Fc Gamma Receptor 3A Polymorphism and Risk for HIV-Associated Cryptococcal Disease

Abstract

Cryptococcus neoformans is one of the most common causes of fungal disease in HIV-infected persons, but not all of those who are infected develop cryptococcal disease (CD). Although CD4+ T cell deficiency is a risk factor for HIV-associated CD, polymorphisms of phagocytic Fc gamma receptors (FCGRs) have been linked to CD risk in HIV-uninfected persons. To investigate associations between FCGR2A 131 H/R and FCGR3A 158 F/V polymorphisms and CD risk in HIV-infected persons, we performed PCR-based genotyping on banked samples from 164 men enrolled in the Multicenter AIDS Cohort Study (MACS): 55 who were HIV infected and developed CD and a matched control group of 54 who were HIV infected and 55 who were HIV uninfected. Using additive and allelic statistical models for analysis, the high-affinity FCGR3A 158V allele was significantly associated with CD status after adjusting for race/ethnicity (odds ratio [OR], 2.1; P = 0.005), as was the FCGR3A 158 VV homozygous genotype after adjusting for race/ethnicity, rate of CD4+ T cell decline, and nadir CD4+ T cell count (OR, 21; P = 0.005). No associations between CD and FCGR2A 131 H/R polymorphism were identified. In binding studies, human IgG (hIgG)-C. neoformans complexes exhibited more binding to CHO-K1 cells expressing FCGR3A 158V than to those expressing FCGR3A 158F, and in cytotoxicity assays, natural killer (NK) cells expressing FCGR3A 158V induced more C. neoformans-infected monocyte cytotoxicity than those expressing FCGR3A 158F. Together, these results show an association between the FCGR3A 158V allele and risk for HIV-associated CD and suggest that this polymorphism could promote C. neoformans pathogenesis via increased binding of C. neoformans immune complexes, resulting in increased phagocyte cargo and/or immune activation.

Efficient phagocytosis and laccase activity affect the outcome of HIV-associated cryptococcosis

“…In this context, it is interesting to note that Rohatgi et al very recently reported that a higher-affinity variant of the phagocytic receptor FcγRIIIA is a risk factor for HIV-associated cryptococcal disease (26). Thus, both host factors (26) and pathogen factors (this study) that enhance phagocytic uptake appear to increase the risk of (severe) cryptococcal disease.…”

Temporal Kinetics and Quantitative Analysis of Cryptococcus neoformans Nonlytic Exocytosis

“…C. neoformans has an antiphagocytic polysaccharide capsule (6) which requires the presence of opsonins in the form of complement or capsule-binding antibodies (Ab) for phagocytosis to occur (3). Fc receptor polymorphisms were associated with susceptibility to C. neoformans (7,8), suggesting a link between phagocytosis and the outcome of infection. Once inside the macrophage, the fungus resides in a mature phagosome and can survive acidification and phagocytic bursts (4,9).…”

Effect of FcγRIIa and FcγRIIIa Gene Polymorphism on Treatment Response and Overall Survival in Diffuse Large B Cell Lymphoma

“…Yapılan birçok çalışmada FcγRIIIa V/V polimorfizminin F/F fenotipine göre yanıtının daha iyi olduğu, yine FcγRIIa H/H fenotipinin R/R fenotipine göre yanıtlarının daha iyi olduğunu bildiren yayınlar mevcuttur (8,9,12). Ancak daha sonraki birçok araştırıcı, bahsedilen bu fenotiplerin hastalıksız yaşam üzerine etkisi olmadığını bildirdiler (20)(21)(22)(23)(24)(25)(26)(27)(28). Ayrıca daha önceki çalışmalardaki araştırıcılar belirtilen fenotiplerde yanıtın nasıl iyi olduğuna dair bir yorumda bulunmamışlardır.…”