Autoantibodies to steroidogenic enzymes in autoimmune polyglandular syndrome, Addison's disease, and premature ovarian failure.

Abstract

Autoantibodies to steroidogenic enzymes, steroid 17 alpha-hydroxylase (17 alpha-OH), cytochrome P450 side-chain cleavage enzyme (P450scc), and steroid 21-hydroxylase (21-OH), were measured using specific and sensitive immunoprecipitation assays (IPAs) in patients with various forms of autoimmune adrenal disease. Autoantibodies to 17 alpha-OH were detected in 6 of 11 (55%) patients with autoimmune polyglandular syndrome (APS) type I, 8 of 24 (33%) patients with APS type II, 11 of 56 (20%) patients with adrenal cortex antibody (ACA; measured by immunofluorescence)-positive patients without Addison's disease, and only 3 of 64 (5%) patients with Addison's disease. Autoantibodies to P450scc were found at a prevalence similar to those to 17 alpha-OH: in 5 of 11 (45%) APS type I patients, 10 of 24 (42%) APS type II patients, 11 of 56 (20%) ACA-positive patients without Addison's disease, and only 6 of 64 (9%) patients of the Addison disease group. Autoantibodies to 21-OH were found in a majority of patients with APS type I (7 of 11;64%), APS type II (23 of 24; 96%), Addison's disease (41 of 64; 64%), and ACA-positive patients without Addison's disease (48 of 56; 86%). All sera that were positive for 17 alpha-OH or P450scc were also positive for 21-OH autoantibodies, except in 1 case. There was good agreement between the presence of ACA measured by immunofluorescence and 21-OH antibodies measured by IPA in all patient groups studied, and this indicates that 21-OH is a major autoantigen in adrenal autoimmune disease regardless of whether the disease presents as isolated Addison's disease or APS type I or type II. Autoantibodies to 17 alpha-OH and P450scc appeared to be the major components of the steroid-producing cell antibodies measured by immunofluorescence. No autoantibodies to 21-OH, 17 alpha-OH, or P450scc were detected in 17 sera from patients with premature ovarian failure without evidence of adrenal autoimmunity (as judged by immunofluorescence studies), except for 1 serum in which low levels of 17 alpha-OH antibodies were found. Overall, our studies indicate that 35S-labeled 17 alpha-OH, P450scc, and 21-OH can be used successfully in IPAs for their respective autoantibodies. Assays such as these may well be valuable in the immunological assessment of patients at risk for or suspected of adrenal autoimmunity.

Adrenal and ovarian autoimmunity

“…There were, however, some discrepancies in the different studies regarding the reactivity and the prevalence of autoantibodies to 17a-OH and P450scc in patients with PGAD type 1, type 2 or isolated AAD (52,53,55,57,58,61). The reasons for these differences could be related, at least in part, to the sources of autoantigens used to detect autoantibodies (62).…”

“…Reports on identification of 21-OH as a major adrenal autoantigen were confirmed by studies in several laboratories using different methods, including Western blotting or immunoprecipitation analyses based on native or recombinant 21-OH expressed in bacteria, yeast, mammalian cells or in vitro transcription/translation system (54-57). In addition, recent studies have shown that 21-OH is the major adrenal autoantigen in AAD irrespective of whether the disease presents as isolated AAD or PGAD type 1 or type 2 or in ACA-positive patients without overt AAD (58,59). Furthermore, a good agreement between the results of ACA (measured by indirect immunofluorescence) and 21-OH autoantibodies (Abs) indicates that 21-OH Abs are the major component of the ACA (56)(57)(58)(59)(60).…”

“…In addition, recent studies have shown that 21-OH is the major adrenal autoantigen in AAD irrespective of whether the disease presents as isolated AAD or PGAD type 1 or type 2 or in ACA-positive patients without overt AAD (58,59). Furthermore, a good agreement between the results of ACA (measured by indirect immunofluorescence) and 21-OH autoantibodies (Abs) indicates that 21-OH Abs are the major component of the ACA (56)(57)(58)(59)(60). Consequently, 21-OH/ ACA have been shown to be markers of progression towards overt AAD in ACA-positive adults and children as described above (31)(32).…”

Ovarian autoimmune disease: clinical concepts and animal models

“…In addition to autoantibodies to CYP21A2, autoantibodies to two other steroidogenic enzymes, P450 side chain cleavage (CYP11A1) and 17a-hydroxylase (CYP17), which convert cholesterol to pregnenolone, and progesterone to 17-hydroxyprogesterone, respectively, are present. 21,[25][26][27] Since these latter enzymes, unlike CYP21A2, are expressed in the ovary, the presence of these antibodies may signify the actual autoimmune targets of the ovary. Antibodies targeting P450ssc and CYP17 are termed 'steroid cell' (SC) antibodies, since in addition to binding the adrenal cortex, they bind placental syncytiotrophoblast cells, Leydig cells of the testes, and theca and luteal cells of the ovary.…”

“…Furthermore, autoantibodies against CYP11A1, CYP21A2 and CYP17 are frequently found. 25 While APS-1 is rare globally, in several populations the frequency is increased (1 : 9000 in Iranian Jews; 1 : 14 000 in Sardinians; 1 : 25 000 in Finns). APS-1 was identified as a monogenic disease caused by function-disrupting mutations in the AutoImmuneREgulator gene (AIRE).…”