Cryptococcus neoformans -Reactive and Total Immunoglobulin Profiles of Human Immunodeficiency Virus-Infected and Uninfected Ugandans

Abstract

We determined total and Cryptococcus neoformans glucuronoxylomannan (GXM)-reactive antibody repertoires of human immunodeficiency virus (HIV)-infected and HIV-uninfectedThe results showed that HIV-infected subjects had significantly lower levels of IgM to GXM but higher levels of total immunoglobulin and IgG and IgA to GXM than those of HIV-uninfected subjects. HIV-infected subjects with a history of pneumonia had higher levels, and those with a history of herpes zoster had lower levels of GXM-binding antibodies than subjects with no history of either disease. Minimal to no cross-reactivity was demonstrated between antibodies to GXM and polysaccharides in a pneumococcal vaccine. No significant differences between the antibody repertoires of HIV ؉ CM ؉ and HIV ؉ CM ؊ subjects were identified, but among subjects without a history of pneumonia, there was a trend towards lower V H 3-positive antibody levels among HIV ؉ CM ؉ than among HIV ؉ CM ؊ subjects. Our findings demonstrate an association between previous infectious diseases and differences in the total and GXM-reactive antibody repertoires of HIV-infected subjects and suggest the question of whether certain microbes modulate subsequent antibody responses to GXM deserves further study.

Antibody Response to Cryptococcus neoformans Capsular Polysaccharide Glucuronoxylomannan in Patients after Solid-Organ Transplantation

“…A loss of IgM memory B cells was implicated in susceptibility to pneumococcus and impaired antibody responses to PPS (23,36,44) and in infections with encapsulated bacteria in patients with common variable immunodeficiency (6). There were no cases of pneumococcal disease in either the C. neoformans-positive or C. neoformans-negative cohort, and a previous study found no association between GXM-and PPS-reactive antibodies (40). However, the foregoing studies suggest an intriguing link to cryptococcal pathogenesis, since reduced memory IgM is a central defect in patients with increased risk for cryptococcosis, such as those with common variable immunodeficiency (2, 38), hyper-IgM (3,19,21,42), and HIV (32).…”

“…The possible roles of antibodies to GXM in resistance and susceptibility to cryptococcosis are unknown, but available data suggest that the naturally occurring GXM-reactive repertoire may contribute to resistance (discussed in references 8 and 10). Studies comparing HIV-infected and HIV-uninfected individuals, groups that are at very high and low risk for cryptococcosis, respectively, have also found lower levels of GXM-reactive IgM in HIV-infected subjects than in HIV-uninfected subjects (13,17,40), including individuals with relatively intact T-cell immunity (13). The data presented herein suggest that a reduced level of GXM-reactive IgM could portend a risk of cryptococcosis in the setting of immunosuppression, although whether it reflects previously unrecognized variation in the population or is induced by HIV infection or transplantation is unknown.…”

“…First, glucuronoxylomannan (GXM)-reactive mouse and human monoclonal antibodies (MAbs) prolong survival in lethal experimental cryptococcosis in mice, and B-cell deficiency alters the pathogenesis of C. neoformans in mice (reviewed in reference 7). Second, in humans, GXM-reactive and nonspecific antibody profiles differ between groups that are at high and low risk for cryptococcosis, namely, HIV-infected subjects and HIV-uninfected subjects, respectively (11,13,17,40). Third, the risk for cryptococcosis is increased in patients with immunoglobulin disorders and deficiency, including hyperimmunoglobulin M (hyper-IgM), hypogammaglobulinemia, X-linked immunodeficiency, common variable immunodeficiency, and B-cell-associated malignancy (19,21,34,38,42).…”

“…The titers of IgM and IgG to GXM (GXM-reactive IgM and IgG) were determined by ELISAs as described previously (13,40). IgA to GXM was not determined in this study due to limited serum availability and the lack of difference in titers between high-risk (HIVinfected) and low-risk (HIV-uninfected) individuals in a previous study (40). Polystyrene plates (96-well plates) (Costar; Corning Glass Works, Corning, NY) were coated for 3 h at room temperature with 1 g/ml of SB4, a serotype A isolate of C. neoformans (provided by A. Casadevall).…”

Of Mice and Men, Revisited: New Insights into an Ancient Molecule from Studies of Complement Activation byCryptococcus neoformans

“…Consistent with this hypothesis, underlying B-cell defects are common in patients with hypogammaglobulinemia and hyper-immunoglobulin M (IgM) syndromes, immunoglobulin disorders that have been linked to an increased risk for cryptococcosis (discussed in reference 61). Lower levels of GXM-reactive IgM have been found among HIV-infected individuals than among HIV-uninfected individuals (61). IgM, like complement, is an important serum opsonin.…”