Characteristics of in‐vitro phenotypes of glutamic acid decarboxylase 65 autoantibodies in high‐titre individuals

Previous studies have indicated phenotypical differences in glutamic acid decarboxylase 65 autoantibodies (GADA) found in type 1 diabetes (T1D) patients, individuals at risk of developing T1D and stiff‐person syndrome (SPS) patients. In a Phase II trial using aluminium‐formulated GAD₆₅ (GAD‐alum) as an immunomodulator in T1D, several patients responded with high GADA titres after treatment, raising concerns as to whether GAD‐alum could induce GADA with SPS‐associated phenotypes. This study aimed to analyse GADA levels, immunoglobulin (Ig)G1–4 subclass frequencies, b78‐ and b96·11‐defined epitope distribution and GAD₆₅ enzyme activity in sera from four cohorts with very high GADA titres: T1D patients (n = 7), GAD‐alum‐treated T1D patients (n = 9), T1D high‐risk individuals (n = 6) and SPS patients (n = 12). SPS patients showed significantly higher GADA levels and inhibited the in‐vitro GAD₆₅ enzyme activity more strongly compared to the other groups. A higher binding frequency to the b78‐defined epitope was found in the SPS group compared to T1D and GAD‐alum individuals, whereas no differences were detected for the b96·11‐defined epitope. GADA IgG1–4 subclass levels did not differ between the groups, but SPS patients had higher IgG2 and lower IgG4 distribution more frequently. In conclusion, the in‐vitro GADA phenotypes from SPS patients differed from the T1D‐ and high‐risk groups, and GAD‐alum treatment did not induce SPS‐associated phenotypes. However, occasional overlap between the groups exists, and caution is indicated when drawing conclusions to health or disease status.