ORCID Profile
0000-0002-6138-690X
Current Organisation
Karolinska Institutet
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Publisher: Frontiers Media SA
Date: 24-06-2022
DOI: 10.3389/FIMMU.2022.908034
Abstract: Long-term protective immunity to infectious disease depends on cell-mediated and humoral immune responses. Induction of a strong humoral response relies on efficient B cell activation and differentiation to long-lived plasma cells and memory B cells. For many viral or bacterial infections, a single encounter is sufficient to induce such responses. In malaria, the induction of long-term immunity can take years of pathogen exposure to develop, if it occurs at all. This repeated pathogen exposure and suboptimal immune response coincide with the expansion of a subset of B cells, often termed atypical memory B cells. This subset is present at low levels in healthy in iduals as well but it is observed to expand in an inflammatory context during acute and chronic infection, autoimmune diseases or certain immunodeficiencies. Therefore, it has been proposed that this subset is exhausted, dysfunctional, or potentially autoreactive, but its actual role has remained elusive. Recent reports have provided new information regarding both heterogeneity and expansion of these cells, in addition to indications on their potential role during normal immune responses to infection or vaccination. These new insights encourage us to rethink how and why they are generated and better understand their role in our complex immune system. In this review, we will focus on recent advances in our understanding of these enigmatic cells and highlight the remaining gaps that need to be filled.
Publisher: Elsevier BV
Date: 05-2021
Publisher: Oxford University Press (OUP)
Date: 13-01-2011
DOI: 10.1189/JLB.0810460
Abstract: The development and quality of a humoral immune response are largely influenced by the environment that supports the activation of naïve B cells. Human PDCs, through their unique capacity to produce high levels of IFN-α, have been shown earlier to enhance B cell responses stimulated by selected TLR ligands. In this study, we investigated whether PDCs also promote B cell activation induced by Th cell interactions and BCR ligation. Sorted human naive CD19+ CD27– B cells were activated in vitro with anti-Ig and irradiated CD4+ T cells. Under these conditions, the presence of supernatants from TLR-stimulated PDCs increased B cell proliferation, the frequency of B cells that differentiated to CD27high CD38high cells, and secretion of IgM. Similar results were observed when the B cells were activated in the presence of purified IFN-α. In contrast, supernatants from stimulated MDCs did not augment these functions. Also, IFN-α treatment of B cells up-regulated the expression of costimulatory molecule CD86 but not CD40, CD80, MHC class II, or CD25. Although direct IFN-α exposure of T cells suppressed their proliferative capacity, IFN-α treatment of B cells led to a small increase in their capacity to induce superantigen-driven activation of autologous CD4+ T cells. In summary, PDCs, via their production of IFN-α, may render B cells more responsive to T cell contact, which in turn, facilitates B cell proliferation and differentiation to antibody-producing cells.
Publisher: Springer Science and Business Media LLC
Date: 15-04-2023
DOI: 10.1038/S41467-023-37835-9
Abstract: Effective humoral immune responses require well-orchestrated B and T follicular helper (Tfh) cell interactions. Whether these interactions are impaired and associated with COVID-19 disease severity is unclear. Here, longitudinal blood s les across COVID-19 disease severity are analysed. We find that during acute infection SARS-CoV-2-specific circulating Tfh (cTfh) cells expand with disease severity. SARS-CoV-2-specific cTfh cell frequencies correlate with plasmablast frequencies and SARS-CoV-2 antibody titers, avidity and neutralization. Furthermore, cTfh cells but not other memory CD4 T cells, from severe patients better induce plasmablast differentiation and antibody production compared to cTfh cells from mild patients. However, virus-specific cTfh cell development is delayed in patients that display or later develop severe disease compared to those with mild disease, which correlates with delayed induction of high-avidity neutralizing antibodies. Our study suggests that impaired generation of functional virus-specific cTfh cells delays high-quality antibody production at an early stage, potentially enabling progression to severe disease.
Publisher: Wiley
Date: 07-10-2011
Publisher: Microbiology Society
Date: 12-2008
DOI: 10.1099/VIR.0.2008/005470-0
Abstract: Strategies to induce potent and broad antibody responses against the human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Env) at both systemic and mucosal sites represent a central goal for HIV-1 vaccine development. Here, we show that the non-toxic CTA1-DD adjuvant promoted mucosal and systemic humoral and cell-mediated immune responses following intranasal (i.n.) immunizations with trimeric or monomeric forms of HIV-1 Env in mice and in non-human primates. Env-specific IgG subclasses in the serum of immunized mice reflected a balanced Th1/Th2 type of response. Strikingly, i.n. immunizations with Env and the CTA1-DD adjuvant induced substantial levels of mucosal anti-Env IgA in bronchial alveolar lavage and also detectable levels in vaginal secretions. By contrast, parenteral immunizations of Env formulated in Ribi did not stimulate mucosal IgA responses, while the two adjuvants induced a similar distribution of Env-specific IgG-subclasses in serum. A single parenteral boost with Env in Ribi adjuvant into mice previously primed i.n. with Env and CTA1-DD, augmented the serum anti-Env IgG levels to similar magnitudes as those observed after three intraperitoneal immunizations with Env in Ribi. The augmenting potency of CTA1-DD was similar to that of LTK63 or CpG oligodeoxynucleotides (ODN). However, in contrast to CpG ODN, the effect of CTA1-DD and LTK63 appeared to be independent of MyD88 and toll-like receptor signalling. This is the first demonstration that CTA1-DD augments specific immune responses also in non-human primates, suggesting that this adjuvant could be explored further as a clinically safe mucosal vaccine adjuvant for humoral and cell-mediated immunity against HIV-1 Env.
Publisher: Frontiers Media SA
Date: 09-03-2022
DOI: 10.3389/FIMMU.2022.799306
Abstract: Identifying the mechanism of naturally acquired immunity against Plasmodium falciparum malaria could contribute to the design of effective malaria vaccines. Using a recently developed multiplexed FluoroSpot assay, we assessed cross-sectional pre-existing memory B-cells (MBCs) and antibody responses against six well known P. falciparum antigens (MSP-1 19 , MSP-2 (3D7), MSP-2 (FC27), MSP-3, AMA-1 and CSP) and measured their associations with previous infections and time to clinical malaria in the ensuing malaria season in Kenyan children. These children were under active weekly surveillance for malaria as part of a long-term longitudinal malaria immunology cohort study, where they are recruited from birth. After performing Cox regression analysis, we found that children with a breadth of three or more antigen-specific MBC or antibody responses at the baseline had a reduced risk for malaria in the ensuing P. falciparum transmission season. Specifically, MBC responses against AMA-1, MSP-2 (3D7) and MSP-3, as well as antibody responses to MSP-2 (3D7) and MSP-3 were prospectively associated with a reduced risk for malaria. The magnitude or breadth of MBC responses were however not correlated with the cumulative number of malaria episodes since birth. We conclude that increased breadth for merozoite antigen-specific MBC and antibody responses is associated with protection against malaria.
Publisher: The American Association of Immunologists
Date: 15-02-2009
Abstract: Selected TLR ligands are under evaluation as vaccine adjuvants and are known to activate dendritic cells (DCs) and B cells to affect vaccine-induced Ab responses. However, the relative contribution of the two main human DC subsets, myeloid (MDCs) and plasmacytoid (PDCs), in supporting B cell responses to TLR ligands remains poorly understood. We found that PDCs but not MDCs markedly enhanced B cell proliferation in response to TLR7/8-L, an imidazoquinoline derivative, and to a lesser extent to TLR9 ligands (CpG ODN classes A, B, and C). PDCs strongly enhanced TLR7/8-L-induced proliferation of both memory and naive B cells but were only able to support memory cells to differentiate to CD27high plasmablasts. In response to TLR7/8 stimulation, PDCs mediated the up-regulation of transcription factors B lymphocyte-induced maturation protein 1 and X-box binding protein 1 and enhanced differentiation of B cells into IgM-, IgG-, and IgA-producing cells. Type I IFN produced to high levels by PDCs was the principal mediator of the effects on TLR7/8 stimulation. Although MDCs expressed higher levels of the known B cell growth factors IL-6, IL-10, and B cell-activating factor in response to TLR7/8 stimulation, they were unable to enhance B cell responses in this system. These data help decipher the different roles of PDCs and MDCs for modulating human B cell responses and can contribute to selection of specific TLR ligands as vaccine adjuvants.
Publisher: Oxford University Press (OUP)
Date: 16-11-2012
Abstract: The envelope glycoproteins (Env) represent a critical component of a successful antibody-mediated human immunodeficiency virus type 1 (HIV-1) vaccine. However, immunization with soluble Env was reported to induce short-lived antibody responses, suggesting that Env has unusual immunogenic properties. Here, we directly compared the magnitude and durability of B-cell responses induced by HIV-1 Env and an unrelated soluble viral protein, influenza virus hemagglutinin (HA), in simultaneously inoculated macaques. We demonstrate robust peak responses followed by rapid contraction of circulating antibody and memory B cells for both antigens, suggesting that short-lived responses are not unique to HIV-1 Env but may be a common feature of soluble protein vaccines.
Publisher: Cold Spring Harbor Laboratory
Date: 05-04-2021
DOI: 10.1101/2021.04.04.434373
Abstract: Upon infection with Mycobacterium tuberculosis (Mtb) the host immune response might clear the bacteria, control its growth leading to latent tuberculosis (LTB), or fail to control its growth resulting in active TB (ATB). There is however no clear understanding of the features underlying a more or less effective response. Mtb glycolipids are abundant in the bacterial cell envelope and modulate the immune response to Mtb, but the patterns of response to glycolipids are still underexplored. To identify the CD45 + leukocyte activation landscape induced by Mtb glycolipids in peripheral blood of ATB and LTB, we performed a detailed assessment of the immune response of PBMCs to the Mtb glycolipids lipoarabinomannan (LAM) and its biosynthetic precursor phosphatidyl-inositol mannoside (PIM), and PPD. At 24 h and 5 days of stimulation, cell profiling and secretome analysis was done using mass cytometry and high-multiplex immunoassay. PIM mainly affected antigen-presenting cells to produce both proinflammatory (IL-2, IL-6, IL-17A, TNF- α and GM-CSF), and IL-4 and IL-10 cytokines, but not IFN-γ. LAM triggered a similar, albeit weaker, response. By contrast, PPD induced an increase in IFN-γ-producing cells. Moreover, PPD also led to increased numbers of IL-2, IL-6, IL-10, IL-17A, TNF- α and GrzB-producing cells. Treatment with an anti-TLR2 antibody led to partial inhibition of PIM-induced IL-6 production in myeloid cells, suggesting that PIM induces IL-6 production through TLR2. Expansion of monocyte subsets in response to PIM or LAM was reduced in both ATB and LTB as compared to healthy controls, suggesting a hyporesponsive/tolerance pattern in Mtb-infected in iduals.
Publisher: Cold Spring Harbor Laboratory
Date: 08-06-2022
DOI: 10.1101/2022.06.08.495295
Abstract: Many vaccine candidate proteins are under strong selective pressure to ersify in terms of antigenicity. We present a sequencing and data analysis platform for epidemiological surveillance and discovery of indel-rich vaccine antigens by long-read circular consensus sequencing (CCS) in multiclonal pathogen isolates. Our platform uses 40 PCR primers to asymmetrically barcode and identify multiclonal infections in pools of up to 384 s les. We validated the method using 235 mock infections combining 10 synthetic variants of the indel-rich gene merozoite surface protein 2 of Plasmodium falciparum at different concentrations and infection complexities, as well as 95 isolates from P. falciparum -infected residents of Nyamisati, Tanzania. We also constructed a fully automated analysis pipeline that streamlines the processing and interpretation of epidemiological and antigenic ersity data from demultiplexed FASTQ files. This platform can be easily adapted to other polymorphic antigens of interest in Plasmodium and other human pathogens.
Publisher: Springer Science and Business Media LLC
Date: 12-03-2015
DOI: 10.1038/SREP08925
Abstract: Protein-based vaccines require adjuvants to achieve optimal responses. Toll-like receptor (TLR) 9 agonists were previously shown to improve responses to protein-based vaccines, such as the Hepatitis B virus vaccine formulated in alum. Here, we used CpG-C together with the clinically relevant saponin-based adjuvant AbISCO-100/Matrix-M (AbISCO), to assess if TLR9 co-stimulation would quantitatively or qualitatively modulate HIV-1 envelope glycoprotein (Env)-specific B and T cell responses in rhesus macaques. The macaques were inoculated with soluble Env trimers in AbISCO, with or without the addition of CpG-C, using an interval similar to the Hepatitis B virus vaccine. Following a comprehensive evaluation of antigen-specific responses in multiple immune compartments, we show that the Env-specific circulating IgG, memory B cells and plasma cells displayed similar kinetics and magnitude in the presence or absence of CpG-C and that there was no apparent difference between the two groups in the elicited HIV-1 neutralizing antibody titers or antigen-specific CD4+ T cell responses. Importantly, the control of SHIV viremia was significantly improved in animals from both Env-immunized groups relative to adjuvant alone controls, demonstrating the potential of AbISCO to act as a stand-alone adjuvant for Env-based vaccines.
Publisher: Elsevier BV
Date: 12-2022
Publisher: American Society for Microbiology
Date: 15-09-2010
DOI: 10.1128/JVI.01015-10
Abstract: We recently reported that rhesus macaques inoculated with CD4-binding-competent and CD4-binding-defective soluble YU2-derived HIV-1 envelope glycoprotein (Env) trimers in adjuvant generate comparable levels of Env-specific binding antibodies (Abs) and T cell responses. We also showed that Abs directed against the Env coreceptor binding site (CoRbs) were elicited only in animals immunized with CD4-binding-competent trimers and not in animals immunized with CD4-binding-defective trimers, indicating that a direct interaction between Env and CD4 occurs in vivo . To investigate both the overall consequences of in vivo Env-CD4 interactions and the elicitation of CoRbs-directed Abs for protection against heterologous simian-human immunodeficiency virus (SHIV) challenge, we exposed rhesus macaques immunized with CD4-binding-competent and CD4-binding-defective trimers to the CCR5-tropic SHIV-SF162P4 challenge virus. Compared to unvaccinated controls, all vaccinated animals displayed improved control of plasma viremia, independent of the presence or absence of CoRbs-directed Abs prior to challenge. Immunization resulted in plasma responses that neutralized the heterologous SHIV challenge stock in vitro , with similar neutralizing Ab titers elicited by the CD4-binding-competent and CD4-binding-defective trimers. The neutralizing responses against both the SHIV-SF162P4 stock and a recombinant virus pseudotyped with a cloned SHIV-SF162P4-derived Env were significantly boosted by the SHIV challenge. Collectively, these results suggest that the capacity of soluble Env trimers to interact with primate CD4 in vivo and to stimulate the production of moderate titers of CoRbs-directed Abs did not influence the magnitude of the neutralizing Ab recall response after viral challenge or the subsequent control of viremia in this heterologous SHIV challenge model.
Publisher: American Society for Microbiology
Date: 15-01-2009
DOI: 10.1128/JVI.01102-08
Abstract: Currently there is limited information about the quality of immune responses elicited by candidate human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env)-based immunogens in primates. Here we describe a comprehensive analysis of neutralizing antibody and T-cell responses obtained in cynomolgus macaques by three selected immunization regimens. We used the previously described YU2-based gp140 protein trimers administered in an adjuvant, preceded by two distinct priming strategies: either alphavirus replicon particles expressing matched gp140 trimers or gp120 core proteins stabilized in the CD4-bound conformation. The rationale for priming with replicon particles was to evaluate the impact of the expression platform on trimer immunogenicity. The stable core proteins were chosen in an attempt to expand selectively lymphocytes recognizing common determinants between the core and trimers to broaden the immune response. The results presented here demonstrate that the platform by which Env trimers were delivered in the priming (either protein or replicon vector) had little impact on the overall immune response. In contrast, priming with stable core proteins followed by a trimer boost strikingly focused the T-cell response on the core sequences of HIV-1 Env. The specificity of the T-cell response was distinctly different from that of the responses obtained in animals immunized with trimers alone and was shown to be mediated by CD4 + T cells. However, this regimen showed limited or no improvement in the neutralizing antibody responses, suggesting that further immunogen design efforts are required to successfully focus the B-cell response on conserved neutralizing determinants of HIV-1 Env.
Publisher: Cold Spring Harbor Laboratory
Date: 12-03-2023
DOI: 10.1101/2023.03.08.531830
Abstract: CD11c, FcRL5, or T-bet are commonly expressed by B cells expanding during inflammation, where they can make up % of mature B cells. However, the association between the proteins and differentiation and function in the host response remain largely unclear. We have assessed the co-expression of CD11c, T-bet and FcRL5 in an in vitro B cell culture system to determine how stimulation via the B cell receptor (BCR), toll-like receptor 9 (TLR9), and different cytokines influence CD11c, T-bet, and FcRL5 expression. We observed different expression dynamics for all markers, but a largely overlapping regulation of CD11c and FcRL5 in response to BCR and TLR9 activation, while T-bet was strongly dependent on IFN-γ signalling. Investigating plasma cell differentiation and antigen-presenting cell (APC) functions, there was no association between marker expression and antibody secretion or T cell help. Rather the functions were associated with TLR9-signalling and B cell-derived IL-6 production, respectively. These results suggest that the expression of CD11c, FcRL5, and T-bet and plasma cell differentiation and improved APC functions occur in parallel and are regulated by similar activation signals, but that they are not interdependent.
Publisher: The American Association of Immunologists
Date: 15-04-2014
Abstract: The nonhuman primate model is important for preclinical evaluation of prophylactic and therapeutic intervention strategies. The recent description of the rhesus macaque germline Ig loci and establishment of a database of germline gene segments offer improved opportunities to delineate Ig gene usage in the overall B cell repertoire as well as in response to vaccination. We applied 454-pyrosequencing and single-cell RT-PCR of bulk and sorted memory B cells, respectively, to investigate IGHV gene segment expression in rhesus macaques. The two methods gave remarkably concordant results and identified groups of gene segments that are frequently or rarely used. We further examined the VH repertoire of Ag-specific memory B cells induced by immunization with recombinant HIV-1 envelope glycoproteins, an important vaccine component. We demonstrate that HIV-1 envelope glycoprotein immunization activates a highly polyclonal response composed of most of the expressed VH gene segments, illustrating the considerable genetic ersity of responding B cells following vaccination.
Publisher: Wiley
Date: 08-2016
DOI: 10.1038/CTI.2016.50
Publisher: The American Association of Immunologists
Date: 05-2016
Abstract: Because of the genetic variability of the HIV-1 envelope glycoproteins (Env), the elicitation of neutralizing Abs to conserved neutralization determinants including the primary receptor binding site, CD4 binding site (CD4bs), is a major focus of vaccine development. To gain insight into the evolution of Env-elicited Ab responses, we used single B cell analysis to interrogate the memory B cell Ig repertoires from two rhesus macaques after five serial immunizations with Env/adjuvant. We observed that the CD4bs-specific repertoire displayed unique features in the third CDR of Ig H chains with minor alterations along the immunization course. Progressive affinity maturation occurred as evidenced by elevated levels of somatic hypermutation (SHM) in Ab sequences isolated at the late immunization time point compared with the early time point. Abs with higher SHM were associated with increased binding affinity and virus neutralization capacity. Moreover, a notable portion of the CD4bs-specific repertoire was maintained between early and late immunization time points, suggesting that persistent clonal lineages were induced by Env vaccination. Furthermore, we found that the predominant persistent CD4bs-specific clonal lineages had larger population sizes and higher affinities than that from the rest of the repertoires, underscoring the critical role of Ag affinity selection in Ab maturation and clonal expansion. Genetic and functional analyses revealed that the accumulation of SHM in both framework regions and CDRs contributed to the clonal affinity and antigenicity evolution. Our longitudinal study provides high-resolution understanding of the dynamically evolving CD4bs-specific B cell response after Env immunization in primates.
Publisher: Cold Spring Harbor Laboratory
Date: 25-08-2022
DOI: 10.1101/2022.08.25.505097
Abstract: The human T cell receptor (TCR) genes are critical for mediating immune responses to pathogens, tumors and regulating self-antigen recognition. A detailed analysis and validation of expressed TCR alpha, beta, gamma, and delta genes in 45 donors from 4 human populations: African, East Asian, South Asian, and European, revealed a total of 175 novel TCR variable and junctional alleles. The majority of novel alleles contained coding changes and were present at widely differing frequencies in the populations, a finding confirmed using DNA s les and sequences from the 1000 Genomes Project. Importantly, we identified three Neanderthal-derived, introgressed TCR regions, including a highly ergent novel TRGV4 variant, present in all archaic assemblies, that was frequent in all modern Eurasian population groups. Our results demonstrate significant variation in TCR genes at both in idual and population levels, providing a strong incentive for including allelic variation in studies of TCR function in human biology.
Publisher: The American Association of Immunologists
Date: 15-06-2015
Abstract: Isolation of mAbs elicited by vaccination provides opportunities to define the development of effective immunity. Ab responses elicited by current HIV-1 envelope glycoprotein (Env) immunogens display narrow neutralizing activity with limited capacity to block infection by tier 2 viruses. Intense work in the field suggests that improved Env immunogens are forthcoming, and it is therefore important to concurrently develop approaches to investigate the quality of vaccine-elicited responses at a higher level of resolution. In this study, we cloned a representative set of mAbs elicited by a model Env immunogen in rhesus macaques and comprehensively characterized their genetic and functional properties. The mAbs were genetically erse, even within groups of Abs targeting the same subregion of Env, consistent with a highly polyclonal response. mAbs directed against two subdeterminants of Env, the CD4 binding site and V region 3, could in part account for the neutralizing activity observed in the plasma of the animal from which they were cloned, demonstrating the power of mAb isolation for a detailed understanding of the elicited response. Finally, through comparative analyses of mAb binding and neutralizing capacity of HIV-1 using matched Envs, we demonstrate complex relationships between epitope recognition and accessibility, highlighting the protective quaternary packing of the HIV-1 spike relative to vaccine-induced mAbs.
Publisher: Rockefeller University Press
Date: 02-08-2010
DOI: 10.1084/JEM.20100025
Abstract: Broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoproteins (Envs) have proven difficult to elicit by immunization. Therefore, to identify effective Env neutralization targets, efforts are underway to define the specificities of bNAbs in chronically infected in iduals. For a prophylactic vaccine, it is equally important to define the immunogenic properties of the heavily glycosylated Env in healthy primates devoid of confounding HIV-induced pathogenic factors. We used rhesus macaques to investigate the magnitude and kinetics of B cell responses stimulated by Env trimers in adjuvant. Robust Env-specific memory B cell responses and high titers of circulating antibodies developed after trimer inoculation. Subsequent immunizations resulted in significant expansion of Env-specific IgG-producing plasma cell populations and circulating Abs that displayed increasing avidity and neutralization capacity. The neutralizing activity elicited with the regimen used was, in most aspects, superior to that elicited by a regimen based on monomeric Env immunization in humans. Despite the potency and breadth of the trimer-elicited response, protection against heterologous rectal simian-HIV (SHIV) challenge was modest, illustrating the challenge of eliciting sufficient titers of cross-reactive protective NAbs in mucosal sites. These data provide important information for the design and evaluation of vaccines aimed at stimulating protective HIV-1 immune responses in humans.
Publisher: Microbiology Society
Date: 10-2007
Abstract: Viral vectors encoding heterologous vaccine antigens are potent inducers of cellular immune responses, but they are generally less efficient at stimulating humoral immunity. To improve the induction of antibody responses by Semliki Forest virus-based vaccines, a vector encoding a translation-enhancer element and a novel internal signal sequence for increased expression and secretion of soluble antigens was designed. Approximately tenfold more human immunodeficiency virus type 1 gp120 was secreted into culture supernatants of infected cells using the enhanced vector compared with the parental vector. This translated into a significant increase in gp120-specific antibodies in immunized mice, suggesting that antigen-expression levels from the parental vector are limiting for induction of antibody responses. These data encourage the use of the enhanced vector for elicitation of immune responses against heterologous antigens during vaccination.
Publisher: Frontiers Media SA
Date: 23-11-2021
DOI: 10.3389/FIMMU.2021.727300
Abstract: Upon infection with Mycobacterium tuberculosis (Mtb) the host immune response might clear the bacteria, control its growth leading to latent tuberculosis (LTB), or fail to control its growth resulting in active TB (ATB). There is however no clear understanding of the features underlying a more or less effective response. Mtb glycolipids are abundant in the bacterial cell envelope and modulate the immune response to Mtb, but the patterns of response to glycolipids are still underexplored. To identify the CD45 + leukocyte activation landscape induced by Mtb glycolipids in peripheral blood of ATB and LTB, we performed a detailed assessment of the immune response of PBMCs to the Mtb glycolipids lipoarabinomannan (LAM) and its biosynthetic precursor phosphatidyl-inositol mannoside (PIM), and purified-protein derivate (PPD). At 24 h of stimulation, cell profiling and secretome analysis was done using mass cytometry and high-multiplex immunoassay. PIM induced a erse cytokine response, mainly affecting antigen-presenting cells to produce both pro-inflammatory and anti-inflammatory cytokines, but not IFN-γ, contrasting with PPD that was a strong inducer of IFN-γ. The effect of PIM on the antigen-presenting cells was partly TLR2-dependent. Expansion of monocyte subsets in response to PIM or LAM was reduced primarily in LTB as compared to healthy controls, suggesting a hyporesponsive/tolerance pattern derived from Mtb infection.
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.JIM.2012.09.003
Abstract: Studies in nonhuman primates offer information of high relevance to clinical medicine due to their close genetic relationship with humans. Here, we established an optimized protocol for the isolation of antibody V(D)J sequences from rhesus macaque B cells. Nested PCR primers were designed to align to sequences flanking the V(D)J coding region to enable lification of highly mutated antibody sequences. The primers were evaluated using cDNA from bulk PBMCs as well as from single-sorted memory and naïve B cells from several macaques to ascertain effective germline coverage. The nested PCR efficiency reached 60.6% positive wells for heavy chain lification, 39.2% for kappa chain, and 23.7% for lambda chain sequences. Matching heavy and light chain sequences, indicating antibodies that potentially can be cloned, were obtained in 50% of the positive wells. Using these primers, we found that the efficiency and specificity of V(D)J lifications were markedly improved compared to when primers designed for human Ab isolation were used. In particular, the lification of recombined light chain VJ sequences was improved. Thus, we describe the design and testing of a new set of rhesus-specific primers that enable efficient and specific lification of heavy, kappa and lambda V(D)J genes from single sorted B cells. The use of these primers will facilitate future efforts to clone and express rhesus macaque MAbs for genetic, functional and structural analyses.
Publisher: Elsevier BV
Date: 04-2017
DOI: 10.1016/J.COI.2017.03.006
Abstract: Germinal centers (GCs) form in secondary lymphoid tissues in response to antigenic challenge and are the site of somatic hypermutation, generating GC B cells with increasing affinity for the inciting agent that are positively selected over time. However, it is not until GC B cells differentiate into memory B cells and plasma cells and egress from the GC back into the circulation that effective long-lived humoral immunity is conferred upon the host. Here we review what is known about the signals that initiate the transition from a GC B cell into the memory B cell and plasma cell compartments and the downstream transcriptional regulation of these processes.
Publisher: Elsevier BV
Date: 03-2020
DOI: 10.1016/J.JIM.2019.112715
Abstract: Analysis of B-cell specificities at the single cell level provides important information on how the B-cell compartment responds when challenged by infection or vaccination. We recently developed a reversed B-cell FluoroSpot assay and showed that it could be used to detect B cells specific for different antigens simultaneously in a mouse model. The aim of this study was to further develop the method to detect and quantify antigen-specific memory B cells (MBCs) in humans where circulating antigen-specific cells are less frequent. We show that MBCs specific for three antigens, tetanus toxoid, hepatitis B surface antigen and cytomegalovirus pp65, could be detected simultaneously in one well. In addition to enumerating antigen-specific MBCs, we also assessed the spot volume to estimate the intensity of the response in in idual cells and found this to be a new and sensitive approach to study MBC responses after vaccination. This unique B-cell FluoroSpot approach provides a simple and sensitive multiplex analysis of MBCs and can be adapted to most antigens and host species.
Publisher: Rockefeller University Press
Date: 08-11-2019
DOI: 10.1084/JEM.20191155
Abstract: Well-ordered HIV-1 envelope glycoprotein (Env) trimers are prioritized for clinical evaluation, and there is a need for an improved understanding about how elicited B cell responses evolve following immunization. To accomplish this, we prime-boosted rhesus macaques with clade C NFL trimers and identified 180 unique Ab lineages from ∼1,000 single-sorted Env-specific memory B cells. We traced all lineages in high-throughput heavy chain (HC) repertoire (Rep-seq) data generated from multiple immune compartments and time points and expressed several as monoclonal Abs (mAbs). Our results revealed broad dissemination and high levels of somatic hypermutation (SHM) of most lineages, including tier 2 virus neutralizing lineages, following boosting. SHM was highest in the Ab complementarity determining regions (CDRs) but also surprisingly high in the framework regions (FRs), especially FR3. Our results demonstrate the capacity of the immune system to affinity-mature large numbers of Env-specific B cell lineages simultaneously, supporting the use of regimens consisting of repeated boosts to improve each Ab, even those belonging to less expanded lineages.
Publisher: BMJ
Date: 07-2022
DOI: 10.1136/BMJOPEN-2022-060985
Abstract: The WHO End-TB Strategy calls for the development of novel diagnostics to detect tuberculosis (TB) earlier and more accurately. Better diagnostics, together with tools to predict disease progression, are critical for achieving WHO End-TB targets. The E arly R isk A ssessment in TB Contacts by new diagno S tic t E sts (ERASE-TB) study aims to evaluate novel diagnostics and testing algorithms for early TB diagnosis and accurate prediction of disease progression among household contacts (HHCs) exposed to confirmed index cases in Mozambique, Tanzania and Zimbabwe. A total of 2100 HHCs (aged ≥10 years) of adults with microbiologically-confirmed pulmonary TB will be recruited and followed up at 6-month intervals for 18–24 months. At each time point, a WHO symptom screen and digital chest radiograph (dCXR) will be performed, and blood and urine s les will be collected. In iduals screening positive (WHO symptom screen or dCXR) will be requested to provide sputum for Xpert MTB/Rif Ultra. At baseline, HHCs will also be screened for HIV, diabetes (HbA1c), chronic lung disease (spirometry), hypertension and anaemia. Study outcomes will be coprevalent TB (diagnosed at enrolment), incident TB (diagnosed during follow-up) or no TB at completion of follow-up. Novel diagnostics will be validated using fresh and biobanked s les with a nested case–control design. Cases are defined as HHCs diagnosed with TB (for early diagnosis) or with incident TB (for prediction of progression) and will be matched by age, sex and country to HHCs who remain healthy (controls). Statistical analyses will include assessment of diagnostic accuracy by constructing receiver operating curves and calculation of sensitivity and specificity. ERASE-TB has been approved by regulatory and ethical committees in each African country and by each partner organisation. Consent, with additional assent for participants years, is voluntary. Attestation by impartial witnesses is sought in case of illiteracy. Confidentiality of participants is being maintained throughout. Study findings will be presented at scientific conferences and published in peer-reviewed international journals. NCT04781257 .Cite Now
Publisher: Rockefeller University Press
Date: 31-03-2017
DOI: 10.1084/JEM.20161533
Abstract: Plasma cells (PCs) derived from germinal centers (GCs) secrete the high-affinity antibodies required for long-term serological immunity. Nevertheless, the process whereby GC B cells differentiate into PCs is uncharacterized, and the mechanism underlying the selective PC differentiation of only high-affinity GC B cells remains unknown. In this study, we show that differentiation into PCs is induced among a discrete subset of high-affinity B cells residing within the light zone of the GC. Initiation of differentiation required signals delivered upon engagement with intact antigen. Signals delivered by T follicular helper cells were not required to initiate differentiation but were essential to complete the differentiation process and drive migration of maturing PCs through the dark zone and out of the GC. This bipartite or two-signal mechanism has likely evolved to both sustain protective immunity and avoid autoantibody production.
Publisher: Oxford University Press (OUP)
Date: 02-05-2022
Abstract: Mucosa-associated invariant T (MAIT) cells are innate-like T cells with specialized antimicrobial functions. Circulating MAIT cells are depleted in chronic human immunodeficiency virus (HIV) infection, but studies examining this effect in peripheral tissues, such as the female genital tract, are lacking. Flow cytometry was used to investigate circulating MAIT cells in a cohort of HIV-seropositive (HIV+) and HIV-seronegative (HIV−) female sex workers (FSWs), and HIV− lower-risk women (LRW). In situ staining and quantitative polymerase chain reaction were performed to explore the phenotype of MAIT cells residing in paired cervicovaginal tissue. The cervicovaginal microbiome was assessed by means of 16S ribosomal RNA gene sequencing. MAIT cells in the HIV+ FSW group were low in frequency in the circulation but preserved in the ectocervix. MAIT cell T-cell receptor gene segment usage differed between the HIV+ and HIV− FSW groups. The TRAV1-2–TRAJ20 transcript was the most highly expressed MAIT TRAJ gene detected in the ectocervix in the HIV+ FSW group. MAIT TRAVJ usage was not associated with specific genera in the vaginal microbiome. MAIT cells residing in the ectocervix are numerically preserved irrespective of HIV infection status and displayed dominant expression of TRAV1-2–TRAJ20. These findings have implications for understanding the role of cervical MAIT cells in health and disease.
Publisher: Proceedings of the National Academy of Sciences
Date: 03-02-2014
Abstract: The development of broadly neutralizing antibodies (bNAbs) to HIV-1 is often thought to be a key component of a successful vaccine. A common target of bNAbs is the conserved CD4 binding site (CD4bs) on the HIV envelope glycoprotein (Env) trimeric spike. Although CD4bs-directed bNAbs have been isolated from infected in iduals, elicitation of such bNAbs by Env vaccination has proven difficult. To help understand the limitations of current immunogens, we structurally characterized two vaccine-elicited, CD4bs-directed non-bNAbs from primates. We demonstrate that these vaccine-elicited Abs attempt a vertical approach to the CD4bs, thereby clashing with the variable region of the trimeric spike cap, whereas CD4bs-directed bNAbs adopt angles of approach that avoid such clashes. This analysis can inform future vaccine redesign.
Publisher: American Society for Clinical Investigation
Date: 02-05-2019
Publisher: Wiley
Date: 2021
DOI: 10.1002/CTI2.1313
Abstract: Human hantavirus infections can cause haemorrhagic fever with renal syndrome (HFRS). The pathogenic mechanisms are not fully understood, nor if they affect the humoral immune system. The objective of this study was to investigate humoral immune responses to hantavirus infection and to correlate them to the typical features of HFRS: thrombocytopenia and transient kidney dysfunction. We performed a comprehensive characterisation of longitudinal antiviral B‐cell responses of 26 hantavirus patients and combined this with paired clinical data. In addition, we measured extracellular adenosine triphosphate (ATP) and its breakdown products in circulation and performed in vitro stimulations to address its effect on B cells. We found that thrombocytopenia was correlated to an elevated frequency of plasmablasts in circulation. In contrast, kidney dysfunction was indicative of an accumulation of CD27 − IgD − B cells and CD27 −/low plasmablasts. Finally, we provide evidence that high levels of extracellular ATP and matrix metalloproteinase 8 can contribute to shedding of CD27 during human hantavirus infection. Our findings demonstrate that thrombocytopenia and kidney dysfunction associate with distinctly different effects on the humoral immune system. Moreover, hantavirus‐infected in iduals have significantly elevated levels of extracellular ATP in circulation.
Publisher: Springer Science and Business Media LLC
Date: 17-01-2022
DOI: 10.1038/S41467-021-27863-8
Abstract: Strengthening malaria surveillance is a key intervention needed to reduce the global disease burden. Reliable serological markers of recent malaria exposure could improve current surveillance methods by allowing for accurate estimates of infection incidence from limited data. We studied the IgG antibody response to 111 Plasmodium falciparum proteins in 65 adult travellers followed longitudinally after a natural malaria infection in complete absence of re-exposure. We identified a combination of five serological markers that detect exposure within the previous three months with % sensitivity and specificity. Using mathematical modelling, we examined the antibody kinetics and determined that responses informative of recent exposure display several distinct characteristics: rapid initial boosting and decay, less inter-in idual variation in response kinetics, and minimal persistence over time. Such serological exposure markers could be incorporated into routine malaria surveillance to guide efforts for malaria control and elimination.
Publisher: Elsevier BV
Date: 03-2023
Publisher: Cold Spring Harbor Laboratory
Date: 15-03-2023
DOI: 10.1101/2023.03.10.23287085
Abstract: Fever is common among in iduals seeking healthcare after traveling to tropical regions. Despite the association with potentially severe disease, the etiology is often not determined. Cytokines are soluble mediators dynamically regulated in the response to infection. Measuring cytokines in the blood can therefore be informative to understanding the host-response to infection and can potentially indicate the type of pathogen that causes the disease. In this study, we measured 49 host-response proteins in the plasma of 124 patients with fever after travel to tropical or subtropical regions. The patients had confirmed diagnosis of either P. falciparum malaria, dengue virus, influenza virus, bacterial respiratory tract infection, or culture-confirmed bacterial gastroenteritis, representing the most common disease etiologies. We used multivariate and machine learning methods to assess host-response protein profiles between the different disease groups and healthy control subjects with the aim to identify disease-specific protein signatures. The host-response varied between disease groups and combinations of cytokines and other proteins could accurately distinguish infected patients from healthy controls, and from each other. Malaria displayed the most unique protein signature, indicating a strong immunoregulatory response with high levels of IL10, sTNFRI and II, and sCD25 but low levels of sCD40L. In contrast, bacterial gastroenteritis had high levels of sCD40L, APRIL, and IFN-γ, while dengue was the only infection with elevated IFNα2. These results suggest that characterization of the inflammatory profile of in iduals with fever can help to identify disease-specific host-responses, which in turn can be used to guide further diagnostic strategies.
Publisher: Cold Spring Harbor Laboratory
Date: 03-09-2021
DOI: 10.1101/2021.09.02.458668
Abstract: The mechanism of acquisition and maintenance of natural immunity against Plasmodium falciparum malaria remains unclear. Although, clinical immunity develops over time with repeated malaria episodes, disease tolerance is more rapidly acquired compared to protective immunity. It remains unclear, how pre-existing immune responses impacts the mechanism responsible for disease tolerance. Here, we investigated a cohort of returning travelers treated for acute symptomatic P. falciparum malaria, either infected for the first time, or with a previous history of malaria. Through repeated s ling over one year in a malaria free setting, we were able to study the acute and longitudinal effects of the infection. We combined comprehensive immune cell and plasma protein profiling with integrated and data driven analysis, describing the immune landscape from acute disease to one year after infection. We identified a strong association between pro-inflammatory signatures and γδ T cell expansion. The association was significantly impacted by previous exposure to malaria, resulting in a d ened pro-inflammatory response, which translated to reduced Vδ2 + γδ T cell expansion compared to primary infected in iduals. The d ened inflammatory signal was associated with early expansion of FcγRIII+ monocytes and parasite-specific antibodies of IgG1 and IgG3 isotypes. Our data suggest that the interplay of FcγRIII+ monocytes and a cytophilic parasite-specific IgG during the early blood stage infection lead to lower parasitemia and a d ened pro-inflammatory response with reduced γδ T cell expansion. This enhanced control and reduced inflammation points to a potential mechanism on how tolerance is established following repeated malaria exposure. A systems immunology analysis on natural malaria sheds light on disease tolerance mechanism associated with gamma delta T cell expansion
Publisher: Cold Spring Harbor Laboratory
Date: 16-12-2020
DOI: 10.1101/2020.12.14.20242768
Abstract: Strengthening malaria surveillance is a key intervention needed to reduce the global disease burden. Reliable serological markers of recent malaria exposure could dramatically improve current surveillance methods by allowing for accurate estimates of infection incidence from limited data. We studied the IgG antibody response to 111 Plasmodium falciparum proteins in travellers followed longitudinally after a natural malaria infection in complete absence of re-exposure. We identified a novel combination of five serological markers (GAMA, MSP1, MSPDBL1 C- and N-terminal, and PfSEA1) that detect exposure within the previous 3-months with % sensitivity and specificity. Using mathematical modelling, we examined the antibody kinetics and determined that responses informative of recent exposure display several distinct characteristics: rapid initial boosting and decay, less inter-in idual variation in response kinetics, and minimal persistence over time. These serological exposure markers can be incorporated into routine malaria surveillance to guide efforts for malaria control and elimination.
Publisher: Elsevier BV
Date: 09-2023
Publisher: Public Library of Science (PLoS)
Date: 28-08-2014
Publisher: Public Library of Science (PLoS)
Date: 30-09-2022
DOI: 10.1371/JOURNAL.PONE.0274415
Abstract: Lipoarabinomannan (LAM), a component of the Mycobacterium tuberculosis (MTB) cell wall, is detectable in the urine of MTB infected patients with active tuberculosis (TB). LAM-specific antibodies (Igs) have been developed by a variety of traditional and recombinant methods for potential use in a rapid diagnostic test (RDT). We evaluated the analytical performance of the TB LAM Igs to identify pairs that offer superior performance over existing urine LAM tests. We assessed 25 new and 4 existing Igs in a matrixed format using a multiplex electrochemiluminescence-based liquid immunoassay. A total of 841 paired Ig combinations were challenged with in vitro cultured LAM (cLAM) derived from MTB strains representing erse phylogenetic lineages, alongside urinary LAM (uLAM) from the urine of adults with active pulmonary TB. Analytical sensitivity of down-selected Ig pairs was determined using MTB Aoyama-B cLAM, while diagnostic accuracy was determined using clinical s les. When testing cLAM, the reactivity of Ig pairs was similar across MTB lineages 1–4 but lineage 5:6 had significantly more reactivity among Ig pairs. Overall, 41 Ig pairs had a strong binding affinity to cLAM, as compared to the reference pair of S4-20/A194-01, and 28 Ig pairs therein exhibited a strong affinity for both cLAM and uLAM. Retrospective testing on clinical urine specimens demonstrated varying sensitivities (12–80%) and specificities (14–100%). The five top pairs had a similar analytical limit of detection to the reference pair but in four instances, the sensitivity and specificity with clinical uLAM s les was poor. Overall, epitopes presented by uLAM are different from cLAM, which may affect antibody performance when testing uLAM in patient s les. Several new Ig pairs had similar ranges of high sensitivity to cLAM but overall, there were no new candidate Ig pairs identified in this round of screening with increased performance with uLAM as compared to an existing optimal pair.
Publisher: Frontiers Media SA
Date: 27-06-2016
Publisher: Springer Science and Business Media LLC
Date: 30-01-2019
Publisher: Frontiers Media SA
Date: 02-12-2022
DOI: 10.3389/FIMMU.2022.1035122
Abstract: Glycolipids constitute a major part of the cell envelope of Mycobacterium tuberculosis (Mtb). They are potent immunomodulatory molecules recognized by several immune receptors like pattern recognition receptors such as TLR2, DC-SIGN and Dectin-2 on antigen-presenting cells and by T cell receptors on T lymphocytes. The Mtb glycolipids lipoarabinomannan (LAM) and its biosynthetic relatives, phosphatidylinositol mannosides (PIMs) and lipomannan (LM), as well as other Mtb glycolipids, such as phenolic glycolipids and sulfoglycolipids have the ability to modulate the immune response, stimulating or inhibiting a pro-inflammatory response. We explore here the downmodulating effect of Mtb glycolipids. A great proportion of the studies used in vitro approaches although in vivo infection with Mtb might also lead to a d ening of myeloid cell and T cell responses to Mtb glycolipids. This d ened response has been explored ex vivo with immune cells from peripheral blood from Mtb-infected in iduals and in mouse models of infection. In addition to the d ening of the immune response caused by Mtb glycolipids, we discuss the hyporesponse to Mtb glycolipids caused by prolonged Mtb infection and/or exposure to Mtb antigens. Hyporesponse to LAM has been observed in myeloid cells from in iduals with active and latent tuberculosis (TB). For some myeloid subsets, this effect is stronger in latent versus active TB. Since the immune response in in iduals with latent TB represents a more protective profile compared to the one in patients with active TB, this suggests that downmodulation of myeloid cell functions by Mtb glycolipids may be beneficial for the host and protect against active TB disease. The mechanisms of this downmodulation, including tolerance through epigenetic modifications, are only partly explored.
Publisher: American Society for Clinical Investigation
Date: 08-03-2018
Publisher: Public Library of Science (PLoS)
Date: 19-01-2021
DOI: 10.1371/JOURNAL.PONE.0245431
Abstract: Malaria is a potentially life-threatening disease with approximately half of the world’s population at risk. Young children and pregnant women are hit hardest by the disease. B cells and antibodies are part of an adaptive immune response protecting in iduals continuously exposed to the parasite. An infection with Plasmodium falciparum can cause dysregulation of B cell homeostasis, while antibodies are known to be key in controlling symptoms and parasitemia. BAFF is an instrumental cytokine for the development and maintenance of B cells. Pregnancy alters the immune status and renders previously clinically immune women at risk of severe malaria, potentially due to altered B cell responses associated with changes in BAFF levels. In this prospective study, we investigated the levels of BAFF in a malaria-endemic area in mothers and their infants from birth up to 9 months. We found that BAFF-levels are significantly higher in infants than in mothers. BAFF is highest in cord blood and then drops rapidly, but remains significantly higher in infants compared to mothers even at 9 months of age. We further correlated BAFF levels to P . falciparum- specific antibody levels and B cell frequencies and found a negative correlation between BAFF and both P . falciparum -specific and total proportions of IgG + memory B cells, as well as CD27 − memory B cells, indicating that exposure to both malaria and other diseases affect the development of B-cell memory and that BAFF plays a part in this. In conclusion, we have provided new information on how natural immunity against malaria is formed.
Publisher: American Society for Microbiology
Date: 15-02-2010
DOI: 10.1128/JVI.01896-09
Abstract: The high-affinity in vivo interaction between soluble HIV-1 envelope glycoprotein (Env) immunogens and primate CD4 results in conformational changes that alter the immunogenicity of the gp120 subunit. Because the conserved binding site on gp120 that directly interacts with CD4 is a major vaccine target, we sought to better understand the impact of in vivo Env-CD4 interactions during vaccination. Rhesus macaques were immunized with soluble wild-type (WT) Env trimers, and two trimer immunogens rendered CD4 binding defective through distinct mechanisms. In one variant, we introduced a mutation that directly disrupts CD4 binding (368D/R). In the second variant, we introduced three mutations (423I/M, 425N/K, and 431G/E) that disrupt CD4 binding indirectly by altering a gp120 subdomain known as the bridging sheet, which is required for locking Env into a stable interaction with CD4. Following immunization, Env-specific binding antibody titers and frequencies of Env-specific memory B cells were comparable between the groups. However, the quality of neutralizing antibody responses induced by the variants was distinctly different. Antibodies against the coreceptor binding site were elicited by WT trimers but not the CD4 binding-defective trimers, while antibodies against the CD4 binding site were elicited by the WT and the 423I/M, 425N/K, and 431G/E trimers but not the 368D/R trimers. Furthermore, the CD4 binding-defective trimer variants stimulated less potent neutralizing antibody activity against neutralization-sensitive viruses than WT trimers. Overall, our studies do not reveal any potential negative effects imparted by the in vivo interaction between WT Env and primate CD4 on the generation of functional T cells and antibodies in response to soluble Env vaccination.
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.JIM.2014.05.004
Abstract: Longitudinal bone marrow aspirates were obtained aseptically from the humerus of 36 rhesus and 6 cynomolgus macaques by using a 20G spinal needle, introduced through the bone close to the greater tuberosity. All s lings were performed without complications, and the animals showed no signs of pain or infections. The amount of total bone marrow cells obtained from each aspiration varied, in part due to animal-to-animal variation, but the yields were not affected by the s ling frequency or the length of time between each aspiration. The frequency of plasma cells in the bone marrow of each animal was also fairly stable over several longitudinal s lings while a greater, age-dependent, variation was observed between different animals.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 11-07-2012
DOI: 10.1126/SCITRANSLMED.3003752
Abstract: Vaccine-elicited mAbs bind the HIV-1 Env CD4bs differently from broadly neutralizing infection-induced mAbs.
Publisher: Wiley
Date: 08-10-2023
Publisher: Frontiers Media SA
Date: 12-02-2021
DOI: 10.3389/FIMMU.2020.619398
Abstract: Memory B cells (MBCs) are believed to be important for the maintenance of immunity to malaria, and these cells need to be explored in the context of different parasite antigens and their breadth and kinetics after natural infections. However, frequencies of antigen-specific MBCs are low in peripheral blood, limiting the number of antigens that can be studied, especially when small blood volumes are available. Here, we developed a multiplexed reversed B-cell FluoroSpot assay capable of simultaneously detecting MBCs specific for the four Plasmodium falciparum blood-stage antigens, MSP-1 19 , MSP-2, MSP-3 and AMA-1. We used the assay to study the kinetics of the MBC response after an acute episode of malaria and up to one year following treatment in travelers returning to Sweden from sub-Saharan Africa. We show that the FluoroSpot assay can detect MBCs to all four merozoite antigens in the same well, and that the breadth and kinetics varied between in iduals. We further found that in iduals experiencing a primary infection could mount and maintain parasite-specific MBCs to a similar extent as previously exposed adults, already after a single infection. We conclude that the multiplexed B-cell FluoroSpot is a powerful tool for assessing antigen-specific MBC responses to several antigens simultaneously, and that the kinetics of MBC responses against merozoite surface antigens differ over the course of one year. These findings contribute to the understanding of acquisition and maintenance of immune responses to malaria.
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.CELREP.2022.110709
Abstract: Natural immunity to malaria develops over time with repeated malaria episodes, but protection against severe malaria and immune regulation limiting immunopathology, called tolerance, develops more rapidly. Here, we comprehensively profile the blood immune system in patients, with or without prior malaria exposure, over 1 year after acute symptomatic Plasmodium falciparum malaria. Using a data-driven analysis approach to describe the immune landscape over time, we show that a d ened inflammatory response is associated with reduced γδ T cell expansion, early expansion of CD16
Publisher: Frontiers Media SA
Date: 11-09-2019
Publisher: Springer Science and Business Media LLC
Date: 10-2009
No related grants have been discovered for Christopher Sundling.