IA-2 antibody isotypes and epitope specificity during the prediabetic process in children with HLA-conferred susceptibility to type I diabetes.
The natural history of preclinical diabetes is partly characterized, but there is still limited information on the dynamics of the immune response to beta-cell autoantigens during the course of preclinical disease. The aim of this work was to assess the maturation of the humoral immune response to the protein tyrosine phosphatase(PTP)-related proteins (IA-2 and IA-2beta) in preclinical type I diabetes (TID). Forty-five children participating in the Finnish Type I Diabetes Prediction and Prevention (DIPP) Study who had seroconverted to IA-2 antibody positivity were analysed. Specific radiobinding assays were used to determine IA-2/IA-2beta epitope-specific antibodies (the juxtamembrane (JM) region of IA-2, PTP-like domain and betaPTP-like domain) and isotype-specific IA-2 antibodies. Individual areas under the curve (AUC) over the observation period were calculated for total IA-2 antibodies, each isotype and specific epitope responses. The children who progressed to TID tended to have an initial IA-2 JM epitope response more frequently (P = 0.06), and this response was more often dominant during the observation period (P < 0.05). The children who did not progress to TID had IgE-IA-2 more frequently (70%; versus progressors 27%; P < 0.05), and had higher integrated titres of IgE-IA-2 antibodies (P < 0.05). The occurrence of IgE-IA-2 antibodies was protective even when combined with positivity for IA-2 JM antibodies (P = 0.002). IgE-IA-2 antibody reactivity may be a marker of a regulatory immune response providing protection against or delaying progression to TID among IA-2 antibody-positive young children with HLA-conferred disease susceptibility.
Hoppu
S
S
Paediatric Research Centre, Medical School, University of Tampere and Department of Paediatrics, Tampere University Hospital, Tampere, Finland.
Härkönen
T
T
Ronkainen
M S
MS
Simell
S
S
Hekkala
A
A
Toivonen
A
A
Ilonen
J
J
Simell
O
O
Knip
M
M
D001323:Autoantibodies / Q000276:immunology*; D002675:Child, Preschool; D003429:Cross Reactions / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D005260:Female; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007132:Immunoglobulin Isotypes / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000276:immunology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000276:immunology; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D013997:Time Factors
D001323:Autoantibodies; D000939:Epitopes; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; C096322:ICA512 autoantibody; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D007075:Immunoglobulin M; D008565:Membrane Proteins; C102889:PTPRN2 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8