B cell compartmentalization in blood and cerebrospinal fluid of HIV-infected ugandans with cryptococcal meningitis

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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. 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.

Original languageEnglish (US)
Article numbere00779-19
JournalInfection and immunity
Volume88
Issue number3
DOIs
StatePublished - Mar 1 2020

Bibliographical note

Funding Information:
Research was supported in part by the National Institutes of Health (U01AI089244 [D.R.B., D.B.M.], R01NS086312 [D.R.B., D.B.M.], K01TW010268 [D.R.B., D.B.M.], R01AI108479 [E.N.J.]), Veterans Affairs Research Service (I01CX001464 [E.N.J.]), the Fogarty International Center (1D43TW009771 [Y.C.M.]), and GlaxoSmithKline Trust in Science Africa (COL100044928 [S.O.]). This work was in part supported by a cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense (DOD).

Funding Information:
We thank Joshua Rhein, Abdu Musubire, Nabeta Henry, Jane Francis Ndyetukira, Cynthia Ahimbisibwe, Florence Kugonza, Alisat Sadiq, Radha Rajasingham, Catherine Nanteza, Richard Kwizera, and Darlisha Williams from Infectious Diseases Institute for patient care. For flow cytometry research support, we thank Jeremy Rahkola, Tina M. Powell (Mucosal and Vaccine Research Center, University of Colorado Denver and Veterans Affairs Research Program), Stefanie Sowinski, and Olive Mbabazi (Infectious Diseases Institute, Makerere University Translational Sciences Laboratory). We thank Barbara Castelnuovo, Stephen Okoboi, Aidah Nanvuma, and Angella Sandra Namwase from Infectious Diseases Institute, Research Department, and Research Capacity Development Unit for mentorship and site supervision. We thank Proscovia Naluyima, Alison Taylor, Britta Flach, and the management of Makerere University Walter Reed Project Mulago Laboratory for supporting the project. We thank Damalie Nakanjako from the Department of Medicine, College of Health Sciences, Makerere University, for healthy subject specimens from her HIV seronegative observational cohort.

Publisher Copyright:
© 2020 Okurut et al.

Keywords

  • Activation
  • B cell activation
  • B cell subsets
  • Blood
  • Cerebrospinal fluid
  • Cryptococcal meningitis
  • HIV
  • HIV coinfection
  • PD-1
  • PD-1 expression
  • Plasmablasts/plasma cells
  • Survival

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