Corrigendum: Chronic Exposure to Malaria Is Associated with Inhibitory and Activation Markers on Atypical Memory B Cells and Marginal Zone-Like B Cells

Memory B cells isolated from human tonsils are characterized by an activated cell surface phenotype, localization to mucosal epithelium, expression of somatically mutated immunoglobulin (Ig) variable (V) region genes, and a preferential differentiation into plasma cells in vitro. In spleens of both humans and rodents, a subset of memory B cells is believed to reside in the marginal zone of the white pulp. Similar to tonsil-derived memory B cells, splenic marginal zone B cells can be distinguished from naive follicular B cells by a distinct cell surface phenotype and by the presence of somatic mutations in their Ig V region genes. Although differences exist between human naive and memory B cells, no cell surface molecules have been identified that positively identify all memory B cells. In this study, we have examined the expression of the receptor-type protein tyrosine phosphatase CD148 on human B cells. CD148+ B cells present in human spleen exhibited characteristics typical of memory B cells. These included an activated phenotype, localization to the marginal zone, the expression of somatically mutated Ig V region genes, and the preferential differentiation into plasma cells. In contrast, CD148− B cells appeared to be naive B cells due to localization to the mantle zone, the expression of surface antigens typical of unstimulated B cells, and the expression of unmutated Ig V region genes. Interestingly, CD148+ B cells also coexpressed CD27, whereas CD148− B cells were CD27−. These results identify CD148 and CD27 as markers which positively identify memory B cells present in human spleen. Thus, assessing expression of these molecules may be a convenient way to monitor the development of memory B cell responses in immunocompromised individuals or in vaccine trials.

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The Eph-related tyrosine kinase ligand Ephrin-B1 marks germinal center and memory precursor B cells

Journal of Experimental Medicine ◽

10.1084/jem.20161461 ◽

2017 ◽

Vol 214 (3) ◽

pp. 639-649 ◽

Cited By ~ 39

Author(s):

Brian J. Laidlaw ◽

Timothy H. Schmidt ◽

Jesse A. Green ◽

Christopher D.C. Allen ◽

Takaharu Okada ◽

...

Keyword(s):

B Cells ◽

Germinal Center ◽

Tyrosine Kinases ◽

Memory B Cells ◽

Transcriptional Analysis ◽

Specific Marker ◽

Significant Heterogeneity ◽

Activation Markers ◽

Wide Range ◽

Precursor B Cells

Identification of germinal center (GC) B cells is typically reliant on the use of surface activation markers that exhibit a wide range of expression. Here, we identify Ephrin-B1, a ligand for Eph-related receptor tyrosine kinases, as a specific marker of mature GC B cells. The number of Ephrin-B1+ GC B cells increases during the course of an immune response with Ephrin-B1+ GC B cells displaying elevated levels of Bcl6, S1pr2, and Aicda relative to their Ephrin-B1– counterparts. We further identified a small proportion of recently dividing, somatically mutated Ephrin-B1+ GC B cells that have begun to down-regulate Bcl6 and S1pr2 and express markers associated with memory B cells, such as CD38 and EBI2. Transcriptional analysis indicates that these cells are developmentally related to memory B cells, and likely represent a population of GC memory precursor (PreMem) B cells. GC PreMem cells display enhanced survival relative to bulk GC B cells, localize near the edge of the GC, and are predominantly found within the light zone. These findings offer insight into the significant heterogeneity that exists within the GC B cell population and provide tools to further dissect signals regulating the differentiation of GC B cells.

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Genomic analysis of Non‐Splenic Marginal Zone Lymphomas (MZL) indicates similarities between nodal and extranodal MZL and supports their derivation from Memory B‐cells

British Journal of Haematology ◽

10.1111/j.1365-2141.2011.08841.x ◽

2011 ◽

Vol 155 (3) ◽

pp. 362-365 ◽

Cited By ~ 12

Author(s):

Urban Novak ◽

Katia Basso ◽

Laura Pasqualucci ◽

Riccardo Dalla‐Favera ◽

Govind Bhagat

Keyword(s):

B Cells ◽

Marginal Zone ◽

Genomic Analysis ◽

Memory B Cells

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Expression of the immunoregulatory molecule FcRH4 defines a distinctive tissue-based population of memory B cells

Journal of Experimental Medicine ◽

10.1084/jem.20050879 ◽

2005 ◽

Vol 202 (6) ◽

pp. 783-791 ◽

Cited By ~ 206

Author(s):

Götz R.A. Ehrhardt ◽

Joyce T. Hsu ◽

Lanier Gartland ◽

Chuen-Miin Leu ◽

Shuangyin Zhang ◽

...

Keyword(s):

B Cells ◽

Cell Surface ◽

Chemokine Receptors ◽

Cell Activation ◽

Somatic Hypermutation ◽

Cell Receptor ◽

Memory B Cells ◽

Cell Surface Expression ◽

Lymphoid Tissues ◽

Activation Markers

The FcRH4 transmembrane molecule, a member of the Fc receptor homologue family, can potently inhibit B cell receptor (BCR) signaling. We show that cell surface expression of this immunoregulatory molecule is restricted to a subpopulation of memory B cells, most of which lack the classical CD27 marker for memory B cells in humans. The FcRH4+ and FcRH4− memory B cells have undergone comparable levels of immunoglobulin isotype switching and somatic hypermutation, while neither subpopulation expresses the transcription factors involved in plasma cell differentiation. The FcRH4+ memory cells are morphologically distinctive large lymphocytes that express the CD69, CD80, and CD86 cell activation markers. They are also shown to be poised to secrete high levels of immunoglobulins in response to stimulation with T cell cytokines, but they fail to proliferate in response either to BCR ligation or Staphylococcus aureus stimulation. A heightened expression of the CCR1 and CCR5 chemokine receptors may facilitate their preferential localization in lymphoid tissues near epithelial surfaces. Cell surface FcRH4 expression thus marks a unique population of memory B cells with distinctive morphology, functional capabilities, and tissue localization.

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Humans with chronic granulomatous disease maintain humoral immunologic memory despite low frequencies of circulating memory B cells

Blood ◽

10.1182/blood-2012-05-430959 ◽

2012 ◽

Vol 120 (24) ◽

pp. 4850-4858 ◽

Cited By ~ 27

Author(s):

Susan Moir ◽

Suk See De Ravin ◽

Brian H. Santich ◽

Jin Young Kim ◽

Jacqueline G. Posada ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Chronic Granulomatous Disease ◽

Somatic Hypermutation ◽

Memory B Cells ◽

Potential Contribution ◽

Granulomatous Disease ◽

Immunologic Memory ◽

Activation Markers ◽

Specific Memory

Abstract CD27+ memory B cells are reduced in the blood of patients with chronic granulomatous disease (CGD) for reasons and consequences that remain unclear. Here we confirm not only decreased CD27+ but also IgG+ B cells in the blood of CGD patients compared with healthy donors (HDs). However, among IgG+ B cells, the ratio of CD27− to CD27+ was significantly higher in CGD patients compared with HDs. Similar to conventional memory B cells, CD27−IgG+ B cells of CGD patients expressed activation markers and had undergone somatic hypermutation, albeit at levels lower than their CD27+ counterparts. Functional analyses revealed slight reductions in frequencies of total IgG but not influenza-specific memory B-cell responses, as measured by Elispot in CGD patients compared with HDs. Serum IgG levels and influenza-specific antibodies were also normal in these CGD patients. Finally, we provide evidence that influenza-specific memory B cells can be present within the CD27−IgG+ B-cell compartment. Together, these findings show that, despite reduced circulating CD27+ memory B cells, CGD patients maintain an intact humoral immunologic memory, with potential contribution from CD27− B cells.

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B cells and T cells Abnormalities in Patients with Selective IgA Deficiency

10.22541/au.161098957.70296425/v1 ◽

2021 ◽

Author(s):

Yasser Bagheri ◽

Tannaz Moeini Shad ◽

shideh namazi ◽

Gholamreza Azizi ◽

Ali Hosseini ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Marginal Zone ◽

Iga Deficiency ◽

Memory B Cells ◽

T Cell Subsets ◽

Effector Memory ◽

Selective Iga Deficiency

Background: Selective IgA deficiency (SIgAD) is the most prevalent primary immunodeficiency with almost unknown etiology. This study aimed to investigate the clinical diagnostic and prognostic values of lymphocytes subsets and function in symptomatic SIgAD patients. Methods: A total of 30 available SIgAD patients from the Iranian registry and 30 age-sex-matched healthy controls were included in the present study. We analyzed B and T cell peripheral subsets and T cell proliferation assay by flow cytometry in SIgAD patients with mild and severe clinical phenotypes. Results: Our results indicated a significant increase in naïve and transitional B cells and a strong decrease in marginal zone-like and switched memory B-cells in SIgAD patients. We found that naïve and central memory CD4+ T cell subsets, as well as Th1, Th2 and regulatory T cells have significantly decreased. On the other hand, there was a significant reduction in central and effector memory CD8+ T cell subsets, whereas proportions of both (CD4+ and CD8+) terminally differentiated effector memory T cells (TEMRA) were significantly elevated in our patients. Although some of T cell subsets in severe SIgAD were similar, decrease in marginal-zone and switched memory B cells and increase in CD21low B cell of severe SIgAD patients were slightly prominent. Moreover, the proliferation activity of CD4+ T cells was strongly impaired in SIgAD patients with a severe phenotype. Conclusion: SIgAD patients have varied cellular and humoral deficiencies. Therefore, T cell and B cell assessment might help in better understanding the heterogeneous pathogenesis and prognosis estimation of the disease. Keywords: Primary immunodeficiency, Selective IgA deficiency, B cell subsets, T cell subsets, flow cytometry, proliferation assay

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High-Throughput Ig Sequencing of Paired Blood and Spleen Samples Allows a Redefinition of Memory IgM Subsets in Humans

Blood ◽

10.1182/blood.v124.21.565.565 ◽

2014 ◽

Vol 124 (21) ◽

pp. 565-565

Author(s):

Davide Bagnara ◽

Margherita Squillario ◽

David Kipling ◽

Thierry Mora ◽

Aleksandra Walczak ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

High Throughput ◽

Germinal Center ◽

Marginal Zone ◽

Cell Subset ◽

Memory B Cells ◽

Double Negative ◽

Marginal Zone B Cells ◽

B Cell Subsets

Abstract In humans, whether B cells with the IgM+IgD+CD27+ phenotype represent an independent lineage involved in T-independent responses, similar to mouse marginal zone B cells, or whether they are part of the germinal center-derived memory B-cell pool generated during responses to T-dependent antigens, is still a debated issue. To address this question, we performed high-throughput Ig sequencing of B-cell subsets from paired blood and spleen samples and analyzed the clonal relationships between them. We isolated and analyzed 3 different B cell subsets based on CD27 and IgD staining from both blood and spleen: IgD+CD27+ (MZ) - amplified with Cmu primers IgD-CD27+ (switched and IgM-only) with Cmu, Cgamma and Calpha primers IgD-CD27- (CD27- memory or double-negative DN) with the same three primers We obtained 95729 unique sequences that clustered in 49199 different clones: 1125 clones were shared between blood and spleen of the same B-cell subset, and 1681 clones were shared between different subsets, allowing us to trace their relationships. We analyzed these clones that share sequences from different subsets/tissues for their mutation frequency distribution, CDR3-length, and VH/JH family usage, and compared these different characteristics with the bulk of sequences from their respective subset of origin. The analysis of clones shared between blood and spleen for switched IgG/IgA and for MZ subsets suggests different recirculation dynamics. For switched cells, the blood appears to be a mixture of splenic and other lymphoid tissues B cells. For MZ B cells in contrast, the blood appear to be only composed of a subgroup of the splenic repertoire, in agreement with the observation that marginal zone B cells recirculate and are mainly generated in the spleen. Clonal relationships between the IgM clones (originating from the MZ, IgM-only and double negative compartments) show that the clones involved display the characteristics of IgM-only B cells whatever their subset of origin, even in the case of the paired MZ/double-negative sequences that were not supposed to include IgM-only sequences. We therefore conclude that the clones shared between the various IgM subsets do not represent b between them, but rather correspond to a heterogeneous phenotype of the IgM-only population that concerns both IgD and CD27 expression, leading to a partial overlap with the MZ and double-negative gates. Clones shared between the MZ and the switched IgG and IgA compartment also show, for their IgM part, the mutation and repertoire characteristics of IgM-only cells and not of MZ B cells, reinforcing the conclusion that IgM-only are true memory B cells, and constitute the only subset showing clonal relationships with switched memory B cells. In summary, we report that MZ B cells have different recirculation characteristics and do not show real clonal relationships with IgM-only and switched memory B cells, in agreement with the notion that they represent a distinct differentiation pathway. In contrast, the only precursor-product relationship between IgM memory and switched B cells appear to concern a B cell subset that has been described as "IgM-only", but appears to have a more heterogeneous expression of IgD than previously reported and therefore contribute to 3-15% of the MZ compartment. Searching for markers that would permit to discriminate between marginal zone and germinal center-derived IgM memory B cells is obviously required to further delineate their respective function. Disclosures No relevant conflicts of interest to declare.

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