Recent advances in adrenal autoimmunity

Abstract

Autoimmune Addison's disease (AAD) results from the immune-mediated destruction of adrenocortical cells. AAD is a major component of the autoimmune polyendocrine syndromes type 1 (APS 1) and type 2. The adrenal autoimmune process is made evident by the apperance of circulating autoantibodies against the steroidogenic enzyme 21-hydroxylase. Detection of 21-hydroxylase in patients with endocrine autoimmune diseases enables the identification of subjects with preclinical AAD. An impaired response to a corticotrophin stimulation test marks the irreversible stage of preclinical AAD and predicts progression towards clinical AAD in over 80% of cases. APS 1 is caused by mutations of the autoimmune regulator (AIRE) gene, which encodes an activator of transcription, Aire, that induces the expression of autoantigens in thymic medullary epithelial cells and promotes immunological tolerance. Isolated and APS 2-related AAD is an autoimmune disease with evidence for complex genetic susceptibility caused by T-cell-mediated destruction of adrenocortical cells, with a major contribution of HLA genes. The target cells in the adrenal cortex participate in the immune reaction by releasing chemokines, such as CXCL-10, that attract Th1 cells.

Autoantibody responses in autoimmune ovarian insufficiency and in Addison's disease are IgG1 dominated and suggest a predominant, but not exclusive, Th1 type of response

“…Both AAD and SCA-POI are considered as the result of an autoimmune, T-cell-mediated destructive inflammation with imbalance of the Th1/Th2 immune responses (3,9). Although the Th1 paradigm has been challenged for human organ-specific autoimmune diseases by some studies (29), and direct measurement of Th1 and Th2 cytokines in the serum has not shown any significant difference between patients with autoimmune endocrinopathies and healthy subjects (30), the prevalent selection of steroidogenic enzyme autoantibodies of the IgG1 subclass is in line with the hypothesis of an antigen-driven, T-cell-dependent type of antibody response, and implies a Th1 profile (31,32).…”

“…Several lines of evidence support the idea that SCAs have no direct pathogenetic role. First, 21OHAbs are detected in w0.5-1.0% of healthy subjects who do not necessarily progress toward overt adrenal insufficiency (7,9). Secondly, the transplacental crossing of adrenal autoantibodies in a mother with AAD does not determine any sign of preclinical or clinical adrenal insufficiency in the newborn (34).…”

“…AAD results from the autoimmune destruction of the adrenal cortex, and is characterized by the appearance of circulating 21OHAb (9). Genetic predisposition for AAD is modulated by polymorphisms of genes influencing the function of the immune system, such as HLA class II genes, CTLA4, CIITA, PTPN22, and others (10).…”

“…The autoimmune destruction of ovarian theca cells and adrenal cortex is thought to be a T-cell-mediated process (3,9), but the molecular targets of autoreactive T-cells are not yet known. The characterization of the autoantibody isotype may provide indirect information on the immune pathways responsible for the ovarian and adrenal damage.…”

Measuring adrenal autoantibody response: Interlaboratory concordance in the first international serum exchange for the determination of 21-hydroxylase autoantibodies

“…The primitive adrenocortical deficit has an heterogeneous etiopathogenesis and may develop through several distinct mechanisms, including autoimmunity, infiltrative adrenalitis, adrenoleukodystrophy (ALD), genetic disorders, metastasis, adrenal hemorrhage, surgery, sepsis, infections or toxic agents [3,4]. Autoimmune Addison's Disease (AAD) is caused by an autoimmune process responsible for the selective destruction of adrenal cortex cells [5,6]. Although AAD is the result of a T-cell mediated process, adrenal autoimmunity is made evident by the appearance of circulating adrenal cortex autoantibodies (ACA), that represent the best immune marker to identify patients with AAD [5,6].…”