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Characterization of the humoral immune response to islet antigen 2 in children with newly diagnosed type 1 diabetes.

¹ Scientific Laboratory, Hospital for Children and Adolescents, University of Helsinki, Helsinki, Biomedicum I, PO Box 63, FI-00014 Helsinki, Finland² Immunogenetics Laboratory,, University of Turku, Turku, Finland³ Department of Clinical Microbiology,, University of Kuopio, Kuopio, Finland and ⁴ Department of Pediatrics,, Tampere University Hospital, Tampere, Finland

(Correspondence should be addressed to M Knip who is now at Hospital for Children and Adolescents, University of Helsinki, PO Box 281, FI-00029 HUCH, Helsinki, Finland; Email: mikael.knip{at}hus.fi)

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-2β 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.