# Cryptococcus: History, Epidemiology and Immune Evasion
## 7 Polysaccharide Capsule
### Glucuronoxylomomogalactan (GXMgGal)  
The polysaccharide glucuronoxylomanogalactan was several times described as galactoxylomanan due to its first structural characterizations showing the presence of galactose, xylose and mannose [111]. However, in later studies, it was found that it had a galactose main chain as opposed to mannose and the residue associated with the galactoxyloman  
tose side chain, previously described as \(\beta\)-(1-3)-xylosyl, was actually a \(\beta\)-(1-3)-glucuronyl bond, thus, adding glucuronic acid to the structure of this polysaccharide. Therefore, a new nomenclature was proposed, identifying it as a glucuronoxylomannogalactan [155]. Furthermore, a high rate of \(O\)-acetylations was recently revealed in the structure of GXMg-Gal from _C. neoformans_ in a capsular growth-inducing medium, demonstrating the higher presence of important binding sites in this polysaccharide that may confer potential immunobiological activity [115]. One of the characteristics that differentiates the species of _C. neoformans_ and _C. gatti_ with regard to the immunoregulatory potential of GXM is the differences in the \(O\)-acetylations of this polysaccharide, suggesting a relationship with the greater virulence of _C. gattii_[124], on the GXMgal of _C. gattii_; the real implications of its potential are still unknown. Another important structural adjustment proposed is the presence of two galactofuranosides, linked by \(\beta\)-(1-2)- and \(\beta\)-(1-3)- bonds to the galactose residues of the main chain of GXMgal from _C. neoformans_, which suggests greater complexity in the structure of this polysaccharide than previously observed [156]. Some immunomododulatory effects of GXMgal have already been observed, such as the activation of cellular apoptosis induced by Fas and FasL, as already observed in GXM [109] and unlike GXM, GXMgal induces NET release by neutrophils instead of inhibiting [128], which shows a clear indication of immunoactivating activity in GXMgal. Regarding GXMgal apoptosis-inducing properties, T lymphocyte glucocorticoids responsible for the interaction with this polysaccharide, such as CD7, CD43 and CD45, have already been described within this mechanism, inducing indirectly and directly by the activation of Bid and Caspase-9 [157]. An interesting finding in this context is the relationship discovered by GXMgal in the activation of immunological paralysis, through the depletion of B lymphocyte populations, due to its pro-apoptotic properties during the course of infection by _C. neoformans_[158, 159]. GXMgal has already been described as a potent inducer of dendritic cell activation in the context of a Th17 profile in vitro and, in addition, treatment with GXMgal before infection by _C. neoformans_ promotes protection against the fungus by a mechanism dependent on the production of IL-6 and IL -17 [160]. The production of IL-6 induced by GXMgal has also been observed in monocytes and appears to be independent of the action of TNF-\(\alpha\)[161]. In addition, it has already been described that GXMgal binds to CD18 receptors on neutrophils [138], inducing iNOS expression in the RAW macrophage line as well as nitric oxide (NO) production [109, 162]. However, some immunoregulatory properties of GXMgal have already been reported, such as the induction of a Treg profile in function and in number of cells [163], the inhibition of IL-17A production in T lymphocytes from patients with rheumatoid arthritis [164] and reduced production of IL-1\(\beta\) and IL-12 [165]. Data on the immunomododulatory effects of GXMgal are diverse and demonstrate the little knowledge elucidated about the real functions and mechanisms that this polysaccharide can elicit; in addition, there are no data on the structure of this polysaccharide in _C. gattii_, demonstrating the importance of further research in order to unravel it, as it must result in possible differences in immunobiological effects between different species of _Cryptococcus_ spp.