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

Samuel Okurut,Yukari C Manabe,David B Meya,Paul R Bohjanen,Harsh Pratap,Michael A Eller,Joseph Olobo,Katharine H Hullsiek,David R Boulware,Freddie Bwanga,Edward N Janoff,Brent E Palmer,Fatim Cham-Jallow,Mairi C Noverr

doi:10.1128/iai.00779-19

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.

Highlights

Activated B cells modulate infection by differentiating into pathogenspecific antibody-producing effector plasmablasts/plasma cells, memory cells, and immune regulatory B cells
Among subjects with cryptococcal meningitis, median survival time was 10 days (95% confidence interval [CI], 4 to 19 days) for those dying by 28 days and 50 days for those dying after 28 days
We describe in detail for the first time the distinct B cell subset maturation, activation, and regulatory markers in paired cerebrospinal fluid (CSF) and blood from human immunodeficiency virus (HIV)-infected individuals with and without cryptococcal meningitis and associated early mortality

Summary

Introduction

Activated B cells modulate infection by differentiating into pathogenspecific 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. The contribution of pathogen-specific antifungal responses can be compromised during HIV-1 infection by polyclonal B cell activation and attenuated humoral responses to primary and recall antigens [14] Both Cryptococcus and HIV may have profound influences on B cell activation and differentiation and their effector and regulatory roles in the central nervous system (CNS) where most fatal cryptococcal disease occurs [15]. (This work was presented in part at the Keystone Symposia on HIV Vaccines (X5) conference joint with the Golden Anniversary of B Cell Discovery Meeting in Banff Springs, Banff, Alberta, Canada, 22 to 27 March 2015 [16], and at the EMBO-AIDS related mycoses workshop in Cape Town, South Africa, 13 to 15 July 2016 [17].)

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