TLR9 activation dampens the early inflammatory response to paracoccidioides brasiliensis, Impacting host survival

Background: Paracoccidioides brasiliensis causes paracoccidioidomycosis, one of the most prevalent systemic mycosis in Latin America. Thus, understanding the characteristics of the protective immune response to P. brasiliensis is of interest, as it may reveal targets for disease control. The initiation of the immune response relies on the activation of pattern recognition receptors, among which are TLRs. Both TLR2 and TLR4 have been implicated in the recognition of P. brasiliensis and regulation of the immune response. However, the role of TLR9 during the infection by this fungus remains unclear.J.F. Menino was supported by a grant from Fundacao para a Ciencia e Tecnologia (FCT), Portugal (SFRH/BD/33446/2008). This work was supported by a grant from FCT (PTDC/BIA-MIC/108309/2008). M. Saraiva is a Ciencia 2007 fellow and M. Sturme is a Ciencia 2008 fellow. We would also like to thank FAPESP (Fundacao para Amparo a Pesquisa do Estado de Sao Paulo) and CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico) for financial support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

IMPAIRED PROLIFERATIVE RESPONSE AND LOW INTERLEUKIN-2 PRODUCTION IN PATIENTS WITH LYMPHOMA

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Cytokines and lymphocyte proliferation in juvenile and adult forms of paracoccidioidomycosis: comparison with infected and non-infected controls

Cellular immune response to Paracoccidiodes brasiliensis antigens (PbAg) was evaluated in patients with the juvenile (JF) and adult (AF) forms of paracoccidioidomycosis as well as in a group of infected individuals living in the endemic area but without any clinical manifestation of the disease. The immune profile of this group of paracoccidioidomycosis-infected individuals was characterized by: 1) a positive skin test to R brasiliensis antigen; 2) absence of specific antibodies; 3) a vigorous lymphoproliferative response to PbAg; and 4) a typical Th1 pattern of cytokines, with production of IFN-gamma and basal levels of IL-4, IL-5 and IL-10, At the opposite end of the spectrum were the JF patients whose proliferative response to PbAg was significantly impaired and whose cytokine pattern was characteristically Th2, i.e. lower IFN-gamma secretion and significantly higher levels of IL-4, IL-5 and IL-10. These profiles are compatible with forms of higher and lower resistance, respectively. Intermediate immune responses were observed in AF patients, whose specific lymphoproliferative response was lower than in the paracoccidioidomycosis-infected group but higher than in the JF patients. The secretion of IFN-gamma and IL-10 did not differ from the JF group, although IL-4 and IL-5 levels were significantly lower. Since AF patients are able to control fungal dissemination for decades, they can be considered more resistant than JF patients, who manifest the disease soon after infection. (C) 2002 Editions scientifiques et medicales Elsevier SAS. All rights reserved.4213914

Enhanced production of specific IgG4, IgE, IgA and TGF-beta in sera from patients with the juvenile form of paracoccidioidomycosis

Paracoccidioidomycosis (PCM) occurs in two distinct forms, the acute or juvenile form (H), and the chronic or adult form (AT). To clarify the basis of this dichotomy, specific IgG subclasses, IgA and IgE anti-gp43 were measured by enzyme-linked immunosorbent assay, in patients with different forms of PCM. Serum levels of tumor necrosis factor-alpha, interleukin (IL)-6, IL-8, macrophage inflammatory protein (MIP)-1alpha and transforming growth factor (TGF)-beta were also quantified. We show here that JF patients have significantly higher titers of IgE antibodies against gp43, an immunodominant antigen specific for Paracoccidioides brasiliensis, than do patients with the unifocal adult form (UF-AF, isolated lesions). Patients with the multifocal adult form (MF-AF, lesions in more than one organ) also produced elevated levels of anti-P. brasiliensis IgE. Furthermore, specific IgE levels were correlated with IgG4, IgA and eosinophilia. Patients with JF showed eosinophilia and increased levels of TGF-beta, a switching factor for IgA. These results indicate a T helper (Th)-2 pattern of cytokine expression in both the JF and the MF-AF of PCM. On the other hand, patients with UF-AF had a significantly lower production of specific IgE, IgG4 and IgA than was seen in the other patient groups.40215315