ORCID Profile
0000-0002-1015-0745
Current Organisations
Universidade de São Paulo
,
Università degli Studi di Roma La Sapienza
,
Universidade de São Paulo Centro de Energia Nuclear na Agricultura
,
University College Dublin
,
University of Leeds
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Publisher: Oxford University Press (OUP)
Date: 24-11-2002
DOI: 10.1046/J.1365-2249.2002.02002.X
Abstract: Hereditary periodic fever syndromes comprise a group of distinct disease entities linked by the defining feature of recurrent febrile episodes. Hyper IgD with periodic fever syndrome (HIDS) is caused by mutations in the mevalonate kinase (MVK) gene. The mechanisms by which defects in the MVK gene cause febrile episodes are unclear and there is no uniformly effective treatment. Mutations of the TNFRSF1A gene may also cause periodic fever syndrome (TRAPS). Treatment with the TNFR-Fc fusion protein, etanercept, is effective in some patients with TRAPS, but its clinical usefulness in HIDS has not been reported. We describe a 3-year-old boy in whom genetic screening revealed a rare combination of two MVK mutations producing clinical HIDS as well as a TNFRSF1A P46L variant present in about 1% of the population. In vitro functional assays demonstrated reduced receptor shedding in proband's monocytes. The proband therefore appears to have a novel clinical entity combining Hyper IgD syndrome with defective TNFRSF1A homeostasis, which is partially responsive to etanercept.
Publisher: Informa UK Limited
Date: 03-2011
DOI: 10.2147/JIR.S11330
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.CYTOGFR.2014.07.016
Abstract: Tumor Necrosis Factor (TNF), initially known for its tumor cytotoxicity, is a potent mediator of inflammation, as well as many normal physiological functions in homeostasis and health, and anti-microbial immunity. It also appears to have a central role in neurobiology, although this area of TNF biology is only recently emerging. Here, we review the basic biology of TNF and its normal effector functions, and discuss the advantages and disadvantages of therapeutic neutralization of TNF - now a commonplace practice in the treatment of a wide range of human inflammatory diseases. With over ten years of experience, and an emerging range of anti-TNF biologics now available, we also review their modes of action, which appear to be far more complex than had originally been anticipated. Finally, we highlight the current challenges for therapeutic intervention of TNF: (i) to discover and produce orally delivered small molecule TNF-inhibitors, (ii) to specifically target selected TNF producing cells or in idual (diseased) tissue targets, and (iii) to pre-identify anti-TNF treatment responders. Although the future looks bright, the therapeutic modulation of TNF now moves into the era of personalized medicine with society's challenging expectations of durable treatment success and of achieving long-term disease remission.
Publisher: Elsevier BV
Date: 2011
DOI: 10.1016/J.CELLIMM.2011.02.007
Abstract: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory condition caused by mutations in the TNFRSF1A gene which encodes the tumor necrosis factor (TNF) receptor, TNFR1. We investigated the effect of three high penetrance and three low penetrance TNFRSF1A mutations upon NF-κB transcription factor family subunit activity, and the resulting impact upon secretion of 25 different cytokines. Whilst certain mutations resulted in elevated NF-κB p65 subunit activity, others instead resulted in elevated c-Rel subunit activity. Interestingly, high p65 activity was associated with elevated IL-8 secretion, whereas high c-Rel activity increased IL-1β and IL-12 secretion. In conclusion, while all six TNFRSF1A mutations showed enhanced NF-κB activity, different mutations stimulated distinct NF-κB family subunit activities, and this in turn resulted in the generation of unique cytokine secretory profiles.
Publisher: Cold Spring Harbor Laboratory
Date: 20-01-2022
DOI: 10.1101/2022.01.18.476760
Abstract: X-ray fluorescence spectroscopy (XRF) is a powerful technique for the in vivo assessment of plant tissues. However, the potential X-ray exposure damages might affect the structure and elemental composition of living plant tissues leading to artefacts in the recorded data. Herein, we exposed soybean ( Glycine max (L.) Merrill) leaves to several X-ray doses through a polychromatic benchtop microprobe X-ray fluorescence spectrometer, modulating the photon flux by adjusting either the beam size, focus, or exposure time. The structure, ultrastructure and physiological responses of the irradiated plant tissues were investigated through light and transmission electron microscopy (TEM). Depending on the dose, the X-ray exposure induced decreased K and X-ray scattering intensities, and increased Ca, P, and Mn signals on soybean leaves. Anatomical analysis indicated necrosis of the epidermal and mesophyll cells on the irradiated spots, where TEM images revealed the collapse of cytoplasm and cell-wall breaking. Furthermore, the histochemical analysis detected the production of reactive oxygen species, as well as inhibition of chlorophyll autofluorescence in these areas. Under certain X-ray exposure conditions, e . g ., high photon flux and exposure time, XRF measurements may affect the soybean leaves structures, elemental composition, and cellular ultrastructure, and induce programmed cell death. These results shed light on the characterization of the radiation damage, and thus, help to assess the X-ray radiation limits and strategies for in vivo for XRF analysis. By exposing soybean leaves to several X-ray doses, we show that the characteristic X-ray induced elemental changes stem from plants’ physiological signalling or responses rather than only s le dehydration.
Publisher: Bentham Science Publishers Ltd.
Date: 30-04-2015
DOI: 10.2174/1381612821666150310144940
Abstract: Given the paucity of effective therapies and the increasing prevalence of osteoarthritis (OA) with ageing and overweight populations, new therapies for this painful, life-impairing condition are desperately needed, for both symptom relief and structural modification. With a growing understanding that OA involves multiple tissue pathologies including inflammation, many more therapeutic targets have been identified. This review will provide a current overview on the role of biologics in OA, including anti-tumour necrosis factor agents, growth factors and interleukin-1 antagonists.
Publisher: Wiley
Date: 07-1995
Publisher: Springer Science and Business Media LLC
Date: 04-2001
Abstract: Tumour necrosis factor (TNF) plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA) and it has been shown that the TNF-lymphotoxin (TNF-LT) region influences susceptibility to RA. To investigate the role of the TNF-LT locus further, inheritance of TNF 5' promoter alleles was determined in multiplex RA families. Six previously defined TNF promoter single nucleotide polymorphisms (SNPs) (-238, -308, -376, -857, -863, -1031) were observed in these families and in addition, a heretofore undocumented adenine (A) to cytosine (C) substitution at position -572 relative to the transcription start site was defined. TNF 5' promoter SNPs were found to co-segregate with specific TNF microsatellite haplotypes. In particular, the SNP -308A allele was found to be inherited with the TNF a2, b3, c1, d1, e3 (H2) microsatellite haplotype (P < 0.001) which had previously been found to be associated with RA in in iduals heterozygous for the HLA-DR 'shared epitope' (SE). When the data were stratified by the presence of the SE with further stratification according to SE DR subtypes and analysed by transmission disequilibrium test (TDT) for which offspring were assumed independent, the -308A and -857T alleles were found to be associated with RA in patients carrying the SE (P = 0.0076 and 0.0063 respectively). The data were further stratified to analyse for association in in iduals homozygous or heterozygous for SE alleles. Results showed that the -308A allele was significantly associated with RA susceptibility in in iduals heterozygous for the SE (P < 0.001) with the significance only occurring in patients carrying HLA-DR4 (P < 0.001), while the -857T allele was significant in in iduals homozygous for the SE (P = 0.0039). Further analysis using the pedigree disequilibrium test (PDT) which conservatively adjusts for all sources of familial correlation except that conferred by linkage disequilibrium still indicated a significant role for the -308A and -857T alleles. These data provide evidence that TNF promoter SNPs may play an independent role in RA susceptibility in specific immunogenetically-defined groups of RA patients.
Publisher: Elsevier BV
Date: 02-1995
Abstract: A highly informative microsatellite marker, D7S485, from the T-cell receptor gamma (TCRG) locus, has been used to study segregation of TCRG genes in 26 multiplex rheumatoid arthritis (RA) families. We used the sib-pair method to assess excess identity-by-descent sharing among affected members in these families and the LINKAGE package of programs was used to calculate two-point lod scores for the D7S485 marker. There was no evidence for segregation of TCRG genes with RA in affected siblings and significantly negative lod scores were obtained from linkage analyses using both autosomal dominant and recessive models of inheritance.
Publisher: Wiley
Date: 28-12-2007
DOI: 10.1002/ART.23123
Abstract: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal-dominant autoinflammatory condition caused by mutations in the TNFRSF1A gene. The cellular mechanisms by which mutations in this gene trigger inflammation are currently unclear. Because NF-kappaB is the major intracellular signaling component inducing secretion of proinflammatory cytokines, we sought to determine whether differences in the clinical phenotype of patients with TRAPS may be attributable to variable effects of TNFRSF1A mutations on TNFRI expression, localization, or NF-kappaB activity. Peripheral blood mononuclear cells were obtained from patients (following informed consent), and cellular nuclear and cytosolic fractions were generated by subcellular fractionation. Localization of IkappaBalpha and NF-kappaB was determined by Western blotting of the resultant fractions. NF-kappaB subunit activity was determined by enzyme-linked immunosorbent assay analysis and confirmed by electrophoretic mobility shift assay. Subcellular localization of TNFRI was determined by immunofluorescence confocal microscopy or by immunoblotting following affinity isolation of plasma membrane by subcellular fractionation. Cells from patients with the fully penetrant C73R mutation had marked activation of the proinflammatory p65 subunit of NF-kappaB. In contrast, cells from patients with the low-penetrant R92Q mutation displayed high levels of DNA binding by the p50 subunit, an interaction previously linked to repression of inflammation. Interestingly, although cells from patients with the C73R mutation have no TNFRI shedding defect, there was nonetheless an unusually high concentration of functional TNFRI at the plasma membrane. High levels of TNFRI at the cell surface in patients with the C73R mutation hypersensitizes cells to stimulation by TNF, leading to increased NF-kappaB p65 subunit activation and an exaggerated proinflammatory response.
Publisher: Wiley
Date: 1995
Abstract: To evaluate the role of the T cell receptor beta chain locus (TCRB) in genetic susceptibility to rheumatoid arthritis (RA). Twenty-eight multiplex RA families were recruited from 3 rheumatology outpatient departments. All members were genotyped for a highly informative microsatellite (V beta 6.7), a V beta 12.2 SSCP marker, and a biallelic C beta restriction fragment length polymorphism. Data were analyzed by the SIBPAL program to assess identity-by-descent in affected sib-pairs. Using the V beta 12.2 marker, there was suggestive evidence of increased sib-pair sharing (P = 0.005) in affected offspring (a P value of 0.001 is generally taken to establish linkage). Data for V beta 6.7 and C beta yielded significance levels of 0.06 and 0.19, respectively. These data suggest that a gene in or linked to the TCRB complex may confer genetic susceptibility to RA in these families. Confirmation in a larger panel of families is required.
Location: Brazil
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Michael F. McDermott.