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

Institute for Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Clinical & Experimental Immunology (Impact Factor: 3.04). 01/2009; 154(3):406-14. DOI: 10.1111/j.1365-2249.2008.03778.x
Source: PubMed


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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Available from: Andrew J Cant, Jul 25, 2014
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    • "Following phagocytosis, DCs migrate to the lymph nodes where the Candida antigen is processed and presented on the surface of the DC to naïve CD4+ T-cells (84–88). Interaction between DCs and T-cells cause the latter to differentiate into mature effective T-cells (89). The type of T-cell generated is thought to be under direction of the DC and examples of effective T-cells include T-helper 1 (Th1), T-helper 2 (Th2), T-helper 17 (Th17), and regulatory T-cells (Tregs). "
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    ABSTRACT: Oral infections caused by yeast of the genus Candida and particularly Candida albicans (oral candidoses) have been recognised throughout recorded history. However, since the 1980s a clear surge of interest and associated research into these infections have occurred. This has largely been due to an increased incidence of oral candidosis over this period, primarily because of the escalation in HIV-infection and the AIDS epidemic. In addition, changes in medical practice leading to a greater use of invasive clinical procedures and a more widespread use of immunosuppressive therapies have also contributed to the problem. Whilst oral candidosis has previously been considered to be a disease mainly of the elderly and very young, its occurrence throughout the general population is now recognised. Candida are true 'opportunistic pathogens' and only instigate oral infection when there is an underlying predisposing condition in the host. Treatment of these infections has continued (and in some regards continues) to be problematic because of the potential toxicity of traditional antifungal agents against host cells. The problem has been compounded by the emergence of Candida species other than C. albicans that have inherent resistance against traditional antifungals. The aim of this review is to give the reader a contemporary overview of oral candidosis, the organisms involved, and the management strategies that are currently employed or could be utilised in the future.
    Journal of Oral Microbiology 01/2011; 3(2011, article 5771). DOI:10.3402/jom.v3i0.5771
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    • "After phagocytosis, DCs migrate to the nearest lymph node where the Candida antigen is processed and presented by the DCs to na¨ıve CD4 + T-cells [13] [14] [15] [16] [17] [18]. The na¨ıve T-cells then differentiate into mature effective Tcells under the direction of the DCs [19]. Examples of such differentiated T-cells include T-helper 1 (Th1), T-helper 2 (Th2), T-helper 17 (Th17), and regulatory T-cells (Tregs). "
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    ABSTRACT: Candida albicans is an opportunistic fungal pathogen that normally exists as a harmless commensal in humans. In instances where host debilitation occurs, Candida can cause a range of clinical infections, and whilst these are primarily superficial, effecting mucosal membranes, systemic infections can develop in severely immunocompromised individuals. The mechanism of host immunity during commensal carriage of C. albicans has been intensively studied. In this paper, we present the most recent information concerning host recognition of C. albicans leading to cytokine production and the subsequent T-cell responses generated in response to C. albicans. Particular focus is given to the role of the IL-12 cytokine family including IL-12, IL-23, IL-27, and IL-35, in host immunity to Candida. CD4(+) T-cells are considered crucial in the regulation of immunity and inflammation. In this regard, the role of Th1/2, helper cells, together with the recently identified Th17 and Treg cells in candidosis will be discussed. Understanding the detailed mechanisms that underlie host immunity to Candida not only will be of benefit in terms of the infections caused by this organism but could also be exploited in the development of therapeutic interventions for other diseases.
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    • "The lack of overt staphylococcal disease in most APS-I patients may result from residual IL-17 immunity, as observed to an even greater extent in patients with IL-12p40 and IL-12R1 deficiencies who also control staphylococcal infections normally (Filipe-Santos et al., 2006). In any case, proof that human IL-17 cytokines play an essential role in immunity to Candida will require the identification of mutations specifically impairing IL-17 immunity in other patients with inherited, isolated CMC without APS-I (Ryan et al., 2008; Hong et al., 2009 "
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