β‐defensin CNV is not associated with susceptibility to Candida albicans infections in Sardinian APS I patients

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Autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy (APECED; MIM# 240300), also known as autoimmune polyglandular syndrome type 1 (APS I), is a rare monogenic disease with autosomal recessive pattern of inheritance. The disease is reported worldwide, but it is most prevalent among genetically homogeneous populations such as Finnish (1:25 000), Ashkenazi Jews (1:9000) and Sardinians (1:14 400) 1.
APECED is caused by mutations in the Auto Immune Regulator (AIRE) gene, mapped on chromosome 21q22.3. AIRE encodes for a transcription factor that governs the thymic expression of peripheral tissue‐restricted antigens, which promotes the deletion of potentially self‐reactive T cells 1. Studies carried out in AIRE knockout mice showed that, in the absence of AIRE, self ‐reactive thymocytes escape the usual clonal deletion that prevents them from emerging into the periphery, resulting most of the times in a rapid and severe autoimmune disease 2. To date, more than 70 different mutations that lie in different AIRE gene motifs, causing loss or defective function of the relative protein, have been characterized (The Human Gene Mutation Database, HGMD). In isolated populations where APECED is relatively frequent, common mutations can be observed due to a clear founder effect. In Sardinia, the R139X mutation accounts for 94% of the mutated alleles in APECED patients. In a previous study, we found that this mutation has a 1.7% frequency in the general Sardinian population, reaching a 3.4% frequency peak in the Ogliastra region 1. In Apulia, another hot spot area where APECED shows an increased prevalence, the W78R mutation represents 56% of the mutated alleles 3. On the other hand, all the Ashkenazi Jewish patients are homozygous for the Y85C mutation, whereas the R257X is the most common mutation in Finland 1.
Clinical diagnosis of APS I requires the presence of at least two of the three major components – chronic mucocutaneous candidiasis (CMC), hypoparathyroidism (HP) and Addison's disease (AD) – or just one if a sibling has been already diagnosed 1. Additional autoimmune components with variable penetrance may appear throughout life, including gonadal failure, type 1 diabetes (T1D), hypothyroidism, pernicious anaemia, hepatitis, alopecia, vitiligo and ectodermal dystrophies 1. The autoimmune manifestations most likely result from the target organ destruction by cell‐ and antibody‐mediated attack 1 and may be accounted to the key role played by AIRE in tolerance.
Candidiasis is usually the first clinical symptom 1 with a very high prevalence in most populations 5. Among Sardinians, the CMC prevalence is 95%, being the first sign in 86% of APS I patients 7. In Finnish APECED patients, candidiasis occurs as first symptom in 47% of cases 4. On the other hand, it has a very low frequency (18%) among Ashkenazi Jews 1.
CMC diagnosis is based on the signs and symptoms, upon the ample growth of Candida albicans in culture and on the rapid resolution of symptoms during anticandidal therapy. Candida infections mainly affect the oral mucosa, where they can lead to intermittent angular cheilitis forms 6. More severe conditions include acute inflammation in most of the oral mucosa, hyperplastic chronic disease with white thick coating on the tongue, atrophic disease with scant coatings and scarred thin mucosa with leucoplakia‐like areas 4. Oesophageal and intestinal candidiasis, characterized by abdominal pain, flatulence and diarrhoea, may also occur 4. Patients suffering from oral and/or persistent oesophageal candidiasis have an increased risk of developing oesophageal squamous cell carcinoma (SCC); therefore, oral infections must be strictly controlled and pharmacologically treated: in fact, 10% of affected Finnish patients over the age of 25 developed oral or oesophageal squamous cell carcinoma 8.

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