Human leukocyte antigen (DQ2/DQ8) and 21-hydroxylase antibodies determine the thyroid peroxidase antibody status of patients in autoimmune Addison's disease

Abstract

Autoimmune Addison's disease (AAD) results from the destruction of adrenal cells by an immune mediated inflammatory process. Autoantibodies (Abs) against 21-hydroxylase (21OH) are diagnostic markers present in 85 – 90% of newly diagnosed patients (pts). This rare disease is of poorly understood etiology, but genetic susceptibility is conferred by human leukocyte antigen (HLA) haplotypes DQ2 and DQ8. In many pts autoimmunity is not limited to adrenal cells, but extends to other hormone systems forming the autoimmune polyglandular syndrome type 2 (APS2). The aim of this study was to test, whether specific HLA alleles in combination with the 21OHAb status were associated with thyroid autoimmunity as detected by thyroid peroxidase autoantibodies (TPOAbs) in pts with AAD. German pts with AAD (n = 194) were genotyped for HLA by PCR. In addition, the TPOAbs were measured using an enzyme-linked immunosorbent assay and 21OHAbs with an in vitro transcription/translation method. The titers of Abs were quantified and defined as positive (pos) or negative (neg) [21OHAb> 48< Index; TPOAb> 100< UI/ml]. HLA high risk (R) alleles (DQ2and/orDQ8), 21OHAbpos and TPOAbpos were present in 71%, 86% and 36% of the AAD pts, respectively (resp.). Furthermore, in order to evaluate the effect of HLA/21OHAbs status on the production of TPOAbs the pts were divided into four groups (Gr):Gr1:HLAhigh-R/21OHAbneg; Gr2:HLAhigh-R/21OHAbpos; Gr3:HLAlow-R/21OHAbneg; Gr4:HLAlow-R/21OHAbpos. While the Gr2 and Gr4 had significantly higher concentration of TPOAbs in median (44.5 and 55 UI/ml) than Gr3 (1.3 UI/ml;p = 7.4 × 10-4 and 7.4 × 10-3, resp.) no difference was observed compared to Gr1. Also a correlation was found between 21OHAbs and TPOAbs titers (rho = 0.21, p = 0.01). Both the genetic background of AAD as detected by the HLA risk alleles DQ2/DQ8 and the status of the 21OHAbs are associated with thyroid autoimmunity in APS2. This combination may be an indicator of the enhanced risk of polyglandular destruction in AAD.