Characterization of the humoral immune response to islet antigen 2 in children with newly diagnosed type 1 diabetes.
OBJECTIVE
To characterize the humoral immune response to islet antigen 2 (IA-2) in patients with newly diagnosed type 1 diabetes (T1D), we compared the profile of epitope- and isotype-specific IA-2 antibodies (IA-2A) between children with a humoral immune response restricted to IA-2 and children with a broad response including insulin autoantibodies (IAA) and antibodies to glutamic acid decarboxylase (GADA) in addition to IA-2A.


METHODS
The study subjects (n=100) were derived from a consecutive series of 1108 patients from the Finnish Pediatric Diabetes Register (investigators listed in the Appendix). Islet cell antibodies, IAA, GADA, total IA-2A levels, IA-2/IA-2beta epitopes, and isotypes were measured, and human leukocyte antigen (HLA) genotypes were analyzed.


RESULTS
There were no significant differences between the two groups in the frequency or levels of epitope-specific IA-2A. Those with an IA-2-restrictive response tested positive more frequently for IgA-IA-2A (P=0.001), had higher titers of IgE-IA-2A (P=0.025), tested positive for more IA-2A isotypes than the broad responders (P=0.04), and carried the high-risk HLA-(DR4)-DQB1*0302 haplotype more frequently than those with a broad antibody response (P=0.019).


CONCLUSIONS
These data show that children with newly diagnosed T1D, who test positive only for IA-2A out of the three molecular antibodies predictive of T1D, have a broader IA-2-specific isotype response and stronger association with the high-risk HLA haplotype than those testing positive for all three molecular antibodies. This may be indicative of a different pathogenetic mechanism in those with their humoral immune response restricted to IA-2 at the time of diagnosis.
Scientific Laboratory, Hospital for Children and Adolescents, University of Helsinki, Helsinki, Biomedicum I, PO Box 63, FI-00014 Helsinki, Finland.
Anna
A
Mäkinen
Taina
T
Härkönen
Jorma
J
Ilonen
Mikael
M
Knip
D000293:Adolescent; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D005260:Female; D005387:Finland; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000276:immunology; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007330:Insulin Antibodies / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology*; D008297:Male; D012042:Registries
D001323:Autoantibodies; D001324:Autoantigens; D006680:HLA Antigens; C096322:ICA512 autoantibody; D007330:Insulin Antibodies; C024211:islet cell antibody; D005968:Glutamate Decarboxylase