Pathogenesis of autoimmune adrenal insufficiency
- Lynnette K Nieman, MD
Lynnette K Nieman, MD
- Section Editor — Adrenal Disease
- Senior Investigator
- Bethesda, MD
The most common cause of primary adrenal insufficiency is autoimmune adrenalitis. This topic will review the pathogenesis of autoimmune adrenal insufficiency, including the roles of humoral and cellular immunity and genetics. The clinical manifestations of this disorder and its association with polyglandular autoimmune syndromes are discussed separately. (See "Clinical manifestations of adrenal insufficiency in adults" and "Causes of primary adrenal insufficiency (Addison's disease)".)
Autoimmune adrenalitis is characterized by the presence of serum antibodies against the steroidogenic enzymes P450scc (CYP11A1, side-chain cleavage enzyme), P450c17 (CYP17, 17-alpha-hydroxylase), and P450c21 (CYP21A2, 21-hydroxylase) [1-3]. These enzymes are involved in the side-chain cleavage and subsequent hydroxylation of steroids (figure 1). The autoantibodies to CYP21A2 are of the IgG1 or IgG2a subclass [4,5], suggesting that T helper (Th) cells are involved in destruction of the adrenal cortex in patients with autoimmune Addison’s disease . Ample evidence demonstrates an important influence of genetic background on the development of adrenal insufficiency.
Anti-adrenal antibodies — Initial studies evaluated the ability of serum antibodies to react with primate adrenal cortex using an indirect immunofluorescence technique. Because the test detects any IgG antibodies that are bound, it is not specific for a given antigen. Thus, the results are commonly referred to as "anti-adrenal" antibodies, reflecting the non-specific nature of the test. Subsequent studies showed that the antiadrenal autoantibodies detected by immunofluorescence on tissue sections were mainly directed against CYP17 and CYP21A2 .
Antibodies to all three zones of the adrenal cortex are present in the serum of 60 to 75 percent of patients with primary adrenal insufficiency caused by autoimmune adrenalitis; in contrast, they are rarely found in patients with other causes of adrenal insufficiency, in first-degree relatives of patients with autoimmune primary adrenal insufficiency, or in normal subjects [1,8-13].
Antiadrenal antibodies are more common in women, particularly those with the polyglandular autoimmune syndrome (type 2). Patients with antibodies develop adrenal insufficiency at a rate of up to 19 percent per year [13-15]. In autoimmune polyendocrinopathy syndrome type 1, or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome, the presence of adrenal autoantibodies has a 92 percent predictive value for the development of adrenal insufficiency [14,16].
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