Marta Feldmesser¹ and Arturo Casadevall^1,2

1Departments of Medicine (Division of Infectious Diseases) and Microbiology and Immunology², Albert Einstein College of Medicine, Golding Building Room 701, 1300 Morris Park Ave., Bronx, NY 10461

Received 1/5/98 Accepted 1/9/98

5. THE AB RESPONSE TO C. NEOFORMANS

5.1 Native Ab production

Normal human serum contains Abs that are reactive with cryptococci. IgG from normal human serum can mediate phagocytosis of acapsular cryptococcal strains through an Fc-dependent attachment process by binding to mannoproteins in the cryptococcal cell wall and allowing attachment (45). Though IgG from normal human serum binds to encapsulated strains, it cannot mediate phagocytosis or agglutination because the cell wall-bound IgG is masked and cannot interact with appropriate receptors on the macrophage cell surface (46).

Studies of prevalence of Ab to the capsule or to GXM in patients without cryptococcal disease have yielded varying results. In one study, three percent of sera from normal patients contained antibody that is neutralizable with CNPS (47). Dromer et al reported the prevalence of Ab reactive with capsular polysaccharide to be 20% in patients with AIDS as opposed to 69% of controls, with similar prevalences of IgM and a significantly decreased prevalence of IgG (48). In a study by Houpt et al, among normal subjects, 98% had serum IgM that reacted with GXM, while 28% had IgG (mainly of the IgG2 subclass) and 3% had IgA. The prevalence of IgM Abs was markedly reduced in HIV-infected patients and this reduction occurred in patients with CD4 cell counts ³ 500/ml (49). A more recent study found that IgA, IgG and IgM Abs to GXM are ubiquitous in human sera from both HIV+ and HIV- individuals, and that the IgG present is of the IgG2 subclass, as is found in response to other organisms with polysaccharide capsules (50). However, Abs to an epitope that are present in HIV^- control sera and that are produced in response to the GXM-tetanus toxoid (TT) conjugate vaccine are not found in sera from HIV⁺ individuals, suggesting that qualitative differences in the Ab response after HIV infection may play a role in susceptibility to C. neoformans infection (51).

The source of GXM-reactive Abs in normal serum is unknown. Their presence may reflect repeated subclinical infection with C. neoformans and/or previous exposure to cryptococcal Ags. An equally likely possibility is that these are cross reactive Abs induced by exposure to other organisms, as Streptococcus pneumoniae, DF-2 and Trichosporon beigleii are antigenically similar to cryptococcal polysaccharide (52-54). Several investigators have reported that naturally occurring Abs are not opsonic for macrophage phagocytosis of C. neoformans in vitro (49,55,56).

5.2 The Ab response to infection and vaccination

In response to infection, studies from the pre-HIV era reported the development of serum Ab to C. neoformans in 39-79% of patients with cryptococcal disease (57-59). Similar studies have not been repeated in HIV infected patients, though evidence that the Ab response to cryptococcal polysaccharide differs quantitatively and qualitatively in HIV-infected individuals is accumulating (see above, (51). In animal models, Ab production in response to infection is species dependent. Small percentages of both BALB/c and C57Bl/6 mice produce significant titers of IgM and IgG to CNPS in response to infection which decline despite persistence of chronic infection (60,61). Endotracheally infected rats make a transient IgM response, followed by persistent IgG production (62). In early mouse studies in Swiss mice, immunization with whole, killed cells or their products did not elicit protective Ab production (63). Production of agglutinating Abs occurs more frequently in immunized rabbits than in mice (64). Susceptibility to infection in rabbits, rats and mice parallel their ability to make Ab. Rabbits and rats are high responders and control infection, whereas mice seldom respond and are a highly susceptible species (62,65).

The effect of Ab produced in response to cryptococcal infection is unknown, though in studies from the pre-AIDS era, the absence of serum Ab correlated with treatment failure (57) and the presence of Ab correlated with cure (59). Though most patients from the pre-AIDS era had underlying cellular immune defects, cases of patients with cryptococcosis whose sole defect was hypogammaglobulinemia were reported (66,67). Disseminated cryptococcosis has also been associated with hyper-IgM syndrome (68). In animal models, the benefit to the host of Ab generated in response to vaccination or infection varied. In a rabbit meningitis model in which rabbits are infected intracisternally, IgG that was opsonic for rabbit peritoneal macrophages was produced in the CNS, and the presence of IgG correlated with reduction in CFU (69). However, in other studies, mice immunized with cryptococcal polysaccharide-bovine gamma globulin conjugates developed high levels of Ab to polysaccharide, but the presence of Ab in these mice did not protect them from infection or prolong survival, and the presence of Ab did not correlate with CFU reduction (70). In a study by Monga, B cell-deficient mice did not have altered survival, CFU, DTH or Ag levels following i.v. infection (71). However, Ab titers were not measured in this study, and the absence of altered outcome may reflect the fact that even normal mice seldom make Ab responses during infection. In rabbits infected intracranially in a chronic meningitis model, preimmunization resulting in production of serum Ab did not affect yeast counts, dissemination from the CSF was not prevented and Ab was not measurable in the CSF (72). Differences in therapeutic efficacy of Ab produced in response to vaccination may reflect differences in the isotype or idiotype produced or differences in animal or cryptococcal strains.