Dendritic cells from X-linked hyper-IgM patients present impaired responses to Candida albicans and Paracoccidioides brasiliensis

• Published in: Journal of allergy and clinical immunology Vol. 129; no. 3; pp. 778 - 786
• Main Authors: Marques, Otavio Cabral, MSc, Arslanian, Christina, BSc, Ramos, Rodrigo Nalio, MSc, Morato, Mariana, MSc, Schimke, LenaFriederike, MD, Soeiro Pereira, Paulo Vitor, MSc, Jancar, Sonia, MD, PhD, Ferreira, Janaíra Fernandes, MD, Weber, Cristina Worm, MD, Kuntze, Gisele, MD, Rosario-Filho, Nelson Augusto, MD, PhD, Costa Carvalho, Beatriz Tavares, MD, Bergami-Santos, Patricia Cruz, PhD, Hackett, Mary J., BSc, Ochs, Hans D., MD, Torgerson, Troy R., MD, PhD, Barbuto, Jose Alexandre Marzagão, MD, PhD, Condino-Neto, Antonio, MD, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.03.2012; Elsevier; Elsevier Limited
• Subjects: Adolescent; Allergy and Immunology; B7-1 Antigen - genetics; B7-1 Antigen - metabolism; B7-2 Antigen - genetics; B7-2 Antigen - metabolism; Bacterial infections; Biological and medical sciences; Candida albicans; Candida albicans - immunology; Candida albicans - pathogenicity; Candidiasis - complications; Candidiasis - genetics; Candidiasis - immunology; CD40 antigen; CD40 Ligand - genetics; CD40 Ligand - immunology; CD40 Ligand - metabolism; CD40 ligand deficiency; CD40L protein; CD80 antigen; CD86 antigen; Cell culture; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cell growth; Cell Proliferation; Cells, Cultured; Child; Child, Preschool; Coculture Techniques; Cytokines - metabolism; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dendritic Cells - pathology; Dendritic Cells - virology; Differentiation; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Fungal infections; Fungi; gamma -Interferon; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Helper cells; Histocompatibility antigen HLA; Histocompatibility Antigens Class II - genetics; Histocompatibility Antigens Class II - metabolism; Humans; Hyper-IgM Immunodeficiency Syndrome, Type 1 - complications; Hyper-IgM Immunodeficiency Syndrome, Type 1 - genetics; Hyper-IgM Immunodeficiency Syndrome, Type 1 - immunology; Immune system; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infection; Interleukin 10; Interleukin 12; Interleukin 17; Interleukin 4; Interleukin 5; Job's syndrome; Lymphocyte Activation - drug effects; Lymphocyte Activation - genetics; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Male; Medical sciences; Metabolic diseases; Miscellaneous; Monocytes; Mutation; Mutation - genetics; Other metabolic disorders; Paracoccidioides - immunology; Paracoccidioides - pathogenicity; Paracoccidioides brasiliensis; Paracoccidioidomycosis - complications; Paracoccidioidomycosis - genetics; Paracoccidioidomycosis - immunology; Pathogens; primary immunodeficiency; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; T cell receptors; Th17 Cells - immunology; Th17 Cells - metabolism; Th17 Cells - pathology; Transforming growth factor- beta; X chromosome; X-linked hyper-IgM syndrome; CD40L; APCs; Immature DCs; Soluble CD40 ligand; X-linked hyper-IgM syndrome; fungal infections; Mature DCs; sCD40L; dendritic cells; Antigen-presenting cells; DCs; mDCs; CD40 ligand; primary immunodeficiency; PTX3; X-HIGM; CD40 ligand deficiency; iDCs; Pentraxin 3; Endocrinopathy; Candida albicans; Sex linked character; Mycosis; Blastomyces brasiliensis; Hyperimmunoglobulinemia M syndrome; Cardiovascular disease; Metabolic syndrome; Fungi; Immunology; Antigen presenting cell; Primary; Fungi Imperfecti; X-Chromosome; Ascomycota; Human; Dendritic cell; Immunopathology; Metabolic diseases; Immune deficiency; Genetic disease; Infection
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2011.10.026

Background Patients with X-linked hyper-IgM syndrome (X-HIGM) due to CD40 ligand (CD40L) mutations are susceptible to fungal pathogens; however, the underlying susceptibility mechanisms remain poorly understood. Objective To determine whether monocyte-derived dendritic cells (DCs) from patients with X-HIGM exhibit normal responses to fungal pathogens. Methods DCs from patients and controls were evaluated for the expression of costimulatory (CD80 and CD86) and MHC class II molecules and for their ability to produce IL-12 and IL-10 in response to Candida albicans and Paracoccidioides brasiliensis. We also evaluated the ability of C albicans– and P brasiliensis– pulsed mature DCs to induce autologous T-cell proliferation, generation of T helper (TH ) 17 cells, and production of IFN-γ, TGF-β, IL-4, IL-5, and IL-17. Results Immature DCs from patients with X-HIGM showed reduced expression of CD80, CD86, and HLA-DR, which could be reversed by exogenous trimeric soluble CD40L. Most important, mature DCs from patients with X-HIGM differentiated by coculturing DCs with fungi secreted minimal amounts of IL-12 but substantial amounts of IL-10 compared with mature DCs from normal individuals. Coculture of mature DCs from X-HIGM patients with autologous T cells led to low IFN-γ production, whereas IL-4 and IL-5 production was increased. T-cell proliferation and IL-17 secretion were normal. Finally, in vitro incubation with soluble CD40L reversed the decreased IL-12 production and the skewed TH 2 pattern response. Conclusion Absence of CD40L during monocyte/DC differentiation leads to functional DC abnormalities, which may contribute to the susceptibility to fungal infections in patients with X-HIGM.