsulin and insulin within diabetic subjects. Similar proportions of diabetic (12%) and healthy (9.5%) subjects displayed T-cell responses to proinsulin. There was no correlation between antibody and T-cell responses to proinsulin within subjects. Amino acid region 56 to 72 was identified as the major T-cell epitope of proinsulin, though significant responses to region 14 to 37 were also present.


CONCLUSIONS
Elevated proinsulin autoantibodies in diabetic subjects confirm proinsulin is an important autoantigen in type 1 diabetes. Though elevated cellular immunity to proinsulin protein was not detected, two dominant T-cell epitopes of proinsulin were identified that span the C-peptide and insulin junctions. Immunity to proinsulin was lower than that reported for childhood-onset type 1 diabetes and we propose that, like insulin, proinsulin may be targeted less frequently in adulthood.
Narendran
Parth
P
University Division of Medicine, Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom.
Williams
Alistair J
AJ
Elsegood
Kathryn
K
Leech
Nicola J
NJ
Dayan
Colin M
CM
D000293:Adolescent; D000328:Adult; D000906:Antibodies / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005968:Glutamate Decarboxylase / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D007328:Insulin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D011384:Proinsulin / Q000276:immunology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000276:immunology; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D013601:T-Lymphocytes / Q000276:immunology
D000906:Antibodies; D001323:Autoantibodies; D018984:Epitopes, T-Lymphocyte; D007328:Insulin; D010446:Peptide Fragments; C024211:islet cell antibody; D011384:Proinsulin; 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