APS-1 (autoimune polyendocrine syndrome-1)
APS-1 (also known as Autoimmune-PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy or APECED) is a rare autosomal recessive disorder caused by mutation of the AIRE gene which is involved in central (thymic) deletion of T-cells capable of recognition of self antigens and thus generation of immune tolerance. More than 60 mutations have been recognised. APS-1 affects three populations in particular: Finns, Sardinians and Iranian jews. The major diagnostic triad is one of chronic muco-cutaneous candidiasis, hypoparathyroidism and adrenocortical failure (Addison's), but the phenotype is exceptionally variable and these features are often absent. The clinical prognosis varies according to the phenotype, but early detection, specialized follow up and screening and treatment for potential complications are needed to ensure the best outcome.
APS-1 is a rare autosomal recessive disorder whose features have slowly emerged since the first partial description in 1929. The condition, which usually presents in infancy, has three major common components:
- Chronic mucocutaneous candidiasis
- Adrenocortical failure
In 1997 the condition was shown to be caused by mutations in the autoimmune regulator or AIRE gene (21q22.3), which was previously unknown. At least 58 mutations are described, but the condition is most commonly encountered in Finns, Iranian Jews and Sardinians. The most common (Finnish) mutation is R257X, present in the homozygous or heterozygous state.
The condition is notable for its phenotypic variability, the most constant feature being chronic mucocutaneous candidiasis, often developing in early chidhood and present in 2/3 of the Finnish series . Candidiasis can affect mucosal surfaces, skin and nails, and aggressive monitoring and treatment are needed to eliminate gastrointestinal candidiasis which may predispose to epithelial cancers.
Hypoparathyroidism is the next most common component, and may present as hypotension, lethargy or fits in childhood. Tooth enamel and nails may also be affected.
The third major component is adrenocortical failure (Addison's disease).
Other features include type 1 diabetes (typically presenting after childhood) alopecia, vitiligo, keratoconjunctivitis, gonadal failure, hypothyroidism, hepatitis, and malabsorptive diarrhoea.
More rarely described features include tubulointerstitial nephritis, asplenia and oral or oesophageal carcinoma in the Finnish series ; the latter is associated with recurrent candidiasis.
The AIRE gene
The full name is the autoimmune regulator gene, which codes for an autoimmune regulator protein. This is located in the thymus and helps in the protective recognition of self antigens. Failure of such recognition predisposes to T-cell mediated autoimmunity . For unknown reasons AIRE mutations mainly affect transcriptional control of endocrine-associated antigens including those present in the adrenals, parathyroid, thyroid and islet beta cells, although predisposing also to non-endocrine autoimmunity.
The orientation of the immune response towards specific tissues is modulated by HLA alleles conferring susceptibility to or protection against the autoimmune condition in question.
Anti-interferon antibodies are commonly present, and interferon-ω-reactive antibodies are present in up to 100%.
Thyroid, islet and adrenal autoantibodies are also present and can be used to identify increased risk of the corresponding autoimmunities. HLA DRB1 *15-DQB1 *06:02, for example, appears protective against diabetes as in the general population.
Knockout of the AIRE gene in animals produces mild autoimmunity affecting the whole body, with lymphocytic infiltration of the liver and thyroid and adrenal atrophy.
Diabetes and APS-1
In the Finnish series, diabetes developed in 17/91 patients, 15 of whom had type 1 diabetes. Lower prevalences have been reported elsewhere.
This rare condition is of major scientific interest because it demonstrates so clearly that dysfunctional antigen presentation in the thymus can lead to a failure of T cell recognition resulting in organ specific autoimmunity, and has helped to identify the molecular basis underlying this pathological development.
The wide and varied spectrum of other types of immune dysfunction associated with the condition in individuals with the same mutation is puzzling, but demonstrates the plasticity of development of the immune repertoire.
In clinical terms, the classic presentation with the diagnostic triad of candidiasis, hypoparathyroidism and adrenocortical failure is diagnostic. This combination is however relatively uncommon, and paediatricians must be alert to the extremely variable phenotype.
Management is conservative, and immunotherapy is reserved for specific manifestations, such as hepatitis or keratoconjunctivitis. Candidiasis requires aggressive management. Autoantibody screening aids diagnosis and prediction of the associated forms of organ-specific autoimmunity. Absence of the spleen requires vaccination against pneumococcus, meningococcus and haemophilus infections. The prognosis reflects the clinical phenotype and is equally variable, but early diagnosis and active management may have a major influence on the outcome.
^ 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;399-403
^ Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab 2006;2843-50
^ Michels AW, Gottlieb PA. Autoimmune polyglandular syndromes. Nat Rev Endocrinol 2010;6: 270-7
^ Kumar PG et al. Population genetics and functions of the immune regulator (AIRE). Endocrinol Metab Clin North Am 2002;31:321-38
^ Halonen M et al. AIRE mutations and human leukocyte antigen genotypes as determinants of the APECED phenotype. J Clin Endocrinol Metab 2002;87:2568-74
^ Meager A et al. Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome. PLoS Med 2006; 3. e289
^ Su MA et al. Mechanisms of an autoimmunity syndrome in mice caused by a dominant mutation in AIRE. J Clin Invest 2008;118:1712-26