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Autoimmune Addison disease: pathophysiology and genetic complexity

Abstract

Autoimmune Addison disease is a rare autoimmune disorder with symptoms that typically develop over months or years. Following the development of serum autoantibodies to the key steroidogenic enzyme, 21-hydroxylase, patients have a period of compensated or preclinical disease, characterized by elevations in adrenocortocotropic hormone and renin, before overt, symptomatic adrenal failure develops. We propose that local failure of steroidogenesis, causing breakdown of tolerance to adrenal antigens, might be a key factor in disease progression. The etiology of autoimmune Addison disease has a strong genetic component in man, and several dog breeds are also susceptible. Allelic variants of genes encoding molecules of both the adaptive and innate immune systems have now been implicated, with a focus on the immunological synapse and downstream participants in T lymphocyte antigen-receptor signaling. With the exception of MHC alleles, which contribute to susceptibility in both human and canine Addison disease, no major or highly penetrant disease alleles have been found to date. Future research into autoimmune Addison disease, making use of genome-wide association studies and next-generation sequencing technology, will address the gaps in our understanding of the etiology of this disease.

Key Points

  • Autoimmune Addison disease (AAD) is among the rarest of the autoimmune endocrinopathies

  • An aberrant immune response directed, at least in part, at the steroidogenic enzymes of the adrenal cortex (in particular 21-hydroxylase) underlies most cases of AAD

  • The progression of AAD can be slow, with an insidious decline into adrenal failure over months and years

  • Circumstantial evidence suggests that the glucocorticoid-rich adrenal milieu might give natural protection to adrenal antigens from the immune system

  • AAD has a strong genetic component, but owing to its rarity the recurrence rate in family members is of the order of 2%

  • Several disease-susceptibility alleles have been identified, including three loci associated with organ-specific autoimmunity (MHC, CTLA4 and PTPN22), and others that encode proteins involved in innate immune responses

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Figure 1: A hypothetical model of the pathogenesis of AAD based on the breakdown of glucocorticoid-induced immune privilege.
Figure 2: An example of a pedigree of Portuguese Water Dogs with heritable Addison disease.
Figure 3: Schematic representation of candidate-gene loci that confer susceptibility to autoimmune Addison disease.
Figure 4: Molecular interactions between antigen-presenting cells and CD4+ lymphocytes that are involved in autoimmunity.

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Acknowledgements

A. L. Mitchell is in receipt of a clinical research training fellowship from the Medical Research Council, UK. S. H. S Pearce's research work is supported by European Union Framework 7 grant 201167 to the Euradrenal Consortium and grants G07017632 & G0900001 from the Medical Research Council, UK. A. L. Mitchell and S. H. S. Pearce thank their collaborator, Professor Eystein Husebye, Dr Martina Ericksen and the group at Haukeland University Hospital, Bergen, Norway, for contributing family data on Addison disease gathered from the Norwegian registry of organ-specific autoimmune diseases for this Review.

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Correspondence to Anna L. Mitchell.

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Mitchell, A., Pearce, S. Autoimmune Addison disease: pathophysiology and genetic complexity. Nat Rev Endocrinol 8, 306–316 (2012). https://doi.org/10.1038/nrendo.2011.245

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