APS-2: autoimmune polyglandular syndrome-2

Type 1 diabetes is closely associated with a number of other organ-specific autoimmune conditions, most probably due to overlapping HLA susceptibility. APS-2 (also known as Schmidt syndrome) describes Addison's disease in conjunction with autoimmune thyroid disease, type 1 diabetes, or both. Other associated autoimmune conditions include coeliac disease, pernicious anaemia, stiff man syndrome and alopecia, and multiple autoimmune conditions are typically present in close family members. Doubt exists as to whether APS-2 is a distinct entity or simply one manifestation of a spectrum of polyendocrine autoimmunity.

Introduction

The coexistence of juvenile diabetes with other immune-mediated disorders, including autoimmune thyroid disease and Addison's, was an early clue that it was itself An autoimmune condition.

Comparative study of this cluster of disorders has yielded valuable insight into the role of the HLA system in modulating and directing susceptibility to autoimmunity.

Addison's Disease

President John F Kennedy was diagnosed with Addison's Disease
President John F Kennedy was diagnosed with Addison's Disease
The syndrome of adrenocortical insufficiency was first described as a complication of tuberculosis, but is now almost always a consequence of autoimmunity.

The natural history of autoimmune Addison's resembles that of type 1 diabetes in that it progresses from the appearance of tissue-specific autoantibodies (directed against the steroid 21-hydroxylase enzyme) to progressive target organ failure and overt disease.

Genetic susceptibility to APS-2

Autoimmune Addison's is closely associated with the_ HLA-DR3_ haplotype; the highest risk genotype is HLA-DR3/4-DQ2/8, found in 30% of patients. Within this subgroup, the HLA-DR4 subtype DRB1 *0404 confers the highest risk of Addison's itself, whereas DQA1 *0501,DQB *0201 gives the highest risk of developing both Addison's and type 1 diabetes. A person with type 1 diabetes who has the DRB *0404 allele and 21-hydroxylase antibodies has a 100-fold risk of developing Addison's [1].

In contrast to APS-1, there is no association between APS-2 and the AIRE gene, but the possible role of other Non-HLA genes in its pathogenesis are under investigation. These include the PTPN22 gene in which a single gain-of-function mutation reduces T cell receptor signalling and increases the risk of autoimmune conditions including Addison's, type 1 diabetes and thyroid autoimmunity[2].

Management

People with autoimmune Addison's disease have a 50% risk of developing another autoimmune condition 1 and regular screening for islet, thyroid and coeliac autoantibodies is recommended, and may usefully be extended to near relatives.

Summary

APS-2 is a complex polygenic condition in which autoimmune Addison's disease is associated with autoimmune diabetes or thyroid disease. The mechanism includes defective central and peripheral tolerance, and is controlled by the interplay between MHC Class II molecules and non-HLA genes concerned with immune recognition. The utility of considering Addison's-based autoimmunity as a distinct clinical entity is uncertain, since there are no distinctive genetic or mechanistic features to distinguish it from other forms of polyendocrine autoimmunity, nor does it overlap with monogenic syndromes such as APS-1.

References

  1. ^ Michels AW, Gottlieb PA. Autoimmune polyglandular syndrome. Nat Rev Endocrinol 2010;6:270-277

  2. ^ Vang T et al. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant.Nat Genet 2005;37:1317-19

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