Immunological memory is a remarkable phenomenon in which survival of an initial infection by a pathogen leads to life-long protection from disease upon subsequent exposure to that same pathogen. For ...many infectious diseases, long-lived protective humoral immunity is induced after only a single infection in a process that depends on the generation of memory B cells (MBCs) and long-lived plasma cells. However, over the past decade it has become increasingly evident that many chronic human infectious diseases to which immunity is not readily established, including HIV-AIDS, malaria and TB, are associated with fundamental alterations in the composition and functionality of MBC compartments. A common feature of these diseases appears to be a large expansion of what have been termed exhausted B cells, tissue-like memory B cells or atypical memory B cells (aMBCs) that, for simplicity’s sake, we refer to here as aMBCs. It has been suggested that chronic immune activation and inflammation drive the expansion of aMBCs and that in some way aMBCs contribute to deficiencies in the acquisition of immunity in chronic infectious diseases. Although aMBCs are heterogeneous both within individuals and between diseases, they have several features in common including low expression of the cell surface markers that define classical MBCs in humans including CD21 and CD27 and high expression of genes not usually expressed by classical MBCs including T-bet, CD11c and a variety of inhibitory receptors, notably members of the FcRL family. Another distinguishing feature is their greatly diminished ability to be stimulated through their B cell receptors to proliferate, secrete cytokines or produce antibodies. In this review, we describe our current understanding of the phenotypic markers of aMBCs, their specificity in relation to the disease-causing pathogen, their functionality, the drivers of their expansion in chronic infections and their life span. We briefly summarize the features of aMBCs in healthy individuals and in autoimmune disease. We also comment on the possible relationship of human aMBCs and T-bet+, CD11c+ age/autoimmune-associated B cells, also a topic of this review volume.
Humoral immunity consists of pre-existing antibodies expressed by long-lived plasma cells and rapidly reactive memory B cells (MBC). Recent studies of MBC development and function after protein ...immunization have uncovered significant MBC heterogeneity. To clarify functional roles for distinct MBC subsets during malaria infection, we generated tetramers that identify Plasmodium-specific MBCs in both humans and mice. Long-lived murine Plasmodium-specific MBCs consisted of three populations: somatically hypermutated immunoglobulin M+ (IgM+) and IgG+ MBC subsets and an unmutated IgD+ MBC population. Rechallenge experiments revealed that high affinity, somatically hypermutated Plasmodium-specific IgM+ MBCs proliferated and gave rise to antibody-secreting cells that dominated the early secondary response to parasite rechallenge. IgM+ MBCs also gave rise to T cell-dependent IgM+ and IgG+B220+CD138+ plasmablasts or T cell-independent B220−CD138+ IgM+ plasma cells. Thus, even in competition with IgG+ MBCs, IgM+ MBCs are rapid, plastic, early responders to a secondary Plasmodium rechallenge and should be targeted by vaccine strategies.
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•Tetramers allow analyses of endogenous Plasmodium-specific B cells in mice and humans•Three phenotypically distinct MBC populations form after murine malaria infection•Plasmodium-specific IgM+ MBCs are somatically hypermutated and high affinity•Plastic IgM+ memory B cells dominate the early response to malaria rechallenge
Heterogeneous types of memory B cells are present in both humans and mice, yet it is unclear how different MBC subsets form or function in response to infection. Pepper and colleagues reveal that phenotypically and functionally distinct populations of polyclonal Plasmodium-specific MBCs form in response to infection and somatically hypermutated, high-affinity, plastic IgM+ memory B cells dominate the early memory response to malaria rechallenge.
Plasmodium falciparum malaria remains a major public health threat for which there is no licensed vaccine. Abs play a key role in malaria immunity, but Ab-mediated protection is only acquired after ...years of repeated infections, leaving children in endemic areas vulnerable to severe malaria and death. Many P. falciparum Ags are extraordinarily diverse and clonally variant, which likely contribute to the inefficient acquisition of protective Abs. However, mounting evidence suggests that there is more to the story and that infection-induced dysregulation of B cell function also plays a role. We herein review progress toward understanding the B cell biology of P. falciparum infection, focusing on what has been learned from population-based studies in malaria-endemic areas. We suggest ways in which advances in immunology and genomics-based technology can further improve our understanding of the B cell response in malaria and perhaps illuminate new pathways to the development of effective vaccines.
Glycosylation processes are under high natural selection pressure, presumably because these can modulate resistance to infection. Here, we asked whether inactivation of the ...UDP-galactose:β-galactoside-α1-3-galactosyltransferase (α1,3GT) gene, which ablated the expression of the Galα1-3Galβ1-4GlcNAc-R (α-gal) glycan and allowed for the production of anti-α-gal antibodies (Abs) in humans, confers protection against Plasmodium spp. infection, the causative agent of malaria and a major driving force in human evolution. We demonstrate that both Plasmodium spp. and the human gut pathobiont E. coli O86:B7 express α-gal and that anti-α-gal Abs are associated with protection against malaria transmission in humans as well as in α1,3GT-deficient mice, which produce protective anti-α-gal Abs when colonized by E. coli O86:B7. Anti-α-gal Abs target Plasmodium sporozoites for complement-mediated cytotoxicity in the skin, immediately after inoculation by Anopheles mosquitoes. Vaccination against α-gal confers sterile protection against malaria in mice, suggesting that a similar approach may reduce malaria transmission in humans.
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•α-gal is expressed at the surface of Plasmodium sporozoites•Anti-α-gal Abs recognizing E. coli O86:B7 are protective against malaria•Anti-α-gal Abs are cytotoxic to Plasmodium sporozoites•Vaccination against α-gal confers sterile protection against malaria
Specific members of the gut microbiota induce antibodies that prevent malaria transmission through recognition of a glycan residue that is shared by the microbiota and the causative agent of malaria, the Plasmodium.
Cerebral malaria remains a major cause of death for African children, and mechanistic insights regarding the establishment of brain pathology are greatly needed. Expression of specific domains of ...parasite's var genes promoting brain adhesion of infected erythrocytes had been previously identified, but binding specificities and the receptor preference in the brain endothelial cells had not been fully described. The study by Storm et al () in this issue of EMBO Molecular Medicine demonstrates that binding to brain endothelial cells via EPCR and ICAM‐1 is increased in parasites causing cerebral malaria compared to parasites causing uncomplicated malaria. Furthermore, expression levels of var genes encoding the CIDRα1 domain with EPCR affinity correlate with the receptor‐dependent binding to brain, but not dermal endothelial cells, highlighting the important role of EPCR in cerebral malaria pathology.
S. Portugal and H. Fleckenstein are here discussing the work of Storm, Craig and coll. Highlighting how binding to brain endothelial cells via EPCR and ICAM‐1 is increased in parasites causing cerebral malaria.
Malaria-specific antibody responses are short lived in children, leaving them susceptible to repeated bouts of febrile malaria. The cellular and molecular mechanisms underlying this apparent immune ...deficiency are poorly understood. Recently, T follicular helper (Tfh) cells have been shown to play a critical role in generating long-lived antibody responses. We show that Malian children have resting PD-1+CXCR5+CD4+ Tfh cells in circulation that resemble germinal center Tfh cells phenotypically and functionally. Within this population, PD-1+CXCR5+CXCR3− Tfh cells are superior to Th1-polarized PD-1+CXCR5+CXCR3+ Tfh cells in helping B cells. Longitudinally, we observed that malaria drives Th1 cytokine responses, and accordingly, the less-functional Th1-polarized Tfh subset was preferentially activated and its activation did not correlate with antibody responses. These data provide insights into the Tfh cell biology underlying suboptimal antibody responses to malaria in children and suggest that vaccine strategies that promote CXCR3− Tfh cell responses may improve malaria vaccine efficacy.
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•Circulating PD-1+CXCR5+CD4+ T cells in malaria-exposed children resemble GC Tfh cells•The CXCR3− Tfh subset is superior to the Th1-like CXCR3+ subset in helping B cells•Malaria induces Th1 cytokines and activates the less-functional CXCR3+ Tfh subset•Tfh cell responses to malaria do not correlate with B cell and antibody responses
Malaria-specific antibody responses are short lived in children, leaving them susceptible to repeated malaria infections. Tfh cells are critical for long-lived antibody responses. Obeng-Adjei et al. provide evidence that malaria activates less-functional Th1-like PD-1+CXCR5+CXCR3+ Tfh cells that are disassociated from B cell/antibody responses.
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