Impaired humoral immune protection associated with prenatal or chronic exposure to P. falciparum is a common immunological abnormality in paediatric populations from malaria-endemic regions [2, 27]. Alterations in B-cell homeostasis [9, 11], and longevity, quantity and quality of humoral responses based on age and malaria transmission dynamics have previously been reported in children [2, 3, 27]. However, it is unknown what the impact of early differential exposure to P. falciparum on infant B cell development. In this study, the development of B cell subsets was investigated in infants followed through 24 months of age from geographically proximate regions of Kenya that experienced divergent P. falciparum transmission dynamics. Infants from the malaria-endemic area had higher overall numbers of CD19+ B cells but reduced populations of circulating IgD+CD27+ memory B cells and expanded populations of CD10+CD34- immature transitional B cells at all ages relative to infants living in an area with unstable malaria transmission. These data suggest that early exposure to P. falciparum infection results in dysregulation of the development of B cell subsets in infants.
Increased frequency and absolute numbers of CD19+ B cells in infants from malaria-endemic region relative to those from an area with unstable malaria transmission at all ages examined suggests that early age or even prenatal exposure to P. falciparum infection results in the expansion of the B cell compartment. The expansion of the immature transitional B cells in the peripheral blood observed in this study as well as previously reported during acute clinical malaria in infants , could result in increases in the total CD19+ population. Moreover, the P. falciparum erythrocyte membrane proteins 1 (PfEMP1) is a polyclonal B cell activator  and could potentially drive expansion of B cells. Overall, these data suggest that impaired antibody responses common in infants from malaria-endemic regions is not due to decline in the frequency of total CD19+ B cells.
Previous studies of individuals with HIV , acute clinical malaria  systemic lupus erythematosus  and X-linked lymphoproliferative disease  have found an expansion of immature transitional B cells characterized by expression of CD10. These cells lack CD34 expression  and have expression of IL-7  as well as CD24 and CD38 [29, 30]. In this study, there was an expansion of this sub-population of immature transitional B cells in infants from Kisumu relative to Nandi at all ages examined. Expansion of transitional B cell populations correlated with impaired humoral immunity  thus suggesting the expansion of this population in infants from a malaria-endemic area could contribute to impaired humoral immunity. However, it should be noted that consistent with previous studies, both cohorts of infants had higher levels of transitional B cells than observed in adult counterparts .
There is some controversy over whether CD19+IgD+CD27+ B cells in peripheral circulation represent circulating marginal zone B cells or non-class switched memory B cells . It is clear however that this B cell subset is present in the peripheral blood of infants and increases with age  and loss of CD19+IgD+CD27+ B cells is observed in pediatric HIV infection . A decline in the frequency of IgD+CD27+ memory B cells was observed in circulation of infants from malaria-endemic regions relative to those from an area with unstable malaria transmission at all ages. Although the immunological pathways that orchestrate the depletion of this subset in infants from malaria-endemic region is unknown, splenectomy has been associated with reduced peripheral circulation of this subset in autoimmune patients . Interestingly, P. falciparum infection has been shown to disrupt splenic architecture , and thus, may interfere with peripheral homeostasis of this B cell subset. Early exposure to P. falciparum may interfere with splenic development and/or disrupt splenic architecture in infants from malaria-endemic region, which could be one possible explanation for the diminution of CD19+IgD+CD27+ B cells observed in the cohort of infants from Kisumu. Moreover, since this subset produce poly-reactive IgM important in innate immunity against bacterial and viral pathogens, the early depletion of this population may result in increased susceptibility to bacterial or viral infections, and reduced efficacy of pneumococcal vaccines in infants from malaria-endemic regions [34, 35]. The age-related increase in the frequency of this subset in both cohorts observed is consistent with previous studies showing an age-dependent increase in this B cell subset in infants .
There were several limitations of this study. First, since infants were enrolled over a three-month period of time changes in malaria transmission could have occurred. However, we analysed samples from both sites every week over the three-month period to minimize any differences that time of year would have on the results. In addition, while there are well-documented differences in malaria transmission between Kisumu and Nandi, it was not possible to generate an accurate record of the number of malaria infections in the infants in our cohort over the period of observation. In rural areas in Kisumu, infants can be treated at home with anti-malarial drugs bought from local shops. Home treatment could reduce measurable parasitaemia. Because only a monthly follow-up was available in the first year, some episodes of malaria could be missed. In addition, the instability of antibody responses to malaria  in infancy prevented using detection of malaria antibody as a surrogate for malaria infections. Finally, it would be ideal to have a more elaborate B cell phenotyping panel, but at the time of this study, only a three-colour analytic flow cytometer was available for analysis in Kenya. For example, while an elevated frequency of CD19+IgD-CD27- B cells was noted in infants from Kisumu relative to Nandi, because this population includes both immature transitional B cell subset (IgD-CD27-CD10+) as well as the atypical exhausted memory cells, the significance of this observation cannot be determined.