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

Abstract

Activated B cells modulate infection by differentiating into pathogen-specific antibody-producing effector plasmablasts/plasma cells, memory cells, and immune regulatory B cells. In this context, the B cell phenotypes that infiltrate the central nervous system during human immunodeficiency virus (HIV) and cryptococcal meningitis coinfection are ill defined. We characterized clinical parameters, mortality, and B cell phenotypes in blood and cerebrospinal fluid (CSF) by flow cytometry in HIV-infected adults with cryptococcal (n = 31) and noncryptococcal (n = 12) meningitis and in heathy control subjects with neither infection (n = 10). Activation of circulating B cells (CD21low) was significantly higher in the blood of subjects with HIV infection than in that of healthy controls and greater yet in matched CSF B cells (P < 0.001). Among B cell subsets, elevated frequencies of memory and plasmablasts/plasma cells most clearly distinguished the CSF from blood compartments. With cryptococcal meningitis, lower frequencies of expression of the regulatory protein programmed death-1 (PD-1) on plasmablasts/plasma cells in blood (median, 7%) at presentation were associated with significantly decreased 28-day survival (29% [4/14 subjects]), whereas higher PD-1 expression (median, 46%) characterized subjects with higher survival (88% [14/16 subjects]). With HIV infection, B cell differentiation and regulatory markers are discrete elements of the circulating and CSF compartments with clinical implications for cryptococcal disease outcome, potentially due to their effects on the fungus and other local immune cells.

Landmark clinical observations and immunopathogenesis pathways linked to HIV and Cryptococcus fatal central nervous system co‐infection

“…24 Surprisingly, from the above studies, activation and differentiation of the CSF cellular phenotype seem to be altered by programmed death-1 (PD-1; CD279) immune checkpoint receptor and programmed death-1 ligand (PD-L1; CD274) expression. 24,66 The PD-1 is a ubiquitous immune checkpoint transmembrane molecule that is expressed on lymphoid cells particularly on T follicular helper cells 67,68 and on cells of the myeloid lineage with B cells, monocyte, macrophages and NK cells being effector cells. [69][70][71] PD-1 expression is triggered following induced cellular activation.…”

“…The Cryptococcus infection of the CNS induces inflow (trafficking) of intervening peripheral immune cells into the CNS, traversing the blood‐brain barrier. Alternatively, Cryptococcus infection of the CNS could induce local CNS cellular activation and differentiation to produce intrathecal activated and inflammatory response 24,25,66 . The difference in immune response in cryptococcal meningitis between blood and the CSF compartments shows the existence of marked activation and increased inflammation in CSF than in blood at onset of cryptococcal meningitis and at onset of cryptococcosis‐IRIS 24,25,66 .…”

“…62,64 Thus, interruption of the pathways that aid Cryptococcus access to the CNS where it establishes fatal disease could alter clinical outcomes. 23,45,65 The evidence that Cryptococcus is predominant in the CSF compartment of individuals with cryptococcal meningitis (Figure 1), 24,66 suggests that the fungus influences host immunological and treatment outcomes via its effects on the central nervous system (brain, spinal cord, and CSF). Thus, the predominance of the facultative extracellular Cryptococcus in the closed CSF interacting with immunocytes may be a translational target to model innate and adaptive immune factors and mechanisms of infection and treatment outcome.…”

“…Among HIV-infected adults (>18 years of age), cryptococcal meningitis is diagnosed in CSF 7-28 days from onset of symptoms. [19][20][21][22][23][24] However, early symptoms including fever and headache may complicate early diagnosis and delay antifungal treatment in regions with other endemic pathogens that present with similar symptoms. 20,21,25,26 Cryptococcosis results in 20%-40% HIVrelated deaths worldwide.…”

“…Of note, in large cryptococcosis cohorts, factors associated with treatment failure have been inconsistently reported. [20][21][22][23][24]36,37 Hence, this review aims to point the field to the cryptococcosis immunopathogenesis factors and pathways to be targeted in further investigations to prevent infection or to alter persistent poor treatment outcome.…”