Anti-Interferon Auto-Antibodies in Autoimmune Polyendocrinopathy Syndrome Type 1

A utoimmunity is a common mechanism underlying many common human diseases. Although the mechanisms are not well understood, autoimmunity is thought to arise from a failure in self-tolerance, resulting in a sustained immunological attack by specifi c antibody, T cells, or both, directed against antigens within the target tissues or organs [1]. Many autoimmune disorders appear to have a genetic basis, but attempts to identify the human genes involved have had only limited success, probably because of the polygenic nature of most common autoimmune disorders, and because of the complexity of the immunological pathways involved [2]. Many of the most important clues as to the working of the human immune system have come from the study of patients with rare single gene defects. Autoimmune Polyendocrinopathy Syndrome Type 1 (APS-1) is a rare, recessively inherited disorder, which is more common in the Finnish, Sardinian, and Iranian Jewish populations than in the general population[3]. The disorder usually presents in early childhood, with chronic mucocutaneous candidiasis, and adrenal or para-thyroid failure. The clinical manifestations of the disorder are extremely variable and include diabetes, keratitis, chronic diarrhoea, alopecia, hepatitis, pernicious anaemia, and primary hypogonadism [4]. Immunologically, the disease is characterised by lymphocytic infi ltration of the target organs and by the presence of auto-antibodies against a wide range of tissue-specifi c antigens [5,6]. Mucocutaneous candidiasis occurs in all patients with APS-1, but the immunological basis of the failure to eliminate candida is not understood. In general, the defect in elimination of candida is not associated with defective handling of other pathogens, suggesting a candida-specifi c immune defect [7]. A breakthrough in understanding the molecular basis of Type 1 APS came from identifi cation of the causative gene by positional cloning [8–10]. The novel gene, named AIRE (autoimmune regulator), codes for a 545–amino acid protein that acts as a transcriptional regulator and which probably plays a role in regulating self-antigen expression in medullary thymic epithelial cells and dendritic cells [11,12]. Different mutations in the coding region of the AIRE gene are responsible for APS-1 in patients carrying homozygous or multiple heterozygous mutations [13]. Although the AIRE gene defi nes novel pathways controlling self-tolerance, many questions about the immunopathogenesis have remained unanswered: 1) the disease is extremely variable in its clinical and immunological manifestations even in patients carrying the same mutation; 2) the relationship between AIRE mutations and impaired immunity to candida remains unknown; and 3) …