Hostname: page-component-74656f9884-c52kr Total loading time: 0 Render date: 2026-11-08T13:54:19.232Z Has data issue: false hasContentIssue false
  • English
  • Français

Immunological processes underlying the slow acquisition of humoral immunity to malaria

Published online by Cambridge University Press:  08 January 2016

VICTORIA RYG-CORNEJO ,
ANN LY  and
DIANA S. HANSEN
VICTORIA RYG-CORNEJO
Affiliation:
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia
ANN LY
Affiliation:
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia
DIANA S. HANSEN*
Affiliation:
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia
*
*Corresponding author: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia. E-mail: hansen@wehi.edu.au
Rights & Permissions [Opens in a new window]

Summary

Malaria is one of the most serious infectious diseases with ~250 million clinical cases annually. Most cases of severe disease are caused by Plasmodium falciparum. The blood stage of Plasmodium parasite is entirely responsible for malaria-associated pathology. Disease syndromes range from fever to more severe complications, including respiratory distress, metabolic acidosis, renal failure, pulmonary oedema and cerebral malaria. The most susceptible population to severe malaria is children under the age of 5, with low levels of immunity. It is only after many years of repeated exposure, that individuals living in endemic areas develop clinical immunity. This form of protection does not result in sterilizing immunity but prevents clinical episodes by substantially reducing parasite burden. Naturally acquired immunity predominantly targets blood-stage parasites and it is known to require antibody responses. A large body of epidemiological evidence suggests that antibodies to Plasmodium antigens are inefficiently generated and rapidly lost in the absence of ongoing exposure, which suggests a defect in the development of B cell immunological memory. This review summarizes the main findings to date contributing to our understanding on cellular processes underlying the slow acquisition of humoral immunity to malaria. Some of the key outstanding questions in the field are discussed.

Keywords

malariahumoral immunityantibodiesB cells

Information

Type
Special Issue Review
Information
Parasitology , Volume 143 , Issue 2: Naturally Acquired Immunity to Malaria , February 2016 , pp. 199 - 207
Check for updates
Copyright
Copyright © Cambridge University Press 2016 

INTRODUCTION

Malaria, the parasitic disease caused by the Plasmodium species, claims the lives of more than half a million people each year, almost 80% of which are young children. Plasmodium falciparum accounts for the bulk of severe disease and deaths (World Health Organization, 2014). Infection with this parasite typically induces an uncomplicated, febrile disease of periodic fevers, chills and nausea, but in a proportion of cases, it can become severe and/or life threatening. Severe malaria can manifest as various disease syndromes, including cerebral malaria, severe malarial anaemia, metabolic acidosis, placental malaria and multi-organ failure (reviewed by White et al. Reference White, Pukrittayakamee, Hien, Faiz, Mokuolu and Dondorp2014b). The clinical spectrum of symptomatic disease is solely caused by the asexual blood stage of infection, where the parasite undergoes cyclic replication within human erythrocytes. Although the pathogenesis of malaria is not completely understood, it is thought to arise from the concerted effects of host and parasite factors, including the sequestration of infected erythrocytes in microvasculature, and local and systemic inflammation (reviewed by Schofield and Grau, Reference Schofield and Grau2005).

Unlike many viral and bacterial pathogens such as smallpox and tetanus, which can induce life-long protection following a single exposure (Maple et al. Reference Maple, Jones, Wall, Vyseb, Edmunds, Andrews and Miller2000; Hammarlund et al. Reference Hammarlund, Lewis, Hansen, Strelow, Nelson, Sexton, Hanifin and Slifka2003; Amanna et al. Reference Amanna, Carlson and Slifka2007), the acquisition of immunity to the Plasmodium parasite is strikingly less efficient. There is long-standing evidence showing that individuals living in malaria endemic areas develop immunity to clinical symptoms only after years of repeated infections (reviewed by Baird, Reference Baird1995). Children become immune to the most severe forms of disease after a few symptomatic infections (Gupta et al. Reference Gupta, Snow, Donnelly, Marsh and Newbold1999); however, remain susceptible to febrile illness. With cumulative parasite exposure, immunity to clinical disease is eventually acquired by the ability to substantially reduce parasite burden, but this form of protection is not paralleled by sterile immunity to infection per se (reviewed by Marsh and Kinyanjui, Reference Marsh and Kinyanjui2006). Despite rarely suffering from clinical episodes, adults continue to be susceptible to re-infection and typically experience asymptomatic infections. Naturally acquired immunity to malaria is primarily directed to the blood stage of infection, and requires both cell-mediated and humoral immune responses (reviewed by Langhorne et al. Reference Langhorne, Ndungu, Sponaas and Marsh2008). Although the relative contribution of these immune mechanisms is unclear, it is likely that interactions between the two are necessary for effective protection against malaria.

Different possible explanations have been proposed to account for the slow acquisition of immunity to malaria, including clonal antigenic variation and expression of highly polymorphic or functionally redundant antigens by the blood-stage merozoite form and on the surface of infected erythrocytes (reviewed by Cowman and Crabb, Reference Cowman and Crabb2006; Scherf et al. Reference Scherf, Lopez-Rubio and Riviere2008). Although these parasite survival mechanisms may partly explain the slow development of immunity to natural infection, growing evidence suggests that malaria may also compromise humoral immunity by interfering with the induction of B cell memory. Here we review our current understanding about the development of humoral immunity to natural malaria infections, and highlight some of the outstanding questions regarding the cellular mechanisms that underlie the slow acquisition of immunity.

THE ROLE OF HUMORAL IMMUNITY IN THE CONTROL OF BLOOD-STAGE MALARIA

Antibodies produced during the humoral response play a crucial role in mediating protection to malaria, particularly to the blood stage of infection. The paramount importance of antibodies was first established by passive transfer of immunoglobulin G (IgG) from clinically immune adults into children with severe malaria, which rapidly attenuated the severity and burden of disease (Cohen et al. Reference Cohen, Carrington and Mcgregor1961; McGregor et al. Reference McGregor, Carrington and Cohen1963). This has been supported by immuno-epidemiological studies, where antibodies to parasite antigens are associated with protection from clinical episodes in endemic areas (Marsh et al. Reference Marsh, Otoo, Hayes, Carson and Greenwood1989; Dodoo et al. Reference Dodoo, Staalsoe, Giha, Kurtzhals, Akanmori, Koram, Dunyo, Nkrumah, Hviid and Theander2001; John et al. Reference John, O'Donnell, Sumba, Moormann, de Koning-Ward, King, Kazura and Crabb2004; Fowkes et al. Reference Fowkes, Richards, Simpson and Beeson2010; Richards et al. Reference Richards, Stanisic, Fowkes, Tavul, Dabod, Thompson, Kumar, Chitnis, Narum, Michon, Siba, Cowman, Müeller and Beeson2010, Reference Richards, Arumugam, Reiling, Healer, Hodder, Fowkes, Cross, Langer, Takeo, Uboldi, Thompson, Gilson, Coppel, Siba, King, Torii, Chitnis, Narum, Müeller, Crabb, Cowman, Tsuboi and Beeson2013; Chiu et al. Reference Chiu, Healer, Thompson, Chen, Kaul, Savergave, Raghuwanshi, Suen, Siba, Schofield, Müeller, Cowman and Hansen2014, Reference Chiu, Hodder, Lin, Li Wai Suen, Schofield, Siba, Müeller, Cowman and Hansen2015). Antibodies may limit the growth of blood-stage parasites and the development of clinical symptoms by several known mechanisms. These include blocking erythrocyte invasion (Blackman et al. Reference Blackman, Heidrich, Donachie, McBride and Holder1990; Persson et al. Reference Persson, Fowkes, McCallum, Gicheru, Reiling, Richards, Wilson, Lopaticki, Cowman, Marsh and Beeson2013), opsonising parasitized erythrocytes for phagocytic clearance (Hill et al. Reference Hill, Eriksson, Suen, Chiu, Ryg-Cornejo, Robinson, Siba, Müeller, Hansen and Schofield2013; Osier et al. Reference Osier, Feng, Boyle, Langer, Zhou, Richards, McCallum, Reiling, Jaworowski, Anders, Marsh and Beeson2014), monocyte-mediated antibody-dependent cellular killing (Bouharoun-Tayoun et al. Reference Bouharoun-Tayoun, Oeuvray, Lunel and Druilhe1995), and complement-mediated lysis (Boyle et al. Reference Boyle, Reiling, Feng, Langer, Osier, Aspeling-Jones, Cheng, Stubbs, Tetteh, Conway, McCarthy, Müller, Marsh, Anders and Beeson2015), as well as interfering with the adherence of infected erythrocytes to vascular endothelium (Beeson et al. Reference Beeson, Mann, Elliott, Lema, Tadesse, Molyneux, Brown and Rogerson2004).

LONGEVITY OF THE ANTIBODY RESPONSE TO MALARIA

Immuno-epidemiological evidence from children and young adults suggests that antibody responses to malaria infection are particularly short-lived and rapidly lost in the absence of continued parasite exposure. Following acute malaria, the decline of antibodies specific for different Plasmodium antigens to very low or undetectable levels has been observed within several months, even weeks, of the last documented clinical episode in endemic areas, despite an initial robust response (Cavanagh et al. Reference Cavanagh, Elhassan, Roper, Robinson, Giha, Holder, Hviid, Theander, Arnot and McBride1998, Reference Cavanagh, Dodoo, Hviid, Kurtzhals, Theander, Akanmori, Polley, Conway, Koram and McBride2004; Kinyanjui et al. Reference Kinyanjui, Bull, Newbold and Marsh2003, Reference Kinyanjui, Conway, Lanar and Marsh2007; Akpogheneta et al. Reference Akpogheneta, Duah, Tetteh, Dunyo, Lanar, Pinder and Conway2008; Weiss et al. Reference Weiss, Traore, Kayentao, Ongoiba, Doumbo, Doumtabe, Kone, Dia, Guindo, Traore, Huang, Miura, Mircetic, Li, Baughman, Narum, Miller, Doumbo, Pierce and Crompton2010). Children exposed to intense transmission have been shown to generate antibodies to hundreds of P. falciparum antigens; however, the breadth and intensity of this response appears to contract during the subsequent dry season when there is little or no malaria transmission. This evidence suggests that the response generated at the peak of transmission might be due to the output of short-lived plasma cells (Crompton et al. Reference Crompton, Kayala, Traore, Kayentao, Ongoiba, Weiss, Molina, Burk, Waisberg, Jasinskas, Tan, Doumbo, Doumtabe, Kone, Narum, Liang, Doumbo, Miller, Doolan, Baldi, Felgner and Pierce2010). It has also been proposed that a large number of parasite antigens may overwhelm the host's immune system to commit sufficient numbers of antigen-specific B cells to the development of long-lived memory compartments following a single malaria season (Crompton et al. Reference Crompton, Kayala, Traore, Kayentao, Ongoiba, Weiss, Molina, Burk, Waisberg, Jasinskas, Tan, Doumbo, Doumtabe, Kone, Narum, Liang, Doumbo, Miller, Doolan, Baldi, Felgner and Pierce2010), explaining why multiple infections are required to induce a protective antibody response. In support of this proposition, parasite-specific antibody levels appear to increase in a stepwise manner with age in endemic areas (Crompton et al. Reference Crompton, Kayala, Traore, Kayentao, Ongoiba, Weiss, Molina, Burk, Waisberg, Jasinskas, Tan, Doumbo, Doumtabe, Kone, Narum, Liang, Doumbo, Miller, Doolan, Baldi, Felgner and Pierce2010; Weiss et al. Reference Weiss, Traore, Kayentao, Ongoiba, Doumbo, Doumtabe, Kone, Dia, Guindo, Traore, Huang, Miura, Mircetic, Li, Baughman, Narum, Miller, Doumbo, Pierce and Crompton2010), and antibodies reportedly decay at slower rates in older individuals children compared with young children in the same endemic area (Akpogheneta et al. Reference Akpogheneta, Duah, Tetteh, Dunyo, Lanar, Pinder and Conway2008).

Mathematical modelling has been used to estimate the longevity of circulating malaria-specific IgG antibodies in children, which have an average half-life of 10 days (Kinyanjui et al. Reference Kinyanjui, Conway, Lanar and Marsh2007; White et al. Reference White, Griffin, Akpogheneta, Conway, Koram, Riley and Ghani2014a). This stands in contrast to the normal IgG catabolic half-life of 21 days (Morell et al. Reference Morell, Terry and Waldmann1970), and the robust IgG response to other pathogens such as measles, which is reported to persist for decades (Amanna et al. Reference Amanna, Carlson and Slifka2007). Additionally, field studies have shown that IgG subclass profiles differ among antibody responses targeted to different malarial antigens (Tongren et al. Reference Tongren, Drakeley, McDonald, Reyburn, Manjurano, Nkya, Lemnge, Gowda, Todd, Corran and Riley2006; Ismail et al. Reference Ismail, Tijani, Langer, Reiling, White, Beeson, Wahlgren, Nwuba and Persson2014; White et al. Reference White, Griffin, Akpogheneta, Conway, Koram, Riley and Ghani2014a). These antibody responses may be influenced by age and transmission intensity, as they appear to decay less and become more polarized in older children, and in individuals living in endemic areas (Tongren et al. Reference Tongren, Drakeley, McDonald, Reyburn, Manjurano, Nkya, Lemnge, Gowda, Todd, Corran and Riley2006; Akpogheneta et al. Reference Akpogheneta, Duah, Tetteh, Dunyo, Lanar, Pinder and Conway2008). A recent study extended these observations, estimating the half-lives of short- and long-lived IgG antibody-secreting cells in African children to range from 2 to 10 days, and 3 to 9 years, respectively (White et al. Reference White, Griffin, Akpogheneta, Conway, Koram, Riley and Ghani2014a), suggesting a sustained humoral response to malaria infection can concurrently develop following the rapid decay phase of the short-lived response (White et al. Reference White, Griffin, Akpogheneta, Conway, Koram, Riley and Ghani2014a). Further validation of this model would be required to more specifically determine the contribution of long-lived plasma cells to sustained protection from clinical infections (Hviid et al. Reference Hviid, Barfod and Fowkes2015).

IS B CELL MEMORY DEVELOPMENT INFLUENCED BY MALARIA TRANSMISSION RATES?

Despite the established role of antibody responses in protection from symptomatic malaria, the cellular processes underlying the slow acquisition of humoral immunity are only beginning to be delineated. As Plasmodium are blood-borne parasites, the spleen constitutes an important secondary lymphoid organ involved in the initiation of immune responses to infection. Distinct splenic microanatomical compartments serve different immune functions. While phagocytic cells in the red pulp survey and sequester parasitized erythrocytes, the white pulp, consisting of B cell follicles and T cell zones, facilitates the recruitment and interaction of lymphocytes in response to infection (reviewed by Mebius and Kraal, Reference Mebius and Kraal2005; Mueller and Germain, Reference Mueller and Germain2009). T-dependent humoral responses classically begin after T- and B cell engagement with their cognate antigen, triggering their migration to the follicle border (Jacob et al. Reference Jacob, Kassir and KELSOE1991; Liu et al. Reference Liu, Zhang, Lane, Chan and MacLennan1991). A bifurcation of the response then occurs, in which one pathway leads to the rapid development of extrafollicular foci of plasmablasts, while another to germinal centre (GC) formation and B cell memory (Jacob et al. Reference Jacob, Kassir and KELSOE1991). Plasmablasts are short-lived but provide an immediate, early wave of low-affinity antibody for initial pathogen control (Jacob et al. Reference Jacob, Kassir and KELSOE1991; Smith et al. Reference Smith, Hewitson, Nossal and Tarlinton1996). Concurrently, some activated B cells migrate into the follicle where they establish GCs. Within a few days of initial antigen encounter, the GC is fully formed and polarized into the dark zone, proximal to the T cell zone, and the light zone, proximal to the marginal zone. Broadly, the dark zone is the site where GC B cells undergo intense proliferation and somatic hypermutation of their immunoglobulin genes, whereas the light zone is the site of affinity-based selection (Allen et al. Reference Allen, Okada, Tang and Cyster2007; Victora et al. Reference Victora, Schwickert, Fooksman, Kamphorst, Meyer-Hermann, Dustin and Nussenzweig2010). Whilst it is not entirely clear what drives affinity-based selection, a specialized subset of T cells named T follicular helper (Tfh) cells are known to play an important role in this process (reviewed by Crotty, Reference Crotty2014). The output of a productive GC reaction is humoral immune memory, comprising recirculating memory B cells that respond rapidly upon antigen re-encounter (Good et al. Reference Good, Avery and Tangye2009), and long-lived plasma cells, which reside in the bone marrow and provide a continuous source of high-affinity antibody (reviewed by Radbruch et al. Reference Radbruch, Muehlinghaus, Luger, Inamine, Smith, Dörner and Hiepe2006).

Consistent with the inefficient development of antibody-mediated immunity, recent studies revealed that the prevalence and breadth of Plasmodium-specific memory B cells increases incrementally with age and exposure (Weiss et al. Reference Weiss, Traore, Kayentao, Ongoiba, Doumbo, Doumtabe, Kone, Dia, Guindo, Traore, Huang, Miura, Mircetic, Li, Baughman, Narum, Miller, Doumbo, Pierce and Crompton2010; Nogaro et al. Reference Nogaro, Hafalla, Walther, Remarque, Tetteh, Conway, Riley and Walther2011). A longitudinal study undertaken in Mali of children and young adults in an area of high seasonal transmission, showed delayed development of memory B cells specific for P. falciparum blood-stage antigens, despite repeated exposure to the parasite (Weiss et al. Reference Weiss, Traore, Kayentao, Ongoiba, Doumbo, Doumtabe, Kone, Dia, Guindo, Traore, Huang, Miura, Mircetic, Li, Baughman, Narum, Miller, Doumbo, Pierce and Crompton2010). This contrasted with the memory B cell response induced by childhood tetanus vaccination, which did not change significantly with age. Particularly, the development of a clinical malaria episode was associated with a contraction of the expanding population of memory B cells to close to baseline levels (Weiss et al. Reference Weiss, Traore, Kayentao, Ongoiba, Doumbo, Doumtabe, Kone, Dia, Guindo, Traore, Huang, Miura, Mircetic, Li, Baughman, Narum, Miller, Doumbo, Pierce and Crompton2010). The longevity of these memory B cells however could not be determined beyond the duration of the dry season in this study as malaria transmission subsequently resumed. Conversely, several studies have identified stable populations of malaria-specific memory B cells in individuals subjected to infrequent exposures and fewer clinical episodes (Migot et al. Reference Migot, Chougnet, Henzel, Dubois, Jambou, Fievet and Deloron1995; Wipasa et al. Reference Wipasa, Suphavilai, Okell, Cook, Corran, Thaikla, Liewsaree, Riley and Hafalla2010; Nogaro et al. Reference Nogaro, Hafalla, Walther, Remarque, Tetteh, Conway, Riley and Walther2011; Clark et al. Reference Clark, Silva, Weiss, Li, Padilla, Crompton, Hernandez and Branch2012; Ndungu et al. Reference Ndungu, Olotu, Mwacharo, Nyonda, Apfeld, Mramba, Fegan, Bejon and Marsh2012; Ayieko et al. Reference Ayieko, Maue, Jura, Noland, Ayodo, Rochford and John2013; Ampomah et al. Reference Ampomah, Stevenson, Ofori, Barfod and Hviid2014a). For example, no decay in P. falciparum-specific memory B cell frequencies could be detected in the absence of malaria episodes spanning up to 5 years in an area of low endemicity in Thailand (Wipasa et al. Reference Wipasa, Suphavilai, Okell, Cook, Corran, Thaikla, Liewsaree, Riley and Hafalla2010). Similarly, memory B cells specific for one or more malarial antigens have been reported to be maintained for more than a decade in individuals with a history of acute malaria following travel but have since lived in the complete absence of infection (Ndungu et al. Reference Ndungu, Lundblom, Rono, Illingworth, Eriksson and Färnert2013), suggesting that parasite-specific memory B cells can be generated and sustained without repeated exposure. Furthermore, memory B cell responses to different malaria antigens can be induced at a similar magnitude to vaccine antigen-specific responses in The Gambia, where malaria transmission is low and sporadic (Nogaro et al. Reference Nogaro, Hafalla, Walther, Remarque, Tetteh, Conway, Riley and Walther2011). Collectively, these findings suggest that variable transmission levels might affect the acquisition and maintenance of memory B cells, and lend weight to the notion that frequent clinical malaria episodes could have a detrimental effect in the generation of immunologic B cell memory.

ATYPICAL MEMORY B CELLS

Ongoing P. falciparum transmission has been associated with the expansion of memory B cells that exhibit an atypical phenotype (Weiss et al. Reference Weiss, Crompton, Li, Walsh, Moir, Traore, Kayentao, Ongoiba, Doumbo and Pierce2009, Reference Weiss, Clark, Li, Traore, Kayentao, Ongoiba, Hernandez, Doumbo, Pierce, Branch and Crompton2011; Ayieko et al. Reference Ayieko, Maue, Jura, Noland, Ayodo, Rochford and John2013; Illingworth et al. Reference Illingworth, Butler, Roetynck, Mwacharo, Pierce, Bejon, Crompton, Marsh and Ndungu2013). Originally described as exhausted memory B cells implicated in humoral deficiencies associated with HIV infection (Moir et al. Reference Moir, Ho, Malaspina, Wang, DiPoto, O'Shea, Roby, Kottilil, Arthos, Proschan, Chun and Fauci2008), a phenotypically similar CD27−CD21− memory B cell subset, expressing several inhibitory receptors has been detected in malaria-exposed populations (Weiss et al. Reference Weiss, Crompton, Li, Walsh, Moir, Traore, Kayentao, Ongoiba, Doumbo and Pierce2009, Reference Weiss, Clark, Li, Traore, Kayentao, Ongoiba, Hernandez, Doumbo, Pierce, Branch and Crompton2011; Nogaro et al. Reference Nogaro, Hafalla, Walther, Remarque, Tetteh, Conway, Riley and Walther2011; Portugal et al. Reference Portugal, Doumtabe, Traore, Miller, Troye-Blomberg, Doumbo, Dolo, Pierce and Crompton2012, Reference Portugal, Tipton, Sohn, Kone, Wang, Li, Skinner, Virtaneva, Sturdevant, Porcella, Doumbo, Doumbo, Kayentao, Ongoiba, Traore, Sanz, Pierce and Crompton2015; Ayieko et al. Reference Ayieko, Maue, Jura, Noland, Ayodo, Rochford and John2013; Illingworth et al. Reference Illingworth, Butler, Roetynck, Mwacharo, Pierce, Bejon, Crompton, Marsh and Ndungu2013; Muellenbeck et al. Reference Muellenbeck, Ueberheide, Amulic, Epp, Fenyo, Busse, Esen, Theisen, Mordmuller and Wardemann2013; Ampomah et al. Reference Ampomah, Stevenson, Ofori, Barfod and Hviid2014b). Although a clear relationship between these cells and disease susceptibility remains to be established (Portugal et al. Reference Portugal, Doumtabe, Traore, Miller, Troye-Blomberg, Doumbo, Dolo, Pierce and Crompton2012), the accumulation of this subset appears to be influenced by the level of parasite exposure. Higher frequencies of atypical memory B cells have been found in Malian adults compared with children with shorter exposure histories (Weiss et al. Reference Weiss, Crompton, Li, Walsh, Moir, Traore, Kayentao, Ongoiba, Doumbo and Pierce2009). Similarly, Malian adults from high transmission settings were found to have higher frequencies of these cells than Peruvian individuals residing in a low transmission area (Weiss et al. Reference Weiss, Clark, Li, Traore, Kayentao, Ongoiba, Hernandez, Doumbo, Pierce, Branch and Crompton2011). A decline in the atypical memory B cell pool was observed during 12 months without malaria transmission (Ayieko et al. Reference Ayieko, Maue, Jura, Noland, Ayodo, Rochford and John2013), further supporting a role of persistent parasite exposure in the maintenance of this population.

The functional relevance of the expansion of atypical B cells in response to malaria remains unclear, but recent work has provided some insight into the function of these cells and their relationship to classical memory B cells. Atypical memory B cells isolated from malaria-exposed adults have been shown to express Ig-encoding V gene transcripts, which suggested that they are able to secrete neutralizing antibodies against P. falciparum antigens (Muellenbeck et al. Reference Muellenbeck, Ueberheide, Amulic, Epp, Fenyo, Busse, Esen, Theisen, Mordmuller and Wardemann2013); however, this finding requires further investigation, as a recent study demonstrated a lack of active antibody secretion by these cells (Portugal et al. Reference Portugal, Tipton, Sohn, Kone, Wang, Li, Skinner, Virtaneva, Sturdevant, Porcella, Doumbo, Doumbo, Kayentao, Ongoiba, Traore, Sanz, Pierce and Crompton2015). Atypical memory B cells from Malian individuals have been recently found to have compromised function, including reduced B cell receptor signalling, impaired cytokine production and hypo-responsiveness to stimuli that classically induce memory B cells to secrete antibodies in vitro (Portugal et al. Reference Portugal, Tipton, Sohn, Kone, Wang, Li, Skinner, Virtaneva, Sturdevant, Porcella, Doumbo, Doumbo, Kayentao, Ongoiba, Traore, Sanz, Pierce and Crompton2015). Despite these reported functional differences to classical memory B cells, analysis of the V gene repertoires of atypical memory B cells revealed a high degree of similarity between the two memory B cell subsets, suggesting that they share a common developmental pathway (Muellenbeck et al. Reference Muellenbeck, Ueberheide, Amulic, Epp, Fenyo, Busse, Esen, Theisen, Mordmuller and Wardemann2013; Portugal et al. Reference Portugal, Tipton, Sohn, Kone, Wang, Li, Skinner, Virtaneva, Sturdevant, Porcella, Doumbo, Doumbo, Kayentao, Ongoiba, Traore, Sanz, Pierce and Crompton2015; Zinöcker et al. Reference Zinöcker, Schindler, Skinner, Rogosch, Waisberg, Schickel, Meffre, Kayentao, Ongoiba, Traore and Pierce2015).

Although the underlying mechanisms that drive the development of atypical memory B cells remain unknown, there is increasing evidence that Plasmodium parasites can directly modulate B cell function. In vitro studies have shown that the parasite can directly interact with human B cells via the cysteine-rich interdomain 1α domain of P. falciparum erythrocyte membrane protein 1, to induce T cell-independent polyclonal B cell activation (Donati et al. Reference Donati, Zhang, Chêne, Chen, Flick, Nyström, Wahlgren and Bejarano2004, Reference Donati, Mok, Chêne, Xu, Thangarajh, Glas, Chen, Wahlgren and Bejarano2006). The specific subsets affected in vivo following malaria infection are yet to be delineated based on these findings, although CD27+ B cells were observed to be the major responding population, suggesting a potential influence on memory B cells. Whether these interactions lead to the activation, exhaustion, or deletion of malaria-specific memory subsets requires further investigation. Notably, recent analysis of circulating B cells following controlled human malaria infection revealed that memory B cell subsets proliferate rapidly after blood-stage infection, likely prior to the induction of GC responses, suggesting generalized immune activation may occur, mediated by the parasite and/or as a bystander-effect of malaria infection (Scholzen et al. Reference Scholzen, Teirlinck, Bijker, Roestenberg, Hermsen, Hoffman and Sauerwein2014). There is also evidence that P. falciparum infection can modulate systemic mediators of B cell activation and survival such as B cell activating factor (BAFF) and BAFF receptor (Nduati et al. Reference Nduati, Gwela, Karanja, Mugyenyi, Langhorne, Marsh and Urban2011; Scholzen et al. Reference Scholzen, Teirlinck, Bijker, Roestenberg, Hermsen, Hoffman and Sauerwein2014), which might have direct implications on B cell survival rates and the overall induction of a malaria-specific B cell compartment.

WHAT CAN MOUSE INFECTION MODELS TEACH US ABOUT B CELL RESPONSES TO MALARIA?

It has been shown that fatal human malaria infections are accompanied by dramatic changes in splenic architecture, including dissolution of the marginal zone, loss of B cells and reduced GC formation (Urban et al. Reference Urban, Hien, Day, Phu, Roberts, Pongponratn, Jones, Mai, Bethell, Turner, Ferguson, White and Roberts2005). This histological evidence is consistent with the idea that the differentiation of B cells to long-lived antibody-secreting cells and memory B cells might be compromised in severe malaria-infected individuals, explaining the deficiencies in antibody responses observed in a large body of serological field studies. However, this proposition is difficult to demonstrate in the human setting, where there is limited access to lymphoid tissue and peripheral blood remains the only source to detect the rare memory B cell populations. Murine models of malaria are a valuable resource to investigate mechanistic immunological processes, which cannot be deduced from human studies. Although experimental models do not mirror all the features of human malaria, there are phenotypic parallels between human malaria parasites and their rodent counterparts (reviewed by Craig et al. Reference Craig, Grau, Janse, Kazura, Milner, Barnwell, Turner, Langhorne and Model2012; Stephens et al. Reference Stephens, Culleton and Lamb2012).

Consistent with human studies, rodent malaria infections have been shown to be accompanied by profound remodelling of the spleen. Most of the available information illustrating this phenomenon has been generated using the non-lethal Plasmodium chabaudi chabaudi AS model, and revealed that infection induces a significant loss of defined B cell follicles and T cell zone integrity. Dissolution of the marginal zone with a loss of marginal zone and metallophilic macrophages has also been observed (Stevenson and Kraal, Reference Stevenson and Kraal1989; Achtman et al. Reference Achtman, Khan, MacLennan and Langhorne2003; Beattie et al. Reference Beattie, Engwerda, Wykes and Good2006; Cadman et al. Reference Cadman, Abdallah, Voisine, Sponaas, Corran, Lamb, Brown, Ndungu and Langhorne2008). Nevertheless, these structural alterations appear to be only transient, and infected mice are able to mount adequate parasite-specific B cell responses that control parasitaemia, with interleukin (IL)-21 cytokine production playing a critical role in this process (Achtman et al. Reference Achtman, Khan, MacLennan and Langhorne2003; Ndungu et al. Reference Ndungu, Cadman, Coulcher, Nduati, Couper, Macdonald, Ng and Langhorne2009; Pérez-Mazliah et al. Reference Pérez-Mazliah, Ng, Freitas do Rosário, McLaughlin, Mastelic-Gavillet, Sodenkamp, Kushinga and Langhorne2015). Consistent with those findings, isotype-switched memory B cells have been detected 20 days following P. chabaudi infection (Castillo-Méndez et al. Reference Castillo-Méndez, Zago, Sardinha, Freitas do Rosário, Álvarez and D'Império Lima2007; Ndungu et al. Reference Ndungu, Cadman, Coulcher, Nduati, Couper, Macdonald, Ng and Langhorne2009; Stephens et al. Reference Stephens, Ndungu and Langhorne2009). Moreover, re-infection of previously P. chabaudi-infected mice has been found to result in an efficient induction of secondary GC responses, accompanied by a weak induction of splenic plasma cells (Stephens et al. Reference Stephens, Ndungu and Langhorne2009), suggesting that mild malaria infections induce memory populations that preferentially induce GCs. Thus, these results are consistent with human studies in low transmission settings, which describe efficient parasite-specific memory B cell responses following few parasite exposures (Migot et al. Reference Migot, Chougnet, Henzel, Dubois, Jambou, Fievet and Deloron1995; Wipasa et al. Reference Wipasa, Suphavilai, Okell, Cook, Corran, Thaikla, Liewsaree, Riley and Hafalla2010; Nogaro et al. Reference Nogaro, Hafalla, Walther, Remarque, Tetteh, Conway, Riley and Walther2011; Clark et al. Reference Clark, Silva, Weiss, Li, Padilla, Crompton, Hernandez and Branch2012; Ndungu et al. Reference Ndungu, Olotu, Mwacharo, Nyonda, Apfeld, Mramba, Fegan, Bejon and Marsh2012; Ayieko et al. Reference Ayieko, Maue, Jura, Noland, Ayodo, Rochford and John2013; Ampomah et al. Reference Ampomah, Stevenson, Ofori, Barfod and Hviid2014a). It should be pointed out that while P. chabaudi-infected mice appear to mount efficient parasite-specific responses, a concomitant infection was found to suppress antibody responses to secondary heterologous antigens (Millington et al. Reference Millington, Di Lorenzo, Phillips, Garside and Brewer2006; Wilmore et al. Reference Wilmore, Maue, Lefebvre, Haynes and Rochford2013). Interestingly, acute P. falciparum malaria has been associated with an accelerated decline in IgG antibody levels specific for common vaccine antigens such as hepatitis B and tetanus in individual Malian children (Banga et al. Reference Banga, Coursen, Portugal, Tran, Hancox, Ongoiba, Traore, Doumbo, Huang, Harty and Crompton2015), suggesting detrimental effects for blood-stage malaria in the induction of humoral immunity.

Unlike P. chabaudi, infection of mice with Plasmodium berghei ANKA results in the induction of severe malaria. This infection has many features in common with human disease and is the best available model for certain aspects of clinical malaria (reviewed by de Souza and Riley, Reference de Souza and Riley2002; Miller et al. Reference Miller, Baruch, Marsh and Doumbo2002). Like in humans, two contributing factors have been identified as the main determinants of severe malaria: sequestration of parasitized erythrocytes in capillaries of target organs and a strong pro-inflammatory response (reviewed by Schofield, Reference Schofield2007). C57BL/6 mice are susceptible to P. berghei ANKA-mediated severe malaria and succumb 1 week post-infection without anti-malarial treatment. Inflammatory responses mediated by cytokines and chemokines such as tumour necrosis factor (TNF), interferon (IFN)-γ, CXC-chemokine ligand 10 and effector cells such as CD4+ T, CD8+ T, natural killer T (NKT) and natural killer (NK) cells contribute to the development of severe malaria in these mice (reviewed by Hansen, Reference Hansen2012). An important disruption of the spleen structure characterized by reduced T cell retention in the white pulp and absent marginal zone has been found to accompany the onset of severe disease symptoms (Carvalho et al. Reference Carvalho, Ferreira-da-Cruz, Daniel-Ribeiro, Pelajo-Machado and Lenzi2007). Moreover, recent work revealed that P. berghei ANKA infection impairs GC formation in the spleen at the time of febrile illness (Ryg-Cornejo et al. Reference Ryg-Cornejo, Ioannidis, Ly, Chiu, Tellier, Hill, Preston, Pellegrini, Yu, Nutt, Kallies and Hansen2016). The impaired GC responses appear to reflect the reduced memory B cells and isotype-switched long-lived plasma cells generated in response to infection.

GC development and function requires the crucial help of Tfh cells, which express the CXC-chemokine receptor 5 (CXCR5) that enables them to migrate into B cell follicles and provide co-stimulatory help via the production of IL-21 to GC B cells (Crotty, Reference Crotty2014). Recent work revealed that Tfh cell differentiation is impaired during P. berghei ANKA infection, despite the induction of high frequencies of precursor Tfh cells (Ryg-Cornejo et al. Reference Ryg-Cornejo, Ioannidis, Ly, Chiu, Tellier, Hill, Preston, Pellegrini, Yu, Nutt, Kallies and Hansen2016). While the Tfh precursors induced during P. berghei ANKA infection expressed normal levels of the Tfh lineage-specifying transcription factor Bcl-6 and IL-21, these cells displayed low levels of programmed cell death-1 (PD-1) and CXCR5, and co-expressed T helper 1 (Th1) cell-associated molecules such as T-bet and chemokine receptor CXCR3. Interestingly, genetic deletion of T-bet or blockade of the pro-inflammatory cytokines TNF and IFN-γ restored Tfh cell differentiation and GC responses to infection (Ryg-Cornejo et al. Reference Ryg-Cornejo, Ioannidis, Ly, Chiu, Tellier, Hill, Preston, Pellegrini, Yu, Nutt, Kallies and Hansen2016). Consistently, administration of exogenous IFN-γ to mice infected with non-lethal blood-stage Plasmodium yoelii has also been shown to reduce Tfh and GC B cell responses in a dose-dependent manner (Zander et al. Reference Zander, Obeng-Adjei, Guthmiller, Kulu, Li, Ongoiba, Traore, Crompton and Butler2015). Thus, these studies are consistent with a model in which the same pro-inflammatory mediators that drive severe malaria pathology have detrimental effects on the induction of humoral immune responses by modulating the balance between Th1 and Tfh cell responses to infection (Fig. 1). Indeed, it has been recently shown that acute P. falciparum malaria induces the activation of circulating Th1 cell-like PD-1+CXCR5+CXCR3+ Tfh cells in Malian children, which were shown to have limited helper capacity (Obeng-Adjei et al. Reference Obeng-Adjei, Portugal, Tran, Yazew, Skinner, Li, Jain, Felgner, Doumbo, Kayentao, Ongoiba, Traore and Crompton2015). Further studies are needed to define how age and transmission intensity might influence the induction of circulating Tfh cell subsets and their contribution to the inefficient acquisition of B cell memory in malaria endemic areas.

Fig. 1.

A hypothetical model describing the role of inflammatory cytokines in Tfh cell differentiation and the development of B cell responses to malaria. Unlike normal Tfh cell differentiation, in which naïve T cells become activated upon encounter with cognate antigen and upregulate Bcl-6 and CXCR5 expression for migration into the GC, in the presence of inflammatory cytokines produced in response to acute malaria, Tfh cell precursors not only express Bcl-6 and low levels of CXCR5, but also express the Th1 lineage transcription factor T-bet and high levels of inflammatory chemokine receptor CXCR3. These cells do not efficiently support GC reactions and in the presence of chemotactic stimuli, they might abandon the lymphoid organ and migrate to inflamed tissue missing on the opportunity to provide help for antibody responses to infection.

Concluding remarks and future directions

Despite the potential significance to global public health, the immunological processes responsible for the slow and imperfect acquisition of protective humoral immunity to malaria remain largely unsolved. Emerging evidence both in human field studies and mouse infection models are beginning to address how malaria negatively impacts the induction of B cell and Tfh cell responses, thereby impeding efficient formation of immunological B cell memory. In addition to a delayed acquisition of classical memory B cell subsets observed in highly endemic areas, there is now substantial evidence that exposure to P. falciparum is associated with altered proportions of circulating B cells, including an expansion of atypical memory B cells. Further studies are required to delineate their specific function, antigen-specificity and the implications of their expansion following infection with regard to the establishment of anti-malarial immunity. To date, it remains unclear whether similar cells exist in mice, thus mechanistic work in rodent malaria models is not currently feasible until functionally relevant markers can be used to identify this memory B cell subset.

Recent evidence suggests that sub-optimal B cell responses to infection are associated with deficient immunological T cell help. Although further investigation is required to determine whether the Tfh cell compartment is compromised in human malaria infection as seen in rodent models, the expression of inhibitory receptors PD-1 and lymphocyte activation gene-3 (LAG-3) has already been reported in CD4+ T cells of children residing in high P. falciparum transmission areas (Butler et al. Reference Butler, Moebius, Pewe, Traore, Doumbo, Tygrett, Waldschmidt, Crompton and Harty2012; Illingworth et al. Reference Illingworth, Butler, Roetynck, Mwacharo, Pierce, Bejon, Crompton, Marsh and Ndungu2013; Zander et al. Reference Zander, Obeng-Adjei, Guthmiller, Kulu, Li, Ongoiba, Traore, Crompton and Butler2015). Malaria exposure appears to drive increased expression of these phenotypic markers of exhaustion, which has been reported to correlate with a decreased proportion of memory B cells among children who are persistently exposed (Illingworth et al. Reference Illingworth, Butler, Roetynck, Mwacharo, Pierce, Bejon, Crompton, Marsh and Ndungu2013). Moreover, the upregulation of PD-1 has been associated with increased parasite burdens during clinical malaria (Zander et al. Reference Zander, Obeng-Adjei, Guthmiller, Kulu, Li, Ongoiba, Traore, Crompton and Butler2015). It remains to be determined whether this phenotype specifically reflects CD4+ T cell exhaustion or compromised Tfh cell responses in human infection.

Strategies aimed at improving Tfh function during malaria infection are already being explored and their use has shown that promoting or inhibiting signalling pathways may improve GC activity (Butler et al. Reference Butler, Pewe, Traore, Doumbo, Tygrett, Waldschmidt and Harty2011; Zander et al. Reference Zander, Obeng-Adjei, Guthmiller, Kulu, Li, Ongoiba, Traore, Crompton and Butler2015). Neutralization of inhibitory signals mediated by PD-1 and LAG-3 (Butler et al. Reference Butler, Pewe, Traore, Doumbo, Tygrett, Waldschmidt and Harty2011) or boosting of co-stimulatory signals via OX40 receptor ligation (Zander et al. Reference Zander, Obeng-Adjei, Guthmiller, Kulu, Li, Ongoiba, Traore, Crompton and Butler2015) has been shown to improve disease outcomes during non-lethal P. yoelii infection by favouring Tfh cell expansion.

An emerging concept arising from human field studies and experimental infections is starting to support a model in which high malaria transmission and excessive pro-inflammatory responses that accompany severe episodes could be playing a detrimental role in the development of protective immunity. In line with this hypothesis, recent work revealed that the reduced production of inflammatory factors, including IL-1β, IL-6 and IL-8, presumably mediated by enhanced immunoregulatory responses to infection, is associated with improved control of peripheral parasitaemia, suggesting that protective immune responses can progress with the attenuation of malaria-induced inflammation (Portugal et al. Reference Portugal, Moebius, Skinner, Doumbo, Doumtabe, Kone, Dia, Kanakabandi, Sturdevant, Virtaneva, Porcella, Li, Doumbo, Kayentao, Ongoiba, Traore and Crompton2014). More longitudinal studies are much needed to extend these observations as well as animal-based findings to the human setting despite obvious challenges. Given the importance of the induction of antibodies and long-lived humoral memory in immunity to malaria, understanding the factors that impair and/or delay this process is of vital importance as it might lead to the development of novel strategies to improve the efficacy of immune responses to the parasite.

ACKNOWLEDGEMENT

We wish to thank Dr Axel Kallies for useful discussions.

FINANCIAL SUPPORT

Supported by the Australian Government National Health and Medical Research Council IRIISS and Project Grant 1058665 (both to DH).

References

REFERENCES

Achtman, A. H., Khan, M., MacLennan, I. C. M. and Langhorne, J. (2003). Plasmodium chabaudi chabaudi infection in mice induces strong B cell responses and striking but temporary changes in splenic cell distribution. Journal of Immunology 171, 317–324.CrossRefGoogle Scholar
Akpogheneta, O. J., Duah, N. O., Tetteh, K. K. A., Dunyo, S., Lanar, D. E., Pinder, M. and Conway, D. J. (2008). Duration of naturally acquired antibody responses to blood-stage Plasmodium falciparum is age dependent and antigen specific. Infection and Immunity 76, 1748–1755.CrossRefGoogle ScholarPubMed
Allen, C. D. C., Okada, T., Tang, H. L. and Cyster, J. G. (2007). Imaging of germinal center selection events during affinity maturation. Science 315, 528–531.CrossRefGoogle ScholarPubMed
Amanna, I. J., Carlson, N. E. and Slifka, M. K. (2007). Duration of humoral immunity to common viral and vaccine antigens. New England Journal of Medicine 357, 1903–1915.CrossRefGoogle ScholarPubMed
Ampomah, P., Stevenson, L., Ofori, M. F., Barfod, L. and Hviid, L. (2014 a). B-cell responses to pregnancy-restricted and -unrestricted Plasmodium falciparum erythrocyte membrane protein 1 antigens in Ghanaian women naturally exposed to malaria parasites. Infection and Immunity 82, 1860–1871.CrossRefGoogle ScholarPubMed
Ampomah, P., Stevenson, L., Ofori, M. F., Barfod, L. and Hviid, L. (2014 b). Kinetics of B cell responses to Plasmodium falciparum erythrocyte membrane protein 1 in Ghanaian women naturally exposed to malaria parasites. Journal of Immunology 192, 5236–5244.CrossRefGoogle ScholarPubMed
Ayieko, C., Maue, A. C., Jura, W. G. Z. O., Noland, G. S., Ayodo, G., Rochford, R. and John, C. C. (2013). Changes in B cell populations and merozoite surface protein-1-specific memory B cell responses after prolonged absence of detectable P. falciparum infection. PLoS ONE 8, e67230.CrossRefGoogle Scholar
Baird, J. K. (1995). Host age as a determinant of naturally acquired immunity to Plasmodium falciparum. Parasitology Today 11, 105–111.CrossRefGoogle ScholarPubMed
Banga, S., Coursen, J. D., Portugal, S., Tran, T. M., Hancox, L., Ongoiba, A., Traore, B., Doumbo, O. K., Huang, C.-Y., Harty, J. T. and Crompton, P. D. (2015). Impact of acute malaria on pre-existing antibodies to viral and vaccine antigens in mice and humans. PLoS ONE 10, e0125090.CrossRefGoogle ScholarPubMed
Beattie, L., Engwerda, C. R., Wykes, M. and Good, M. F. (2006). CD8+ T lymphocyte-mediated loss of marginal metallophilic macrophages following infection with Plasmodium chabaudi chabaudi AS. Journal of Immunology 177, 2518–2526.CrossRefGoogle ScholarPubMed
Beeson, J. G., Mann, E. J., Elliott, S. R., Lema, V. M., Tadesse, E., Molyneux, M. E., Brown, G. V. and Rogerson, S. J. (2004). Antibodies to variant surface antigens of Plasmodium falciparum-infected erythrocytes and adhesion inhibitory antibodies are associated with placental malaria and have overlapping and distinct targets. Journal of Infectious Diseases 189, 540–551.CrossRefGoogle ScholarPubMed
Blackman, M. J., Heidrich, H. G., Donachie, S., McBride, J. S. and Holder, A. A. (1990). A single fragment of a malaria merozoite surface protein remains on the parasite during red cell invasion and is the target of invasion-inhibiting antibodies. Journal of Experimental Medicine 172, 379–382.CrossRefGoogle ScholarPubMed
Bouharoun-Tayoun, H., Oeuvray, C., Lunel, F. and Druilhe, P. (1995). Mechanisms underlying the monocyte-mediated antibody-dependent killing of Plasmodium falciparum asexual blood stages. Journal of Experimental Medicine 182, 409–418.CrossRefGoogle ScholarPubMed
Boyle, M. J., Reiling, L., Feng, G., Langer, C., Osier, F. H., Aspeling-Jones, H., Cheng, Y. S., Stubbs, J., Tetteh, K. K. A., Conway, D. J., McCarthy, J. S., Müller, I., Marsh, K., Anders, R. F. and Beeson, J. G. (2015). Human antibodies fix complement to inhibit Plasmodium falciparum invasion of erythrocytes and are associated with protection against malaria. Immunity 42, 580–590.CrossRefGoogle ScholarPubMed
Butler, N. S., Pewe, L. L., Traore, B., Doumbo, O. K., Tygrett, L. T., Waldschmidt, T. J. and Harty, J. T. (2011). Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection. Nature Immunology 13, 188–195.CrossRefGoogle ScholarPubMed
Butler, N. S., Moebius, J., Pewe, L. L., Traore, B., Doumbo, O. K., Tygrett, L. T., Waldschmidt, T. J., Crompton, P. D. and Harty, J. T. (2012). Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection. Nature Immunology 13, 188–195.CrossRefGoogle Scholar
Cadman, E. T., Abdallah, A. Y., Voisine, C., Sponaas, A.-M., Corran, P., Lamb, T., Brown, D., Ndungu, F. and Langhorne, J. (2008). Alterations of splenic architecture in malaria are induced independently of Toll-like receptors 2, 4, and 9 or MyD88 and may affect antibody affinity. Infection and Immunity 76, 3924–3931.CrossRefGoogle ScholarPubMed
Carvalho, L. J. M., Ferreira-da-Cruz, M. F., Daniel-Ribeiro, C. T., Pelajo-Machado, M. and Lenzi, H. L. (2007). Germinal center architecture disturbance during Plasmodium berghei ANKA infection in CBA mice. Malaria Journal 6, 59.CrossRefGoogle ScholarPubMed
Cavanagh, D. R., Elhassan, I. M., Roper, C., Robinson, V. J., Giha, H., Holder, A. A., Hviid, L., Theander, T. G., Arnot, D. E. and McBride, J. S. (1998). A longitudinal study of type-specific antibody responses to Plasmodium falciparum merozoite surface protein-1 in an area of unstable malaria in Sudan. Journal of Immunology 161, 347–359.CrossRefGoogle Scholar
Cavanagh, D. R., Dodoo, D., Hviid, L., Kurtzhals, J. A., Theander, T. G., Akanmori, B. D., Polley, S., Conway, D. J., Koram, K. and McBride, J. S. (2004). Antibodies to the N-terminal block 2 of Plasmodium falciparum merozoite surface protein 1 are associated with protection against clinical malaria. Infection and Immunity 72, 6492–6502.CrossRefGoogle Scholar
Castillo-Méndez, S. I., Zago, C. A., Sardinha, L. R., Freitas do Rosário, A. P.Álvarez, J. M. and D'Império Lima, M. R. (2007). Characterization of the spleen B-cell compartment at the early and late blood-stage Plasmodium chabaudi malaria. Scandinavian Journal of Immunology 66, 309–319.CrossRefGoogle ScholarPubMed
Chiu, C. Y. H., Healer, J., Thompson, J. K., Chen, L., Kaul, A., Savergave, L., Raghuwanshi, A., Suen, C. S. N. L. W., Siba, P. M., Schofield, L., Müeller, I., Cowman, A. F. and Hansen, D. S. (2014). Association of antibodies to Plasmodium falciparum reticulocyte binding protein homolog 5 with protection from clinical malaria. Frontiers in Microbiology 5, 314. doi: 10.3389/fmicb.2014.00314.CrossRefGoogle ScholarPubMed
Chiu, C. Y. H., Hodder, A. N., Lin, C. S., Li Wai Suen, C. S. N., Schofield, L., Siba, P. M., Müeller, I., Cowman, A. F. and Hansen, D. S. (2015). Antibodies to the Plasmodium falciparum proteins MSPDBL1 and MSPDBL2 opsonize merozoites, inhibit parasite growth, and predict protection from clinical malaria. Journal of Infectious Diseases 212, 406–415.CrossRefGoogle Scholar
Clark, E. H., Silva, C. J., Weiss, G. E., Li, S., Padilla, C., Crompton, P. D., Hernandez, J. N. and Branch, O. H. (2012). Plasmodium falciparum malaria in the Peruvian Amazon, a region of low transmission, is associated with immunologic memory. Infection and Immunity 80, 1583–1592.CrossRefGoogle ScholarPubMed
Cohen, S., Carrington, S. and Mcgregor, I. A. (1961). Gamma-globulin and acquired immunity to human malaria. Nature 192, 733.CrossRefGoogle ScholarPubMed
Cowman, A. F. and Crabb, B. S. (2006). Invasion of red blood cells by malaria parasites. Cell 124, 755–766.CrossRefGoogle ScholarPubMed
Craig, A. G., Grau, G. E., Janse, C., Kazura, J. W., Milner, D., Barnwell, J. W., Turner, G., Langhorne, J. and Model, H. R. M. A. (2012). The role of animal models for research on severe malaria. PLoS Pathogens 8, e1002401. doi: 10.1371/journal.ppat.1002401.CrossRefGoogle ScholarPubMed
Crompton, P. D., Kayala, M. A., Traore, B., Kayentao, K., Ongoiba, A., Weiss, G. E., Molina, D. M., Burk, C. R., Waisberg, M., Jasinskas, A., Tan, X., Doumbo, S., Doumtabe, D., Kone, Y., Narum, D. L., Liang, X., Doumbo, O. K., Miller, L. H., Doolan, D. L., Baldi, P., Felgner, P. L. and Pierce, S. K. (2010). A prospective analysis of the Ab response to Plasmodium falciparum before and after a malaria season by protein microarray. Proceedings of the National Academy of Sciences of the United States of America 107, 6958–6963.CrossRefGoogle ScholarPubMed
Crotty, S. (2014). T follicular helper cell differentiation, function, and roles in disease. Immunity 41, 529–542.CrossRefGoogle ScholarPubMed
de Souza, J. B. and Riley, E. M. (2002). Cerebral malaria: the contribution of studies in animal models to our understanding of immunopathogenesis. Microbes and Infection 4, 291–300.CrossRefGoogle ScholarPubMed
Dodoo, D., Staalsoe, T., Giha, H., Kurtzhals, J. A., Akanmori, B. D., Koram, K., Dunyo, S., Nkrumah, F. K., Hviid, L. and Theander, T. G. (2001). Antibodies to variant antigens on the surfaces of infected erythrocytes are associated with protection from malaria in Ghanaian children. Infection and Immunity 69, 3713–3718.CrossRefGoogle ScholarPubMed
Donati, D., Zhang, L. P., Chêne, A., Chen, Q., Flick, K., Nyström, M., Wahlgren, M. and Bejarano, M. T. (2004). Identification of a polyclonal B-cell activator in Plasmodium falciparum. Infection and Immunity 72, 5412–5418.CrossRefGoogle ScholarPubMed
Donati, D., Mok, B., Chêne, A., Xu, H., Thangarajh, M., Glas, R., Chen, Q., Wahlgren, M. and Bejarano, M. T. (2006). Increased B cell survival and preferential activation of the memory compartment by a malaria polyclonal B cell activator. Journal of Immunology 177, 3035–3044.CrossRefGoogle ScholarPubMed
Fowkes, F. J.I., Richards, J. S., Simpson, J. A. and Beeson, J. G. (2010). The relationship between anti-merozoite antibodies and incidence of Plasmodium falciparum malaria: a systematic review and meta-analysis. PLoS Medicine 7, e1000218.CrossRefGoogle ScholarPubMed
Good, K. L., Avery, D. T. and Tangye, S. G. (2009). Resting human memory B cells are intrinsically programmed for enhanced survival and responsiveness to diverse stimuli compared to naive B cells. Journal of Immunology 182, 890–901. doi: 10.4049/jimmunol.182.2.890.CrossRefGoogle ScholarPubMed
Gupta, S., Snow, R. W., Donnelly, C. A., Marsh, K. and Newbold, C. (1999). Immunity to non-cerebral severe malaria is acquired after one or two infections. Nature Medicine 5, 340–343.CrossRefGoogle ScholarPubMed
Hammarlund, E., Lewis, M. W., Hansen, S. G., Strelow, L. I., Nelson, J. A., Sexton, G. J., Hanifin, J. M. and Slifka, M. K. (2003). Duration of antiviral immunity after smallpox vaccination. Nature Medicine 9, 1131–1137.CrossRefGoogle ScholarPubMed
Hansen, D. S. (2012). Inflammatory responses associated with the induction of cerebral malaria: lessons from experimental murine models. PLoS Pathogens 8, e1003045.CrossRefGoogle ScholarPubMed
Hill, D. L., Eriksson, E. M., Suen, C. S. N. L. W., Chiu, C. Y., Ryg-Cornejo, V., Robinson, L. J., Siba, P. M., Müeller, I., Hansen, D. S. and Schofield, L. (2013). Opsonising Antibodies to P. falciparum merozoites associated with immunity to clinical malaria. PLoS ONE 8, e74627. doi: 10.1371/journal.pone.0074627.CrossRefGoogle Scholar
Hviid, L., Barfod, L. and Fowkes, F. J. I. (2015). Trying to remember: immunological B cell memory to malaria. Trends in Parasitology 31, 89–94.CrossRefGoogle ScholarPubMed
Illingworth, J., Butler, N. S., Roetynck, S., Mwacharo, J., Pierce, S. K., Bejon, P., Crompton, P. D., Marsh, K. and Ndungu, F. M. (2013). Chronic exposure to Plasmodium falciparum is associated with phenotypic evidence of B and T cell exhaustion. Journal of Immunology 190, 1038–1047.CrossRefGoogle ScholarPubMed
Ismail, H. A., Tijani, M. K., Langer, C., Reiling, L., White, M. T., Beeson, J. G., Wahlgren, M., Nwuba, R. and Persson, K. E. (2014). Subclass responses and their half-lives for antibodies against EBA175 and PfRh2 in naturally acquired immunity against Plasmodium falciparum malaria. Malaria Journal 13, 425.CrossRefGoogle Scholar
Jacob, J., Kassir, R. and KELSOE, G. (1991). In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl) acetyl. I. The architecture and dynamics of responding cell populations. Journal of Experimental Medicine 173, 1165–1175.CrossRefGoogle ScholarPubMed
John, C. C., O'Donnell, R. A., Sumba, P. O., Moormann, A. M., de Koning-Ward, T. F., King, C. L., Kazura, J. W. and Crabb, B. S. (2004). Evidence that invasion-inhibitory antibodies specific for the 19-kDa fragment of merozoite surface protein-1 (MSP-1 19) can play a protective role against blood-stage Plasmodium falciparum infection in individuals in a malaria endemic area of Africa. Journal of Immunology 173, 666–672.CrossRefGoogle Scholar
Kinyanjui, S. M., Bull, P., Newbold, C. I. and Marsh, K. (2003). Kinetics of antibody responses to plasmodium falciparum-infected erythrocyte variant surface antigens. Journal of Infectious Diseases 187, 667–674.CrossRefGoogle ScholarPubMed
Kinyanjui, S. M., Conway, D. J., Lanar, D. E. and Marsh, K. (2007). IgG antibody responses to Plasmodium falciparum merozoite antigens in Kenyan children have a short half-life. Malaria Journal 6, 82.CrossRefGoogle ScholarPubMed
Langhorne, J., Ndungu, F. M., Sponaas, A.-M. and Marsh, K. (2008). Immunity to malaria: more questions than answers. Nature Immunology 9, 725–732.CrossRefGoogle ScholarPubMed
Liu, Y. J., Zhang, J., Lane, P. J., Chan, E. Y. and MacLennan, I. C. (1991). Sites of specific B cell activation in primary and secondary responses to T cell-dependent and T cell-independent antigens. European Journal of Immunology 21, 2951–2962.CrossRefGoogle Scholar
Maple, P. A., Jones, C. S., Wall, E. C., Vyseb, A., Edmunds, W. J., Andrews, N. J. and Miller, E. (2000). Immunity to diphtheria and tetanus in England and Wales. Vaccine 19, 167–173.CrossRefGoogle ScholarPubMed
Marsh, K. and Kinyanjui, S. (2006). Immune effector mechanisms in malaria. Parasite Immunology 28, 51–60.CrossRefGoogle ScholarPubMed
Marsh, K., Otoo, L., Hayes, R. J., Carson, D. C. and Greenwood, B. M. (1989). Antibodies to blood stage antigens of Plasmodium falciparum in rural Gambians and their relation to protection against infection. Transactions of the Royal Society of Tropical Medicine and Hygiene 83, 293–303.CrossRefGoogle ScholarPubMed
McGregor, I. A., Carrington, S. P. and Cohen, S. (1963). Treatment of East African P. falciparum malaria with West African human γ-globulin. Transactions of the Royal Society of Tropical Medicine and Hygiene 57, 170–175.CrossRefGoogle Scholar
Mebius, R. E. and Kraal, G. (2005). Structure and function of the spleen. Nature Reviews Immunology 5, 606–616.CrossRefGoogle ScholarPubMed
Migot, F., Chougnet, C., Henzel, D., Dubois, B., Jambou, R., Fievet, N. and Deloron, P. (1995). Anti-malaria antibody-producing B cell frequencies in adults after a Plasmodium falciparum outbreak in Madagascar. Clinical and Experimental Immunology 102, 529–534.CrossRefGoogle ScholarPubMed
Miller, L. H., Baruch, D. I., Marsh, K. and Doumbo, O. K. (2002). The pathogenic basis of malaria. Nature 415, 673–679.CrossRefGoogle ScholarPubMed
Millington, O. R., Di Lorenzo, C., Phillips, R. S., Garside, P. and Brewer, J. M. (2006). Suppression of adaptive immunity to heterologous antigens during Plasmodium infection through hemozoin-induced failure of dendritic cell function. Journal of Biology 5, 5.CrossRefGoogle ScholarPubMed
Moir, S., Ho, J., Malaspina, A., Wang, W., DiPoto, A. C., O'Shea, M. A., Roby, G., Kottilil, S., Arthos, J., Proschan, M. A., Chun, T. W. and Fauci, A. S. (2008). Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals. Journal of Experimental Medicine 205, 1797–1805.CrossRefGoogle Scholar
Morell, A., Terry, W. D. and Waldmann, T. A. (1970). Metabolic properties of IgG subclasses in man. Journal of Clinical Investigation 49, 673–680.CrossRefGoogle ScholarPubMed
Muellenbeck, M. F., Ueberheide, B., Amulic, B., Epp, A., Fenyo, D., Busse, C. E., Esen, M., Theisen, M., Mordmuller, B. and Wardemann, H. (2013). Atypical and classical memory B cells produce Plasmodium falciparum neutralizing antibodies. Journal of Experimental Medicine 210, 389–399.CrossRefGoogle ScholarPubMed
Mueller, S. N. and Germain, R. N. (2009). Stromal cell contributions to the homeostasis and functionality of the immune system. Nature Reviews Immunology 9, 618–629. doi: 10.1038/nri2588.CrossRefGoogle Scholar
Nduati, E., Gwela, A., Karanja, H., Mugyenyi, C., Langhorne, J., Marsh, K. and Urban, B. C. (2011). The plasma concentration of the B cell activating factor is increased in children with acute malaria. Journal of Infectious Diseases 204, 962–970.CrossRefGoogle Scholar
Ndungu, F. M., Cadman, E. T., Coulcher, J., Nduati, E., Couper, E., Macdonald, D. W., Ng, D. and Langhorne, J. (2009). Functional memory B cells and long-lived plasma cells are generated after a single Plasmodium chabaudi infection in mice. PLoS Pathogens 5, e1000690.CrossRefGoogle ScholarPubMed
Ndungu, F. M., Olotu, A., Mwacharo, J., Nyonda, M., Apfeld, J., Mramba, L. K., Fegan, G. W., Bejon, P. and Marsh, K. (2012). Memory B cells are a more reliable archive for historical antimalarial responses than plasma antibodies in no-longer exposed children. Proceedings of the National Academy of Sciences of the United States of America 109, 8247–8252.CrossRefGoogle ScholarPubMed
Ndungu, F. M., Lundblom, K., Rono, J., Illingworth, J., Eriksson, S. and Färnert, A. (2013). Long-lived Plasmodium falciparum specific memory B cells in naturally exposed Swedish travelers. European Journal of Immunology 43, 2919–2929.CrossRefGoogle ScholarPubMed
Nogaro, S. I., Hafalla, J. C., Walther, B., Remarque, E. J., Tetteh, K. K., Conway, D. J., Riley, E. M. and Walther, M. (2011). The breadth, but not the magnitude, of circulating memory B cell responses to P. falciparum increases with age/exposure in an area of low transmission. PLoS ONE 6, e25582.CrossRefGoogle ScholarPubMed
Obeng-Adjei, N., Portugal, S., Tran, T. M., Yazew, T. B., Skinner, J., Li, S., Jain, A., Felgner, P. L., Doumbo, O. K., Kayentao, K., Ongoiba, A., Traore, B. and Crompton, P. D. (2015). Circulating Th1-cell-type Tfh cells that exhibit impaired B cell help are preferentially activated during acute malaria in children. Cell Reports 13, 425–439. doi: 10.1016/j.celrep.2015.09.004.CrossRefGoogle ScholarPubMed
Osier, F. H., Feng, G., Boyle, M. J., Langer, C., Zhou, J., Richards, J. S., McCallum, F. J., Reiling, L., Jaworowski, A., Anders, R. F., Marsh, K. and Beeson, J. G. (2014). Opsonic phagocytosis of Plasmodium falciparum merozoites: mechanism in human immunity and a correlate of protection against malaria. BMC Medicine 12, 108. doi: 10.1186/1741-7015-12-108.CrossRefGoogle Scholar
Pérez-Mazliah, D., Ng, D. H. L., Freitas do Rosário, A. P., McLaughlin, S., Mastelic-Gavillet, B., Sodenkamp, J., Kushinga, G. and Langhorne, J. (2015). Disruption of IL-21 signaling affects T cell-B cell interactions and abrogates protective humoral immunity to malaria. PLoS Pathogens 11, e1004715.CrossRefGoogle ScholarPubMed
Persson, K. E. M., Fowkes, F. J. I., McCallum, F. J., Gicheru, N., Reiling, L., Richards, J. S., Wilson, D. W., Lopaticki, S., Cowman, A. F., Marsh, K. and Beeson, J. G. (2013). Erythrocyte-binding antigens of Plasmodium falciparum are targets of human inhibitory antibodies and function to evade naturally acquired immunity. Journal of Immunology 191, 785–794.CrossRefGoogle ScholarPubMed
Portugal, S., Doumtabe, D., Traore, B., Miller, L. H., Troye-Blomberg, M., Doumbo, O. K., Dolo, A., Pierce, S. K. and Crompton, P. D. (2012). B cell analysis of ethnic groups in Mali with differential susceptibility to malaria. Malaria Journal 11, 162. doi: 10.1186/1475-2875-11-162.CrossRefGoogle ScholarPubMed
Portugal, S., Moebius, J., Skinner, J., Doumbo, S., Doumtabe, D., Kone, Y., Dia, S., Kanakabandi, K., Sturdevant, D. E., Virtaneva, K., Porcella, S. F., Li, S., Doumbo, O. K., Kayentao, K., Ongoiba, A., Traore, B. and Crompton, P. D. (2014). Exposure-dependent control of malaria-induced inflammation in children. PLoS Pathogens 10, e1004079.CrossRefGoogle ScholarPubMed
Portugal, S., Tipton, C. M., Sohn, H., Kone, Y., Wang, J., Li, S., Skinner, J., Virtaneva, K., Sturdevant, D. E., Porcella, S. F., Doumbo, O. K., Doumbo, S., Kayentao, K., Ongoiba, A., Traore, B., Sanz, I., Pierce, S. K. and Crompton, P. D. (2015). Malaria-associated atypical memory B cells exhibit markedly reduced B cell receptor signaling and effector function. eLife 4, e07218. doi: 10.7554/eLife.07218.CrossRefGoogle ScholarPubMed
Radbruch, A., Muehlinghaus, G., Luger, E. O., Inamine, A., Smith, K. G. C., Dörner, T. and Hiepe, F. (2006). Competence and competition: the challenge of becoming a long-lived plasma cell. Nature Reviews Immunology 6, 741–750. doi: 10.1038/nri1886.CrossRefGoogle ScholarPubMed
Richards, J. S., Stanisic, D. I., Fowkes, F. J. I., Tavul, L., Dabod, E., Thompson, J. K., Kumar, S., Chitnis, C. E., Narum, D. L., Michon, P., Siba, P. M., Cowman, A. F., Müeller, I. and Beeson, J. G. (2010). Association between naturally acquired antibodies to erythrocyte-binding antigens of Plasmodium falciparum and protection from malaria and high-density parasitemia. Clinical Infectious Diseases 51, e50–e60.CrossRefGoogle ScholarPubMed
Richards, J. S., Arumugam, T. U., Reiling, L., Healer, J., Hodder, A. N., Fowkes, F. J. I., Cross, N., Langer, C., Takeo, S., Uboldi, A. D., Thompson, J. K., Gilson, P. R., Coppel, R. L., Siba, P. M., King, C. L., Torii, M., Chitnis, C. E., Narum, D. L., Müeller, I., Crabb, B. S., Cowman, A. F., Tsuboi, T. and Beeson, J. G. (2013). Identification and prioritization of merozoite antigens as targets of protective human immunity to Plasmodium falciparum malaria for vaccine and biomarker development. Journal of Immunology 191, 795–809.CrossRefGoogle ScholarPubMed
Ryg-Cornejo, V., Ioannidis, L. J., Ly, A., Chiu, C. Y., Tellier, J., Hill, D. L., Preston, S. P., Pellegrini, M., Yu, D., Nutt, S. L., Kallies, A. and Hansen, D. S. (2016) Severe malaria infections impair germinal centre responses by inhibiting T follicular helper cell differentiation. Cell Reports 14, 1–14.CrossRefGoogle ScholarPubMed
Scherf, A., Lopez-Rubio, J. J. and Riviere, L. (2008). Antigenic variation in Plasmodium falciparum. Annual Review of Microbiology 62, 445–470.CrossRefGoogle ScholarPubMed
Schofield, L. (2007). Intravascular infiltrates and organ-specific inflammation in malaria pathogenesis. Immunology and Cell Biology 85, 130–137.CrossRefGoogle ScholarPubMed
Schofield, L. and Grau, G. E. (2005). Immunological processes in malaria pathogenesis. Nature Reviews Immunology 5, 722–735.CrossRefGoogle ScholarPubMed
Scholzen, A., Teirlinck, A. C., Bijker, E. M., Roestenberg, M., Hermsen, C. C., Hoffman, S. L. and Sauerwein, R. W. (2014). BAFF and BAFF receptor levels correlate with B cell subset activation and redistribution in controlled human malaria infection. Journal of Immunology 192, 3719–3729.CrossRefGoogle ScholarPubMed
Smith, K. G., Hewitson, T. D., Nossal, G. J. and Tarlinton, D. M. (1996). The phenotype and fate of the antibody-forming cells of the splenic foci. European Journal of Immunology 26, 444–448.CrossRefGoogle ScholarPubMed
Stephens, R., Ndungu, F. M. and Langhorne, J. (2009). Germinal centre and marginal zone B cells expand quickly in a second Plasmodium chabaudi malaria infection producing mature plasma cells. Parasite Immunology 31, 20–31.CrossRefGoogle Scholar
Stephens, R., Culleton, R. L. and Lamb, T. J. (2012). The contribution of Plasmodium chabaudi to our understanding of malaria. Trends in Parasitology 28, 73–82.CrossRefGoogle ScholarPubMed
Stevenson, M. M. and Kraal, G. (1989). Histological-changes in the spleen and liver of C57bl/6 and a/J mice during Plasmodium-Chabaudi as infection. Experimental and Molecular Pathology 51, 80–95.CrossRefGoogle Scholar
Tongren, J. E., Drakeley, C. J., McDonald, S. L., Reyburn, H. G., Manjurano, A., Nkya, W. M., Lemnge, M. M., Gowda, C. D., Todd, J. E., Corran, P. H. and Riley, E. M. (2006). Target antigen, age, and duration of antigen exposure independently regulate immunoglobulin G subclass switching in malaria. Infection and Immunity 74, 257–264.CrossRefGoogle ScholarPubMed
Urban, B. C., Hien, T. T., Day, N. P., Phu, N. H., Roberts, R., Pongponratn, E., Jones, M., Mai, N. T. H., Bethell, D., Turner, G. D. H., Ferguson, D., White, N. J. and Roberts, D. J. (2005). Fatal Plasmodium falciparum malaria causes specific patterns of splenic architectural disorganization. Infection and Immunity 73, 1986–1994.CrossRefGoogle ScholarPubMed
Victora, G. D., Schwickert, T. A., Fooksman, D. R., Kamphorst, A. O., Meyer-Hermann, M., Dustin, M. L. and Nussenzweig, M. C. (2010). Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell 143, 592–605.CrossRefGoogle ScholarPubMed
Weiss, G. E., Crompton, P. D., Li, S., Walsh, L. A., Moir, S., Traore, B., Kayentao, K., Ongoiba, A., Doumbo, O. K. and Pierce, S. K. (2009). Atypical memory B cells are greatly expanded in individuals living in a malaria-endemic area. Journal of Immunology 183, 2176–2182.CrossRefGoogle Scholar
Weiss, G. E., Traore, B., Kayentao, K., Ongoiba, A., Doumbo, S., Doumtabe, D., Kone, Y., Dia, S., Guindo, A., Traore, A., Huang, C. Y., Miura, K., Mircetic, M., Li, S., Baughman, A., Narum, D. L., Miller, L. H., Doumbo, O. K., Pierce, S. K. and Crompton, P. D. (2010). The Plasmodium falciparum-specific human memory B cell compartment expands gradually with repeated malaria infections. PLoS Pathogens 6, e1000912.CrossRefGoogle ScholarPubMed
Weiss, G. E., Clark, E. H., Li, S., Traore, B., Kayentao, K., Ongoiba, A., Hernandez, J. N., Doumbo, O. K., Pierce, S. K., Branch, O. H. and Crompton, P. D. (2011). A positive correlation between atypical memory B cells and Plasmodium falciparum transmission intensity in cross-sectional studies in Peru and Mali. PLoS ONE 6, e15983.CrossRefGoogle ScholarPubMed
White, M. T., Griffin, J. T., Akpogheneta, O., Conway, D. J., Koram, K. A., Riley, E. M. and Ghani, A. C. (2014 a). Dynamics of the antibody response to Plasmodium falciparum infection in African children. Journal of Infectious Diseases 210, 1115–1122.CrossRefGoogle ScholarPubMed
White, N. J., Pukrittayakamee, S., Hien, T. T., Faiz, M. A., Mokuolu, O. A. and Dondorp, A. M. (2014 b). Malaria. Lancet 383, 723–735.CrossRefGoogle ScholarPubMed
Wilmore, J. R., Maue, A. C., Lefebvre, J. S., Haynes, L. and Rochford, R. (2013). Acute Plasmodium chabaudi infection dampens humoral responses to a secondary T-dependent antigen but enhances responses to a secondary T-independent antigen. Journal of Immunology 191, 4731–4739.CrossRefGoogle ScholarPubMed
Wipasa, J., Suphavilai, C., Okell, L. C., Cook, J., Corran, P. H., Thaikla, K., Liewsaree, W., Riley, E. M. and Hafalla, J. C. (2010). Long-lived antibody and B cell memory responses to the human malaria parasites, Plasmodium falciparum and Plasmodium vivax. PLoS Pathogens 6, e1000770.CrossRefGoogle Scholar
World Health Organization (2014). World Malaria Report 2014. World Health Organisation, Geneva, Switzerland.Google Scholar
Zander, R. A., Obeng-Adjei, N., Guthmiller, J. J., Kulu, D. I., Li, J., Ongoiba, A., Traore, B., Crompton, P. D. and Butler, N. S. (2015). PD-1 co-inhibitory and OX40 co-stimulatory crosstalk regulates helper T cell differentiation and anti-plasmodium humoral immunity. Cell Host and Microbe 17, 628–641.CrossRefGoogle ScholarPubMed
Zinöcker, S., Schindler, C. E., Skinner, J., Rogosch, T., Waisberg, M., Schickel, J.-N., Meffre, E., Kayentao, K., Ongoiba, A., Traore, B. and Pierce, S. K. (2015). The V gene repertoires of classical and atypical memory B cells in malaria-susceptible West African children. Journal of Immunology 194, 929–939.CrossRefGoogle Scholar
Figure 0

Fig. 1. A hypothetical model describing the role of inflammatory cytokines in Tfh cell differentiation and the development of B cell responses to malaria. Unlike normal Tfh cell differentiation, in which naïve T cells become activated upon encounter with cognate antigen and upregulate Bcl-6 and CXCR5 expression for migration into the GC, in the presence of inflammatory cytokines produced in response to acute malaria, Tfh cell precursors not only express Bcl-6 and low levels of CXCR5, but also express the Th1 lineage transcription factor T-bet and high levels of inflammatory chemokine receptor CXCR3. These cells do not efficiently support GC reactions and in the presence of chemotactic stimuli, they might abandon the lymphoid organ and migrate to inflamed tissue missing on the opportunity to provide help for antibody responses to infection.