Exploring B cell responses in Plasmodium falciparum malaria

Plasmodium falciparum malaria remains one of the most devastating infectious diseases today. Small children in sub-Saharan Africa carry the heaviest burden of morbidity and mortality. Immunity to malaria is not well understood, although humoral immunity has proven an integral part of protection from disease. Antibodies are produced by B cells and have been directly linked to clinical immunity to malaria. There is a need to further characterize the development of B cell responses during and following a malaria infection, in order to understand the basis of clinical immunity.

In Study I we developed a method for the identification of P. falciparum-specific B cells using Quantum dots in flow cytometry. We found almost a third of B cells from individuals living in a malaria-endemic area to be specific for P. falciparum. In Study II we followed a cohort of mothers and infants in Uganda with prospective blood sampling from birth up to nine months. Levels of the cytokine, B cell activating factor, were measured and in infants found to be highest in cord blood with a subsequent decrease, while the levels in mothers remained stable. Furthermore, B cell activating factor was inversely correlated with IgG+ memory B cells and CD27-memory B cells at different time points in infants and mothers. Study III was a prospective study in Stockholm enrolling individuals with acute malaria with subsequent sampling over a year. We found that B cells responding to infection with P. falciparum expressed CD11c with a dynamic shift within B cell compartments. Differences between individuals with a primary malaria infection and those previously infected, revealed differential expansion with a higher frequency of atypical memory B cells in previously infected individuals. In Study IV we established a novel co-culture method for human B cells and P. falciparum-infected red blood cells to mimic in vivo conditions. Parasitemia increased more rapidly when parasites were cultured with B cells than when cultured alone, and B cells exhibited phenotypic changes after ten days in co-culture with P. falciparum.

Within the scope of this thesis we provide new methodology for the study of B cell responses to malaria, and present longitudinal data on B cell remodeling after acute malaria, as well as B cell activating factor in an endemic area. These novel methods and findings contribute valuable knowledge and can be used to inform the design of future studies to increase our understanding of the immune system in malaria.

List of scientific papers

I. Allan Lugaajju, Sreenivasulu B. Reddy, Caroline Rönnberg, Mats Wahlgren, Fred Kironde and Kristina E. M. Persson. Novel flow cytometry technique for detection of Plasmodium falciparum specific B-cells in humans: increased levels of specific B-cells in ongoing infection. Malar J. 2015;14:370.
https://doi.org/10.1186/s12936-015-0911-0

II. Caroline Rönnberg, Allan Lugaajju, Anna Nyman, Ulf Hammar, Matteo Bottai, Christopher Sundling, Fred Kironde, Kristina E M Persson. A longitudinal study of plasma BAFF levels in mothers and infants in Uganda. [Manuscript]

III. Christopher Sundling*, Caroline Rönnberg*, Victor Yman, Muhammad Asghar, Peter Jahnmatz, Tadepally Lakshmikanth, Yang Chen, Jaromir Mikes, Mattias N. Forsell, Klara Sondén, Adnane Achour, Petter Brodin, Kristina E.M. Persson, and Anna Färnert. B cell profiling in malaria reveals expansion and remodeling of CD11c+ B cell subsets. JCI Insight. 2019;4(9):e126492. *Equal contribution.
https://doi.org/10.1172/jci.insight.126492

IV. Sreenivasulu B. Reddy, Noemi Nagy, Caroline Rönnberg, Francesca Chiodi, Allan Lugaajju, Frank Heuts, Laszlo Szekely, Mats Wahlgren, Kristina E. M. Persson. Direct contact between Plasmodium falciparum and human B-cells affects parasite growth and FcRL4 expression in novel long-term co-culture method. [Submitted]