The V Gene Repertoires of Classical and Atypical Memory B Cells in Malaria-Susceptible West African Children

Zinöcker, Severin; Schindler, Christine E.; Skinner, Jeff; Rogosch, Tobias; Waisberg, Michael; Schickel, Jean-Nicolas; Meffre, Eric; Kayentao, Kassoum; Ongoïba, Aïssata; Traoré, Boubacar

doi:10.4049/jimmunol.1402168

Cited by 36 publications

(41 citation statements)

References 48 publications

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“…The FCRL5 2 subset proliferates more robustly than does the FCRL5 + subset in response to stimuli and expresses lower levels of inhibitory receptors. Intriguingly, we found that FCRL5 + TLM B cells from healthy adults displayed significantly lower SHM rate and shorter replication history than did classical memory B cells, similarly to what was reported in children exposed to malaria (45). However, adults exposed to malaria, who presumably encountered more rounds of malaria infection than did children, display similar SHM rates and replication histories in their TLM and classical memory B cell subsets (12,40).…”

supporting

confidence: 83%

Fc Receptor–like 5 Expression Distinguishes Two Distinct Subsets of Human Circulating Tissue–like Memory B Cells

Borrego

Nagata

et al. 2016

The Journal of Immunology

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Fc receptor–like (FCRL) 5 is a novel IgG binding protein expressed on B cells, with the capacity to regulate Ag receptor signaling. We assessed FCRL5 expression on circulating B cells from healthy donors and found that FCRL5+ cells are most enriched among atypical CD21−/lo/CD27− tissue-like memory (TLM) B cells, which are abnormally expanded in several autoimmune and infectious diseases. Using multicolor flow cytometry, FCRL5+ TLM cells were found to express more CD11c and several inhibitory receptors than did the FCRL5− TLM subset. The homing receptor profiles of the two TLM subsets shared features consistent with migration away from lymphoid tissues, but they also displayed distinct differences. Analysis of IgH V regions in single cells indicated that although both subsets are diverse, the FCRL5+ subset accumulated significantly more somatic mutations. Furthermore, the FCRL5+ subset had more switched isotype expression and more extensive proliferative history. Microarray analysis and quantitative RT-PCR demonstrated that the two TLM subsets possess distinct gene expression profiles, characterized by markedly different CD11c, SOX5, T-bet, and RTN4R expression, as well as differences in expression of inhibitory receptors. Functional analysis revealed that the FCRL5+ TLM subset responds poorly to multiple stimuli compared with the FCRL5− subset, as reflected by reduced calcium mobilization and blunted cell proliferation. We propose that the FCRL5+ TLM subset, but not the FCRL5− TLM subset, underwent Ag-driven development and is severely dysfunctional. The present study elucidates the heterogeneity of TLM B cells and provides the basis to dissect their roles in the pathogenesis of inflammatory and infectious diseases.

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supporting

confidence: 83%

Fc Receptor–like 5 Expression Distinguishes Two Distinct Subsets of Human Circulating Tissue–like Memory B Cells

Borrego

Nagata

et al. 2016

The Journal of Immunology

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“…1), including malaria, in which V gene repertoires and parasite-specific mAbs isolated from IgG + classical memory (equivalent to RM) and atypical memory (equivalent to TLM) B cells have been described recently (56, 57). Few differences were found between the 2 B cell populations, since both contributed to protective B cell immunity; where differences were found, they functionally favored atypical memory B cells, namely, higher levels of SHM and frequencies of polyreactivity (56).…”

Section: Discussionmentioning

confidence: 99%

Maturational characteristics of HIV-specific antibodies in viremic individuals

Meffre¹,

Louie²,

Bannock³

et al. 2016

JCI Insight

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Despite the rare appearance of potent HIV-neutralizing mAbs in infected individuals requiring prolonged affinity maturation, little is known regarding this process in the majority of viremic individuals. HIV-infected individuals with chronic HIV viremia have elevated numbers of nonconventional tissue-like memory (TLM) B cells that predominate in blood over conventional resting memory (RM) B cells. Accordingly, we investigated affinity maturation in these 2 memory B cell populations. Analysis of IgG-expressing TLM B cells revealed a higher number of cell divisions compared with RM B cells; however, TLM B cells paradoxically displayed significantly lower frequencies of somatic hypermutation (SHM). To assess Ab reactivity in TLM and RM B cells, single-cell cloning was performed on HIV envelope CD4–binding site–sorted (CD4bs-sorted) B cells from 3 individuals with chronic HIV viremia. Several clonal families were present among the 127 cloned recombinant mAbs, with evidence of crosstalk between TLM and RM B cell populations that was largely restricted to non-VH4 families. Despite evidence of common origins, SHM frequencies were significantly decreased in TLM-derived mAbs compared with SHM frequencies in RM-derived mAbs. However, both cell populations had lower frequencies of SHMs than did broadly neutralizing CD4bs–specific mAbs. There was a significant correlation between SHM frequencies and the HIV-neutralizing capacities of the mAbs. Furthermore, HIV neutralization was significantly higher in the RM-derived mAbs compared with that seen in the TLM-derived mAbs, and both SHM frequencies and neutralizing capacity were lowest in TLM-derived mAbs with high polyreactivity. Thus, deficiencies in memory B cells that arise during chronic HIV viremia provide insight into the inadequacy of the Ab response in viremic individuals.

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“…Immune repertoire next generation sequencing of the VH and VL in naïve, classical MBCs and aMBCs from malaria-exposed individuals showed no significant differences in their SHM rate (26, 30). Both populations had undergone a similar number of cell divisions, had similar clonal expansion profiles and shared approximately 10% of their VH clones.…”

Section: Introductionmentioning

confidence: 93%

Atypical memory B cells in human chronic infectious diseases: An interim report

Portugal

Obeng-Adjei

Moir

et al. 2017

Cellular Immunology

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161

177

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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.

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The V Gene Repertoires of Classical and Atypical Memory B Cells in Malaria-Susceptible West African Children

Cited by 36 publications

References 48 publications

Fc Receptor–like 5 Expression Distinguishes Two Distinct Subsets of Human Circulating Tissue–like Memory B Cells

Fc Receptor–like 5 Expression Distinguishes Two Distinct Subsets of Human Circulating Tissue–like Memory B Cells

Maturational characteristics of HIV-specific antibodies in viremic individuals

Atypical memory B cells in human chronic infectious diseases: An interim report

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