ORCID Profile
0000-0001-6844-3463
Current Organisation
Queensland University of Technology
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Publisher: Oxford University Press (OUP)
Date: 11-06-2015
DOI: 10.1093/RHEUMATOLOGY/KEV218
Abstract: There has been significant progress in our understanding of the pathogenesis of AS. The advent of genome-wide association studies has increased the known loci associated with AS to more than 40. The endoplasmic reticulum resident aminopeptidases (ERAP) 1 and 2 were identified in this manner and are of particular interest. There appears to be a genetic as well as a functional interaction of ERAP1 and 2 with HLA-B27 based on the known functions of these molecules. Recent studies on the structure, immunological effects and the peptide-trimming properties of ERAP 1 and 2 have helped to provide insight into their pathogenic potential in AS. In this review, we explore the role of ERAP 1 and 2 in the pathogenesis of AS.
Publisher: Wiley
Date: 26-04-2012
DOI: 10.1002/ART.33507
Abstract: Ankylosing spondylitis (AS) is a common inflammatory arthritis affecting primarily the axial skeleton. IL23R is genetically associated with AS. This study was undertaken to investigate and characterize the role of interleukin-23 (IL-23) signaling in AS pathogenesis. The study population consisted of patients with active AS (n = 17), patients with psoriatic arthritis (n = 8), patients with rheumatoid arthritis, (n = 9), and healthy subjects (n = 20). IL-23 receptor (IL-23R) expression in T cells was determined in each subject group, and expression levels were compared. The proportion of IL-23R-expressing T cells in the periphery was 2-fold higher in AS patients than in healthy controls, specifically driven by a 3-fold increase in IL-23R-positive γ/δ T cells in AS patients. The proportions of CD4+ and CD8+ cells that were positive for IL-17 were unchanged. This increased IL-23R expression on γ/δ T cells was also associated with enhanced IL-17 secretion, with no observable IL-17 production from IL-23R-negative γ/δ T cells in AS patients. Furthermore, γ/δ T cells from AS patients were heavily skewed toward IL-17 production in response to stimulation with IL-23 and/or anti-CD3/CD28. Recently, mouse models have shown IL-17-secreting γ/δ T cells to be pathogenic in infection and autoimmunity. Our data provide the first description of a potentially pathogenic role of these cells in a human autoimmune disease. Since IL-23 is a maturation and growth factor for IL-17-producing cells, increased IL-23R expression may regulate the function of this putative pathogenic γ/δ T cell population.
Publisher: Elsevier BV
Date: 10-2004
Publisher: Wiley
Date: 13-07-2020
DOI: 10.1002/ART.41252
Publisher: The American Association of Immunologists
Date: 15-08-2003
DOI: 10.4049/JIMMUNOL.171.4.1775
Abstract: A major group of murine NK T (NKT) cells express an invariant Vα14Jα18 TCR α-chain specific for glycolipid Ags presented by CD1d. Murine Vα14Jα18+ account for 30–50% of hepatic T cells and have potent antitumor activities. We have enumerated and characterized their human counterparts, Vα24Vβ11+ NKT cells, freshly isolated from histologically normal and tumor-bearing livers. In contrast to mice, human NKT cells are found in small numbers in healthy liver (0.5% of CD3+ cells) and blood (0.02%). In contrast to those in blood, most hepatic Vα24+ NKT cells express the Vβ11 chain. They include CD4+, CD8+, and CD4−CD8− cells, and many express the NK cell markers CD56, CD161, and/or CD69. Importantly, human hepatic Vα24+ T cells are potent producers of IFN-γ and TNF-α, but not IL-2 or IL-4, when stimulated pharmacologically or with the NKT cell ligand, α-galactosylceramide. Vα24+Vβ11+ cell numbers are reduced in tumor-bearing compared with healthy liver (0.1 vs 0.5% p & 0.04). However, hepatic cells from cancer patients and healthy donors release similar amounts of IFN-γ in response to α-galactosylceramide. These data indicate that hepatic NKT cell repertoires are phenotypically and functionally distinct in humans and mice. Depletions of hepatic NKT cell subpopulations may underlie the susceptibility to metastatic liver disease.
Publisher: Elsevier BV
Date: 02-2023
Publisher: Frontiers Media SA
Date: 10-01-2019
Publisher: Wiley
Date: 29-12-2018
DOI: 10.1002/ART.40369
Abstract: Endoplasmic reticulum aminopeptidase 1 ( ERAP ‐1) and ERAP ‐2 , encoded on chromosome 5q15, trim endogenous peptides for HLA ‐mediated presentation to the immune system. Polymorphisms in ERAP 1 and/or ERAP 2 are strongly associated with several immune‐mediated diseases with specific HLA backgrounds, implicating altered peptide handling and presentation as prerequisites for autoreactivity against an arthritogenic peptide. Given the thorough characterization of disease risk–associated polymorphisms that alter ERAP activity, this study aimed instead to interrogate the expression effect of chromosome 5q15 polymorphisms to determine their effect on ERAP isoform and protein expression. RNA sequencing and genotyping across chromosome 5q15 were performed to detect genetic variants in ERAP 1 and ERAP 2 associated with altered total gene and isoform‐specific expression. The functional implication of a putative messenger RNA splice‐altering variant on ERAP ‐1 protein levels was validated using mass spectrometry. Polymorphisms associated with ankylosing spondylitis ( AS ) significantly influenced the transcript and protein expression of ERAP‐1 and ERAP‐2. Disease risk–associated polymorphisms in and around both genes were also associated with increased gene expression. Furthermore, key risk‐associated ERAP 1 variants were associated with altered transcript splicing, leading to allele‐dependent alternate expression of 2 distinct isoforms and significant differences in the type of ERAP ‐1 protein produced. In accordance with studies demonstrating that polymorphisms that increase aminopeptidase activity predispose to immune disease, the increased risk also attributed to increased expression of ERAP 1 and ERAP 2 supports the notion of using aminopeptidase inhibition to treat AS and other ERAP ‐associated conditions.
Publisher: Public Library of Science (PLoS)
Date: 05-03-2015
Publisher: Springer Science and Business Media LLC
Date: 19-09-2016
DOI: 10.1007/S11926-016-0612-X
Abstract: Ankylosing spondylitis (AS) is a highly heritable disease for which there is a great unmet need for improved therapies. Genetics research has identified several major pathways involved in the disease, from which treatments have either now entered clinical practice or are in development. In particular, therapies targeting the IL-23 pathway were repositioned for use in AS following the discovery of multiple genes in the pathway as determinants of AS risk. Discovery of the association of aminopeptidase genes with AS, and subsequently with psoriasis, inflammatory bowel disease and other conditions, has triggered research into therapies targeting this pathway. The AS-genetic associations point to involvement of gut mucosal immunity in driving disease, and metagenomic studies have provided strong support that AS is a disease driven by interaction between the gut microbiome and host immune system, providing a rationale for the exploration of gut-targeted therapies for the disease.
Publisher: MDPI AG
Date: 07-10-2020
DOI: 10.3390/V12101137
Abstract: Dengue, chikungunya and Zika viruses share similar disease features, rendering them difficult to distinguish clinically. Incapacitating arthralgia/arthritis is a specific manifestation associated with chikungunya virus infection. However, the profile of arthralgia/arthritis in Zika virus (ZIKV) cases has not been well characterized. Articles were extracted from PubMed and Scopus databases reporting original data from patients with arthralgia/arthritis, according to the Cochrane Collaboration. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, 137 articles reporting ZIKV-associated joint symptoms were reviewed. Arthralgia was more frequently reported (n = 124 from case studies, n = 1779 from population-based studies) than arthritis (n = 7 and n = 121, respectively). Arthralgia was resolved in week in 54%, and within 1–2 weeks in 40% of cases. The meta-analysis of cases in population-based studies identified a pooled prevalence of 53.55% for arthralgia. The pooled prevalence of arthralgia/arthritis during outbreaks depended on the geographic location, with a higher joint symptom burden observed in the Americas compared to South East Asia (Brazil: 60.79% Puerto Rico: 68.89% and South East Asia: 26.46%). We conclude that non-specific constitutional arthralgia is the most common joint manifestation during ZIKV infection, being present in nearly half of cases but resolving by two weeks in % of these. We found no evidence of chronic rheumatic manifestations following ZIKV infection.
Publisher: Springer Science and Business Media LLC
Date: 11-12-2013
Abstract: The proinflammatory cytokine IL-17 has an important role in pathogenesis of several inflammatory diseases. In immune-mediated joint diseases, IL-17 can induce secretion of other proinflammatory cytokines such as IL-1, IL-6 and TNF, as well as matrix metalloproteinase enzymes, leading to inflammation, cartilage breakdown, osteoclastogenesis and bone erosion. In animal models of inflammatory arthritis, mice deficient in IL-17 are less susceptible to development of disease. The list of IL-17-secreting cells is rapidly growing, and mast cells have been suggested to be a dominant source of IL-17 in inflammatory joint disease. However, many other innate sources of IL-17 have been described in both inflammatory and autoinflammatory conditions, raising questions as to the role of mast cells in orchestrating joint inflammation. This article will critically assess the contribution of mast cells and other cell types to IL-17 production in the inflammatory milieu associated with inflammatory arthritis, understanding of which could facilitate targeted therapeutic approaches.
Publisher: Springer Science and Business Media LLC
Date: 03-2022
Publisher: Wiley
Date: 18-07-2006
DOI: 10.1002/IJC.22019
Abstract: There is an increasing awareness of the therapeutic potential for combining immune-based therapies with chemotherapy in the treatment of malignant diseases, but few published studies evaluate possible cytotoxic synergies between chemotherapy and cytotoxic immune cells. Human V alpha 24+/V beta 11+ NKT cells are being evaluated for use in cell-based immunotherapy of malignancy because of their immune regulatory functions and potent cytotoxic potential. In this study, we evaluated the cytotoxicity of combinations of chemotherapy and NKT cells to determine whether there is a potential to combine these treatment modalities for human cancer therapy. The cytotoxicity of NKT cells was tested against solid-tumor derived cell lines NCI-H358, DLD-1, HT-29, DU-145, TSU-Pr1 and MDA-MB231, with or without prior treatment of these target cells, with a range of chemotherapy agents. Low concentrations of chemotherapeutic agents led to sensitization of cell lines to NKT-mediated cytotoxicity, with the greatest effect being observed for prostate cancer cells. Synergistic cytotoxicity occurred in an NKT cell in a dose-dependent manner. Chemotherapy agents induced upregulation of cell surface TRAIL-R2 (DR5) and Fas (CD95) expression, increasing the capacity for NKT cells to recognize and kill via TRAIL- and FasL-mediated pathways. We conclude that administration of cytotoxic immune cells after chemotherapy may increase antitumor activities in comparison with the use of either treatment alone.
Publisher: Springer Science and Business Media LLC
Date: 19-04-2005
Publisher: Springer Science and Business Media LLC
Date: 10-05-2014
DOI: 10.1007/S10067-014-2664-5
Abstract: The purpose of this study is to review the potential causal role of the microbiome in the pathogenesis of spondyloarthritis. The method used for the study is literature review. The microbiome plays a major role in educating the immune response. The microbiome is strongly implicated in inflammatory bowel disease which has clinical and genetic overlap with spondyloarthritis. The microbiome also plays a causal role in bowel and joint disease in HLA B27/human beta 2 microglobulin transgenic rats. The mechanism(s) by which HLA B27 could influence the microbiome is unknown but theories include an immune response gene selectivity, an effect on dendritic cell function, or a mucosal immunodeficiency. Bacteria are strongly implicated in the pathogenesis of spondyloarthritis. Studies to understand how HLA B27 affects bacterial ecosystems should be encouraged.
Publisher: BMJ
Date: 27-03-2023
Abstract: The ‘MHC-I (major histocompatibility complex class I)-opathy’ concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet’s disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is h ered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway. Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.
Publisher: Springer Science and Business Media LLC
Date: 31-01-2007
DOI: 10.1007/S00262-007-0279-2
Abstract: Combinations of cellular immune-based therapies with chemotherapy and other antitumour agents may be of significant clinical benefit in the treatment of many forms of cancer. Gamma delta (gammadelta) T cells are of particular interest for use in such combined therapies due to their potent antitumour cytotoxicity and relative ease of generation in vitro. Here, we demonstrate high levels of cytotoxicity against solid tumour-derived cell lines with combination treatment utilizing Vgamma9Vdelta2 T cells, chemotherapeutic agents and the bisphosphonate, zoledronate. Pre-treatment with low concentrations of chemotherapeutic agents or zoledronate sensitized tumour cells to rapid killing by Vgamma9Vdelta2 T cells with levels of cytotoxicity approaching 90%. In addition, zoledronate enhanced the chemotherapy-induced sensitization of tumour cells to Vgamma9Vdelta2 T cell cytotoxicity resulting in almost 100% lysis of tumour targets in some cases. Vgamma9Vdelta2 T cell cytotoxicity was mediated by perforin following TCR-dependent and isoprenoid-mediated recognition of tumour cells. Production of IFN-gamma by Vgamma9Vdelta2 T cells was also induced after exposure to sensitized targets. We conclude that administration of Vgamma9Vdelta2 T cells at suitable intervals after chemotherapy and zoledronate may substantially increase antitumour activities in a range of malignancies.
Publisher: OMICS Publishing Group
Date: 04-2013
DOI: 10.2217/IJR.12.84
Publisher: Public Library of Science (PLoS)
Date: 24-03-2011
Publisher: Springer Science and Business Media LLC
Date: 06-10-2016
Abstract: Ankylosing spondylitis (AS), an immune-mediated arthritis, is the prototypic member of a group of conditions known as spondyloarthropathies that also includes reactive arthritis, psoriatic arthritis and enteropathic arthritis. Patients with these conditions share a clinical predisposition for spinal and pelvic joint dysfunction, as well as genetic associations, notably with HLA-B(*)27. Spondyloarthropathies are characterized by histopathological inflammation in entheses (regions of high mechanical stress where tendons and ligaments insert into bone) and in the subchondral bone marrow, and by abnormal osteoproliferation at involved sites. The association of AS with HLA-B(*)27, first described >40 years ago, led to hope that the cause of the disease would be rapidly established. However, even though many theories have been advanced to explain how HLA-B(*)27 is involved in AS, no consensus about the answers to this question has been reached, and no successful treatments have yet been developed that target HLA-B27 or its functional pathways. Over the past decade, rapid progress has been made in discovering further genetic associations with AS that have shed new light on the aetiopathogenesis of the disease. Some of these discoveries have driven translational ideas, such as the repurposing of therapeutics targeting the cytokines IL-12 and IL-23 and other factors downstream of this pathway. AS provides an excellent ex le of how hypothesis-free research can lead to major advances in understanding pathogenesis and to the development of innovative therapeutic strategies.
Publisher: Elsevier BV
Date: 06-2095
DOI: 10.1038/JID.2010.17
Abstract: Keratinocytes expressing tumor or viral antigens can be eliminated by antigen-primed CD8 cytotoxic T cells. CD4 T-helper cells help induction of CD8 cytotoxic T cells from naive precursors and generation of CD8 T-cell memory. In this study, we show, unexpectedly, that CD4 cells are also required to assist primed CD8 effector T cells in rejection of skin expressing human growth hormone, a neo-self-antigen, in keratinocytes. The requirement for CD4 cells can be substituted by CD40 costimulation. Rejection of skin expressing ovalbumin (OVA), a non-self-antigen, by primed CD8 cytotoxic T cells can in contrast occur without help from antigen-specific CD4 T cells. However, rejection of OVA expressing keratinocytes is helped by antigen-specific CD4 T cells if only low numbers of primed or naive OVA-specific CD8 T cells are available. Effective immunotherapy directed at antigens expressed in squamous cancer may therefore be facilitated by induction of tumor antigen-specific CD4 helper T cells, as well as cytotoxic CD8 T cells.
Publisher: Springer Science and Business Media LLC
Date: 03-2014
DOI: 10.1038/NATURE13182
Publisher: Wiley
Date: 2022
DOI: 10.1002/CTI2.1400
Abstract: The complexity of the cellular and acellular players within the tumor microenvironment (TME) allows for significant variation in TME constitution and role in anticancer treatment response. Spatial alterations in populations of tumor cells and adjacent non‐malignant cells, including endothelial cells, fibroblasts and tissue‐infiltrating immune cells, often have a major role in determining disease progression and treatment response in cancer. Many current standard systemic antineoplastic treatments target the cancer cells and could be further refined to directly target commonly dysregulated cell populations of the TME. Recent developments in immuno‐oncology and bioengineering have created an attractive potential to model these complexities at the level of the in idual patient. These developments, along with the increasing momentum in precision medicine research and application, have catalysed exciting new discoveries in understanding drug–TME interactions, target identification, and improved efficacy of therapies. While rapid progress has been made, there are still many challenges to overcome in the development of accurate in vitro, in vivo and ex vivo models incorporating the cellular interactions that take place in the TME. In this review, we describe how advances in immuno‐oncology and patient‐derived models, such as patient‐derived organoids and explant cultures, have enhanced the landscape of personalised immunotherapy prediction and treatment of solid organ malignancies. We describe and compare different immunological targets and perspectives on two‐dimensional and three‐dimensional modelling approaches that may be used to better rationalise immunotherapy use, ultimately providing a knowledge base for the integration of the autologous TME into these predictive models.
Publisher: Cold Spring Harbor Laboratory
Date: 17-12-2021
DOI: 10.1101/2021.12.16.21267808
Abstract: Ankylosing Spondylitis (AS) is a highly heritable inflammatory arthritis which occurs more frequently in men than women. In their recent publication examining sex differences in the genetic aetiology of common complex traits and diseases, Bernabeu et al. (2021) observe differences in heritability of AS between sexes, and a genome-wide significant genotype by sex interaction in risk of AS at the major histocompatability (MHC) locus 1 . The authors then present evidence suggesting that this genotype by sex interaction arises primarily as a result of differential expression of the gene MICA across the sexes in skeletal muscle tissue. Through a series of conditional association analyses in the UK Biobank, reanalysis of the GTEx gene expression resource and RNASeq experiments on peripheral blood cells from AS cases and controls, we show that the genotype by sex interaction the authors’ report is unlikely to be a result of variation in MICA , but probably reflects a known interaction between the HLA-B gene, sex and risk of AS. We demonstrate that the diagnostic accuracy of AS in the UK Biobank is low, particularly amongst women, likely explaining some of the observed differences in heritability across the sexes and the difficulty in precisely locating association signals in the cohort.
Publisher: Wiley
Date: 13-07-2004
Abstract: T cells expressing NK cell receptors (NKR) display rapid MHC-unrestricted cytotoxicity and potent cytokine secretion and are thought to play roles in immunity against tumors. We have quantified and characterized NKR+ T cells freshly isolated from epithelial and lamina propria layers of duodenum and colon from 16 in iduals with no evidence of gastrointestinal disease and from tumor and uninvolved tissue from 19 patients with colorectal cancer. NKR+ T cell subpopulations were differentially distributed in different intestinal compartments, and CD161+ T cells accounted for over one half of T cells at all locations tested. Most intestinal CD161+ T cells expressed alpha beta TCR and either CD4 or CD8. Significant proportions expressed HLA-DR,CD69 and Fas ligand. Upon stimulation in vitro, CD161+ T cells produced IFN-gamma and TNF-alpha but not IL-4. NKT cells expressing the Valpha24Vbeta11 TCR, which recognizes CD1d,were virtually absent from the intestine, but colonic cells produced IFN-gamma in response to the NKT cell agonist ligand alpha-galactosylceramide. NKR+ T cells were not expanded in colonic tumors compared to adjacent uninvolved tissue. The predominance, heterogeneity and differential distribution of NKR+ T cells at different intestinal locations suggests that they are central to intestinal immunity.
Publisher: American Chemical Society (ACS)
Date: 10-08-2004
DOI: 10.1021/JA047649E
Abstract: Photodynamic therapy (PDT) is an emerging treatment modality for a range of disease classes, both cancerous and noncancerous. This has brought about an active pursuit of new PDT agents that can be optimized for the unique set of photophysical characteristics that are required for a successful clinical agent. We now describe a totally new class of PDT agent, the BF2-chelated 3,5-diaryl-1H-pyrrol-2-yl-3,5-diarylpyrrol-2-ylideneamines (tetraarylazadipyrromethenes). Optimized synthetic procedures have been developed to facilitate the generation of an array of specifically substituted derivatives to demonstrate how control of key therapeutic parameters such as wavelength of maximum absorbance and singlet-oxygen generation can be achieved. Photosensitizer absorption maxima can be varied within the body's therapeutic window between 650 and 700 nm, with high extinction coefficients ranging from 75,000 to 85,000 M(-1) cm(-1). Photosensitizer singlet-oxygen generation level was modulated by the exploitation of the heavy-atom effect. An array of photosensitizers with and without bromine atom substituents gave rise to a series of compounds with varying singlet-oxygen generation profiles. X-ray structural evidence indicates that the substitution of the bromine atoms has not caused a planarity distortion of the photosensitizer. Comparative singlet-oxygen production levels of each photosensitizer versus two standards demonstrated a modulating effect on singlet-oxygen generation depending upon substituent patterns about the photosensitizer. Confocal laser scanning microscopy imaging of 18a in HeLa cervical carcinoma cells proved that the photosensitizer was exclusively localized to the cellular cytoplasm. In vitro light-induced toxicity assays in HeLa cervical carcinoma and MRC5-SV40 transformed fibroblast cancer cell lines confirmed that the heavy-atom effect is viable in a live cellular system and that it can be exploited to modulate assay efficacy. Direct comparison of the efficacy of the photosensitizers 18b and 19b, which only differ in molecular structure by the presence of two bromine atoms, illustrated an increase in efficacy of more than a 1000-fold in both cell lines. All photosensitizers have very low to nondeterminable dark toxicity in our assay system.
Publisher: The American Association of Immunologists
Date: 27-12-2010
Abstract: Memory T cells develop early during the preclinical stages of autoimmune diseases and have traditionally been considered resistant to tolerance induction. As such, they may represent a potent barrier to the successful immunotherapy of established autoimmune diseases. It was recently shown that memory CD8+ T cell responses are terminated when Ag is genetically targeted to steady-state dendritic cells. However, under these conditions, inactivation of memory CD8+ T cells is slow, allowing transiently expanded memory CD8+ T cells to exert tissue-destructive effector function. In this study, we compared different Ag-targeting strategies and show, using an MHC class II promoter to drive Ag expression in a erse range of APCs, that CD8+ memory T cells can be rapidly inactivated by MHC class II+ hematopoietic APCs through a mechanism that involves a rapid and sustained downregulation of TCR, in which the effector response of CD8+ memory cells is rapidly truncated and Ag-expressing target tissue destruction is prevented. Our data provide the first demonstration that genetically targeting Ag to a broad range of MHC class II+ APC types is a highly efficient way to terminate memory CD8+ T cell responses to prevent tissue-destructive effector function and potentially established autoimmune diseases.
Publisher: Springer Science and Business Media LLC
Date: 29-08-2017
Abstract: In the FANTOM5 project, transcription initiation events across the human and mouse genomes were mapped at a single base-pair resolution and their frequencies were monitored by CAGE (Cap Analysis of Gene Expression) coupled with single-molecule sequencing. Approximately three thousands of s les, consisting of a variety of primary cells, tissues, cell lines, and time series s les during cell activation and development, were subjected to a uniform pipeline of CAGE data production. The analysis pipeline started by measuring RNA extracts to assess their quality, and continued to CAGE library production by using a robotic or a manual workflow, single molecule sequencing, and computational processing to generate frequencies of transcription initiation. Resulting data represents the consequence of transcriptional regulation in each analyzed state of mammalian cells. Non-overlapping peaks over the CAGE profiles, approximately 200,000 and 150,000 peaks for the human and mouse genomes, were identified and annotated to provide precise location of known promoters as well as novel ones, and to quantify their activities.
Publisher: Springer Science and Business Media LLC
Date: 2013
DOI: 10.1186/AR4228
Publisher: Public Library of Science (PLoS)
Date: 18-12-2015
Publisher: The American Association of Immunologists
Date: 15-12-2012
Abstract: Adoptive T cell therapy uses the specificity of the adaptive immune system to target cancer and virally infected cells. Yet the mechanism and means by which to enhance T cell function are incompletely described, especially in the skin. In this study, we use a murine model of immunotherapy to optimize cell-mediated immunity in the skin. We show that in vitro–derived central but not effector memory-like T cells bring about rapid regression of skin-expressing cognate Ag as a transgene in keratinocytes. Local inflammation induced by the TLR7 receptor agonist imiquimod subtly yet reproducibly decreases time to skin graft rejection elicited by central but not effector memory T cells in an immunodeficient mouse model. Local CCL4, a chemokine liberated by TLR7 agonism, similarly enhances central memory T cell function. In this model, IL-2 facilitates the development in vivo of effector function from central memory but not effector memory T cells. In a model of T cell tolerogenesis, we further show that adoptively transferred central but not effector memory T cells can give rise to successful cutaneous immunity, which is dependent on a local inflammatory cue in the target tissue at the time of adoptive T cell transfer. Thus, adoptive T cell therapy efficacy can be enhanced if CD8+ T cells with a central memory T cell phenotype are transferred, and IL-2 is present with contemporaneous local inflammation.
Publisher: Wiley
Date: 14-09-2023
DOI: 10.1002/RMV.2477
Publisher: Springer Science and Business Media LLC
Date: 02-06-2021
DOI: 10.1038/S41467-021-23143-7
Abstract: Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism.
Publisher: Elsevier
Date: 2017
Publisher: Springer Science and Business Media LLC
Date: 03-2014
DOI: 10.1038/NBT.2840
Publisher: Springer Science and Business Media LLC
Date: 07-07-2022
DOI: 10.1186/S13075-022-02853-3
Abstract: Multiple studies have confirmed dysbiosis in ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) however, due to methodological differences across studies, it has not been possible to determine if these diseases have similar or different gut microbiomes. In this study, faecal and intestinal biopsies were obtained from 33 Australian AS patients (including 5 with concomitant IBD, ‘AS-IBD’), 59 IBD patients and 105 healthy controls. Stool s les were also obtained from 16 Italian AS patients and 136 Swedish AS patients. Focusing on the Australian cohort, AS, AS-IBD and IBD patients differed from one another and from healthy controls in both alpha and beta ersity. AS patients with and without clinical IBD could be distinguished from one another with moderate accuracy using stool microbiome (AUC=0.754). Stool microbiome also accurately distinguished IBD patients from healthy controls (AUC=0.757). Microbiome composition was correlated with disease activity measured by BASDAI and faecal calprotectin (FCP) levels. Enrichment of potentially pathogenic Streptococcus was noted in AS, AS-IBD and IBD patients. Furthermore, enrichment of another potentially pathogenic genus, Haemophilus , was observed in AS, AS-IBD, IBD, AS patients with increased BASDAI, and IBD patients with faecal calprotectin μg/mg. Apart from these genera, no other taxa were shared between AS and IBD patients. In conclusion, the distinct gut microbiome of AS and AS-IBD patients compared to IBD patients and healthy controls is consistent with immunological and genetic evidence suggesting that the gut plays a different role in driving AS compared with IBD. However, enrichment of two potentially pathogenic genera in both diseases suggests that the presence of a shared/common microbial trigger of disease cannot be discounted.
Publisher: Springer Science and Business Media LLC
Date: 15-06-2017
DOI: 10.1038/GENE.2017.11
Abstract: Ankylosing spondylitis (AS) is a common immune-mediated arthropathy primarily affecting the spine and pelvis. Most AS patients have subclinical intestinal inflammation, suggesting the gut microbiome and the immune response play a role in pathogenesis. Susceptibility to AS is primarily genetic, and at least 114 susceptibility variants have been identified to date. We applied bioinformatic methods utilizing epigenetic and gene and protein expression data to identify the cell types through which AS-associated variants operate. Variants were enriched in transcriptionally regulated regions in monocytes, CD4
Publisher: Frontiers Media SA
Date: 08-06-2022
DOI: 10.3389/FGENE.2022.913196
Abstract: Systemic sclerosis (SSc) is an autoinflammatory, fibrotic condition of unknown aetiology. The presence of detectable autoantibodies against erse nuclear antigens, as well as strong HLA associations with disease, suggest autoimmune involvement, however the links between endogenous and exogenous risk factors and SSc pathology remain undetermined. We have conducted a genetic analysis of HLA inheritance in two independent and meta-analysed cohorts of 1,465 SSc cases and 13,273 controls, including stratified association analyses in clinical and autoantibody positive subgroups of disease. Additionally, we have used patient genotypes to impute gene dosages across the KIR locus, encoding paired activating and inhibitory lymphocyte receptors for Class I HLA ligands, to conduct the largest analysis of KIR-HLA epistatic interactions in SSc to date. We confirm previous Class II HLA associations with SSc risk and report a new Class I association with haplotype HLA-B*44:03-HLA-C*16:01 at genome-wide significance (GWS). We further report statistically significant HLA associations with clinical and serological subtypes of disease through direct case-case comparison, and report a new association of HLA-DRB1*15:01 , previously shown to bind topoisomerase-1 derived peptides, with anti-topoisomerase (ATA) positive disease. Finally, we identify genetic epistasis between KIRs and HLA class I ligands, suggesting genetic modulation of lymphocyte activation may further contribute to an in idual’s underlying disease risk. Taken together, these findings support future functional investigation into endogenous immunological and environmental stimuli for disrupted immune tolerance in SSc.
Publisher: BMJ
Date: 06-2021
DOI: 10.1136/BMJOPEN-2020-044463
Abstract: The perinatal–postnatal family environment is associated with childhood outcomes including impacts on physical and mental health and educational attainment. Family longitudinal cohort studies collect in-depth data that can capture the influence of an era on family lifestyle, mental health, chronic disease, education and financial stability to enable identification of gaps in society and provide the evidence for changes in government in policy and practice. The Queensland Family Cohort (QFC) is a prospective, observational, longitudinal study that will recruit 12 500 pregnant families across the state of Queensland (QLD), Australia and intends to follow-up families and children for three decades. To identify the immediate and future health requirements of the QLD population pregnant participants and their partners will be enrolled by 24 weeks of gestation and followed up at 24, 28 and 36 weeks of gestation, during delivery, on-ward, 6 weeks postpartum and then every 12 months where questionnaires, biological s les and physical measures will be collected from parents and children. To examine the impact of environmental exposures on families, data related to environmental pollution, household pollution and employment exposures will be linked to pregnancy and health outcomes. Where feasible, data linkage of state and federal government databases will be used to follow the participants long term. Biological s les will be stored long term for future discoveries of biomarkers of health and disease. Ethical approval has been obtained from the Mater Research Ethics (HREC/16/MHS/113). Findings will be reported to (1) QFC participating families (2) funding bodies, institutes and hospitals supporting the QFC (3) federal, state and local governments to inform policy (4) presented at local, national and international conferences and (5) disseminated by peer-review publications.
Publisher: Springer Science and Business Media LLC
Date: 24-08-2017
DOI: 10.1038/GENE.2017.19
Abstract: Tumor necrosis factor-α (TNF-α) inhibitors are highly effective in suppressing inflammation in ankylosing spondylitis (AS) patients, and operate by suppression of TFN-α and downstream immunological pathways. To determine the mechanisms of action of TNF-α inhibitors in AS patients, we used transcriptomic and bioinformatic approaches on peripheral blood mononuclear cells from AS patients pre and post treatment. We found 656 differentially expressed genes, including the genome-wide significant AS-associated genes, IL6R, NOTCH1, IL10, CXCR2 and TNFRSF1A. A distinctive gene expression profile was found between male and female patients, mainly because of sex chromosome-linked genes and interleukin 17 receptor C, potentially accounting for the differences in clinical manifestation and treatment response between the genders. In addition to immune and inflammation regulatory pathways, like intestinal immune network for IgA production, cytokine-cytokine receptor interaction, Ras signaling pathway, allograft rejection and hematopoietic cell lineage, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses revealed that infection-associated pathways (influenza A and toxoplasmosis) and metabolism-associated pathways were involved in response to TNF-α inhibitor treatment, providing insight into the mechanism of TNF-α inhibitors.
Publisher: The American Association of Immunologists
Date: 15-11-2003
Publisher: Elsevier BV
Date: 05-2019
DOI: 10.1016/J.HUMIMM.2018.11.002
Abstract: The oxytocinase subfamily of M1 aminopeptidases plays an important role in processing and trimming of peptides for presentation on major histocompatibility (MHC) Class I molecules. Several large-scale genomic studies have identified association of members of this family of enzymes, most notably ERAP1 and ERAP2, with immune-mediated diseases including ankylosing spondylitis, psoriasis and birdshot chorioretinopathy. Much is now known about the genetics of these enzymes and how genetic variants alter their function, but how these variants contribute to disease remains largely unresolved. Here we discuss what is known about their structure and function and highlight some of the knowledge gaps that affect development of drugs targeting these enzymes.
Publisher: Proceedings of the National Academy of Sciences
Date: 17-07-2017
Abstract: Life-threatening susceptibility to common respiratory infections in previously healthy children can be indicative of pathogen-specific primary immunodeficiencies due to rare deleterious variants in key genes and pathways of the immune system. These findings have implications for prevention and treatment of susceptible children.
Publisher: Springer Science and Business Media LLC
Date: 30-05-2017
Publisher: Frontiers Media SA
Date: 17-08-2017
Publisher: Springer Science and Business Media LLC
Date: 2023
Publisher: BMJ
Date: 13-05-2020
DOI: 10.1136/ANNRHEUMDIS-2020-217309
Abstract: The human enthesis conventional T cells are poorly characterised. To study the biology of the conventional T cells in human enthesis. CD4+ and CD8+ T cells were investigated in 25 enthesis s les using immunofluorescence, cytometrically, bulk RNAseq and quantitative real-time PCR following anti-CD3/CD28 bead stimulation to determine interleukin (IL)-17A and tumour necrosis factor (TNF) levels. T-cell receptor (TCR) repertoires were characterised and a search for putative T-cell reactivity was carried out using TCR3 database. The impact of pharmacological antagonism with retinoic acid receptor-related orphan nuclear receptor gamma t inhibitor (RORγti), methotrexate and phosphodiesterase type 4 inhibitor (PDE4i) was investigated. Immunofluorescence and cytometry suggested entheseal resident CD4+ and CD8+ T cells with a resident memory phenotype (CD69+/CD45RA-) and tissue residency gene transcripts (higher NR4A1/AhR and lower KLF2/T-bet transcripts). Both CD4+ and CD8+ T cells showed increased expression of immunomodulatory genes including IL-10 and TGF-β compared with peripheral blood T cells with entheseal CD8+ T cells having higher CD103, CD49a and lower SIPR1 transcript that matched CD4+ T cells. Following stimulation, CD4+ T cells produced more TNF than CD8+ T cells and IL-17A was produced exclusively by CD4+ T cells. RNAseq suggested both Cytomegalovirus and influenza A virus entheseal resident T-cell clonotype reactivity. TNF and IL-17A production from CD4+ T cells was effectively inhibited by PDE4i, while RORγti only reduced IL-17A secretion. Healthy human entheseal CD4+ and CD8+ T cells exhibit regulatory characteristics and are predicted to exhibit antiviral reactivity with CD8+ T cells expressing higher levels of transcripts suggestive of tissue residency. Inducible IL-17A and TNF production can be robustly inhibited in vitro.
Publisher: BMJ
Date: 11-04-2016
DOI: 10.1136/JMEDGENET-2015-103647
Abstract: Acromelic dysplasias are a group of disorders characterised by short stature, brachydactyly, limited joint extension and thickened skin and comprises acromicric dysplasia (AD), geleophysic dysplasia (GD), Myhre syndrome and Weill-Marchesani syndrome. Mutations in several genes have been identified for these disorders (including latent transforming growth factor β (TGF-β)-binding protein-2 (LTBP2), ADAMTS10, ADAMSTS17 and fibrillin-1 (FBN1) for Weill-Marchesani syndrome, ADAMTSL2 for recessive GD and FBN1 for AD and dominant GD), encoding proteins involved in the microfibrillar network. However, not all cases have mutations in these genes. In iduals negative for mutations in known acromelic dysplasia genes underwent whole exome sequencing. A heterozygous missense mutation (exon 14: c.2087C>G: p.Ser696Cys) in latent transforming growth factor β (TGF-β)-binding protein-3 (LTBP3) was identified in a dominant AD family. Two distinct de novo heterozygous LTPB3 mutations were also identified in two unrelated GD in iduals who had died in early childhood from respiratory failure-a donor splice site mutation (exon 12 c.1846+5G>A) and a stop-loss mutation (exon 28: c.3912A>T: p.1304*Cysext*12). The constellation of features in these AD and GD cases, including postnatal growth retardation of long bones and lung involvement, is reminiscent of the null ltbp3 mice phenotype. We conclude that LTBP3 is a novel component of the microfibrillar network involved in the acromelic dysplasia spectrum.
Publisher: Springer Science and Business Media LLC
Date: 03-06-2019
Publisher: Public Library of Science (PLoS)
Date: 17-08-1970
Publisher: Public Library of Science (PLoS)
Date: 04-04-2019
Publisher: Springer Science and Business Media LLC
Date: 22-08-2006
DOI: 10.1007/S00262-006-0215-X
Abstract: CD1d-restricted natural killer T (NKT) cells expressing invariant Valpha14Jalpha18 T cell receptor alpha-chains are abundant in murine liver and are implicated in the control of malignancy, infection and autoimmunity. Invariant NKT cells have potent anti-metastatic effects in mice and phase I clinical trials involving their homologues in humans are ongoing. However, invariant NKT cells are less abundant in human liver ( approximately 0.5% of hepatic T cells) than in murine liver (up to 50%) and it is not known if other hepatic T cells are CD1-restricted. We have examined expression of CD1a, CD1b, CD1c and CD1d mRNA and protein in human liver and evaluated the reactivity of mononuclear cells (MNC) from histologically normal and tumour-bearing human liver specimens against these CD1 isoforms. Messenger RNA for all CD1 isotypes was detectable in all liver s les. CD1c and CD1d were expressed at the protein level by hepatic MNC. CD1d, only, was detectable at the cell surface, but CD1c and CD1d were found at an intracellular location in significant numbers of liver MNC. CD1b was not expressed by MNC from healthy livers but was detectable within MNC in all tumour s les tested. Hepatic T cells exhibited reactivity against C1R cells expressing transfected CD1c and CD1d, but neither CD1a nor CD1b. These cells secreted interferon-gamma (IFN-gamma) but not interleukin-4 (IL-4) upon stimulation. In contrast, similar numbers of peripheral T cells released 13- and 16-fold less IFN-gamma in response to CD1c and CD1d, respectively. CD1c and CD1d expression and T cell reactivity were not altered in tumour-bearing liver specimens compared to histologically normal livers. These data suggest that, in addition to invariant CD1d-restricted NKT cells, autoreactive T cells that recognise CD1c and CD1d and release inflammatory cytokines are abundant in human liver.
Publisher: Wiley
Date: 25-02-2015
DOI: 10.1002/ART.38967
Abstract: Ankylosing spondylitis (AS) is a common, highly heritable immune-mediated arthropathy that occurs in genetically susceptible in iduals exposed to an unknown but likely ubiquitous environmental trigger. There is a close relationship between the gut and spondyloarthritis, as exemplified in patients with reactive arthritis, in whom a typically self-limiting arthropathy follows either a gastrointestinal or urogenital infection. Microbial involvement in AS has been suggested however, no definitive link has been established. The aim of this study was to determine whether the gut in patients with AS carries a distinct microbial signature compared with that in the gut of healthy control subjects. Microbial profiles for terminal ileum biopsy specimens obtained from patients with recent-onset tumor necrosis factor antagonist-naive AS and from healthy control subjects were generated using culture-independent 16S ribosomal RNA gene sequencing and analysis techniques. Our results showed that the terminal ileum microbial communities in patients with AS differ significantly (P < 0.001) from those in healthy control subjects, driven by a higher abundance of 5 families of bacteria (Lachnospiraceae [P = 0.001], Ruminococcaceae [P = 0.012], Rikenellaceae [P = 0.004], Porphyromonadaceae [P = 0.001], and Bacteroidaceae [P = 0.001]) and a decrease in the abundance of 2 families of bacteria (Veillonellaceae [P = 0.01] and Prevotellaceae [P = 0.004]). We show evidence for a discrete microbial signature in the terminal ileum of patients with AS compared with healthy control subjects. The microbial composition was demonstrated to correlate with disease status, and greater differences were observed between disease groups than within disease groups. These results are consistent with the hypothesis that genes associated with AS act, at least in part, through effects on the gut microbiome.
Publisher: Frontiers Media SA
Date: 02-12-2020
Publisher: American Society of Hematology
Date: 15-02-2008
DOI: 10.1182/BLOOD-2007-07-103200
Abstract: Antigen stimulation of naive T cells in conjunction with strong costimulatory signals elicits the generation of effector and memory populations. Such terminal differentiation transforms naive T cells capable of differentiating along several terminal pathways in response to pertinent environmental cues into cells that have lost developmental plasticity and exhibit heightened responsiveness. Because these cells exhibit little or no need for the strong costimulatory signals required for full activation of naive T cells, it is generally considered memory and effector T cells are released from the capacity to be inactivated. Here, we show that steady-state dendritic cells constitutively presenting an endogenously expressed antigen inactivate fully differentiated memory and effector CD8+ T cells in vivo through deletion and inactivation. These findings indicate that fully differentiated effector and memory T cells exhibit a previously unappreciated level of plasticity and provide insight into how memory and effector T-cell populations may be regulated.
Publisher: Springer Science and Business Media LLC
Date: 11-01-0007
No related grants have been discovered for Tony Kenna.