The Role of AIRE in the Immunity Against Candida Albicans in a Model of Human Macrophages

Abstract

Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a primary immunodeficiency caused by mutations in the autoimmune regulator gene (AIRE). Patients with AIRE mutations are susceptible to Candida albicans infection and present with autoimmune disorders. We previously demonstrated that cytoplasmic AIRE regulates the Syk-dependent Dectin-1 pathway. In this study, we further evaluated direct contact with fungal elements, synapse formation, and the response of macrophage-like THP-1 cells to C. albicans hyphae to determine the role of AIRE upon Dectin receptors function and signaling. We examined the fungal synapse (FS) formation in wild-type and AIRE-knockdown THP-1 cells differentiated to macrophages, as well as monocyte-derived macrophages from APECED patients. We evaluated Dectin-2 receptor signaling, phagocytosis, and cytokine secretion upon hyphal stimulation. AIRE co-localized with Dectin-2 and Syk at the FS upon hyphal stimulation of macrophage-like THP-1 cells. AIRE-knockdown macrophage-like THP-1 cells exhibited less Dectin-1 and Dectin-2 receptors accumulation, decreased signaling pathway activity at the FS, lower C. albicans phagocytosis, and less lysosome formation. Furthermore, IL-1β, IL-6, or TNF-α secretion by AIRE-knockdown macrophage-like THP-1 cells and AIRE-deficient patient macrophages was decreased compared to control cells. Our results suggest that AIRE modulates the FS formation and hyphal recognition and help to orchestrate an effective immune response against C. albicans.

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

“…8,112,113 Alterations in C-type lectin receptor signaling in macrophages and impaired production of antimicrobial factors in mucosal secretions have also been proposed as potential contributing factors. [114][115][116] Thus far, the antifungal immune studies in APECED patients have focused on their systemic, but not their mucosal, immune responses. Because the immune response requirements for effective mucosal versus systemic host defense against Candida are strictly segregated, it is likely that yet-unknown defects at the mucosal level in these patients may also contribute to CMC susceptibility.…”

Primary Immunodeficiency with Severe Multi-Organ Immune Dysregulation

“…AIRE is also required for the function of the antifungal responses of Dectin-1 and Dectin-2 receptors [8]. ese defects explain the predisposition of patients with APECED to developing candidiasis [9].…”

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“…По ширеність в загальній популяції невідома. Існують країни з вищою частотою (Фінляндія -1:25000; Сардинія -1:14000 та серед Перських євреїв що проживають в Ізраїлі -1:9000) [6,7]. Захворювання однаково часто уражає чоловіків та жінок, може виникати в будь-якому віці.…”