Abstract
In APECED, the key abnormality is in the T cell defect that may lead to tissue destruction chiefly in endocrine organs. Besides, APECED is characterized by high-titer antibodies against a wide variety of cytokines that could partly be responsible for the clinical symptoms during APECED, mainly chronic mucocutaneous candidiasis, and linked to antibodies against Th17 cells effector molecules, IL-17 and IL-22. On the other hand, the same antibodies, together with antibodies against type I interferons may prevent the patients from other immunological diseases, such as psoriasis and systemic lupus erythematous. The same effector Th17 cells, present in the lymphocytic infiltrate of target organs of APECED, could be responsible for the tissue destruction. Here again, the antibodies against the corresponding effector molecules, anti-IL-17 and anti-IL-22 could be protective. The occurrence of several effector mechanisms (CD4+ Th17 cell and CD8+ CTL and the effector cytokines IL-17 and IL-22), and simultaneous existence of regulatory mechanisms (CD4+ Treg and antibodies neutralizing the effect of the effector cytokines) may explain the polymorphism of APECED. Almost all the patients develop the characteristic manifestations of the complex, but temporal course and severity of the symptoms vary considerably, even among siblings. The autoantibody profile does not correlate with the clinical picture. One could speculate that a secondary homeostatic balance between the harmful effector mechanisms, and the favorable regulatory mechanisms, finally define both the extent and severity of the clinical condition in the AIRE defective individuals. The proposed hypothesis that in APECED, in addition to strong tissue destructive mechanisms, a controlling regulatory mechanism does exist, allow us to conclude that APECED could be treated, and even cured, with immunological manipulation.
Highlights
Autoimmune polyendocrinopathy syndrome type 1 (APS-1) or autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy syndrome (APECED; OMIM 240300) is a rare recessively inherited disorder (Perheentupa, 2002; Betterle and Zanchetta, 2003; Perheentupa, 2006; Husebye et al, 2009). It is caused by mutations in the autoimmune regulator (AIRE) gene located on locus 21q22.3 (Bjorses et al, 1996; Nagamine et al, 1997; The Finnish–German APECED Consortium, 1997)
APECED displays a worldwide distribution, but specific clusters of high prevalence of the disease are observed among Finns
1990) and Sardinians 1 (1:14,500; Rosatelli et al, 1998; Meloni et al, 2012). It is characterized by the variable association of autoimmune endocrine [hypoparathyroidism (HP), Addison’s disease (AD), hypothyroidism, gonadal insufficiency, insulin-dependent diabetes mellitus, atrophic gastritis, and Biermer’s disease] and non-endocrine disorders and a specific predisposition to chronic mucocutaneous candidiasis (CMC)
Summary
Autoimmune polyendocrinopathy syndrome type 1 (APS-1) or autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy syndrome (APECED; OMIM 240300) is a rare recessively inherited disorder (Perheentupa, 2002; Betterle and Zanchetta, 2003; Perheentupa, 2006; Husebye et al, 2009) It is caused by mutations in the autoimmune regulator (AIRE) gene located on locus 21q22.3 (Bjorses et al, 1996; Nagamine et al, 1997; The Finnish–German APECED Consortium, 1997). The APECED gene was renamed as AIRE in 1997 (Nagamine et al, 1997; The Finnish–German APECED Consortium, 1997) Another immunopathy, termed originally as autoimmune enteropathy (AIE) and later identified as immune dysregulation, polyendocrinopathy, enteropathy and X-linked (IPEX), was described in the 1980s and 1990s (Powell et al, 1982). The same mutation, R257X was detected in Swiss patients on a different haplotype with closely linked polymorphic markers (Nagamine et al, 1997) and in Frontiers in Immunology | Primary Immunodeficiencies www.frontiersin.org
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