Macrophage expression of class II major histocompatibility complex gene products in Paracoccidioides brasiliensis-infected mice.

Abstract

Abstract. C57Bl/6 isogenic mice infected with Paracoccidioides brasiliensis strains showed a disruption in the expression of Ia antigen. Expression slowly decreased during the course of the infection with a slight variation dependent on the route of inoculation and the fungal strain used, but production of interferon-␥ and tumor necrosis factor-␣ were observed. Suppression of Ia antigen expression and depression of the immunoproliferative responses of spleen cells were strongly correlated with nitric oxide levels. These parameters were inhibited when the animals were treated with nitro-L-arginine, which resulted in inhibition the activation of nitric oxide (NO) production. Analysis of the data showed that changes in the expression of the Ia antigen occur in P. brasiliensis infection and are strongly correlated with NO levels. These phenomena may be interrelated and reflect macrophage activation that contributes to the control of the disease and to the immunosuppression observed during the course of the infection.Paracoccidioidomycosis is a systemic fungal disease characterized by T cell-mediated granulomas. 1 The dimorphic fungus Paracoccidioides brasiliensis, the etiologic agent, is an intracellular parasite and parasitism of host mononuclear phagocytes is the central event in the dissemination of the disease. 2 Natural infections start by inhalation of conidia and/or mycelial fragments of the saprophytic phase. 3,4 The initial pulmonary lesions are asymptomatic in most cases, and may then regress spontaneously, become latent, or disseminate contiguously and/or via the lymphatics.5 Immunologic studies on patients with paracoccidioidomycosis have shown a range of responsiveness similar to that described in leprosy and leishmaniasis. 6 In the localized or regressive forms of the mycosis, delayed cutaneous sensitivity exists, and only rarely are antifungal antibodies detected. However, the generalized forms show high serum antibody concentrations associated with varying degrees of depression of T cell activity. 7 The basic mechanism responsible for the defective host response is not understood. Nevertheless, in a systemic fungal infection such as paracoccidioidomycosis, cell-mediated immunity is a significant factor and activated macrophages appear to be the major line of defense.8 Macrophages and their products are involved in the development of granulomatous inflammation and also promote antigen recognition and processing. These antigens may then be presented to other lymphoid cells on the surface of macrophage in the context of class II major histocompatibility complex gene products (Ia molecules). Thus, macrophages are of central importance in the induction of antigen-specific T lymphocyte activation.The surface expression of Ia molecules is essential for the functions of activated macrophages and is strictly regulated.9-11 Paracoccidioides brasiliensis usually engages in intracellular parasitism of macrophages, possibly causing disorders of the regulation of Ia expression at several levels. Therefore, this me...

Dual Role for Nitric Oxide in Paracoccidioidomycosis: Essential for Resistance, but Overproduction Associated with Susceptibility

“…‫,ء‬ significant difference (p Ͻ 0.05) between AG-treated vs untreated group. MHC class II expression (8) and that macrophages from susceptible mice are less effective in Ag presentation (25). However, our results with IA k expression are in contrast to those reports, as we showed that macrophage IA k expression of susceptible mice was not impaired and actually was higher in susceptible than in resistant mice throughout the infection.…”

“…Macrophage responses were assessed by the production of NO, TNF, and H 2 O 2 and by the expression of IA k molecules. These molecules were selected for analysis based on previous reports suggesting that they might influence the outcome of P. brasiliensis infection (7,8,23,24). Minor differences in macrophage responses of susceptible or resistant mice were observed when IA k expression and H 2 O 2 production were analyzed, while major differences were related to NO and TNF production.…”

“…A previous study indicated that Pb infection inhibited MHC class II Ag expression (8). As susceptible and resistant animals in our experimental model share the same IA k molecule in MHC class II complex, we could compare macrophage IA k expression during Pb infection in these mouse strains.…”

“…These discrepancies may be due to the different experimental protocols used. We analyzed IA k expression by freshly explanted macrophages, while Bocca et al (8) used thioglycolate-elicited macrophages that were incubated with IFN-␥. Regarding APC function it will be of interest to ascertain whether the Ag presentation of freshly explanted macrophages from susceptible mice is different from that of resistant mice.…”

“…Although NO production is involved in Pb killing (6), it can also be involved in immunosuppression, because NO inhibits lymphoproliferation, TNF-␣ production, and MHC class II molecule expression (7,8).…”