Clinical immunology

Abstract

Paracoccidioides brasiliensis, a thermo-dimorphic fungus, is the etiologic agent of paracoccidioidomycosis (PCM). The recidive is the greatest obstacle of this disease, because the yeast usually returns after the long treatment period. In the present work, we have investigated the cellular immune response of cells from peripheral blood drawn from patients with different duration of PCM. The classification of patients ranged from no treated to those with longstanding disease over 5 years. No stimulated as well as cells stimulated with phytohemaglutinin or two different antigen preparations, secreted (MEXO) or somatic (PbAg) of P. brasiliensis, were characterized. We found that cells from patients with disease proliferate considerably upon stimulation with the antigen preparations and that cells from patients with disease of long duration does not proliferate that vigorously as from patients with more recent diagnosis. Both interferon (IFN)-γ and interleukin (IL)-4 appear to be increased in patients, but IFN-γ tended to increase upon treatment while IL-4-secretion decreased. With respect to CD28 and CD86, we found that the subset of CD28 positive CD8 cells is decreased in all stages of the disease as compared to control individuals. A subset of CD86 positive CD19 cells appeared to be considerably increased compared to the controls. Indeed, our results demonstrated that the treatment of PCM patients promoted a regulation of IFN-γ, IL-4 levels and CD28, CD86 expression bringing new insight to the cellular immune response in PCM. In order to balance the host-parasite interaction in its favor, P. brasiliensis must take advantage of a number of mechanisms to dampen hosts´ immune responses at several checkpoints, either to allow its dissemination from the initial site of infection or to allow its safe persistence within the host for years or decades. In our pursue to dissect such mechanisms we have shown, on one hand, that stimulation with the main P. brasiliensis antigen (gp43) of PBMC from patients with active PCM lead to decreased IL-12, IL-2 and IFN-g secretion but high IL-10 levels. In parallel, gp43 induced low (or not at all) IL-12R β2 expression in patients' T-cells, but high expression in controls; C. albicans antigen (CMA) did it quite comparably in both groups. MODULATION OF THE ANTIGEN-SPECIFIC RESPONSES IN PARACOCCIDIOIDOMYCOSIS PATIENTS: THE ROLE OF CYTOKINES AND COSTIMULATORY MOLECULESGilThese findings suggest a specific imbalance in the IL-12/INF-γ/IL-10 regulation. In this regard, it has recently been shown that cytokines modulate the expression and activity of the family of "signal transducers and activators of transcription" (STATs): e.g., IFN-γ enhances its functionality. We will show that this also holds true in PCM patients. We will show that there is a severe impairment of STAT1 expression in T cells from patients as compared to controls. This likely may impact the anti-P. brasiliensis macrophage activities and the host´s ability in mounting Th-1 type responses.On the other hand, we have shown tha...