Polyglandular Autoimmune Syndrome Type 1 (PAS-1)
Prepared by: Daniela Cihakova MD, PhD|
Definition: Polyglandular autoimmune syndrome type 1(PAS-1) is an autoimmune disease characterized by destruction of endocrine tissues, chronic mucocutaneous candidiasis, and additional ectodermal disorders.
Description: The clinical diagnosis of PAS-1 is based on the presence of at least two out of the three following diagnostic criteria:
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.
- chronic mucocutaneous candidiasis,
- chronic hypoparathyroidism, and
- autoimmune adrenal insufficiency
PAS-1 is characterized by an autosomal recessive inheritance. PAS-1 is caused by mutations in the AIRE gene, which encodes the AIRE protein. The protein probably acts as a transcription factor.
- Chronic mucocutaneous candidiasis (CMC) is usually the first and the most common symptom of PAS-1. Therefore, the immune system and endocrine functions need to be examined in all patients and in particular in children with CMC. CMC in PAS-1 patients is usually mild; in most cases it is chronic. It is found in 73–100 percent of PAS-1 patients. It typically attacks skin, but very commonly also nails, mouth, vagina, esophagus and intestine.
- The first endocrine disease among PAS-1 patients is hypoparathyreosis (HP). HP is found in 76–93 percent of PAS-1 patients.
- Autoimmune Addison’s disease (AAD) affects 72-100 percent of PAS-1 patients. Still many of them die for unrecognized or late diagnosed AAD, so regular follow-up for children in suspicion of PAS-1 (with CMC or/and HP) is necessary.
- 17–50 percent of patients with PAS-1 have hypergonadotrophic hypogonadism (up to 72 percent of women).
- Frequency of alopecia in PAS-1 patients is 29–40 percent. Alopecia can afflict not only hair, but also eyebrows, eyelashes, armpit, and genital pubes.
- Ectodermal dystrophy affects nails, enamel and tympanic membranes.
Diagnosis: The discovery of the AIRE protein enables an exact diagnosis of PAS-1, but it is not routinely available. Therefore, the diagnosis is clinical, based on the above diagnosis criterion. Possible PAS-1 should be suspected in children with CMC or primary HP.
Incidence: PAS-1 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 PAS-1 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 PAS-1 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, is the only components of APS-1 treated regularly by an immunosuppressive therapy. Prednisone, azathioprine, and cyclosporine A are typically used.
Pathogenesis: PAS-1 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 PAS-1 is clear, other factors may play a role in patient’s phenotype as well. HLA II class, CTLA-4 polymorphism, and PAS-1 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 PAS-1 is an autoimmune disease.
- The components of the PAS-1 are typical autoimmune organ specific diseases – hypoparathyreosis, Addison’s disease, thyroid disease, and alopecia. However, it is not yet understood why PAS-1 patients have so high incidence of CMC (close to 100 percent).
- Many serum autoantibodies are present in PAS-1 patients.
- HLA association. It was found recently that PAS-1 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 PAS-1 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 PAS-1. 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 PAS-1 patients. However, the HLA association was weaker in PAS-1 than in the main autoimmune diseases.
- 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 the damage of endocrine organs.
- In a transfer experiment, recipients developed lymphocytes infiltrates in several
organs similar to these find in AIRE KO mice.