# Cryptococcus: History, Epidemiology and Immune Evasion
## 7 Polysaccharide Capsule
### Glucuronoxylomanan (GXM)  
The glucuronoxylomanan polysaccharide is the major component in the _Cryptococcus_ spp. capsule and its effects on the immune system are diverse, converging mainly on an immunoregulatory response [100]. GXM is diffused in body tissues during a cryptococcal infection, with the highest concentrations being found in the lungs, largely due to the persistence of the fungus during pulmonary infection, while the lowest levels are in the spleen, blood and cerebrospinal fluid [127]. Studies investigating the immunomodulatoryeffects in the presence of GXM use non-encapsulated strains as a control, since they do not have GXM [128, 129]. This polysaccharide still has an antiphagocytic character, since it generates electrostatic repulsion due to its negative charge, reducing the interaction between effector cell and pathogen [130]. This is exemplified by the reduction in cell adhesion of non-capsulated yeasts; when they are experimentally coated with GXM, the phagocytosis is drastically reduced [131]. A characteristic that GXM brings to the table is the affinity for specific anti-GXM antibodies generated in the course of an infection and the influence that these antibodies have in increasing phagocytosis in yeasts by macrophages [132, 133]. GXM increases affinity not only depending on specific antibodies, but also on the action of complement proteins, such as C3, which reinforces the importance that complement receptors have in fighting infection [134]. These receptors are not only found in macrophages but also in B cells [135], and their presence is associated with the maintenance of the B-1 lymphocyte population [136]. In addition, the complement receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18) have already been described as contributing to the phagocytosis of _C. neoformans_, independently of the action of antibodies [137]. In addition to binding soluble molecules, GXM has already shown interaction with receptors of innate immunity cells, mainly in the incorporation of the polysaccharide into the cell interior, mediated by: CD18 receptor on neutrophils [138], FcyRII and CD206, important in the antigenic presentation of dendritic cells during cryptococcosis [139]. Although these receptors are not associated with GXM clearance during infection [140], their accumulation within phagocytes leads to the modulation of intracellular cytokine production, such as the regulation of TNF-\(\alpha\) by the interaction with CD14 and TLR4 via GXM binding [141], and GXM-CD14 interaction that induces IL-8 production in alveolar macrophages [142]. The negative modulation of GXM in the production of cytokines associated with the inflammatory response has already been observed, as was the reduction in secreted TNF-\(\alpha\), IL-\(\beta\) and IFN-\(\gamma\)[143, 144] and the increase in IL-10 associated with an anti-inflammatory profile [145]. Furthermore, high levels of IL-10 are associated with the presence of GXM in cerebrospinal fluid, and this has already been described as a predictor of death from cryptococcal meningoencephalitis [146]. Another mechanism generated by the interaction with GXM is the induction of cellular apoptosis [145, 147]. This mechanism has already been described as being triggered on the production of nitric oxide induced by GXM [148], and the action of caspase-8 via the induction of Fas and FasL receptor expression [109, 149]. Furthermore, GXM is able to suppress the expression of MHCII, reducing antigen presentation by dendritic cells and, consequently, the proliferation of T lymphocytes. However, GXM also non-specifically prevents T cell proliferation [150, 151, 152]. Another mechanism observed is the inhibition in the production of neutrophil extracellular traps (NET) by the presence of GXM in an in vitro model, which further reinforces the immunoregulatory potential of this polysaccharide [128]. Interestingly, that is evidence that fractions of different molecular weights of GXM from _C. neoformans_ elicit different immunomodulatory activities in vitro.