DOCTOR'S VIEW ARCHIVE

Autoimmune Polyglandular Syndrome…Exploring Autoimmunity

December 5, 1997) - Autoimmune polyglandular syndrome type I (APS 1) is a mouthful. It also goes by the even more cumbersome name of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Even though APS 1 is a rare disease, it is important to geneticists and immunologists because APS 1 is the first and only systemic (bodywide) autoimmune disease whose cause has been attributable to a defect in a single gene.

By "autoimmune" is meant that the immune system (which normally wards off foreign invaders of the body, such as infections) turns and attacks tissues (such as skin, joints, liver, lungs, etc.) of the body. Examples of common systemic autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, diabetes mellitus, Sjogren's syndrome, scleroderma, Goodpasture's syndrome, vitiligo, Addison's disease, thyroiditis, and many others.

Chromosomes (located inside every cell in the body) contain genetic information inherited from each parent. Humans have 23 pairs of chromosomes (one chromosome inherited from each parent). Different regions on the chromosomes contain genes for diverse traits (hair color, eye color, height, blood groups, etc.). Changes (mutations) in these genes can cause disease. By locating (mapping), isolating and sequencing genes and analyzing the ways in which they act, scientists aim to understand (on the molecular, genetic and clinical levels) the causes of many diseases. And they hope to understand the predispositions (tendencies) to even more diseases.

In the December issue of the medical journal Nature Genetics, scientists reported the identification of a novel gene mapped to chromosome region 21q22.3. The gene has been named AIRE (for autoimmune regulator).

Changes in the AIRE gene have been shown to be responsible for APS1. The discovery that this gene is the culprit in a systemic autoimmune disease is of great importance. For the first time researchers have a genetic tool to explore the basis of autoimmunity at the level of molecules!

APS 1 is inherited as an autosomal recessive trait. That means a child with APS 1 has received two changed AIRE genes, one from each parent. A child who gets just one of the APS 1 genes from one parent is normal, but is a carrier of the abnormal gene.

The child with APS 1 syndrome develops problems in numerous glands (polyglandular). These problems include hypoparathyroidism (underfunction of the parathyroid glands which control calcium), hypogonadism (with sex gland failure), adrenal insufficiency (underfunction of the adrenal gland), the insulin-dependent type of diabetes mellitus (juvenile form of diabetes mellitus with absence of insulin production by the pancreas gland), and latent hypothyroidism (underfunction of the thyroid gland).

Persons affected by APS 1 have total baldness (alopecia totalis), inflammation of the cornea and whites of the eye (keratoconjunctivitis), underdevelopment (hypoplasia) of the enamel of the teeth, childhood-onset moniliasis (a fungal infection), juvenile-onset pernicious anemia, gastrointestinal problems (malabsorption, diarrhea), and chronic active hepatitis.

The laboratory studies in APS 1 (alias APECED) attest to an immune disease with low gamma globulin antibodies in blood (hypogammaglobulinemia) and a low T4/T8 cell ratio (as in AIDS). There is specific evidence for autoimmunity with antibodies directed against the adrenal and thyroid glands and against cell nuclei (antiadrenal, antithyroid and antinuclear antibodies).

For more information, an excellent (highly technical) review of the disease is provided by:

Online Mendelian Inheritance in Man, edited by VA McKusick

(at http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim? 240300)

The discovery of the AIRE gene was reported simultaneously by two research groups, as follows:

Positional cloning of the APECED gene, by K Nagamine, P Peterson, HS Scott, J Kudoh, S Minoshima, M Heino, KJE Krohn, MD Lalioti, PE Mullis, SE Antonarakis, K Kawasaki, S Asakawa, F Ito & N Shimizu. Nature Genetics 17:393, 1997

(at http://genetics.nature.com/cgi- bin/wilma.cgi/v17n4.880036016.html)

An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains by The Finnish-German APECED Consortium. Nature Genetics 17: 399, 1997.

(at http://genetics.nature.com/cgi- bin/wilma.cgi/v17n4.880036175.html)


Last Editorial Review: 12/31/1997