ORCID Profile
0000-0002-1989-2024
Current Organisation
James Cook University
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Springer Science and Business Media LLC
Date: 07-2002
Publisher: The American Association of Immunologists
Date: 04-2011
Abstract: Allelic variation of SLAM expression on CD4+CD8+ thymocytes has been proposed to play a major role in NKT cell development. In this article, this hypothesis is tested by the production of subcongenic mouse strains and Slamf1 transgenic lines. The long isoform of the C57BL/6 allele of Slamf1 was transgenically expressed on CD4+CD8+ thymocytes under control of an hCD2 minigene. NOD.Nkrp1b.Tg(Slamf1)1 mice, which had a 2-fold increase in SLAM protein expression on CD4+CD8+ thymocytes, had a 2-fold increase in numbers of thymic NKT cells. The additional thymic NKT cells in NOD.Nkrp1b.Tg(Slamf1)1 mice were relatively immature, with a similar subset distribution to those of congenic NOD.Nkrp1b.Nkt1 and NOD.Nkrp1b.Slamf1 mice, which also express increased levels of SLAM on CD4+CD8+ thymocytes and produce larger numbers of NKT cells. Transgenic enhancement of SLAM expression also increased IL-4 and IL-17 production in response to TCR-mediated stimulation. Paradoxically, NOD.Nkrp1b.Tg(Slamf1)2 mice, which had a 7-fold increase in SLAM expression, showed no significant increase in NKT cells numbers on the contrary, at high transgene copy number, SLAM expression levels correlated inversely with NKT cell numbers, consistent with a contribution to negative selection. These data confirm a role for SLAM in controlling NKT cell development and are consistent with a role in both positive and negative thymic selection of NKT cells.
Publisher: Elsevier
Date: 2013
Publisher: The American Association of Immunologists
Date: 09-2008
DOI: 10.4049/JIMMUNOL.181.5.3400
Abstract: Type 1 NKT cells play a critical role in controlling the strength and character of adaptive and innate immune responses. We have previously reported deficiencies in the numbers and function of NKT cells in the NOD mouse strain, which is a well-validated model of type 1 diabetes and systemic lupus erythematosus. Genetic control of thymic NKT cell numbers was mapped to two linkage regions: Nkt1 on distal chromosome 1 and Nkt2 on chromosome 2. Herein, we report the production and characterization of a NOD.Nkrp1b.Nkt2bb congenic mouse strain, which has increased thymic and peripheral NKT cells, a decreased incidence of type 1 diabetes, and enhanced cytokine responses in vivo and increased proliferative responses in vitro following challenge with α-galactosylceramide. The 19 highly differentially expressed candidate genes within the congenic region identified by microarray expression analyses included Pxmp4. This gene encodes a peroxisome-associated integral membrane protein whose only known binding partner is Pex19, an intracellular chaperone and component of the peroxisomal membrane insertion machinery encoded by a candidate for the NKT cell control gene Nkt1. These findings raise the possibility that peroxisomes play a role in modulating glycolipid availability for CD1d presentation, thereby influencing NKT cell function.
Publisher: Life Science Alliance, LLC
Date: 09-06-2020
Abstract: At least 200 single-nucleotide polymorphisms (SNPs) are associated with multiple sclerosis (MS) risk. A key function that could mediate SNP-encoded MS risk is their regulatory effects on gene expression. We performed microarrays using RNA extracted from purified immune cell types from 73 untreated MS cases and 97 healthy controls and then performed Cis expression quantitative trait loci mapping studies using additive linear models. We describe MS risk expression quantitative trait loci associations for 129 distinct genes. By extending these models to include an interaction term between genotype and phenotype, we identify MS risk SNPs with opposing effects on gene expression in cases compared with controls, namely, rs2256814 MYT1 in CD4 cells (q = 0.05) and rs12087340 RF00136 in monocyte cells (q = 0.04). The rs703842 SNP was also associated with a differential effect size on the expression of the METTL21B gene in CD8 cells of MS cases relative to controls (q = 0.03). Our study provides a detailed map of MS risk loci that function by regulating gene expression in cell types relevant to MS.
Publisher: Springer Science and Business Media LLC
Date: 06-03-2015
DOI: 10.1038/NCOMMS7436
Abstract: Tight control of T follicular helper (Tfh) cells is required for optimal maturation of the germinal centre (GC) response. The molecular mechanisms controlling Tfh-cell differentiation remain incompletely understood. Here we show that microRNA-146a (miR-146a) is highly expressed in Tfh cells and peak miR-146a expression marks the decline of the Tfh response after immunization. Loss of miR-146a causes cell-intrinsic accumulation of Tfh and GC B cells. MiR-146a represses several Tfh-cell-expressed messenger RNAs, and of these, ICOS is the most strongly cell autonomously upregulated target in miR-146a-deficient T cells. In addition, miR-146a deficiency leads to increased ICOSL expression on GC B cells and antigen-presenting cells. Partial blockade of ICOS signalling, either by injections of low dose of ICOSL blocking antibody or by halving the gene dose of Icos in miR-146a-deficient T cells, prevents the Tfh and GC B-cell accumulation. Collectively, miR-146a emerges as a post-transcriptional brake to limit Tfh cells and GC responses.
Publisher: Springer Science and Business Media LLC
Date: 12-2001
DOI: 10.1007/S00251-001-0391-Y
Abstract: BALB/c mice thymectomized on their third day of life develop a high incidence of experimental autoimmune gastritis (EAG) which closely resembles human chronic atrophic (type A, autoimmune) gastritis. Linkage analysis of (BALB/cCrSlcxC57BL/6)F2 mice previously demonstrated that the Gasa1 and Gasa2 genes on distal Chromosome (Chr) 4 have major effects on the development of EAG in this murine model, while other loci displayed a trend towards linkage. Here, we implemented partitioned chi(2)-analysis in order to develop a better understanding of the genotypes contributing to susceptibility and resistance at each linkage region. This approach revealed that linkage of Gasa1 and Gasa2 to EAG was due to codominant and recessive BALB/cCrSlc alleles, respectively. To identify additional EAG susceptibility genes, separate linkage studies were performed on Gasa1 heterozygotes and Gasa2 C57BL/6 homozygotes plus heterozygotes so as to minimize the effects of these disease genes. The enhanced sensitivity of these analyses confirmed the existence of a third EAG susceptibility gene (designated Gasa3) on Chr 6. Epistatic interactions between the Gasa2 EAG susceptibility gene and the H2 were also identified, and the presence of an H2-linked susceptibility gene (Gasa4) confirmed by analysis of H2 congenic mice.
Publisher: Elsevier BV
Date: 03-2010
DOI: 10.1016/J.BIOPSYCH.2009.11.004
Abstract: Accumulating evidence suggests the involvement of inflammatory processes and cytokines in particular in the pathophysiology of major depression (MDD) and resistance to antidepressant treatment. Furthermore, amygdala and anterior cingulate cortex (ACC) responsiveness to emotional stimuli has been suggested as a predictor of treatment response. This study investigated the association between genetic variants of the interleukin 1 beta (IL1B) gene and amygdala and ACC responsiveness to emotional stimuli and response to antidepressant treatment. In this analysis, 256 Caucasian patients with MDD (145 women, 111 men) were genotyped for variants rs16944, rs1143643, and rs1143634 in the IL1B gene (2q14). Response to antidepressant treatment over 6 weeks was defined as remission ( 50% decrease on Hamilton Rating Scale for Depression-21-question). Brain activity under visual presentation of emotional faces was assessed in a subs le of 32 depressed patients by means of functional magnetic resonance imaging at 3 T. Pharmacogenetic analyses show significant associations of the GG genotypes of single nucleotide polymorphisms (SNPs) rs16944 (odds ratio = 1.74 95% confidence interval 1.2-4.3) and rs1143643 (odds ratio = 3.1 95% confidence interval 1.3-7.8) (compared with the AA genotype) with nonremission after 6 weeks. The imaging analyses show that the number of G-alleles in both SNPs (rs16944 and rs1143643) was associated with reduced responsiveness of the amygdala and ACC to emotional stimulation. The present study suggests a negative effect of the IL1B gene on pharmacological response and amygdala and ACC function involving the same genotypes of two SNPs (rs16944, rs116343), which taken together increase the risk of nonremission over 6 weeks of antidepressant treatment in MDD.
Publisher: IntechOpen
Date: 29-06-2022
DOI: 10.5772/INTECHOPEN.105681
Abstract: Multiple sclerosis (MS) is an autoimmune disease in which discrete central nervous system lesions result from perivascular immune cell infiltration associated with damage to myelin (demyelination), oligodendrocytes and neurons. This culminates in debilitating neurological symptoms, primarily affecting women in their child-bearing years. Both the innate and adaptive branches of the immune system have been implicated in disease initiation and progression, and although the underlying cause remains elusive, there is compelling evidence for a complex interaction between genetic and environmental factors, leading to inflammation and neurodegeneration. Both direct cellular toxicity and antibody-dependent cellular cytotoxicity (ADCC) involving several cell types have been identified in playing major roles. These cells and their interactions in the pathogenesis of MS will be discussed.
Publisher: Springer Science and Business Media LLC
Date: 08-12-2021
DOI: 10.1038/S41598-021-02885-W
Abstract: iNKT cells play a critical role in controlling the strength and character of adaptive and innate immune responses. Their unique functional characteristics are induced by a transcriptional program initiated by positive selection mediated by CD1d expressed by CD4 + CD8 + (double positive, DP) thymocytes. Here, using a novel Vα14 TCR transgenic strain bearing greatly expanded numbers of CD24 hi CD44 lo NKT cells, we examined transcriptional events in four immature thymic iNKT cell subsets. A transcriptional regulatory network approach identified transcriptional changes in proximal components of the TCR signalling cascade in DP NKT cells. Subsequently, positive and negative selection, and lineage commitment, occurred at the transition from DP NKT to CD4 NKT. Thus, this study introduces previously unrecognised steps in early NKT cell development, and separates the events associated with modulation of the T cell signalling cascade prior to changes associated with positive selection and lineage commitment.
Publisher: JCFCorp SG PTE LTD
Date: 2009
Publisher: Public Library of Science (PLoS)
Date: 18-03-2016
Publisher: The American Association of Immunologists
Date: 08-2000
DOI: 10.4049/JIMMUNOL.165.3.1673
Abstract: Systemic lupus erythematosus induced by Mycobacterium bovis in diabetes-prone nonobese diabetic mice was mapped in a backcross to the BALB/c strain. The subphenotypes—hemolytic anemia, antinuclear autoantibodies, and glomerular immune complex deposition—did not cosegregate, and linkage analysis for each trait was performed independently. Hemolytic anemia mapped to two loci: Bah1 at the MHC on chromosome 17 and Bah2 on distal chromosome 16. Antinuclear autoantibodies mapped to three loci: Bana1 at the MHC on chromosome 17, Bana2 on chromosome 10, and Bana3 on distal chromosome 1. Glomerular immune complex deposition did not show significant linkage to any genomic region. Mapping of autoantibodies (Coombs’ or antinuclear autoantibodies) identified two loci: Babs1 at the MHC and Babs2 on distal chromosome 1. It has previously been reported that genes conferring susceptibility to different autoimmune diseases map nonrandomly to defined regions of the genome. One possible explanation for this clustering is that some alleles at loci within these regions confer susceptibility to multiple autoimmune diseases—the “common gene” hypothesis. With the exception of the H2, this study failed to provide direct support for the common gene hypothesis, because the loci identified as conferring susceptibility to systemic lupus erythematosus did not colocalize with those previously implicated in diabetes. However, three of the four regions identified had been previously implicated in other autoimmune diseases.
Publisher: The American Association of Immunologists
Date: 02-2007
DOI: 10.4049/JIMMUNOL.178.3.1618
Abstract: Invariant NKT cells play a critical role in controlling the strength and character of adaptive immune responses. We have previously reported deficiencies in the numbers and function of NKT cells in the NOD mouse strain, which is a well-validated model of type 1 diabetes and systemic lupus erythematosus. Genetic control of thymic NKT cell numbers was mapped to two linkage regions: Nkt1 on distal chromosome 1 and Nkt2 on chromosome 2. In this study, we report the production and characterization of a NOD.Nkrp1b.Nkt1b congenic mouse strain, apply microarray expression analyses to limit candidate genes within the 95% confidence region, identify Slamf1 (encoding signaling lymphocyte activation molecule) and Slamf6 (encoding Ly108) as potential candidates, and demonstrate retarded signaling lymphocyte activation molecule expression during T cell development of NOD mice, resulting in reduced expression at the CD4+CD8+ stage, which is consistent with decreased NKT cell production and deranged tolerance induction in NOD mice.
Publisher: Oxford University Press (OUP)
Date: 13-08-2007
Abstract: Autoimmune gastritis is a CD4+ T cell-mediated disease induced in genetically susceptible mice by thymectomy on the third day after birth. Previous linkage analysis indicated that Gasa1 and Gasa2, the major susceptibility loci for gastritis, are located on mouse chromosome 4. Here we verified these linkage data by showing that BALB.B6 congenic mice, in which the distal approximately 40 Mb of chromosome 4 was replaced by C57BL/6 DNA, were resistant to autoimmune gastritis. Analysis of further BALB.B6 congenic strains demonstrated that Gasa1 and Gasa2 can act independently to cause full expression of susceptibility to autoimmune disease. Gasa1 and Gasa2 are located between D4Mit352-D4Mit204 and D4Mit343-telomere, respectively. Numerical differences in Foxp3+ regulatory T cells were apparent between the BALB/c and congenic strains, but it is unlikely that this phenotype accounted for differences in autoimmune susceptibility. The positions of Gasa1 and Gasa2 correspond closely to the positions of Idd11 and Idd9, two autoimmune diabetes susceptibility loci in nonobese diabetic (NOD), mice and this prompted us to examine autoimmune gastritis in NOD mice. After neonatal thymectomy, NOD mice developed autoimmune gastritis, albeit at a slightly lower incidence and severity of disease than in BALB/c mice. Diabetes-resistant congenic NOD.B6 mice, harbouring a B6-derived interval encompassing the Gasa1/2-Idd9/11 loci, demonstrated a slight reduction in the incidence of autoimmune gastritis. This reduction was not significant compared with the reduction observed in BALB.B6 congenic mice, suggesting a difference in the genetic aetiology of autoimmune gastritis in NOD and BALB mice.
Publisher: Frontiers Media SA
Date: 06-07-2022
DOI: 10.3389/FIMMU.2022.931630
Abstract: Cytotoxic lymphocytes are essential for anti-tumor immunity, and for effective responses to cancer immunotherapy. Natural killer cell granule protein 7 (NKG7) is expressed at high levels in cytotoxic lymphocytes infiltrating tumors from patients treated with immunotherapy, but until recently, the role of this protein in cytotoxic lymphocyte function was largely unknown. Unexpectedly, we found that highly CD8+ T cell-immunogenic murine colon carcinoma (MC38-OVA) tumors grew at an equal rate in Nkg7 +/+ and Nkg7 -/- littermate mice, suggesting NKG7 may not be necessary for effective CD8+ T cell anti-tumor activity. Mechanistically, we found that deletion of NKG7 reduces the ability of CD8+ T cells to degranulate and kill target cells in vitro . However, as a result of inefficient cytotoxic activity, NKG7 deficient T cells form a prolonged immune synapse with tumor cells, resulting in increased secretion of inflammatory cytokines, including tumor necrosis factor alpha (TNF). By deleting the TNF receptor, TNFR1, from MC38-OVA tumors, we demonstrate that this hyper-secretion of TNF compensates for reduced synapse-mediated cytotoxic activity against MC38-OVA tumors in vivo , via increased TNF-mediated tumor cell death. Taken together, our results demonstrate that NKG7 enhances CD8+ T cell immune synapse efficiency, which may serve as a mechanism to accelerate direct cytotoxicity and limit potentially harmful inflammatory responses.
Publisher: Elsevier BV
Date: 11-2008
DOI: 10.1016/J.JAUT.2008.04.010
Abstract: The immune repertoire of normal, healthy in iduals contains autoreactive T cells and natural antibodies that, under normal conditions, are controlled, either through central tolerance or by the activity of immunoregulatory T cells to prevent the onset of autoimmune diseases. Over the years, several types of immunoregulatory T cells have been identified. These include natural CD4+CD25+Foxp3+T (Treg) cells and type 1 NKT cells, which develop in the thymus, as well as acquired immunoregulatory T cells, such as type 1 cells (Tr1), Th3 cells, Ts cells and anergic CD4 T cells, which all appear to be products of peripheral immune activation. While little is understood about the genetics of most types of immunoregulatory T cell, detailed information on the genetic control of NKT and Treg cells is now available and may contribute significantly to our understanding of the aetiology of autoimmune disease.
Publisher: Wiley
Date: 19-12-2023
DOI: 10.1002/PRI.1988
Abstract: In iduals with multiple sclerosis (MS) want health advice regarding participation in their choice of exercise. To address this need, a flexible exercise participation programme (FEPP) was developed, underpinned by the MS aerobic exercise guidelines and supported by a physiotherapist using behaviour change techniques. The aim of this study was to investigate the feasibility of the FEPP for in iduals with minimal disability from MS. A feasibility study utilising a single group pre ost‐intervention design was conducted. The 12‐week FEPP was completed by 10 in iduals with MS (EDSS 0–3.5). Exercise progression in duration, intensity or frequency of exercise (in line with MS exercise guidelines) was guided by a self‐perceived weekly energy level score, and weekly telephone coaching sessions using behavioural change techniques. Trial feasibility was assessed via measures of process (recruitment and retention), resources/management (communication time data entry) and scientific feasibility (safety compliance). Secondary FEPP feasibility outcomes included the Goal Attainment Scale (GAS) T‐score, exercise participation (weekly exercise diary), high‐level mobility (HiMAT), vitality (Subjective Vitality Scale), biomarkers for inflammation (cytokines levels [IL2, IL4, IL6, IL10, TNF and IFNγ]), and acceptability (participant survey). Process: In total, 11 (85%) of 13 eligible participants enroled at baseline with 10 (91%) completing the study. Resources/management: Coaching sessions included a baseline interview—mean 39 min (SD: 6.6) and telephone coaching—mean 10 min (SD: 3.8) per week. Outcome measure data collection time—mean 44 min (SD: 2.1). Scientific feasibility: Two participants experienced a fall during their exercise participation. Self‐reported compliance was high (99%). GAS T‐scores increased significantly, indicating achievement of exercise participation goals. Secondary outcomes showed trends towards improvement. The FEPP was feasible, safe and highly acceptable for use with in iduals with MS and warrants a larger trial to explore effectiveness.
Publisher: Frontiers Media SA
Date: 16-03-2018
Publisher: Informa UK Limited
Date: 2005
DOI: 10.1080/08830180590884404
Abstract: A familial component to the tendency to develop autoimmune gastritis has long been recognized. Although linkage to certain HLA alleles and an association with the endocrine autoimmune diseases thyroiditis and type 1 diabetes have been reported, little further progress has been achieved in clinical studies. In contrast, the mouse model of gastritis induced in the BALB/c strain by thymectomy in the third day of life has identified four linkage regions two on distal chromosome 4 (Gasa1 and Gasa2), one on chromosome 6 (Gasa3) and one in the H2 (Gasa4). Three of these four genes colocalize with NOD mouse diabetes susceptibility genes--the strongest concordance identified to date between any two autoimmune diseases--reflecting the association between autoimmune diabetes and type 1 gastritis in humans.
Publisher: Elsevier
Date: 2020
Publisher: Springer Science and Business Media LLC
Date: 05-08-2013
DOI: 10.1038/CMI.2013.29
Publisher: The American Association of Immunologists
Date: 15-09-2003
DOI: 10.4049/JIMMUNOL.171.6.2873
Abstract: Natural killer T cells are an immunoregulatory population of lymphocytes that plays a critical role in controlling the adaptive immune system and contributes to the regulation of autoimmune responses. We have previously reported deficiencies in the numbers and function of NKT cells in the nonobese diabetic (NOD) mouse strain, a well-validated model of type 1 diabetes and systemic lupus erythematosus. In this study, we report the results of a genetic linkage analysis of the genes controlling NKT cell numbers in a first backcross (BC1) from C57BL/6 to NOD.Nkrp1b mice. The numbers of thymic NKT cells of 320 BC1 mice were determined by fluorescence-activated cell analysis using anti-TCR Ab and CD1/α-galactosylceramide tetramer. Tail DNA of 138 female BC1 mice was analyzed for PCR product length polymorphisms at 181 simple sequence repeats, providing greater than 90% coverage of the autosomal genome with an average marker separation of 8 cM. Two loci exhibiting significant linkage to NKT cell numbers were identified the most significant (Nkt1) was on distal chromosome 1, in the same region as the NOD mouse lupus susceptibility gene Babs2/Bana3. The second most significant locus (Nkt2) mapped to the same region as Idd13, a NOD-derived diabetes susceptibility gene on chromosome 2.
Publisher: Wiley
Date: 27-11-2007
Abstract: Of the contentious issues surrounding the clonal selection theory, one of the most influential was that of the mechanism for the generation of ersity of antibody specificity. While Burnet's qualitative theory assumed a very large antibody repertoire, Talmage provided a detailed quantitative argument supporting only 5000 in idual globulin patterns that provided an antiserum its specificity through combinatorial action. This methodological difference between the two men, and the mechanistic difference between their models, is key to the understanding of the clonal selection theory, its later acceptance and the proportion of credit paid to Burnet.
Publisher: JCFCorp SG PTE LTD
Date: 2012
Publisher: Wiley
Date: 06-2004
Location: Australia
No related grants have been discovered for Margaret Jordan.