B cell sub-types following acute malaria and associations with clinical immunity
- Richard T. Sullivan1Email author,
- Isaac Ssewanyana2, 3,
- Samuel Wamala2,
- Felistas Nankya2,
- Prasanna Jagannathan1,
- Jordan W. Tappero4,
- Harriet Mayanja-Kizza2, 5,
- Mary K. Muhindo2,
- Emmanuel Arinaitwe2,
- Moses Kamya2, 5,
- Grant Dorsey1,
- Margaret E. Feeney1,
- Eleanor M. Riley3,
- Chris J. Drakeley3 and
- Bryan Greenhouse1
© Sullivan et al. 2016
Received: 18 December 2015
Accepted: 23 February 2016
Published: 3 March 2016
The Erratum to this article has been published in Malaria Journal 2016 15:188
Repeated exposure to Plasmodium falciparum is associated with perturbations in B cell sub-set homeostasis, including expansion atypical memory B cells. However, B cell perturbations immediately following acute malaria infection have been poorly characterized, especially with regard to their relationship with immunity to malaria.
To better understand the kinetics of B cell sub-sets following malaria, the proportions of six B cell sub-sets were assessed at five time points following acute malaria in four to 5 years old children living in a high transmission region of Uganda. B cell sub-set kinetics were compared with measures of clinical immunity to malaria—lower parasite density at the time of malaria diagnosis and recent asymptomatic parasitaemia.
Atypical memory B cell and transitional B cell proportions increased following malaria. In contrast, plasmablast proportions were highest at the time of malaria diagnosis and rapidly declined following treatment. Increased proportions of atypical memory B cells were associated with greater immunity to malaria, whereas increased proportions of transitional B cells were associated with evidence of less immunity to malaria.
These findings highlight the dynamic changes in multiple B cell sub-sets following acute, uncomplicated malaria, and how these sub-sets are associated with developing immunity to malaria.
Malaria caused by Plasmodium falciparum continues to cause over a half million deaths each year, with children being disproportionately affected . Children suffer the greatest morbidity and mortality from malaria since immunity to malaria takes years to develop, increasing with age and exposure [2, 3]. One manifestation of acquired immunity to malaria is control of blood stage parasites, resulting in lower parasite densities and lack of febrile symptoms of disease [4–6]. Antibodies have been shown to be an important mediator of this blood stage immunity [7–10].
Effective B cell and antibody responses to Plasmodium infection generally develop only after years of repeated exposure, likely due to immune immaturity of the host and antigenic variation of parasites [8–12]. Another hypothesis for the slow development of immunity is that Plasmodium infection may interfere with B cell development and maintenance of memory responses [13–17]. After initial maturation in the bone marrow, B cells pass through a series of developmental differentiation stages, many of which can be detected in the peripheral blood. Transitional B cells emerge from the bone marrow and mature into naïve B cells prior to antigen exposure. After antigen exposure, B cells in secondary lymphoid organs differentiate into class-switched classical memory B cells (MBCs) non-class switched ‘innate-like’ MBCs and antibody-secreting plasmablasts/plasma cells ; these cells can be detected in blood as they migrate to other secondary lymphoid organs and tissues. Exposure to Plasmodium alters the distribution of these B cell sub-sets, and has been associated with an expansion of ‘atypical’ MBCs in individuals living in malaria-endemic areas [13–15, 19]. Atypical MBCs are class-switched but lack the classical MBC marker CD27, and unlike classical MBCs, do not appear to readily produce antibodies [13, 20, 21]. This functional difference has led to the hypothesis that atypical MBCs may be ‘exhausted’ and may interfere with development of effective immunity [13, 21]. On the other hand, higher circulating proportions of atypical MBCs and immunity to malaria are both associated with increasing age and P. falciparum exposure [13, 14, 22–24]. Thus, the relationship between atypical MBCs and immunity to malaria remains unclear.
B cell sub-sets generated during malaria episodes may indicate which B cells are associated with developing immunity. Various studies have described multiple B cell sub-sets in people exposed to varying levels of malaria [11, 13, 14, 20–23, 25, 26], but the kinetics of B cell responses following malaria have not been well described in humans. One study tracked the kinetics transitional B cells following malaria and found that the relative proportion of these cells increased following malaria . Studies of experimental infection of mice with Plasmodium chabaudi have found that newly differentiated plasmablasts only circulate in the blood for a short time following primary or secondary infection while other sub-sets such as transitional, naïve B cells and MBCs fluctuate greatly but remain readily detectable in the peripheral blood . These findings suggest that there are likely to be dynamic changes in the composition of the B cell pool both during and following acute malaria in humans, and that these changes may be reflected in the peripheral blood. Here, the kinetics of six distinct sub-sets of B cells were evaluated during and after treatment for symptomatic malaria, and sub-set proportions were evaluated for associations with measures of immunity to malaria.
Samples were obtained from participants between 4.6 and 5.0 years of age enrolled in the Tororo Child Cohort (TCC) study in Tororo, Uganda, an area of intense malaria transmission (annual entomological inoculation rate in the region estimated at 125 infectious bites per person year) . Cohort details have been described elsewhere [28–30], but in brief, TCC children were enrolled at infancy (mean 2.7 months old) and followed to 5 years of age at a dedicated study clinic, providing all medical care. Febrile participants (>38 °C tympanic temperature or reported fever in the previous 24 h) were tested for P. falciparum parasites by thick blood smear. Febrile participants that had any detectable parasites by thick blood smear were diagnosed with symptomatic malaria and treated with an artemisinin-based combination therapy. Participants also had monthly blood smears to assess parasitaemia regardless of symptoms. For this study, 38 consecutive children were enrolled that presented with symptomatic malaria, with parasite densities greater than 2000 parasites/µl. Asymptomatic parasitaemia was defined by parasitaemia in afebrile participants occurring at least 14 days after and five days before a malaria episode.
All study participants or their parents or guardians provided individual written informed consent. Approval was granted by the Uganda National Council of Science and Technology, the Makerere University Research and Ethics Committee, the University of California, San Francisco Committee on Human Research,
Whole blood staining
Changes in B cell sub-type proportions between day 0 and other days were tested using the Wilcoxon signed rank test. Linear trends in proportion during follow-up were evaluated using generalized estimating equations  to account for repeated measures in the same individual. To test the hypothesis that clinical immunity was associated with proportions of B cell sub-sets, the proportions during and following malaria with parasite density on day 0, with lower parasite density indicating greater immunity, and with the number of asymptomatic parasitaemia episodes in the prior 180 days, with more episodes indicating greater immunity. Parasite density was evaluated as a binary variable based on the median parasite density of 23,080 parasite/μl. Asymptomatic parasitaemia was evaluated as an ordinal variable of 0, 1 or greater than 1 episode in the last 180 days, with a linear trend across the three categories evaluated. Associations between the clinical metrics and B cell sub-types were evaluated using generalized estimating equations. To account for the potential confounding effects of prior exposure, a multivariate analysis including the incidence of malaria between 12 and 24 months of age was performed, when the effect of acquired immunity was likely to be minimal as an estimate of prior exposure.
Characteristics of study participants
Participants’ characteristic (n = 38)
Parasite density on day 0 (parasites/µl)
Asymptomatic parasitaemia episodes in the prior 180 days
Symptomatic malaria episodes in the prior 180 days
Proportion of participants with recurrent malariab
Atypical MBCs and transitional B cell proportions increased, whereas plasma cell and naïve B cell proportions decreased, following malaria
In contrast, proportions of plasmablasts/plasma (PC) cells and naïve B cells decreased following malaria. Mean PC proportion was highest at 6.1 % on day 0 and then rapidly declined to 3.3 % by day 7 (p = 0.002). Participants with a second malaria episode during the 28-day study had increased PC proportions following second episode diagnosis (Fig. 3b), and this increase in PC proportion was significantly higher in participants with a second malaria episode compared to the rest of the cohort. This suggests that plasmablasts, known to only circulate briefly in the peripheral blood, can be readily detected in significant numbers in the peripheral blood at the time of symptomatic malaria. Naïve B cell proportion decreases were moderate, from 57 to 51 % from day 0 to day 28 (p = 0.016). Classical memory B cell proportions had a transient drop on days 3 and 7 only, but otherwise remained unchanged throughout observation. No significant fluctuations in innate-like MBC proportions was detected over the 28-day study.
Atypical memory B cell proportions were higher among children with evidence of immunity to malaria
Associations between measures of clinical immunity and proportions of B cell sub-sets
B cell sub-set
Day 0 parasite density <mediana
Mean difference in % proportion (p value)
Asymptomatic parasitaemia prior 180 daysb
Mean difference in % proportion (p value)
Transitional B cell proportions were lower among children with evidence of immunity to malaria
In contrast to atypical MBCs, transitional B cell proportions were lower in participants that had parasite density less than the median at the time of malaria (Table 2), but no significant association with asymptomatic parasitaemia was found. The association with parasite density remained significant after adjusting the analysis for varied P. falciparum exposure. Further, this association was consistent throughout the 28 days following malaria (Fig. 4c). A similar association was found between the geometric mean parasite density over the previous 180 days and the proportion of transitional B cells following malaria. This finding indicates that participants with evidence of greater immunity to malaria tend to have lower proportions of transitional B cells in the peripheral blood following malaria.
Associations between other B cell sub-types and immunity to malaria
Proportions of circulating plasma cells/plasmablasts rapidly decreased following malaria (day 0), but were not significantly associated with measures of immunity to malaria. There were no significant associations between measures of immunity to malaria and the proportions of classical MBCs, innate-like MBCs or naïve B cells.
This study investigated the kinetics of different B cell sub-sets at the time of and following symptomatic malaria and then evaluated whether proportions of these sub-sets were associated with measures of immunity to malaria. The proportions of atypical MBCs and transitional B cells both increased during the 28 days following symptomatic malaria, whereas naïve B cell proportions declined slowly and circulating PCs proportions declined rapidly following treatment of malaria, increasing again in participants who had a second episode of malaria. Notably, children with evidence of greater immunity to malaria had higher proportions of atypical MBCs and lower proportions of transitional B cells following malaria, and these associations remained stable over the 28 days following malaria. These findings suggest that children with higher proportions of these cells during and following malaria have improved immune responses to P. falciparum infection.
People living in malaria-endemic regions have increased proportions of atypical MBCs, with these proportions increasing with age and with cumulative Plasmodium exposure [11, 13, 14]. Atypical MBCs have been characterized as having upregulated inhibitory pathways compared to classical MBCs [13, 20, 21]. Despite one report suggesting serum antibodies may be produced by atypical MBCs , other studies have reported that atypical MBCs have a poor capacity for differentiation and antibody production [13, 20, 21]. With no direct evidence for an alternative function for atypical MBCs, these cells have been hypothesized to represent a dysfunctional or ‘exhausted’ phenotype. However, atypical MBC proportion, like immunity to symptomatic malaria, is associated with age and transmission intensity [20, 24]. This study was not able to evaluate a causal relationship between atypical MBCs and immunity to malaria, but it demonstrates that the accumulation of atypical MBCs in the peripheral blood during and after malaria is associated with measures of clinical immunity. This association did not appear to merely be an artifact of age, since all participants in this study were nearly the same age, or of varied P. falciparum exposure, as results were unchanged in a multivariate analysis including estimates of exposure. One possibility is that the ability to sustain asymptomatic infections, which tend to be of longer duration than treated symptomatic malaria infections, leads to higher proportions of atypical MBCs due to chronic antigen exposure. Alternatively, it may be that higher parasite densities seen in less immune individuals drive down the proportion of atypical MBCs, possibly as a result of apoptosis or homing of atypical MBCs to tissues. It is also possible that atypical MBCs contribute, in an as-yet undefined manner, to anti-malarial immunity. Further studies are necessary to determine if atypical MBCs are causally associated with immunity to malaria.
Increases in transitional B cell proportions following malaria have been previously noted, and this expansion was hypothesized to be due to disruption of B cell homeostasis . This study replicates the finding of increased proportions of circulating transitional B cell following malaria. In addition, this study found participants with greater parasite density at the time of malaria had higher proportions of transitional B cells. It is possible that this association could be driven by greater P. falciparum induced, non-specific, polyclonal B cell activation  and apoptosis  in individuals with higher parasite burdens, leading to a homeostatic expansion of transitional B cells. It is also possible that transitional B cells function in an immunoregulatory capacity , similar to IL-10 producing T cells, in the context of malaria . Transitional B cells from healthy US adults have been shown to secrete IL-10, a potent immunoregulatory cytokine, following CpG stimulation, and regulate T cell responses in vitro through IL-10 secretion [41, 43, 44]. Further studies would be necessary in order to determine whether higher proportions of transitional B cells causally interfere with immunity to malaria, are a result of inadequate immune control of parasites, or whether expansion of this sub-set is associated with increased parasite densities for other reasons.
Outside of vaccine trials, plasmablasts/plasma cells can be difficult to characterize due to their paucity in the peripheral blood and highly synchronous migration to the bone marrow. Development and migration of PCs has been characterized in experimental infection of mice with P. chabaudi [9, 45, 46], but is not well described in humans. Although difficult to assess, these cells provide a snapshot of effector B cell responses formed in response to recent exposure. This study demonstrates that the day a person presents with symptomatic malaria may be an optimum time to characterize plasmablasts/plasma cells in peripheral blood. Given the findings, it may be possible in future studies to assess responding plasmablasts formed in response to acute infection and provide insight into emerging B cell responses to natural infection.
Some unique strengths of this study are the detailed longitudinal follow up of participants, allowing characterization of relevant clinical outcomes and the measurement of numerous B cell sub-type proportions at multiple timepoints during and following an episode of symptomatic malaria. By evaluating proportions of these sub-types at the time of malaria and following treatment, the potential confounding effects of the duration of time since malaria, which can affect the proportions of different cell types, was limited. Similarly, by evaluating children in a very narrow age range, the potential confounding effect of age, which is associated with immunity to malaria and proportions of B cell sub-types, was reduced [11, 13]. The extensive longitudinal data available on study participants allowed the evaluation and adjustment for the individual’s varied exposure to P. falciparum, an important consideration when evaluating immunity.
A limitation of this study is the inability to determine whether associations between clinical phenotypes and proportions of B cell sub-sets represent a direct effect of these cell types. In addition, evaluation was limited to B cell sub-sets trafficking through peripheral blood which, while clearly an important compartment for interaction with a blood stage pathogen, may not represent proportions in other important compartments such as secondary lymphoid organs or peripheral tissues. There is evidence using experimental mouse infection with P. chabaudi that memory B cell responses circulating in the blood reflected the general composition of B cells in peripheral tissues . Since peripheral lymphoid tissues are not easily sampled, understanding circulating responses may provide the closest accessible insights to general B cell responses and homeostasis in humans. Another caveat to this study is that increased or decreased B cell sub-set proportions could be a result of perturbations in another B cell sub-set, e.g., observed decreases in circulating naïve B cell proportions could be the result of increases in transitional cell proportions. Consistent with methods from several earlier prior studies [11, 13, 14, 22, 47], the design of this study only allowed for measurement of relative proportions and not absolute B cell counts; future studies may want to account for changes in absolute numbers of cells as well as proportions. Additional studies focusing on the mechanisms of action of atypical MBCs and transitional B cells are also needed to provide insight into the causal relationships underlying the associations observed.
The findings of this study highlight the importance of investigating the dynamics of multiple B cell sub-sets, including consideration of the timing of these measurements with respect to malaria, in order to understand the contribution of the humoral immune system in developing immunity to malaria. Infection by P. falciparum greatly affects B cell homeostasis, but further research is necessary to understand the full implications of these changes. Since most vaccines are designed to induce a protective B cell response that can be sustained over time, it is vital to understand consequences of P. falciparum infection on the humoral immune system, memory formation and maintenance of memory.
All authors contributed to the study design (RS, PJ, JT, HMZ, MM, EA, MK, GD, MEF, EMR, CJD, and BG), implementation (RS, IS, SW, FN, PJ, GD, MEF, and BG), and/or processing of the data collected (RS, IS, PJ, and BG), as well as in the preparation of this manuscript. All authors read and approved the final manuscript.
We are grateful to all the parents and guardians for giving their consent and to the study participants for their cooperation. We thank all the members of the study team for their tireless effort and excellent work. This work was supported by the Centers for Disease Control and Prevention [Cooperative Agreement No. U62P024421] (JT and GD), National Institutes of Health International Centers of Excellence in Malaria Research (ICMER) program U19 [AI089674] (RTS, IS, MK, MEF, CJD and BG), NIH R01 [AI093615] (MEF), UCSF Centers for AIDS Research [P30AI027763] (MEF), Burroughs Wellcome Fund/American Society of Tropical Medicine and Hygiene (PJ), NIH R21 [AI107200] (BG), and by the Doris Duke Charitable Foundation (Doris Duke Clinical Scientist Development Award to (BG). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or any funding institution.
The authors declare that they have no competing interests.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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