Background: Insulinoma antigen-2 (IA2) is a major self-antigen in T1D with post translational modification (PTM) of the extracellular domain (IA2ec) by deamidation eliciting T cell responses in T1D patients. Yet the autoantibodies (Abs) to these IA2ec PTM epitopes in T1D has not been studied.
Methods: IA2ec protein containing all the four T-cell responsive deamidated Q>E epitopes (aa 198-216, 467-482, 523-536 and 545-562) was produced. Sera from 269 new onset T1D children (median age= 12.6yrs) and 3age-matched healthy children were tested for Abs to IA2ecQ>E and wide type (WT) IA2ec with radiobinding assay (RBA) .
Results: The assay cut-offs were set at the 99th percentile for both IA2ecQ>E Ab and IA2ecWT Ab. In T1D children, positivity for IA2ecQ>E Ab was 60.6% (163/269) vs. IA2ecWT Ab 19.3% (52/269, P<0.0001) . In two subgroups of T1D patients who were positive (n=157) or negative (n=112) for current Abs to IA2 intra-cellular domain (IA2ic) , the positivity of IA2ecQ>E Ab were significantly higher than IA2ecWT Ab (Fig) , 58% (91/157) vs. 15.3% (24/157, P<0.0001) and 64.3% (72/112) vs. 25% (28/112, p<0.0001) . However, the positivity of IA2ec Ab did not differ between the patients with or without IA2ic Ab.
Conclusion: IA2ecQ>E Ab was detected in a large proportion of T1D patients, independent of the prototypical IA2ic Ab. IA2ecQ>E Ab is potentially a new novel predictive and diagnostic biomarker for T1D.
X.Jia: None. D.Miao: None. C.Zhang: None. A.W.Michels: Employee; ImmunoMolecular Therapeutics, Stock/Shareholder; ImmunoMolecular Therapeutics. L.Yu: None. J.M.Wenzlau: None.
National Institutes of Health (R21- AI153665) National Institutes of Health (RDK032083) Diabetes Research Center (DRC) grant P30 DK116073
