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].
- Nerup J. Addison's disease--serological studies. Acta Endocrinol (Copenh) 1974; 76:142.
- Boscaro M, Betterle C, Sonino N, et al. Early adrenal hypofunction in patients with organ-specific autoantibodies and no clinical adrenal insufficiency. J Clin Endocrinol Metab 1994; 79:452.
- Song YH, Connor EL, Muir A, et al. Autoantibody epitope mapping of the 21-hydroxylase antigen in autoimmune Addison's disease. J Clin Endocrinol Metab 1994; 78:1108.
- Chen S, Sawicka J, Prentice L, et al. Analysis of autoantibody epitopes on steroid 21-hydroxylase using a panel of monoclonal antibodies. J Clin Endocrinol Metab 1998; 83:2977.
- Brozzetti A, Marzotti S, La Torre D, et al. 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. Eur J Endocrinol 2010; 163:309.
- Bøe AS, Bredholt G, Knappskog PM, et al. Autoantibodies against 21-hydroxylase and side-chain cleavage enzyme in autoimmune Addison's disease are mainly immunoglobulin G1. Eur J Endocrinol 2004; 150:49.
- Chen S, Sawicka J, Betterle C, et al. Autoantibodies to steroidogenic enzymes in autoimmune polyglandular syndrome, Addison's disease, and premature ovarian failure. J Clin Endocrinol Metab 1996; 81:1871.
- Blizzard RM, Chee D, Davis W. The incidence of adrenal and other antibodies in the sera of patients with idiopathic adrenal insufficiency (Addison's disease). Clin Exp Immunol 1967; 2:19.
- Irvine, WJ, Barnes, EW. Addison's disease, ovarian failure and hypoparathyroidism. Clin Endocrinol Metab 1975; 4:379.
- Irvine WJ, Stewart AG, Scarth L. A clinical and immunological study of adrenocortical insufficiency (Addison's disease). Clin Exp Immunol 1967; 2:31.
- Irvine WJ, Barnes EW. Adrenocortical insufficiency. Clin Endocrinol Metab 1972; 1:549.
- Colls J, Betterle C, Volpato M, et al. Immunoprecipitation assay for autoantibodies to steroid 21-hydroxylase in autoimmune adrenal diseases. Clin Chem 1995; 41:375.
- Falorni A, Nikoshkov A, Laureti S, et al. High diagnostic accuracy for idiopathic Addison's disease with a sensitive radiobinding assay for autoantibodies against recombinant human 21-hydroxylase. J Clin Endocrinol Metab 1995; 80:2752.
- Ahonen P, Miettinen A, Perheentupa J. Adrenal and steroidal cell antibodies in patients with autoimmune polyglandular disease type I and risk of adrenocortical and ovarian failure. J Clin Endocrinol Metab 1987; 64:494.
- Betterle C, Scalici C, Presotto F, et al. The natural history of adrenal function in autoimmune patients with adrenal autoantibodies. J Endocrinol 1988; 117:467.
- Gylling M, Tuomi T, Björses P, et al. ss-cell autoantibodies, human leukocyte antigen II alleles, and type 1 diabetes in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab 2000; 85:4434.
- Falorni A, Chen S, Zanchetta R, et al. Measuring adrenal autoantibody response: interlaboratory concordance in the first international serum exchange for the determination of 21-hydroxylase autoantibodies. Clin Immunol 2011; 140:291.
- Myhre AG, Undlien DE, Løvås K, et al. Autoimmune adrenocortical failure in Norway autoantibodies and human leukocyte antigen class II associations related to clinical features. J Clin Endocrinol Metab 2002; 87:618.
- Betterle C, Volpato M, Rees Smith B, et al. II. Adrenal cortex and steroid 21-hydroxylase autoantibodies in children with organ-specific autoimmune diseases: markers of high progression to clinical Addison's disease. J Clin Endocrinol Metab 1997; 82:939.
- Betterle C, Volpato M, Rees Smith B, et al. I. Adrenal cortex and steroid 21-hydroxylase autoantibodies in adult patients with organ-specific autoimmune diseases: markers of low progression to clinical Addison's disease. J Clin Endocrinol Metab 1997; 82:932.
- Coco G, Dal Pra C, Presotto F, et al. Estimated risk for developing autoimmune Addison's disease in patients with adrenal cortex autoantibodies. J Clin Endocrinol Metab 2006; 91:1637.
- Söderbergh A, Myhre AG, Ekwall O, et al. Prevalence and clinical associations of 10 defined autoantibodies in autoimmune polyendocrine syndrome type I. J Clin Endocrinol Metab 2004; 89:557.
- Wolff AS, Erichsen MM, Meager A, et al. Autoimmune polyendocrine syndrome type 1 in Norway: phenotypic variation, autoantibodies, and novel mutations in the autoimmune regulator gene. J Clin Endocrinol Metab 2007; 92:595.
- Meager A, Visvalingam K, Peterson P, et al. Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLoS Med 2006; 3:e289.
- Falorni A, Laureti S, De Bellis A, et al. Italian addison network study: update of diagnostic criteria for the etiological classification of primary adrenal insufficiency. J Clin Endocrinol Metab 2004; 89:1598.
- Saenger P, Levine LS, Irvine WJ, et al. Progressive adrenal failure in polyglandular autoimmune disease. J Clin Endocrinol Metab 1982; 54:863.
- De Bellis A, Bizzarro A, Rossi R, et al. Remission of subclinical adrenocortical failure in subjects with adrenal autoantibodies. J Clin Endocrinol Metab 1993; 76:1002.
- Laureti S, De Bellis A, Muccitelli VI, et al. Levels of adrenocortical autoantibodies correlate with the degree of adrenal dysfunction in subjects with preclinical Addison's disease. J Clin Endocrinol Metab 1998; 83:3507.
- Blizzard RM, Chee D, Davis W. The incidence of parathyroid and other antibodies in the sera of patients with idiopathic hypoparathyroidism. Clin Exp Immunol 1966; 1:119.
- McHardy-Young S, Lessof MH, Maisey MN. Serum TSH and thyroid antibody studies in Addison's disease. Clin Endocrinol (Oxf) 1972; 1:45.
- Zelissen PM, Bast EJ, Croughs RJ. Associated autoimmunity in Addison's disease. J Autoimmun 1995; 8:121.
- Li Y, Song YH, Rais N, et al. Autoantibodies to the extracellular domain of the calcium sensing receptor in patients with acquired hypoparathyroidism. J Clin Invest 1996; 97:910.
- Ketchum CH, Riley WJ, Maclaren NK. Adrenal dysfunction in asymptomatic patients with adrenocortical autoantibodies. J Clin Endocrinol Metab 1984; 58:1166.
- Scherbaum WA, Berg PA. Development of adrenocortical failure in non-Addisonian patients with antibodies to adrenal cortex. A clinical follow-up study. Clin Endocrinol (Oxf) 1982; 16:345.
- Brewer KW, Parziale VS, Eisenbarth GS. Screening patients with insulin-dependent diabetes mellitus for adrenal insufficiency. N Engl J Med 1997; 337:202.
- Yu L, Brewer KW, Gates S, et al. DRB1*04 and DQ alleles: expression of 21-hydroxylase autoantibodies and risk of progression to Addison's disease. J Clin Endocrinol Metab 1999; 84:328.
- Triolo TM, Armstrong TK, McFann K, et al. Additional autoimmune disease found in 33% of patients at type 1 diabetes onset. Diabetes Care 2011; 34:1211.
- Furmaniak J, Kominami S, Asawa T, et al. Autoimmune Addison's disease--evidence for a role of steroid 21-hydroxylase autoantibodies in adrenal insufficiency. J Clin Endocrinol Metab 1994; 79:1517.
- Wulffraat NM, Drexhage HA, Bottazzo GF, et al. Immunoglobulins of patients with idiopathic Addison's disease block the in vitro action of adrenocorticotropin. J Clin Endocrinol Metab 1989; 69:231.
- Wardle CA, Weetman AP, Mitchell R, et al. Adrenocorticotropic hormone receptor-blocking immunoglobulins in serum from patients with Addison's disease: a reexamination. J Clin Endocrinol Metab 1993; 77:750.
- Boscaro M, Betterle C, Volpato M, et al. Hormonal responses during various phases of autoimmune adrenal failure: no evidence for 21-hydroxylase enzyme activity inhibition in vivo. J Clin Endocrinol Metab 1996; 81:2801.
- Neville, AM, Mackay, AM. The structure of the human adrenal cortex in health and disease. Clin Endocrinol Metab 1972; 1:361.
- Fairchild RS, Schimke RN, Abdou NI. Immunoregulation abnormalities in familial Addison's disease. J Clin Endocrinol Metab 1980; 51:1074.
- Rabinowe SL, Jackson RA, Dluhy RG, Williams GH. Ia-positive T lymphocytes in recently diagnosed idiopathic Addison's disease. Am J Med 1984; 77:597.
- Nerup J, Bendixen G. Anti-adrenal cellular hypersensitivity in Addison's disease. II. Correlation with clinical and serological findings. Clin Exp Immunol 1969; 5:341.
- Husebye ES, Bratland E, Bredholt G, et al. The substrate-binding domain of 21-hydroxylase, the main autoantigen in autoimmune Addison's disease, is an immunodominant T cell epitope. Endocrinology 2006; 147:2411.
- Bratland E, Skinningsrud B, Undlien DE, et al. T cell responses to steroid cytochrome P450 21-hydroxylase in patients with autoimmune primary adrenal insufficiency. J Clin Endocrinol Metab 2009; 94:5117.
- Leshin M. Polyglandular autoimmune syndromes. Am J Med Sci 1985; 290:77.
- Nerup J. Addison's disease--clinical studies. A report fo 108 cases. Acta Endocrinol (Copenh) 1974; 76:127.
- Neufeld M, Maclaren NK, Blizzard RM. Two types of autoimmune Addison's disease associated with different polyglandular autoimmune (PGA) syndromes. Medicine (Baltimore) 1981; 60:355.
- Spinner MW, Blizzard RM, Childs B. Clinical and genetic heterogeneity in idiopathic Addison's disease and hypoparathyroidism. J Clin Endocrinol Metab 1968; 28:795.
- Farid NR, Bear JC. The human major histocompatibility complex and endocrine disease. Endocr Rev 1981; 2:50.
- Maclaren NK, Riley WJ. Thyroid, gastric, and adrenal autoimmunities associated with insulin-dependent diabetes mellitus. Diabetes Care 1985; 8 Suppl 1:34.
- Partanen J, Peterson P, Westman P, et al. Major histocompatibility complex class II and III in Addison's disease. MHC alleles do not predict autoantibody specificity and 21-hydroxylase gene polymorphism has no independent role in disease susceptibility. Hum Immunol 1994; 41:135.
- Badenhoop K, Walfish PG, Rau H, et al. Susceptibility and resistance alleles of human leukocyte antigen (HLA) DQA1 and HLA DQB1 are shared in endocrine autoimmune disease. J Clin Endocrinol Metab 1995; 80:2112.
- Ghaderi M, Gambelunghe G, Tortoioli C, et al. MHC2TA single nucleotide polymorphism and genetic risk for autoimmune adrenal insufficiency. J Clin Endocrinol Metab 2006; 91:4107.
- Gambelunghe G, Falorni A, Ghaderi M, et al. Microsatellite polymorphism of the MHC class I chain-related (MIC-A and MIC-B) genes marks the risk for autoimmune Addison's disease. J Clin Endocrinol Metab 1999; 84:3701.
- Miller WL. Molecular biology of steroid hormone synthesis. Endocr Rev 1988; 9:295.
- Butler MG, Hodes ME, Conneally PM, et al. Linkage analysis in a large kindred with autosomal dominant transmission of polyglandular autoimmune disease type II (Schmidt syndrome). Am J Med Genet 1984; 18:61.
- Aaltonen J, Björses P, Sandkuijl L, et al. An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome 21. Nat Genet 1994; 8:83.
- Nagamine K, Peterson P, Scott HS, et al. Positional cloning of the APECED gene. Nat Genet 1997; 17:393.
- Finnish-German APECED Consortium. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet 1997; 17:399.
- Sparkes RS, Klisak I, Miller WL. Regional mapping of genes encoding human steroidogenic enzymes: P450scc to 15q23-q24, adrenodoxin to 11q22; adrenodoxin reductase to 17q24-q25; and P450c17 to 10q24-q25. DNA Cell Biol 1991; 10:359.
- Blomhoff A, Lie BA, Myhre AG, et al. Polymorphisms in the cytotoxic T lymphocyte antigen-4 gene region confer susceptibility to Addison's disease. J Clin Endocrinol Metab 2004; 89:3474.
- Jackson R, McNicol AM, Farquharson M, Foulis AK. Class II MHC expression in normal adrenal cortex and cortical cells in autoimmune Addison's disease. J Pathol 1988; 155:113.
- Guttman PH. Addison's disease. A statistical analysis of five hundred and sixty-six cases and a study of the pathology. Arch Pathol 1930; 10:742.
- Barker NW. The pathologic anatomy in twenty-eight cases of Addison's disease. Arch Pathol 1929; 8:432.
- Cedermark BJ, Sjöberg HE. The clinical significance of metastases to the adrenal glands. Surg Gynecol Obstet 1981; 152:607.