The role of CD40L-CD40 interaction in the antifungal immune response mediated by neutrophils and macrophages in humans

Abstract

The increasing number of individuals affected by serious fungal infections demands a better understanding of their immunopathological and genetic bases. PIDs represent a great opportunity to understand the genes in nature and mechanisms of the immune response involved in host-fungus relationship in humans. Patients with IDP caused by deficiency of CD40 ligand (CD40L) are susceptible to invasive fungal infections, which despite treatment through replacement of immunoglobulins, still affect these individuals, result in severe morbidity and high mortality rates. Neutrophils and macrophages are the effector cells of the immune system responsible for the fungicidal! activity, however, since the discovery of the deficiency of CD40L in 1993, the immune response mediated by these phagocytes has not been investigated in these patients. Studies with human cells of healthy Controls and murine models have shown that CD40-CD40L interaction plays an important regulatory function during ontogeny and activation of phagocytes. These cells after recognition of PAMPs by PRRs produce cytokines, reactive oxygen intermediates, acidify the phagolysosome, and trigger other mechanisms essential to the antifungal immune response. The efficient activation of phagocytes mediated by PRRs occurs through the activation of the transcription factor NF-kB, which depends at least partially of the CD40-CD40L interaction. In the absence of this interaction, the activation of NF-kB and function of these receptors may be compromised. We believe that failures in the function Cf neutrophils and macrophages in CD40L- deficient patients contribute to the susceptibility to fungai infections. So our objective is to study the immune response against fungi mediated by neutrophils and macrophages from CD40L-deficient patients and to analyze in vitro the action of IFN-γ and soluble CD40L (CD40Ls) on these phagocytes. This project aims to contribute to the advancement of knowledge about the CD40L-CD40 interaction in the antifungal immune response in humans, as well as envision new therapeutic applications for IFN-γ and / or CD40Ls in the treatment of fungal infections in these patients. (AU)