Abstract
Background 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 HIV and cryptococcal meningitis co-infection are ill defined.
Methods We characterized clinical parameters, mortality and B cell phenotypes in blood and CSF by flow cytometry in HIV-infected adults with cryptococcal (n=31), and non-cryptococcal meningitis (n=12), and heathy control subjects with neither infection (n=10).
Results Activation of circulating B cells (CD21low) was significantly higher in blood of subjects with HIV infection compared with 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 PD-1 on plasmablasts/plasma cells in blood (median 7%) at presentation was 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)).
Conclusion 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.
Footnotes
Funding This research was supported in part by the National Institutes of Health (U01AI089244 (DRB, DBM), R01NS086312(DRB, DBM), K01TW010268 (DRB, DBM), R01AI108479 (ENJ)) and Veterans Affairs Research Service I01CX001464 (ENJ), the Fogarty International Center 1D43TW009771 (YCM), the GlaxoSmithKline-Trust in Science Africa (COL100044928) (SO). 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). The views expressed are those of the authors and should not be construed to represent the positions of the U.S. Army or the Department of Defense. The funders had no role in the study design, data collection, data analysis, manuscript preparation and the decision to publish the work.
Conflicts of Interest Authors declare no conflict of interest and all the authors read and approved the final version of the manuscript.
Footnotes 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, poster number X5 2023, 22-27th March 2015 and at the EMBO-AIDS related mycoses workshop, in Cape Town, South Africa, poster number 24, 13-15 Jul 2016.