Autoimmunity and the adrenal cortex

The autoimmune basis for most cases of idiopathic Addison disease is very well established. Since the demonstration of antibodies reacting with the adrenal cortex, the disease has been recognized as one of the organ-specific autoimmune diseases. Steroidogenic side-chain cleavage enzymes, (P450scc), 17α-hydroxylase (P450c17), and 21 -hydroxylase (P450c21) have recently been shown to be relevant autoantigens recognized by sera from patients with Addison disease either as an isolated entity or as a component of the autoimmune polyglandular syndrome type I or type II. As in other autoimmune endocrine diseases, the eliciting event in the adrenal damage in Addison disease remains to be identified. The role of adrenal autoantibodies in the primary pathogenic response is not yet clear, but it is likely that they arise as a secondary consequence of T-cell-mediated tissue damage. In concordance with animal models, T-cell-mediated destruction seems to be a major event in pathogenesis. At present, there appears to be no common antigens shared uniquely among organs targeted by the autoimmune processes underlying the autoimmune polyglandular syndrome. Addison disease, in the context of autoimmune polyglandular syndrome type II has been associated with HLA DRB1*03 and DRB1*04. Our most recent studies indicate that Addison disease is primarily associated with the HLA DRB1*03/DQB1*0201 haplotype and only with HLA DRB1*04/DQB1*0302 when it is accompanied by pancreatic beta cell autoimmunity. Autoimmune polyglandular syndrome type I is not HLA associated. Recently, autoimmune polyglandular syndrome type I was linked to an autosomal locus located on chromosome 21 q22.3. Until the issue of genetics has been resolved, the clinician must rely entirely on the recognition of subtle symptoms and a knowledge of serum autoantibody profiles to swiftly diagnose and treat adrenal failure occurring in isolated Addison disease or autoimmune polyglandular syndrome. In this review we discuss new insights into the autoimmune basis of Addison disease including its association with other autoimmune diseases in the context of autoimmune polyglandular syndrome.