Shared transcriptional profiles at the single cell level of atypical memory B cells suggest common drivers of expansion and function in malaria, HIV and autoimmune diseases [HIV scRNA-seq]
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ABSTRACT:
PROVIDER: PRJNA663562 | ENA |
REPOSITORIES: ENA
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Project description:Human chronic infectious diseases, including malaria and HIV and autoimmune diseases, notably SLE, are accompanied by a striking expansion of a subpopulation of B cells termed atypical memory B cells (MBCs). We compared the single cell transcriptional profiles of B cells in malaria and HIV, characterizing and uncovering heterogeneity within each B cell subset. Remarkably, atypical MBC clusters in these two diseases showed significant similarities to each other as well as to atypical MBCs in autoimmune diseases, suggesting a common driver of their expansion and shared functions. Focusing on atypical MBCs in malaria we identified an IgD+IgMlo subpopulation that expanded in children upon the onset of febrile malaria, showed a distinct V gene usage characteristic of antigen-driven B cell populations and unexpectedly, had acquired high antigen-affinity thresholds for activation. We speculate that in malaria IgD+IgMlo atypical MBCs expand to limit responses to low-affinity self-antigens, a function that may be shared by atypical MBCs in other chronic infections and autoimmune diseases.
2020-09-30 | GSE157966 | GEO
Project description:Human chronic infectious diseases have been shown to alter the composition and phenotype of the B cell compartment, which, in part, can attribute to failure to acquire protective immunity. However, the extent of such alterations is poorly understood. Here, using a combination of bulk and single cell RNA-sequencing (scRNA-seq) of B cells in individuals living in malaria-endemic Africa, we characterized changes in naïve B cell, classical memory B cell (MBC) and atypical MBC subsets. Of particular interest were unswitched atypical MBCs that expanded in children upon the onset of febrile malaria. This subpopulation expressed IgD but only low levels of IgM (IgD+IgMlo), high levels of the atypical MBC markers, Tbet and CD11c, as well as the intrinsically autoreactive VH4-34. IgD+IgMlo atypical MBCs were distinguished functionally by their acquisition of high antigen-affinity thresholds for activation, suggesting the IgD+IgMlo atypical MBC expansion during febrile malaria may reduce responses to low affinity self-antigens during acute malaria
2020-09-30 | GSE157967 | GEO
Project description:Chronic infectious diseases have a substantial impact on the human B cell compartment including a notable expansion of B cells here termed atypical B cells (ABCs). Using unbiased single-cell RNA sequencing (scRNA-seq), we uncovered and characterized heterogeneities in naïve B cell, classical memory B cells, and ABC subsets. We showed remarkably similar transcriptional profiles for ABC clusters in malaria, HIV, and autoimmune diseases and demonstrated that interferon-γ drove the expansion of ABCs in malaria. These observations suggest that ABCs represent a separate B cell lineage with a common inducer that further diversifies and acquires disease-specific characteristics and functions. In malaria, we identified ABC subsets based on isotype expression that differed in expansion in African children and in B cell receptor repertoire characteristics. Of particular interest, IgD+IgMlo and IgD-IgG+ ABCs acquired a high antigen affinity threshold for activation, suggesting that ABCs may limit autoimmune responses to low-affinity self-antigens in chronic malaria.
| S-EPMC8153733 | biostudies-literature
Project description:Shared transcriptional profiles at the single cell level of atypical memory B cells suggest common drivers of expansion and function in malaria, HIV and autoimmune diseases [Malaria VDJ+GEX scRNA-seq]
| PRJNA663561 | ENA
Project description:Plasmodium falciparum malaria is a deadly infectious disease for which we have no licensed vaccine. Antibodies confer protection against malaria and individuals exposed to P. falciparum acquire protective antibodies, but only after years of repeated infections. We recently showed that malaria exposure is associated with a large expansion of a population of atypical memory B cells (MBCs) that phenotypically resemble B cell populations expanded in chronic viral infections, including HIV. At present the relationship of atypical MBCs to classical MBCs and their function are not known. We provide evidence that the expressed VH gene repertoires and somatic hypermutation rates of atypical and classical MBCs are indistinguishable, indicating the two populations are closely related developmentally. Atypical MBCs can be distinguished by their expression of multiple inhibitory receptors, including Fc receptor-like-5. B cell receptor (BCR) signaling is stunted in atypical MBCs, resulting in impaired Ca2+ mobilization, proliferation and cytokine production. Atypical MBCs do not spontaneously secrete antibodies and cannot be stimulated to differentiate into antibody-secreting cells in vitro. These results suggest that in individuals chronically exposed to malaria, atypical MBCs differentiate from classical MBCs and assume a phenotype refractory to BCR-mediated activation, potentially contributing to the inefficient acquisition of immunity to malaria. Comparison of human atypical B cell versus classical B cell versus naïve B cell.
2015-05-07 | E-GEOD-65928 | biostudies-arrayexpress
Project description:Plasmodium falciparum malaria is a deadly infectious disease for which we have no licensed vaccine. Antibodies confer protection against malaria and individuals exposed to P. falciparum acquire protective antibodies, but only after years of repeated infections. We recently showed that malaria exposure is associated with a large expansion of a population of atypical memory B cells (MBCs) that phenotypically resemble B cell populations expanded in chronic viral infections, including HIV. At present the relationship of atypical MBCs to classical MBCs and their function are not known. We provide evidence that the expressed VH gene repertoires and somatic hypermutation rates of atypical and classical MBCs are indistinguishable, indicating the two populations are closely related developmentally. Atypical MBCs can be distinguished by their expression of multiple inhibitory receptors, including Fc receptor-like-5. B cell receptor (BCR) signaling is stunted in atypical MBCs, resulting in impaired Ca2+ mobilization, proliferation and cytokine production. Atypical MBCs do not spontaneously secrete antibodies and cannot be stimulated to differentiate into antibody-secreting cells in vitro. These results suggest that in individuals chronically exposed to malaria, atypical MBCs differentiate from classical MBCs and assume a phenotype refractory to BCR-mediated activation, potentially contributing to the inefficient acquisition of immunity to malaria.
2015-05-07 | GSE65928 | GEO
Project description:Human chronic infectious diseases have been shown to alter the composition and phenotype of the B cell compartment, which, in part, can attribute to failure to acquire protective immunity. However, the extent of such alterations is poorly understood. Here, using a combination of bulk and single cell RNA-sequencing (scRNA-seq) of B cells in individuals living in malaria-endemic Africa, we characterized changes in naïve B cell, classical memory B cell (MBC) and atypical MBC subsets. Of particular interest were unswitched atypical MBCs that expanded in children upon the onset of febrile malaria. This subpopulation expressed IgD but only low levels of IgM (IgD+IgMlo), high levels of the atypical MBC markers, Tbet and CD11c, as well as the intrinsically autoreactive VH4-34. IgD+IgMlo atypical MBCs were distinguished functionally by their acquisition of high antigen-affinity thresholds for activation, suggesting the IgD+IgMlo atypical MBC expansion during febrile malaria may reduce responses to low affinity self-antigens during acute malaria
2020-09-30 | GSE149727 | GEO
Project description:Human chronic infectious diseases have been shown to alter the composition and phenotype of the B cell compartment, which, in part, can attribute to failure to acquire protective immunity. However, the extent of such alterations is poorly understood. Here, using a combination of bulk and single cell RNA-sequencing (scRNA-seq) of B cells in individuals living in malaria-endemic Africa, we characterized changes in naïve B cell, classical memory B cell (MBC) and atypical MBC subsets. Of particular interest were unswitched atypical MBCs that expanded in children upon the onset of febrile malaria. This subpopulation expressed IgD but only low levels of IgM (IgD+IgMlo), high levels of the atypical MBC markers, Tbet and CD11c, as well as the intrinsically autoreactive VH4-34. IgD+IgMlo atypical MBCs were distinguished functionally by their acquisition of high antigen-affinity thresholds for activation, suggesting the IgD+IgMlo atypical MBC expansion during febrile malaria may reduce responses to low affinity self-antigens during acute malaria
2020-09-30 | GSE149728 | GEO
Project description:Chronic infections such as HIV, tuberculosis and malaria in humans are associated with the appearance of atypical memory B cells in peripheral blood. It has been suggested that these B cells do not function normally as memory cells, and thus may be responsible for poor acquisition of immunity and maintenance of chronic infections. Studies on these cells in human infections are limited by the lack of accessibility to lymphoid organs, and relevant mouse models would be valuable to investigate their development, functional capacities, and role. To investigate Plasmodium-specific memory B-cell responses during malaria, we generated an immunoglobin heavy chain knock-in mouse with a B-cell receptor that recognizes the merozoite surface protein (MSP)-1 of the rodent malaria parasite, Plasmodium chabaudi. Using this mouse and a P. chabaudi infection initiated by infected mosquito bites we show that antigen-specific B cells with many characteristics of human atypical memory B cells are generated. These cells are immunoglobulin class-switched and express, among others, the cell surface molecules CD11c, CD11b, FCRL5, and some inhibitory receptors including PD1 and LAIR-1, as well as the transcription factor T-bet. Antigen-specific atypical memory B cells are detected side-by-side with classical memory B cells during chronic blood-stage infection. Whereas classical memory B cells persist after complete infection clearance, atypical memory B cells are short-lived and disappear from the spleen at the resolution of chronic infection. Short-lived Plasmodium-specific atypical B cells also appear transiently after immunization with a TLR7/8 ligand and MSP-1. Our data suggest that these atypical memory B cells are not a subset of memory B cells, but rather antigen-experienced activated cells, and part of a normal ongoing response. Their persistence over weeks in malaria and other infections may be a consequence of continued and chronic antigenic stimulation.
2018-11-01 | GSE115155 | GEO
Project description:The effect of human immunodeficiency virus (HIV) infection and high-level HIV replication on the function of monocytes was investigated. HIV-positive patients had elevated levels of spontaneous production of some or all of the monocyte proinflammatory cytokines measured (interleukin-1beta [IL-1beta], IL-6, and tumor necrosis factor alpha [TNF-alpha]) compared to uninfected controls. In patients on therapy with high frequencies of monocytes producing proinflammatory cytokines, this frequency was diminished in the context of viremia during an interruption of therapy. Diminished production of proinflammatory cytokines during viremia was restored by culture with autologous CD4(+) T cells or monocytes from an on-therapy time point or lipopolysaccharide (LPS). Microarray analysis demonstrated that diminished monocyte production of proinflammatory cytokines was correlated with elevated type I interferon-stimulated gene transcripts. The addition of exogenous alpha 2A interferon diminished the spontaneous production of IL-1beta, IL-6, and TNF-alpha but did not affect responses to LPS, recapitulating the changes observed for HIV-viremic patients. These results suggest that monocyte function is diminished during high-level HIV viremia and that this effect is mediated by chronic stimulation by type I interferons. This effect on monocytes during viremia may play a role in diminished innate or adaptive immune system functions in HIV-infected patients. In addition, the restoration of these functions may also play a role in some immune reconstitution syndromes observed during initiation of therapy.
2007-10-26 | E-GEOD-5220 | biostudies-arrayexpress