Impaired dendritic cell maturation and cytokine production in patients with chronic mucocutanous candidiasis with or without APECED.

Institute for Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Clinical & Experimental Immunology (Impact Factor: 3.28). 01/2009; 154(3):406-14. DOI: 10.1111/j.1365-2249.2008.03778.x
Source: PubMed

ABSTRACT Patients with chronic mucocutaneous candidiasis (CMC) suffer persistent infections with the yeast Candida. CMC includes patients with autoimmune regulator (AIRE) gene mutations who have autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), and patients without known mutations. CMC patients have dysregulated cytokine production, and dendritic cells (DCs), as central orchestrators, may underlie pathogenic disease mechanisms. In 29 patients with CMC (13 with APECED) and controls, we generated monocyte-derived DCs, stimulated them with Candida albicans, Toll-like receptor-2/6 ligand and lipopolysaccharide to assess cytokine production [interleukin (IL)-12p70, IL-23, interferon (IFN)-gamma, IL-2, tumour necrosis factor (TNF)-alpha, IL-6, transforming growth factor-beta, IL-10, IL-5, IL-13] and cell-surface maturation marker expression (CD83, CD86, human leucocyte antigen D-related). In both APECED and non-APECED CMC patients, we demonstrate impairment of DC function as evidenced by altered cytokine expression profiles and DC maturation/activation: (1) both groups over-produce IL-2, IFN-gamma, TNF-alpha and IL-13 and demonstrate impaired DC maturation. (2) Only non-APECED patients showed markedly decreased Candida-stimulated production of IL-23 and markedly increased production of IL-6, suggesting impairment of the IL-6/IL-23/T helper type 17 axis. (3) In contrast, only APECED patients showed DC hyperactivation, which may underlie altered T cell responsiveness, autoimmunity and impaired response to Candida. We demonstrate different pathogenic mechanisms on the same immune response pathway underlying increased susceptibility to Candida infection in these patients.

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    ABSTRACT: Loss-of-function mutations in the Autoimmune Regulator (AIRE) gene cause a rare inherited form of autoimmune disease, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, also known as autoimmune polyglandular syndrome type 1. The patients suffer from multiple endocrine deficiencies, the most common manifestations being hypoparathyroidism, Addison's disease, hypogonadism, and secondary amenorrhea, usually accompanied by typical autoantibodies against the target tissues. Chronic mucocutaneous candidiasis is also a prominent part of the disease. The highest expression of AIRE is found in medullary thymic epithelial cells (mTECs). Murine studies suggest that it promotes ectopic transcription of self antigens in mTECs and is thus important for negative selection. However, failed negative selection alone is not enough to explain key findings in human patients, necessitating the search for alternative or additional pathogenetic mechanisms. A striking feature of the human AIRE-deficient phenotype is that all patients develop high titers of neutralizing autoantibodies against type I interferons, which have been shown to downregulate the expression of interferon-controlled genes. These autoantibodies often precede clinical symptoms and other autoantibodies, suggesting that they are a reflection of the pathogenetic process. Other cytokines are targeted as well, notably those produced by Th17 cells; these autoantibodies have been linked to the defect in anti-candida defenses. A defect in regulatory T cells has also been reported in several studies and seems to affect already the recent thymic emigrant population. Taken together, these findings in human patients point to a widespread disruption of T cell development and regulation, which is likely to have its origins in an abnormal thymic milieu. The absence of functional AIRE in peripheral lymphoid tissues may also contribute to the pathogenesis of the disease.
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