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

• Autor(a) principal: Marques, Otavio Cabral
• Data de Publicação: 2012
• Outros Autores: Arslanian, Christina, Ramos, Rodrigo Nalio, Morato, Mariana, Schimke, LenaFriederike, Soeiro, Paulo Vitor, Jancar, Sonia, Ferreira, Janira Fernandes, Weber, Cristina Worm, Kuntze, Gisele, Rosario-Filho, Nelson Augusto, Costa-Carvalho, Beatriz Tavares [UNIFESP], Bergami-Santos, Patricia Cruz, Hackett, Mary J., Ochs, Hans D., Torgerson, Troy R., Marzagao Barbuto, Jose Alexandre, Condino-Neto, Antonio
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UNIFESP
• Texto Completo: http://repositorio.unifesp.br/handle/11600/34634; http://dx.doi.org/10.1016/j.jaci.2011.10.026
• topic: CD40 ligand deficiency; fungal infections; dendritic cells; X-linked hyper-IgM syndrome; primary immunodeficiency

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 (T-H) 17 cells, and production of IFN-gamma, TGF-beta, 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-g 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 T-H(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. (J Allergy Clin Immunol 2012; 129: 778-86.)