Antibody Responses in HIV-Infected Patients With Advanced Immunosuppression and Asymptomatic Cryptococcal Antigenemia

Abstract

BackgroundThere are no host biomarkers of risk for HIV-associated cryptococcal meningitis (CM) except CD4+ T-cell deficiency. At present, serum cryptococcal antigen (CrAg) screening of those with CD4 <100 cells/µL is used to identify persons at risk for HIV-associated CM. We determined if plasma antibody profiles could discriminate CrAg+ from CrAg- patients.MethodsWe performed serological analyses of 237 HIV-infected asymptomatic Zimbabwean patients with CD4 <100 cells/µL; 125 CrAg- and CrAg+ but cerebrospinal fluid CrAg- by CrAg lateral flow assay. We measured plasma immunoglobulin M (IgM), immunoglobulin G (IgG) 1, and IgG2 concentrations by Luminex, and titers of Cryptococcus neoformans (Cn) glucuronoxylomannan (GXM) polysaccharide and naturally occurring Laminarin (natural Lam, a β-(1–3)-glucan linked polysaccharide)-binding IgM and IgG by enzyme-linked immunosorbent assay.ResultsGXM-IgG, -IgM, and -IgG2 levels were significantly higher in CrAg+ patients, whereas natural Lam-IgM and Lam-IgG were higher in CrAg- patients before and after adjustment for age, sex, and CD4 T-cell count, despite overlap of values. To address this variability and better discriminate the groups, we used Akaike Information Criteria to select variables that independently predicted CrAg+ status and included them in a receiver operating characteristic curve to predict CrAg status. By inclusion of CD4, GXM-IgG, GXM-IgM, and Lam-IgG, -IgG2, and -IgM, this model had an 80.4% probability (95% confidence interval, 0.75–0.86) of predicting CrAg+ status.ConclusionsStatistical models that include multiple serological variables may improve the identification of patients at risk for CM and inform new directions in research on the complex role that antibodies may play in resistance and susceptibility to CM.

B Cell Compartmentalization in Blood and Cerebrospinal Fluid of HIV-Infected Ugandans with Cryptococcal Meningitis

“…This distinction is important in determining whether patients with such advanced disease can actually generate a specific response to this systemic and local neurologic cryptococcal infection. The fact that T cells to the fungus are detected in blood (30) and antibodies in blood (31,32) and CSF (E. Finn, S. Okurut, and E. N. Janoff, unpublished data) suggests that they can. In this context, these data build on a limited but well-derived set of observations about the presence of B cells in the CSF during HIV infection.…”

Human IgM Inhibits the Formation of Titan-Like Cells in Cryptococcus neoformans

“…These findings may help explain why C. neoformans in the lungs of C. neoformans-infected IgM-deficient XID mice were markedly larger than those in control mice (28). In humans, cryptococcal disease status is associated with lower levels of IgM memory B cells (which produce IgM) and/or IgM in multiple studies (22,25,26,34). This lends strength to the idea that patient immunoglobulin levels may affect C. neoformans biology in vivo.…”

“…S6B) of C. neoformans by HL-60 cells were not affected by IgM, IgG, or PBS. (21,22,24,31), which are ␤-1-3-glucans contained within the C. neoformans cell wall. We depleted antibodies that bind to these determinants from serum IgM and compared the effects of depleted and undepleted IgMs on titan-like cell formation.…”

“…In addition, B-1b cells produce IgA (39, 40). IgA was not examined in studies of C. neoformans pathogenesis in B celldeficient mice, and human IgA was not measured in studies of patients with or at risk for cryptococcal disease (22,(24)(25)(26)34). Human IgA measurements should be incorporated into further studies.…”

“…Important mediators of the innate immune responses are naturally occurring serum antibodies that bind conserved microbial determinants, including fungal cell wall glucans (20)(21)(22)(23). Prior work demonstrated that levels of laminarin (branched 1-3-␤-glucan)-binding antibodies were lower and inversely associated with serum cryptococcal antigen (CrAg) levels in HIV-infected patients with positive compared to those with negative CrAg assays (22). Lower laminarin antibody levels were also found in patients with HIVassociated cryptococcal immune reconstitution inflammatory syndrome (C-IRIS) than in those without C-IRIS (24).…”