Polymorphisms in Receptors Involved in Opsonic and Nonopsonic Phagocytosis, and Correlation with Risk of Infection in Oncohematology Patients.

High-risk hematological malignancies are a privileged setting for infection by opportunistic microbes, with invasive mycosis being one of the most serious complications. Recently, genetic background has emerged as an unanticipated risk factor. For this reason, polymorphisms for genes encoding archetypal receptors involved in the opsonic and nonopsonic clearance of microbes, pentraxin-3 (PTX3) and Dectin-1, respectively, were studied and correlated with the risk of infection. Fungal, bacterial, and viral infections were registered for a group of 198 patients with high-risk hematological malignancies. Polymorphisms for the pentraxin-3 gene (PTX3) showed a significant association with the risk of fungal infection by Candida spp. and, especially, by Aspergillus spp. This link remained even for patients undergoing antifungal prophylaxis, thus demonstrating the clinical relevance of PTX3 in the defense against fungi. CLEC7A polymorphisms did not show any definite correlation with the risk of invasive mycosis, nor did they influence the expression of Dectin-1 isoforms generated by alternative splicing. The PTX3 mRNA expression level was significantly lower in samples from healthy volunteers who showed these polymorphisms, although no differences were observed in the extents of induction elicited by bacterial lipopolysaccharide and heat-killed Candidaalbicans, thus suggesting that the expression of PTX3 at the start of infection may influence the clinical outcome. PTX3 mRNA expression can be a good biomarker to establish proper antifungal prophylaxis in immunodepressed patients.

Profound blockade of T cell activation requires concomitant inhibition of different class I PI3K isoforms.

PI3K inhibitors have emerged as potential therapeutic tools for a variety of diseases, and thus, a vast array of compounds with specificity for different PI3K isoforms is being developed. Gaining knowledge about the contribution of the different isoforms to PI3K function will allow selecting the most appropriate inhibitor for each pathology. In this study, we have addressed the effect of PI3K inhibitors with specificity for different class I PI3K isoforms on primary human T cell activation. In particular, we have analyzed proliferation, expression of activation and differentiation markers, apoptosis induction, cytokine secretion and Akt phosphorylation in T cells stimulated in vitro with anti-CD3 and anti-CD28 monoclonal antibodies and cultured with either one of these compounds: p110ß-specific inhibitor TGX-221, p110δ-specific inhibitor IC-87114, p110γ inhibitor AS-242525 or pan-class I PI3K inhibitor BKM120. Inhibition of any of the isoforms led to an impairment of T cell activation, mainly of cytokine secretion and granzyme B expression. However, only complete blockade of class I PI3K activity with the pan-class I inhibitor effectively abrogated T cell proliferation. These results indicate that these three p110 isoforms (ß, δ and γ) take part in T cell activation, but all of them are dispensable for T cell proliferation.