INTRODUCTION — 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, diagnosis, and treatment of adrenal insufficiency and its association with polyglandular autoimmune syndromes are discussed separately. (See "Clinical manifestations of adrenal insufficiency in adults" and "Diagnosis of adrenal insufficiency in adults" and "Treatment of adrenal insufficiency in adults" and "Causes of primary adrenal insufficiency (Addison's disease)".)
AUTOIMMUNE PRIMARY ADRENAL INSUFFICIENCY — 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 [6]. Ample evidence demonstrates an important influence of genetic background on the development of adrenal insufficiency.
HUMORAL IMMUNITY
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 nonspecific nature of the test. Subsequent studies showed that the anti-adrenal autoantibodies detected by immunofluorescence on tissue sections were mainly directed against CYP17 and CYP21A2 [7]. The clinical use of anti-adrenal antibodies is reviewed in more detail below and in a separate topic. (See 'Prediction of adrenal insufficiency' below and "Causes of primary adrenal insufficiency (Addison's disease)", section on 'Other endocrine disorders'.)
Polyglandular autoimmune syndromes — Autoimmune adrenalitis underlies most cases of isolated primary adrenal insufficiency in the developed world, as well as the adrenal insufficiency of autoimmune polyendocrinopathy syndrome type 1 (or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy [APECED]) and autoimmune polyendocrinopathy syndrome type 2. (See "Causes of primary adrenal insufficiency (Addison's disease)", section on 'Other endocrine disorders'.)
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]. (See "Causes of primary adrenal insufficiency (Addison's disease)", section on 'Autoimmune adrenalitis'.)
The incidence of anti-adrenal antibodies in serum from patients with normal adrenal function who have other autoimmune endocrine diseases is low (2 percent), with the exception of those with hypoparathyroidism (16 percent) (table 1) [11,14-17]. In three reports comprising more than 2000 children and adults, 1 to 2 percent of patients with type 1 diabetes had antibodies against 21-hydroxylase (CYP21A2) [18-20]. Given the low prevalence, routine screening of patients with type 1 diabetes for 21-hydroxylase antibodies is not indicated.
Anti-adrenal antibodies are more common in women, particularly those with the polyglandular autoimmune syndrome type 2. (See "Causes of primary adrenal insufficiency (Addison's disease)", section on 'Other endocrine disorders'.)
Prediction of adrenal insufficiency — Specific tests for antibodies against the steroidogenic enzymes P450scc (CYP11A1, side-chain cleavage enzyme), P450c17 (CYP17, 17-alpha-hydroxylase), and p450c21 (CYP21A2, 21-hydroxylase) have been developed (figure 1) [1-3].
●CYP21A2 autoantibodies are those most commonly detected in patients with APECED (13 to 14 of 15 patients) and sporadic disease (82 to 84 percent of 205 patients) based on a comparison of results from four laboratories [21]. In that study, autoantibodies against CYP11A1 or CYP17 were detected in up to 50 percent of patients with polyglandular autoimmune disorders but less than 10 percent of those with sporadic disease. In a larger study of 52 Norwegian patients with APECED, 33 of 52 had autoimmune adrenal insufficiency. Of these, antibodies to CYP21A2 were most common (92 percent), followed by CYP11A1 (63 percent) [22].
●Patients with antibodies develop adrenal insufficiency at a rate of up to 19 percent per year [13,14,23]. In APECED syndrome, the presence of adrenal autoantibodies has a 92 percent predictive value for the development of adrenal insufficiency [23,24].
In one study of 94 Norwegian APECED patients, 38 of the 40 patients (95 percent) who had adrenal insufficiency for less than five years and 6 of the 10 patients (60 percent) who had adrenal insufficiency for more than 35 years had the autoantibodies against 21-hydroxylase [25].
In a study of 90 patients from Sweden, Norway, and Germany with type 1 polyglandular autoimmune syndrome, testing of CYP21A2 alone was sufficient for the prediction of adrenal insufficiency [26].
●The presence of adrenal autoantibodies may be a stronger predictor of adrenal insufficiency in children than adults. One study evaluated 10 children with autoimmune hypoparathyroidism or diabetes mellitus who had adrenal cortex autoantibodies and antibodies to CYP21A2; nine developed adrenal insufficiency during 3 to 121 months of follow-up [27]. In contrast, another report evaluated 48 adults with an autoimmune disorder and adrenal cortex autoantibodies (44 of whom had antibodies to CYP21A2); only 21 percent developed overt adrenal insufficiency and 29 percent subclinical adrenal insufficiency in four years [28].
The same investigators reported that of 100 patients with adrenal cortex autoantibodies, the estimated cumulative risk (using a life-table analysis) of developing overt adrenal insufficiency during a mean follow-up period of six years was 100 percent in children and 32 percent in adults [29].
Other antibodies — Antibodies against other organs and endocrine glands and cytokines are common in patients with autoimmune adrenal insufficiency (regardless of the cause) but rare in normal subjects (table 2) [8,10,11,15,30]. The presence of these antibodies correlates with clinical features.
In patients with isolated autoimmune adrenal insufficiency and polyglandular autoimmune syndrome type 2 (see "Causes of primary adrenal insufficiency (Addison's disease)", section on 'Polyglandular autoimmune syndrome type 2'):
●Approximately 60 percent of patients have high serum antithyroid peroxidase (microsomal) antibody concentrations [31], and almost one-half of these patients have overt hypothyroidism. Many other patients have subclinical hypothyroidism (ie, high serum thyroid-stimulating hormone [TSH] and normal serum thyroxine concentrations) and are at risk for developing overt hypothyroidism [8,10,30].
●The presence of gastric parietal cell and intrinsic factor antibodies correlates with the presence of atrophic gastritis and pernicious anemia.
In patients with polyglandular autoimmune syndrome type 1 (see "Causes of primary adrenal insufficiency (Addison's disease)", section on 'Polyglandular autoimmune syndrome type 1'):
●Acquired hypoparathyroidism sometimes occurs in association with antiparathyroid gland antibodies that are directed against the calcium-sensing receptor in the parathyroid gland [32] or against NACHT leucine-rich-repeat protein 5 (NALP5)/maternal antigen that embryo requires (MATER) [22,33]. The latter is a parathyroid autoantigen also found in the ovary. (See "Etiology of hypocalcemia in adults".)
●Autoantibodies predicted gonadal failure (CYP11A1) and type 1 diabetes (tyrosine phosphatase-like protein IA-2) in a study of 90 patients [26]. In a study of 68 Finnish patients, the presence of autoantibodies against the IA-2 tyrosine phosphatase-like protein or insulin had a 67 percent predictive value for type 1 diabetes [24].
●Mucocutaneous candidiasis was associated with autoantibodies against interleukin (IL)-22 in 30 of 42 patients with this manifestation in the Norwegian study mentioned above [22]. In the same study, autoantibodies against aromatic L-amino acid decarboxylase (AADC) were present in seven of eight patients with vitiligo. Anti-tryptophan hydroxylase antibodies were associated with both intestinal dysfunction and autoimmune hepatitis.
●Anti-interferon autoantibodies, particularly to interferon omega and interferon alpha-2, are more common than the standard autoantibodies and correlate extremely well with mutated AIRE (autoimmune regulator), so they may be the diagnostic markers of choice, especially for early or atypical patients who have not developed the full polyglandular autoimmune syndrome type 1 picture [22,26,34,35].
CELLULAR IMMUNITY — The autoantibodies to CYP21A2 in patients with isolated autoimmune adrenal insufficiency or autoimmune polyglandular syndromes type 1 or 2 are of the IgG1 or IgG2a subclass, implicating a type 1 T helper (Th1) cell response [4,5]. The Th1 response is characterized by the production of interferon gamma, an antigen-specific, Th cell-driven process with cytotoxic T lymphocytes and activated macrophages mediating the destruction of the adrenal cortex. The presence of lymphocytic infiltration of the adrenal glands further supports a possible role for cellular immunity [36].
Decreased suppressor T-cell function [37] and increased numbers of circulating Ia-positive T cells [38] have been described in these patients. In addition, human adrenal homogenate inhibited the in vitro migration of leukocytes from 14 of 30 patients with idiopathic adrenal insufficiency, but only one of seven patients with tuberculous adrenal insufficiency [39]. The substrate-binding domain of 21-hydroxylase is an immunodominant T cell epitope. Peripheral blood mononuclear cells (PBMCs) proliferate and secrete interferon gamma in the presence of CYP21A2 [40] and PBMCs from patients with autoimmune adrenal insufficiency proliferate and increase interferon gamma secretion in the presence of CYP21A2 [41].
GENETICS — Autoimmune adrenal insufficiency may be familial or nonfamilial. It is somewhat less likely to be familial when it occurs alone. Approximately one-third of such patients have affected family members, as compared with approximately one-half of patients who have adrenal insufficiency as part of polyglandular autoimmune syndrome type 1 or 2 [42-45]. (See "Causes of primary adrenal insufficiency (Addison's disease)", section on 'Polyglandular autoimmune syndrome type 1' and "Causes of primary adrenal insufficiency (Addison's disease)", section on 'Polyglandular autoimmune syndrome type 2'.)
HLA associations
●Genetic susceptibility – Genetic susceptibility to autoimmune adrenal insufficiency is strongly associated with human leukocyte antigen (HLA) B8, DR3, and DR4 alleles, except when it occurs as part of polyglandular autoimmune syndrome type 1, in which no HLA association has been found [44,46,47]. Several specific HLA antigens, including DQA1*0301, DQA1*0501, DQB1*0201, DQB1*0302, DRB1*0404, and DRB1*0301, are associated with sporadic autoimmune adrenal insufficiency and polyglandular autoimmune syndrome type 2 [19,48-50]. These studies were carried out in individuals from Finland, Germany, and Italy, and race was not reported. There are insufficient data available to comment on HLA allele prevalence in Black, Asian, or Hispanic individuals with adrenal insufficiency.
Alterations in the major histocompatibility complex (MHC) class I chain-related microsatellite also confer susceptibility. In a study of 28 patients and 75 normal subjects in Italy, the combination of the HLA DRB1*03-DQA1*0501-DQB1*0201 (DR3/DQ2) haplotype and the major histocompatibility complex class I chain-related microsatellite polymorphism MIC-A5.1, both of which are located in the same region of chromosome 6, was necessary to confer increased genetic risk for Addison's disease [51]. Compared with subjects homozygous for MIC-A6, MIC-A5.1 homozygotes had a 60-fold greater risk of developing Addison's disease. The normal function of the MIC-A gene product, which is expressed mostly in epithelial cells, and the role of the MIC-A5.1 allele in the pathogenesis of Addison's disease are unknown.
DQA1*0501 is associated with adrenal insufficiency, diabetes mellitus, and Graves' disease, and an Arg52 substitution in either DQA1*0501 or DQA1*0301 is also linked strongly with adrenal insufficiency [49]. Type 1 diabetic patients with a DRB1*0404/DQ8 genotype or the heterozygous DR3-DQ2/DR4B1*0404-DQ8 genotype and circulating anti-CYP21A2 autoantibodies are at high risk for Addison's disease, while those with DRB1*0401/DQ8 or DRB1*0402/DQ8 have much less risk, even though they have anti-CYP21A2 autoantibodies [19,25]. Presence of the DQB1*0602 allele appears to protect patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) from developing type 1 diabetes, as it does in the general population, but not patients with polyglandular autoimmune syndrome type 2 [24].
These associations result from the location of the CYP21A1P (P450c21A) and CYP21A2 (P450c21B) genes, along with the tumor necrosis factor TNFB*1 gene and complement C4A and C4B genes, in the class III region between the class I and class II MHC loci on the short arm of chromosome 6 [52]. A variant in the NFATC1 gene may be associated with autoimmune adrenal insufficiency [53].
There is no HLA linkage in some families with polyglandular autoimmune syndrome type 2 [46,54]. Furthermore, chronic autoimmune thyroiditis, pernicious anemia, and premature ovarian failure, all components of polyglandular autoimmune syndrome type 2, are not closely linked to any HLA haplotypes [46,47]. These observations suggest that a gene or genes linked to certain HLA haplotypes convey susceptibility to autoimmune adrenal insufficiency and diabetes mellitus and that different non-HLA-associated genes are linked to chronic autoimmune thyroiditis and gastric autoimmune disease.
●Protective factors – Conversely, certain HLA alleles may confer protection against development of adrenal insufficiency. In one study of 118 individuals with antibodies against CYP21A2 who were positive for the HLA DR4 allele, patients with confirmed adrenal insufficiency were much less likely to carry the HLA-B15 allele (1 of 55 [2 percent]) compared with those who did not have adrenal insufficiency (24 of 63 [40 percent]). On follow-up, none of those with HLA-B15 allele progressed to adrenal insufficiency, while 25 percent of those without the HLA-B15 did progress [55].
Non-HLA genes — The gene responsible for polyglandular autoimmune syndrome type 1 is located on chromosome 21q22.3 [56]. It is termed AIRE (autoimmune regulator) and encodes a protein that is probably a transcription factor [57,58]. An Arg257 stop mutation was found in 10 of 12 Finnish APECED patients, and a Lys83Glu mutation was found in Swiss and the remaining two Finnish patients [57]. Eleven mutations were described in a nationwide study that identified 36 Norwegian patients [34].
However, the genes for CYP11A1 and CYP17, the targets for the anti-adrenal antibodies in most patients with autoimmune adrenal insufficiency, lie on chromosomes 15q23-q24 and 10q24-q25, respectively [59]. These genes are therefore not linked to HLA haplotypes or implicated in the genetic susceptibility to autoimmune adrenalitis.
Polymorphisms in the cytotoxic T lymphocyte antigen (CTLA)-4 gene (on chromosome 2q33), which have been reported to be associated with autoimmune thyroid disease, may also confer susceptibility to autoimmune adrenal insufficiency [60]. (See "Pathogenesis of Graves' disease".)
A polymorphism in the class II transactivator (CIITA) gene, MHC2TA, is positively associated with genetic risk for autoimmune Addison's disease, independently from HLA class II gene polymorphism [50]. This gene regulates HLA-D gene expression.
Normal adrenocortical cells express MHC class II molecules. Thus, inappropriate expression of these molecules is probably not involved in the pathogenesis of autoimmune adrenal insufficiency [61].
Recent work implicates a number of other gene variants, many of which are involved in T-cell function, including CYP27B1, NLRP-1, PDL-1, STAT4, and GATA3 [62-64].
SUMMARY
●Humoral immunity
•Autoimmune primary adrenal insufficiency is characterized by the presence of serum antibodies against the steroidogenic enzymes, mostly P450c21 (CYP21A2, 21-hydroxylase) and less frequently P450scc (CYP11A1, side-chain cleavage enzyme) and P450c17 (CYP17, 17-alpha-hydroxylase). Ample evidence demonstrates an important influence of genetic background on the development of adrenal insufficiency (figure 1). (See 'Autoimmune primary adrenal insufficiency' above.)
•Anti-adrenal 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. 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. (See 'Anti-adrenal antibodies' above and "Causes of primary adrenal insufficiency (Addison's disease)", section on 'Other endocrine disorders'.)
•Antibodies against other endocrine glands are common in patients with autoimmune adrenal insufficiency but rare in normal subjects. Polyglandular autoimmune syndromes are discussed separately. (See 'Other antibodies' above and "Causes of primary adrenal insufficiency (Addison's disease)", section on 'Other endocrine disorders'.)
●Genetic susceptibility
•Autoimmune adrenal insufficiency may be familial or nonfamilial. It is somewhat less likely to be familial when it occurs alone. Approximately one-third of such patients have affected family members, as compared with approximately one-half of patients who have adrenal insufficiency as part of polyglandular autoimmune syndrome type 1 or 2. (See 'Genetics' above and "Causes of primary adrenal insufficiency (Addison's disease)", section on 'Polyglandular autoimmune syndrome type 1' and "Causes of primary adrenal insufficiency (Addison's disease)", section on 'Polyglandular autoimmune syndrome type 2'.)
•Genetic susceptibility to autoimmune adrenal insufficiency is strongly associated with human leukocyte antigen (HLA) B8, DR3, and DR4 alleles, except when it occurs as part of polyglandular autoimmune syndrome type 1, in which no HLA association has been found. (See 'HLA associations' above.)
•The gene responsible for polyglandular autoimmune syndrome type 1 is located on chromosome 21q22.3. It is termed AIRE (autoimmune regulator) and encodes a protein that is probably a transcription factor. However, the genes for CYP11A1 and CYP17, the other two targets for the anti-adrenal antibodies in patients with autoimmune adrenal insufficiency, lie on chromosomes 15q23-q24 and 10q24-q25, respectively. These genes are therefore not linked to HLA haplotypes or implicated in the genetic susceptibility to autoimmune adrenalitis. (See 'Non-HLA genes' above.)
DISCLOSURE — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.
