ORCID Profile
0000-0002-4909-2984
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In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Optical Physics | Immunology | Organic Chemical Synthesis | Biomechanical Engineering | Cellular Immunology | Proteins and Peptides | Photonics, Optoelectronics and Optical Communications | Biological Physics | Cell Development, Proliferation and Death
Medical Instruments | Scientific Instruments | Expanding Knowledge in Engineering | Human Diagnostics | Expanding Knowledge in the Biological Sciences | Immune System and Allergy |
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.CELL.2015.07.055
Abstract: Dynamic interactions between B and T cells underpin the development of adaptive humoral immune responses to infections and vaccines. Recent advances in the molecular and spatiotemporal control of these interactions during primary responses have contributed greatly to elucidating the molecular pathogenesis of numerous immunodeficiency and autoimmune diseases. The next challenge is to determine how and where memory B and T cells interact during secondary responses to facilitate the rapid and robust response that characterizes anamnestic immunity.
Publisher: Springer Science and Business Media LLC
Date: 22-08-2018
DOI: 10.1038/S41467-018-05772-7
Abstract: Vaccine-induced immunity depends on the generation of memory B cells (MBC). However, where and how MBCs are reactivated to make neutralising antibodies remain unknown. Here we show that MBCs are prepositioned in a subcapsular niche in lymph nodes where, upon reactivation by antigen, they rapidly proliferate and differentiate into antibody-secreting plasma cells in the subcapsular proliferative foci (SPF). This novel structure is enriched for signals provided by T follicular helper cells and antigen-presenting subcapsular sinus macrophages. Compared with contemporaneous secondary germinal centres, SPF have distinct single-cell molecular signature, cell migration pattern and plasma cell output. Moreover, SPF are found both in human and mouse lymph nodes, suggesting that they are conserved throughout mammalian evolution. Our data thus reveal that SPF is a seat of immunological memory that may be exploited to rapidly mobilise secondary antibody responses and improve vaccine efficacy.
Publisher: American Society for Clinical Investigation
Date: 06-06-2019
Publisher: Rockefeller University Press
Date: 31-03-2003
DOI: 10.1084/JEM.20022144
Abstract: In both humans and animals, immunoglobulin (Ig)G autoantibodies are less frequent but more pathogenic than IgM autoantibodies, suggesting that controls over Ig isotype switching are required to reinforce B cell self-tolerance. We have used gene targeting to produce mice in which hen egg lysozyme (HEL)-specific B cells can switch to all Ig isotypes (SWHEL mice). When crossed with soluble HEL transgenic (Tg) mice, self-reactive SWHEL B cells became anergic. However, in contrast to anergic B cells from the original nonswitching anti-HEL × soluble HEL double Tg model, self-reactive SWHEL B cells also displayed an immature phenotype, reduced lifespan, and exclusion from the splenic follicle. These differences were not related to their ability to Ig class switch, but instead to competition with non-HEL–binding B cells generated by VH gene replacement in SWHEL mice. When activated in vitro with B cell receptor (BCR)-independent stimuli such as anti-CD40 monoclonal antibody plus interleukin 4 or lipopolysaccharide (LPS), anergic SWHEL double Tg B cells proliferated and produced IgG anti-HEL antibodies as efficiently as naive HEL-binding B cells from SWHEL Ig Tg mice. These results demonstrate that no intrinsic constraints to isotype switching exist in anergic self-reactive B cells. Instead, production of IgG autoantibodies is prevented by separate controls that reduce the likelihood of anergic B cells encountering BCR-independent stimuli. That bacteria-derived LPS could circumvent these controls may explain the well-known association between autoantibody-mediated diseases and episodes of systemic infection.
Publisher: Springer Science and Business Media LLC
Date: 27-04-2007
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1053/J.GASTRO.2017.05.056
Abstract: Many patients with inflammatory bowel diseases (IBD) have ongoing bowel symptoms of diarrhea or abdominal pain despite mucosal healing. We investigated whether impaired intestinal permeability contributes to these symptoms. We performed a prospective study of intestinal permeability, measured by endoscopic confocal laser endomicroscopy in 110 consecutive subjects (31 with ulcerative colitis [UC], 57 with Crohn's disease [CD], and 22 healthy in iduals [controls]) in Sydney, Australia from May 2009 and September 2015. Symptomatic CD was defined by a CD Activity Index score of 150 or more and symptomatic UC by a partial Mayo score of 2 or more. Mucosal healing was defined as CD Endoscopic Index of Severity of 0 in CD or Mayo endoscopic sub-score of 0-1 for patients with UC. Intestinal permeability was quantified by the Confocal Leak Score (CLS range: 0=no impaired permeability to 100=complete loss of barrier function). The primary endpoint was intestinal permeability in patients with symptomatic IBD in mucosal healing vs patients with asymptomatic IBD in mucosal healing. We determined the sensitivity and specificity of CLS in determining symptoms based on receiver operating characteristic analysis. Ongoing bowel symptoms were present in 16.3% of patients with IBD and mucosal healing (15.4% of patients with CD, 17.4% with UC). Patients with symptomatic IBD had a significantly higher median CLS (19.0) than patients with asymptomatic IBD (7.3 P < .001) or controls (5.9, P < .001). There were no significant differences between patients with IBD in remission vs controls (P = .261). Median CLS was significantly higher in patients with symptomatic than asymptomatic CD (17.7 vs 8.1 P = .009) and patients with symptomatic than asymptomatic UC (22.2 vs 6.9 P = .021). A CLS of 13.1 or more identified ongoing bowel symptoms in patients with IBD and mucosal healing with 95.2% sensitivity and 97.6% specificity the receiver operating characteristic area under curve value was 0.88. Based on this cutoff, 36.2% of patients with IBD in mucosal healing have increased intestinal permeability. On regression analysis, every increase in CLS of 1.9 correlated with an additional diarrheal motion per day (P = .008). In a prospective study of intestinal permeability in patients with IBD and mucosal healing, we associated impaired intestinal permeability with ongoing bowel symptoms increases in permeability correlated with increased severity of diarrhea. Resolution of mucosal permeability beyond mucosal healing might improve outcomes of patients with IDB (ANZCTR.org.au: ACTRN12613001248752).
Publisher: Elsevier BV
Date: 2022
Publisher: Springer Science and Business Media LLC
Date: 02-06-2020
Publisher: Wiley
Date: 30-05-2020
DOI: 10.1111/IMR.12862
Publisher: American Society of Hematology
Date: 29-06-2017
DOI: 10.1182/BLOOD-2017-03-773341
Abstract: Anti-sclerostin treatment increases bone mass and fracture resistance in MM Anti-sclerostin in combination with zoledronic acid is superior to zoledronic acid alone in increasing fracture resistance.
Publisher: Public Library of Science (PLoS)
Date: 11-2011
Publisher: Rockefeller University Press
Date: 17-07-2018
DOI: 10.1084/JEM.20180010
Abstract: Gain-of-function (GOF) mutations in PIK3CD, encoding the p110δ subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected in iduals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd. In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110δ inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected in iduals with p110δ inhibitors.
Publisher: Rockefeller University Press
Date: 09-04-2012
DOI: 10.1084/JEM.20112391
Abstract: Patients with the primary immunodeficiency X-linked lymphoproliferative disease (XLP), which is caused by mutations in SH2D1A, are highly susceptible to Epstein-Barr virus (EBV) infection. Nonetheless, some XLP patients demonstrate less severe clinical manifestations after primary infection. SH2D1A encodes the adaptor molecule SLAM-associated protein (SAP), which is expressed in T and natural killer cells and is required for cytotoxicity against B cells, the reservoir for EBV. It is not known why the clinical presentation of XLP is so variable. In this study, we report for the first time the occurrence of somatic reversion in XLP. Reverted SAP-expressing cells resided exclusively within the CD8+ T cell subset, displayed a CD45RA−CCR7− effector memory phenotype, and were maintained at a stable level over time. Importantly, revertant CD8+ SAP+ T cells, but not SAP− cells, proliferated in response to EBV and killed EBV-infected B cells. As somatic reversion correlated with EBV infection, we propose that the virus exerts a selective pressure on the reverted cells, resulting in their expansion in vivo and host protection against ongoing infection.
Publisher: Springer New York
Date: 2015
DOI: 10.1007/978-1-4939-2498-1_9
Abstract: T cell-dependent B cell responses generate optimal antibodies to combat foreign antigens. Naïve B cells responding to antigen undergo a complex series of differentiation events and cell fate decisions to provide long-lived memory B cells and plasma cells. Historically, B cell biologists have been challenged by the task of investigating rare antigen-specific B cells in an in vivo setting such that their interactions with antigen, regulation and migration may be accurately tracked. We have developed the SW(HEL) experimental system capable of accurately monitoring B cells that interact with a protein antigen and then subsequently undergo isotype switching, somatic hypermutation, and affinity maturation within germinal centers (GC) to generate high-affinity antibodies. Here we provide a comprehensive description of the procedures involved in establishing and using the SW(HEL) system to assess B cell responses to a foreign antigen. This system can provide a valuable measure of the functional capabilities of T follicular helper cells, whose role is ultimately to support and shape long-term humoral immunity.
Publisher: Cold Spring Harbor Laboratory
Date: 02-2022
DOI: 10.1101/2022.01.30.478400
Abstract: Children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop less severe coronavirus disease 2019 (COVID-19) than adults. The mechanisms for the age-specific differences and the implications for infection-induced immunity are beginning to be uncovered. We show by longitudinal multimodal analysis that SARS-CoV-2 leaves a small footprint in the circulating T cell compartment in children with mild/asymptomatic COVID-19 compared to adult household contacts with the same disease severity who had more evidence of systemic T cell interferon activation, cytotoxicity and exhaustion. Children harbored erse polyclonal SARS-CoV- 2-specific naïve T cells whereas adults harbored clonally expanded SARS-CoV-2-specific memory T cells. More naïve interferon-activated CD4 + T cells were recruited into the memory compartment and recovery was associated with the development of robust CD4 + memory T cell responses in adults but not children. These data suggest that rapid clearance of SARS-CoV-2 in children may compromise their cellular immunity and ability to resist reinfection. Children have erse polyclonal SARS-CoV-2-specific naïve T cells Adults have clonally expanded exhausted SARS-CoV-2-specific memory T cells Interferon-activated naïve T cells differentiate into memory T cells in adults but not children Adults but not children develop robust memory T cell responses to SARS-CoV-2
Publisher: Springer Science and Business Media LLC
Date: 12-05-2017
DOI: 10.1038/NCOMMS15373
Abstract: Interleukin-2 (IL-2) is an established therapeutic agent used for cancer immunotherapy. Since treatment efficacy is mediated by CD8 + and NK cell activity at the tumour site, considerable efforts have focused on generating variants that expand these subsets systemically, as exemplified by IL-2/antibody complexes and ‘superkines’. Here we describe a novel determinant of antitumour activity using fusion proteins consisting of IL-2 and the antibody fragment crystallizable (Fc) region. Generation of long-lived IL-2-Fc variants in which CD25 binding is abolished through mutation effectively prevents unwanted activation of CD25 + regulatory T-cells (Tregs) and results in strong expansion of CD25 − cytotoxic subsets. Surprisingly, however, such variants are less effective than wild-type IL-2-Fc in mediating tumour rejection. Instead, we report that efficacy is crucially dependent on depletion of Tregs through Fc-mediated immune effector functions. Our results underpin an unexpected mechanism of action and provide important guidance for the development of next generation IL-2 therapeutics.
Publisher: Springer Science and Business Media LLC
Date: 05-05-2021
DOI: 10.1038/S41467-021-22517-1
Abstract: Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders ( P = 2.4 × 10 −22 ) and are associated with the polygenic diseases osteoporosis ( P = 1.8 × 10 −13 ) and osteoarthritis ( P = 1.6 × 10 −7 ). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease.
Publisher: American Association for Cancer Research (AACR)
Date: 2015
DOI: 10.1158/2159-8290.CD-14-0621
Abstract: Recent clinical trials have shown that bisphosphonate drugs improve breast cancer patient survival independent of their antiresorptive effects on the skeleton. However, because bisphosphonates bind rapidly to bone mineral, the exact mechanisms of their antitumor action, particularly on cells outside of bone, remain unknown. Here, we used real-time intravital two-photon microscopy to show extensive leakage of fluorescent bisphosphonate from the vasculature in 4T1 mouse mammary tumors, where it initially binds to areas of small, granular microcalcifications that are engulfed by tumor-associated macrophages (TAM), but not tumor cells. Importantly, we also observed uptake of radiolabeled bisphosphonate in the primary breast tumor of a patient and showed the resected tumor to be infiltrated with TAMs and to contain similar granular microcalcifications. These data represent the first compelling in vivo evidence that bisphosphonates can target cells in tumors outside the skeleton and that their antitumor activity is likely to be mediated via TAMs. Significance: Bisphosphonates are assumed to act solely in bone. However, mouse models and clinical trials show that they have surprising antitumor effects outside bone. We provide unequivocal evidence that bisphosphonates target TAMs, but not tumor cells, to exert their extraskeletal effects, offering a rationale for use in patients with early disease. Cancer Discov 5(1) 35–42. ©2014 AACR. See related commentary by Sterling, p. 14 This article is highlighted in the In This Issue feature, p. 1
Publisher: Elsevier BV
Date: 08-2022
DOI: 10.1016/J.GIM.2022.04.021
Abstract: The study aimed to determine the diagnostic yield, optimal timing, and methodology of next generation sequencing data reanalysis in suspected Mendelian disorders. We conducted a systematic review and meta-analysis of studies that conducted data reanalysis in patients with suspected Mendelian disorders. Random effects model was used to pool the estimated outcome with subgroup analysis stratified by timing, sequencing methodology, s le size, segregation, use of research validation, and artificial intelligence (AI) variant curation tools. A search of PubMed, Embase, Scopus, and Web of Science between 2007 and 2021 yielded 9327 articles, of which 29 were selected. Significant heterogeneity was noted between studies. Reanalysis had an overall diagnostic yield of 0.10 (95% CI = 0.06-0.13). Literature updates accounted for most new diagnoses. Diagnostic yield was higher after 24 months, although this was not statistically significant. Increased diagnoses were obtained with research validation and data sharing. AI-based tools did not adversely affect reanalysis diagnostic rate. Next generation sequencing data reanalysis can improve diagnostic yield. Owing to the heterogeneity of the studies, the optimal time to reanalysis and the impact of AI-based tools could not be determined with confidence. We propose standardized guidelines for future studies to reduce heterogeneity and improve the quality of the conclusions.
Publisher: American Society of Hematology
Date: 15-05-2004
DOI: 10.1182/BLOOD-2003-09-3109
Abstract: Plasma cells (PCs) represent the final stage of B-cell differentiation and are devoted to the production of immunoglobulin (Ig). Perturbations to their development can result in human disorders characterized by PC expansion and hypergammaglobulinemia. Ig-secreting cells (ISCs) have been identified in secondary lymphoid tissues and bone marrow (BM). Most ISCs in lymphoid tissue are short-lived in contrast, ISCs that migrate to the BM become long-lived PCs and continue to secrete immunoglobulin for extended periods. However, a small population of long-lived PCs has been identified in rodent spleen, suggesting that PCs may persist in secondary lymphoid tissue and that the spleen, as well as the BM, plays an important role in maintaining long-term humoral immunity. For these reasons, we examined ISCs in human spleen and identified a population that appears analogous to long-lived rodent splenic PCs. Human splenic ISCs shared morphologic, cellular, molecular, and functional characteristics with long-lived PCs in BM, demonstrating their commitment to the PC lineage. Furthermore, the detection of highly mutated immunoglobulin V region genes in splenic ISCs suggested they are likely to be antigen-selected and to secrete high-affinity immunoglobulin. Thus, our results suggest that splenic ISCs have an important role in humoral immunity and may represent the affected cell type in some B-cell dyscrasias.
Publisher: Springer Science and Business Media LLC
Date: 19-06-2020
Publisher: Elsevier BV
Date: 06-2004
Publisher: Elsevier BV
Date: 10-2015
Publisher: eLife Sciences Publications, Ltd
Date: 09-07-2018
DOI: 10.7554/ELIFE.35800
Abstract: Intravital microscopy can provide unique insights into the function of biological processes in a native context. However, physiological motion caused by peristalsis, respiration and the heartbeat can present a significant challenge, particularly for functional readouts such as fluorescence lifetime imaging (FLIM), which require longer acquisition times to obtain a quantitative readout. Here, we present and benchmark Galene, a versatile multi-platform software tool for image-based correction of s le motion blurring in both time resolved and conventional laser scanning fluorescence microscopy data in two and three dimensions. We show that Galene is able to resolve intravital FLIM-FRET images of intra-abdominal organs in murine models and NADH autofluorescence of human dermal tissue imaging subject to a wide range of physiological motions. Thus, Galene can enable FLIM imaging in situations where a stable imaging platform is not always possible and rescue previously discarded quantitative imaging data.
Publisher: Wiley
Date: 26-11-2012
Abstract: The potential usefulness of intravital two-photon microscopy for fate mapping is limited by its inability to track cells beyond the confines of the imaging volume. Therefore, we have developed and validated a novel method for in vivo photolabelling of spatially-restricted cells expressing the Kaede optical highlighter by two-photon excitation. This has allowed us to optically mark a cohort of follicular B cells and track their dissemination from the original imaging volume in the lymph node to the spleen and contralateral lymph node. We also present the first demonstration, to our knowledge, of in vivo photoconversion of a freely moving single cell in a live adult animal. This method of `discontinuous' cell tracking therefore significantly extends the fate mapping capabilities of two-photon microscopy to delineate the spatiotemporal dynamics of cellular processes that span multiple anatomical sites at the single cell level.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-04-2017
DOI: 10.1126/SCITRANSLMED.AAI8504
Abstract: Fine-tuned manipulation of tumor tension and vasculature enhances response to chemotherapy and impairs metastatic spread in pancreatic cancer.
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.IMMUNI.2015.04.010
Abstract: The mechanistic links between genetic variation and autoantibody production in autoimmune disease remain obscure. Autoimmune lymphoproliferative syndrome (ALPS) is caused by inactivating mutations in FAS or FASL, with autoantibodies thought to arise through failure of FAS-mediated removal of self-reactive germinal center (GC) B cells. Here we show that FAS is in fact not required for this process. Instead, FAS inactivation led to accumulation of a population of unconventional GC B cells that underwent somatic hypermutation, survived despite losing antigen reactivity, and differentiated into a large population of plasma cells that included autoantibody-secreting clones. IgE(+) plasma cell numbers, in particular, increased after FAS inactivation and a major cohort of ALPS-affected patients were found to have hyper-IgE. We propose that these previously unidentified cells, designated "rogue GC B cells," are a major driver of autoantibody production and provide a mechanistic explanation for the linked production of IgE and autoantibodies in autoimmune disease.
Publisher: The Optical Society
Date: 24-04-2014
DOI: 10.1364/BOE.5.001626
Publisher: Elsevier BV
Date: 03-2021
Publisher: Springer Science and Business Media LLC
Date: 22-05-2019
Publisher: American Association for the Advancement of Science (AAAS)
Date: 28-04-2023
Abstract: Aberrant AKT activation occurs in a number of cancers, metabolic syndrome, and immune disorders, making it an important target for the treatment of many diseases. To monitor spatial and temporal AKT activity in a live setting, we generated an Akt-FRET biosensor mouse that allows longitudinal assessment of AKT activity using intravital imaging in conjunction with image stabilization and optical window technology. We demonstrate the sensitivity of the Akt-FRET biosensor mouse using various cancer models and verify its suitability to monitor response to drug targeting in spheroid and organotypic models. We also show that the dynamics of AKT activation can be monitored in real time in erse tissues, including in in idual islets of the pancreas, in the brown and white adipose tissue, and in the skeletal muscle. Thus, the Akt-FRET biosensor mouse provides an important tool to study AKT dynamics in live tissue contexts and has broad preclinical applications.
Publisher: Springer Science and Business Media LLC
Date: 09-07-2018
Publisher: Cold Spring Harbor Laboratory
Date: 24-09-2018
DOI: 10.1101/424945
Abstract: High-throughput single-cell RNA-Sequencing is a powerful technique for gene expression profiling of complex and heterogeneous cellular populations such as the immune system. However, these methods only provide short-read sequence from one end of a cDNA template, making them poorly suited to the investigation of gene-regulatory events such as mRNA splicing, adaptive immune responses or somatic genome evolution. To address this challenge, we have developed a method that combines targeted long-read sequencing with short-read based transcriptome profiling of barcoded single cell libraries generated by droplet-based partitioning. We use Repertoire And Gene Expression sequencing (RAGE-seq) to accurately characterize full-length T cell (TCR) and B cell (BCR) receptor sequences and transcriptional profiles of more than 7,138 lymphocytes s led from the primary tumour and draining lymph node of a breast cancer patient. With this method we show that somatic mutation, alternate splicing and clonal evolution of T and B lymphocytes can be tracked across these tissue compartments. Our results demonstrate that RAGE-Seq is an accessible and cost-effective method for high-throughput deep single cell profiling, applicable to a wide range of biological challenges.
Publisher: Springer Science and Business Media LLC
Date: 17-02-2019
DOI: 10.1038/S41467-019-11049-4
Abstract: High-throughput single-cell RNA sequencing is a powerful technique but only generates short reads from one end of a cDNA template, limiting the reconstruction of highly erse sequences such as antigen receptors. To overcome this limitation, we combined targeted capture and long-read sequencing of T-cell-receptor (TCR) and B-cell-receptor (BCR) mRNA transcripts with short-read transcriptome profiling of barcoded single-cell libraries generated by droplet-based partitioning. We show that Repertoire and Gene Expression by Sequencing (RAGE-Seq) can generate accurate full-length antigen receptor sequences at nucleotide resolution, infer B-cell clonal evolution and identify alternatively spliced BCR transcripts. We apply RAGE-Seq to 7138 cells s led from the primary tumor and draining lymph node of a breast cancer patient to track transcriptome profiles of expanded lymphocyte clones across tissues. Our results demonstrate that RAGE-Seq is a powerful method for tracking the clonal evolution from large numbers of lymphocytes applicable to the study of immunity, autoimmunity and cancer.
Publisher: eLife Sciences Publications, Ltd
Date: 22-05-2018
Publisher: Wiley
Date: 17-02-2015
DOI: 10.1038/ICB.2015.12
Publisher: Springer Science and Business Media LLC
Date: 19-10-2023
Publisher: EMBO
Date: 21-04-2020
Publisher: Wiley
Date: 2021
DOI: 10.1002/CTI2.1308
Abstract: A recent single‐cell RNA sequencing study by Wilk et al . suggested that plasmablasts can transdifferentiate into ‘developing neutrophils’ in patients with severe COVID‐19 disease. We explore the evidence for this. We downloaded the original data and code used by the authors in their study to replicate their findings and explore the possibility that regressing out variables may have led the authors to overfit their data. The lineage relationship between plasmablasts and developing neutrophils breaks down when key features are not regressed out, and the data are not overfitted during the analysis. Plasmablasts do not transdifferentiate into developing neutrophils. The single‐cell RNA sequencing is a powerful technique for biological discovery and hypothesis generation. However, caution should be exercised in the bioinformatic analysis and interpretation of the data and findings cross‐validated by orthogonal techniques.
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.IMMUNI.2015.03.002
Abstract: B helper follicular T (Tfh) cells are critical for long-term humoral immunity. However, it remains unclear how these cells are recruited and contribute to secondary immune responses. Here we show that primary Tfh cells segregate into follicular mantle (FM) and germinal center (GC) subpopulations that display distinct gene expression signatures. Restriction of the primary Tfh cell subpopulation in the GC was mediated by downregulation of chemotactic receptor EBI2. Following collapse of the GC, memory T cells persisted in the outer follicle where they scanned CD169(+) subcapsular sinus macrophages. Reactivation and intrafollicular expansion of these follicular memory T cells in the subcapsular region was followed by their extrafollicular dissemination via the lymphatic flow. These data suggest that Tfh cells integrate their antigen-experience history to focus T cell help within the GC during primary responses but act rapidly to provide systemic T cell help after re-exposure to the antigen.
Publisher: Elsevier BV
Date: 04-2017
DOI: 10.1016/J.COI.2017.03.005
Abstract: Immunological memory is a cornerstone of adaptive immune responses in higher vertebrates. The remarkable ability to generate memory cells following Ag exposure, in the context of natural infection or immunization, provides long-lived protection against infectious diseases, often for the hosts' lifetime. Indeed, the generation of memory B cells and long-lived plasma cells underpins the success of most vaccines. The concept of immunological memory is not new-it was first proposed nearly 2500 years ago. While our understanding of the complexities of humoral and cell-mediated memory continues to evolve, important aspects of this process remain unresolved. Here, we will provide an overview of recent advances in B-cell memory in mice and humans, and in health and disease.
Publisher: Rockefeller University Press
Date: 09-10-2006
DOI: 10.1084/JEM.20061254
Abstract: A hallmark of T cell–dependent immune responses is the progressive increase in the ability of serum antibodies to bind antigen and provide immune protection. Affinity maturation of the antibody response is thought to be connected with the preferential survival of germinal centre (GC) B cells that have acquired increased affinity for antigen via somatic hypermutation of their immunoglobulin genes. However, the mechanisms that drive affinity maturation remain obscure because of the difficulty in tracking the affinity-based selection of GC B cells and their differentiation into plasma cells. We describe a powerful new model that allows these processes to be followed as they occur in vivo. In contrast to evidence from in vitro systems, responding GC B cells do not undergo plasma cell differentiation stochastically. Rather, only GC B cells that have acquired high affinity for the immunizing antigen form plasma cells. Affinity maturation is therefore driven by a tightly controlled mechanism that ensures only antibodies with the greatest possibility of neutralizing foreign antigen are produced. Because the body can sustain only limited numbers of plasma cells, this “quality control” over plasma cell differentiation is likely critical for establishing effective humoral immunity.
Publisher: Rockefeller University Press
Date: 10-04-2006
DOI: 10.1084/JEM.20060087
Abstract: B cells responding to T-dependent antigen either differentiate rapidly into extrafollicular plasma cells or enter germinal centers and undergo somatic hypermutation and affinity maturation. However, the physiological cues that direct B cell differentiation down one pathway versus the other are unknown. Here we show that the strength of the initial interaction between B cell receptor (BCR) and antigen is a primary determinant of this decision. B cells expressing a defined BCR specificity for hen egg lysozyme (HEL) were challenged with sheep red blood cell conjugates of a series of recombinant mutant HEL proteins engineered to bind this BCR over a 10,000-fold affinity range. Decreasing either initial BCR affinity or antigen density was found to selectively remove the extrafollicular plasma cell response but leave the germinal center response intact. Moreover, analysis of competing B cells revealed that high affinity specificities are more prevalent in the extrafollicular plasma cell versus the germinal center B cell response. Thus, the effectiveness of early T-dependent antibody responses is optimized by preferentially steering B cells reactive against either high affinity or abundant epitopes toward extrafollicular plasma cell differentiation. Conversely, responding clones with weaker antigen reactivity are primarily directed to germinal centers where they undergo affinity maturation.
Publisher: Wiley
Date: 20-11-2007
Abstract: Burnet's original description of the clonal selection hypothesis of antibody production included many prescient predictions of how 'lymphocytes carrying reactive sites' for foreign antigens might respond during immune responses. Somatic mutation, plasma cell differentiation and transition into memory cells were all described as potential fates for the 'variety of descendents' derived from proliferative expansion of antigen-reactive clones. After 50 years much is known about the molecular controls that drive these various processes. Comparatively little insight has been gained, however, into why particular daughter cells progress down one response pathway versus another. In this article, we briefly describe the evolution of the genetic technologies that now allow us to visualize the very processes predicted by Burnet. An in-depth description of the recently developed SW(HEL) mouse model and its utility for tracking in vivo B-cell responses to various forms of hen-egg lysozyme (HEL) is also provided. Recent data obtained with this system indicate that antigen-dependent variables play a critical role in regulating the differentiation of responding B cells into antibody-secreting plasma cells.
Publisher: American Society of Hematology
Date: 04-07-2019
Abstract: The era of targeted therapies has seen significant improvements in depth of response, progression-free survival, and overall survival for patients with multiple myeloma. Despite these improvements in clinical outcome, patients inevitably relapse and require further treatment. Drug-resistant dormant myeloma cells that reside in specific niches within the skeleton are considered a basis of disease relapse but remain elusive and difficult to study. Here, we developed a method to sequence the transcriptome of in idual dormant myeloma cells from the bones of tumor-bearing mice. Our analyses show that dormant myeloma cells express a distinct transcriptome signature enriched for immune genes and, unexpectedly, genes associated with myeloid cell differentiation. These genes were switched on by coculture with osteoblastic cells. Targeting AXL, a gene highly expressed by dormant cells, using small-molecule inhibitors released cells from dormancy and promoted their proliferation. Analysis of the expression of AXL and coregulated genes in human cohorts showed that healthy human controls and patients with monoclonal gammopathy of uncertain significance expressed higher levels of the dormancy signature genes than patients with multiple myeloma. Furthermore, in patients with multiple myeloma, the expression of this myeloid transcriptome signature translated into a twofold increase in overall survival, indicating that this dormancy signature may be a marker of disease progression. Thus, engagement of myeloma cells with the osteoblastic niche induces expression of a suite of myeloid genes that predicts disease progression and that comprises potential drug targets to eradicate dormant myeloma cells.
No related organisations have been discovered for Tri Phan.
Start Date: 06-2011
End Date: 06-2014
Amount: $324,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 07-2021
End Date: 07-2022
Amount: $875,000.00
Funder: Australian Research Council
View Funded Activity