Polyglandular Autoimmune Syndrome Type 1 or Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED)

Polyglandular autoimmune syndrome type 1 or Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) is an autoimmune disease characterized by destruction of endocrine tissues, chronic mucocutaneous candidiasis, and additional ectodermal disorders.

 

Description

The clinical diagnosis of APECED is based on the presence of at least two out of the three following diagnostic criteria:

  • chronic mucocutaneous candidiasis,
  • chronic hypoparathyroidism, and
  • autoimmune adrenal insufficiency


However, patients often develop other diseases as well, such as: hypogonadism, alopecia, chronic hepatitis, chronic atrophic gastritis, erniciose anemia, vitiligo, malabsorption, hypothyroidism, keratoconjunctivitis, hypophysitis, and IMDM.

APECED is characterized by an autosomal recessive inheritance. APECED is caused by mutations in the AIRE gene, which encodes the AIRE protein. The protein probably acts as a transcription factor.

Symptoms

  • Chronic mucocutaneous candidiasis (CMC) is usually the first and the most common symptom of APECED. Therefore, the immune system and endocrine functions need to be examined in all patients and in particular in children with CMC. CMC in APECED patients is usually mild; in most cases it is chronic. It is found in 73-100 percent of APECED patients. It typically attacks skin, but very commonly also attacks nails, mouth, vagina, esophagus, and intestine.
  • The first endocrine disease among APECED patients is hypoparathyreosis (HP). HP is found in 76-93 percent of APECED patients.
  • Autoimmune Addison’s disease (AAD) affects 72-100 percent of APECED patients. Still many of them die for unrecognized or late diagnosed AAD, so regular follow-up for children in suspicion of APECED (with CMC or/and HP) is necessary.
  • 17-50 percent of patients with APECED have hypergonadotrophic hypogonadism (up to 72 percent of women).
  • Frequency of alopecia in APECED patients is 29-40 percent. Alopecia can affect not only hair, but also eyebrows, eyelashes, armpit, and genital pubic hair.
  • Ectodermal dystrophy affects nails, enamel and tympanic membranes.

 

Diagnosis

The discovery of the AIRE protein enables an exact diagnosis of APECED, but it is not routinely available. Therefore, the diagnosis is clinical, based on the above diagnosis criterion. Possible APECED should be suspected in children with CMC or primary HP.

Incidence

APECED is a rare disease with the incidence of 1:100,000. It is more common among Finns (1:25,000), Sardinians (1:14,000), and Iranian Jews (1:6,500 to 1:9,000). The age of onset is usually early childhood, but new symptoms can develop throughout life. It affects both sexes equally.

Treatment

Hormone replacement therapy. Treatment of CMC within A is challenging. Good results were reported after using ketoconazol. However, this imidazole derivate inhibits the biosynthesis of cortisol and testosterone. Caution must therefore be used when treating APECED patients. Even a low dose of ketoconasol can deteriorate the adrenal function of patients with a limited pituitary-adrenal reserve. Chronic hepatitis, together with a few cases of intestinal dysfunction, are the only components of APS-1 treated regularly by an immunosuppressive therapy. Prednisone, azathioprine, and cyclosporine A are typically used.

Pathogenesis

APECED gained a unique position among the autoimmune diseases, because it is the only known monogenetic autoimmune diseases with full gene penetration.

The AIRE gene (autoimmune regulator) is 13 kb long and has 14 exons. The main protein coded by this gene contains 545 amino acids and was named the AIRE protein. The AIRE protein seems to function predominantly as a transcriptional activator and it may control autoimmunity by promoting ectopic expression of peripheral tissue-restricted antigens in medullary epithelial cells of the thymus. Even though the relationship between AIRE gene and APECED is clear, other factors may play a role in a patient’s phenotype as well. HLA II class, CTLA-4 polymorphism, and APECED association were suggested by recent research, which has also found several examples of AIRE mutations behaving in a dominant fashion.

The following is the circumstantial and indirect evidence that APECED is an autoimmune disease:

Circumstantial Evidence:

  • The components of the APECED are typical autoimmune organ specific diseases – hypoparathyreosis, Addison’s disease, thyroid disease, and alopecia. However, it is not yet understood why APECED patients have so high incidence of CMC (close to 100 percent).
  • Many serum autoantibodies are present in APECED patients.
  • HLA association. It was found recently that the APECED phenotype is associated with HLA II. Phenotypes differ between patients with the same AIRE mutations, even in one family. HLA II class seems to be one of the factors contributing to these differences. The same risk and protective HLA II that apply in APECED are the same as in individual organ specific autoimmune diseases. Addison’s disease is positively associated with DRB1*03 allele, which is also more prevalent among patients with Addison’s disease without APECED. Alopecia is strongly positively associated with DRB1*04 and DRB1*0302. DRB1*04 is also more bound with alopecia totalis and universalis. The most common protective haplotype for type 1 diabetes – DRB1*15-DQB1*0602 – was found protective also for diabetes in APECED patients. However, the HLA association was weaker in APECED than in the main autoimmune diseases.


Indirect Evidence:

  • AIRE knockout mice were produced by two groups in 2002. A high percentage of the mice were infertile. They developed several autoantibodies, periportal lymphocyte infiltration, and lymphocyte infiltration in other organs. In contrast to the human disease, the mice did not develop damage of the endocrine organs.


In a transfer experiment, recipients developed lymphocytes infiltrates in several organs similar to those find in AIRE KO mice.