A model gene for a general predisposition for organ-specific autoimmune diseases is the autoimmune regulator (AIRE), which was recently cloned. Severe reduction of AIRE function causes a genetic disease, called autoimmune polyendocrine syndrome type 1 (APS1) . Patients with APS1 usually develop mucocutaneous candidiasis at least once in their lives and a broad spectrum of different autoimmune diseases . The most frequent autoimmune diseases are hypoparathyroidism (80%) and adrenal insufficiency (70%). In addition to endocrine disorders, ectodermal dystrophies are frequently noted as well as hepatogastroin-testinal dysfunction (Table 23.1). Ten to twenty per cent of patients with APS1 develop AIH.
AIRE is the first gene known outside of the MHC locus which is strongly associated with the development of autoimmune diseases in humans. AIRE encodes a nuclear transcription factor , characterized by two plant homeodomain-type (PHD-type) zinc finger motifs, a newly described SAND domain, a putative nuclear targeting signal, a proline-rich region and four LXXLL nuclear receptor-binding motifs  (Figure 23.3). The AIRE protein shows colocalization with cytoskeletal filaments and is also found in spotlike domains of the cell [23, 24]. The AIRE protein is not detected in the target cells of autoimmune destruction, but in cells involved in the induction and maintenance of tolerance, i.e. dendritic and epithelial cells of the thymus medulla and dendritic cells of the spleen and lymph nodes [23, 24]. Thirty different mutations have been described to date in patients with APS1, many of which cause frameshift mutations and destruction of at least one of the two PHD-finger motives. For several mutations, it has been shown that mutated AIRE proteins show an altered subcellular localization and that transcriptional activity is altered. While defects in the AIRE coding sequence do not play a major role for AIH , AIRE is a model gene for demonstrating that genes involved in T-cell selection and antigen presentation may play a pivotal
Table 23.1. Autoimmune diseases caused by the AIRE gene defect
Disease components Prevalence (%)
Mucocutaneous candidiasis 100
Adrenal failure 72
Autoimmune thyroid disease 2
Gonadal failure 50
Chronic hepatitis 12
Parietal cell atrophy 13
Intestinal malabsorption 18
Enamel hypoplasia 77
Nail dystrophy 52
Data in this table are from Ahonen et al. 
role in the development of autoimmune diseases. The AIRE gene defect also demonstrates that it is susceptibility and not the specific autoimmune disease that is inherited with such defects. In spite of a homogeneous gene defect in Finns, in whom 90% share the same disease allele, the clinical spectrum of disease components in AIRE is extremely heterogeneous. Therefore, for a specific basic gene defect, outcome of the clinical disease is modified by several other genes. The genetic basis of these 'risk factors' contrasts with others that may be environmental - e.g. immune reactions induced by virus infections - which may act as triggers for specific autoimmune diseases.
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