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Search Results: 1 - 10 of 309746 matches for " Andrew J. McMichael "
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Alternative Spliced CD1D Transcripts in Human Bronchial Epithelial Cells
Kambez Hajipouran Benam, Wai Ling Kok, Andrew J. McMichael, Ling-Pei Ho
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0022726
Abstract: CD1d is a MHC I like molecule which presents glycolipid to natural killer T (NKT) cells, a group of cells with diverse but critical immune regulatory functions in the immune system. These cells are required for optimal defence against bacterial, viral, protozoan, and fungal infections, and control of immune-pathology and autoimmune diseases. CD1d is expressed on antigen presenting cells but also found on some non-haematopoietic cells. However, it has not been observed on bronchial epithelium, a site of active host defence in the lungs. Here, we identify for the first time, CD1D mRNA variants and CD1d protein expression on human bronchial epithelial cells, describe six alternatively spliced transcripts of this gene in these cells; and show that these variants are specific to epithelial cells. These findings provide the basis for investigations into a role for CD1d in lung mucosal immunity.
HLA-B27: natural function and pathogenic role in spondyloarthritis
Andrew McMichael, Paul Bowness
Arthritis Research & Therapy , 2002, DOI: 10.1186/ar571
Abstract: This chapter will first describe the natural function of HLA-B27, before presenting possible mechanisms by which HLA-B27 might be involved in disease pathogenesis. We will review the data available from HLA-B27 transgenic animals, from structural studies and from biochemical analysis of HLA-B27 function. A concluding section will identify key lines of current and future research.Possession of the human leukocyte antigen (HLA) class 1 allele HLA-B27 is strongly associated with development of the spondyloarthritides, a group of related diseases including ankylosing spondylitis and reactive arthritis (see Table 1). Ankylosing spondylitis is a common inflammatory rheumatic disease, affecting up to 0.5% of the population. The association of HLA-B27 with ankylosing spondylitis was first described in 1973 [1], and is among the strongest described for a HLA locus. A recent study found that 94% of ankylosing spondylitis patients are HLA-B27-positive, compared with 9.4% of controls, giving an odds ratio of 161 with a 95% confidence interval of 113–230 [2]. HLA-B27 is also less significantly associated with reactive arthritis [3] and with the spondyloarthritis associated with psoriasis and inflammatory bowel disease [4]. These conditions share clinical features including arthritis of the spine and large joints, and involvement of the skin, eye, genital mucosa and heart.While the pathogenic role of HLA-B27 in the spondyloarthropathies is unknown, numerous theories have been proposed. These theories are reviewed in [5], and many are applicable to the HLA associations with other autoimmune diseases (reviewed in [6]). Some theories suggest that the pathogenic role of HLA-B27 is independent of its immune function; for example, suggesting that HLA-B27 acts as a receptor for a disease-causing microorganism or is even merely a genetic marker for the true gene responsible. We favour theories suggesting that the pathogenic role of HLA-B27 stems from its immunological role. The 'arthrito
APOBEC3G-Induced Hypermutation of Human Immunodeficiency Virus Type-1 Is Typically a Discrete “All or Nothing” Phenomenon
Andrew E. Armitage,Koen Deforche,Chih-hao Chang,Edmund Wee,Beatrice Kramer,John J. Welch,Jan Gerstoft,Lars Fugger,Andrew McMichael,Andrew Rambaut ,Astrid K. N. Iversen
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002550
Abstract: The rapid evolution of Human Immunodeficiency Virus (HIV-1) allows studies of ongoing host–pathogen interactions. One key selective host factor is APOBEC3G (hA3G) that can cause extensive and inactivating Guanosine-to-Adenosine (G-to-A) mutation on HIV plus-strand DNA (termed hypermutation). HIV can inhibit this innate anti-viral defense through binding of the viral protein Vif to hA3G, but binding efficiency varies and hypermutation frequencies fluctuate in patients. A pivotal question is whether hA3G-induced G-to-A mutation is always lethal to the virus or if it may occur at sub-lethal frequencies that could increase viral diversification. We show in vitro that limiting-levels of hA3G-activity (i.e. when only a single hA3G-unit is likely to act on HIV) produce hypermutation frequencies similar to those in patients and demonstrate in silico that potentially non-lethal G-to-A mutation rates are ~10-fold lower than the lowest observed hypermutation levels in vitro and in vivo. Our results suggest that even a single incorporated hA3G-unit is likely to cause extensive and inactivating levels of HIV hypermutation and that hypermutation therefore is typically a discrete “all or nothing” phenomenon. Thus, therapeutic measures that inhibit the interaction between Vif and hA3G will likely not increase virus diversification but expand the fraction of hypermutated proviruses within the infected host.
Paleoclimate and bubonic plague: a forewarning of future risk?
Anthony J McMichael
BMC Biology , 2010, DOI: 10.1186/1741-7007-8-108
Abstract: See research article http://www.biomedcentral.com/1741-7007/8/112 webciteToday's diverse populations within the vast Eurasian continent, whether east, west, central or south, retain a horror of 'the plague' - as dreadful an agent of gruesome death as Ebola virus and yellow fever. Over the past two millennia, several pandemics of bubonic plague, caused by the flea-borne bacterium Yersinia pestis, have occurred within Eurasia, spreading quickly and often then lingering. Using a stepped approach to a set of long historical time-series data, including climatic, pandemic, epidemic and social-political variables, a study by Kausrud and colleagues [1] published in BMC Biology concludes that naturally occurring climatic fluctuations, acting through their environmental, ecological and political impacts, may have influenced the human pandemic outbreaks.Descriptions and theories about the occurrence of bubonic plague, particularly the Black Death (estimated to have killed one-third to one-half of Western Europe's population), have engrossed many medical historians. In particular, the two great, recognized historical pandemics of bubonic plague have spawned various controversies.The first was the Justinian Plague of 542 AD, which devastated Constantinople (by then the seat of the embattled Roman Empire). That great outbreak spread to engulf the greater Eastern Mediterranean region during the later sixth and seventh centuries. Second, in the 14th century, was the pandemic extending from China, through Central Asia, and eventually reaching Europe (the Black Death). Both pandemics occurred when great and complex political structures were becoming vulnerable. Did the Justinian Plague contribute to the terminal weakening of the eastern Roman Empire [2]? Did the Black Death hasten the collapse of Europe's feudal system, and the advent of liberalizing moves towards mercantilism, literacy and the Renaissance [3]? (And was the rise and fall of the Mongol-controlled Yuan Dynasty in China
The urban environment and health in a world of increasing globalization: issues for developing countries
McMichael,Anthony J.;
Bulletin of the World Health Organization , 2000, DOI: 10.1590/S0042-96862000000900007
Abstract: urban living is the keystone of modern human ecology. cities have multiplied and expanded rapidly worldwide over the past two centuries. cities are sources of creativity and technology, and they are the engines for economic growth. however, they are also sources of poverty, inequality, and health hazards from the environment. urban populations have long been incubators and gateways for infectious diseases. the early industrializing period of unplanned growth and laissez-faire economic activity in cities in industrialized countries has been superseded by the rise of collective management of the urban environment. this occurred in response to environmental blight, increasing literacy, the development of democratic government, and the collective accrual of wealth. in many low-income countries, this process is being slowed by the pressures and priorities of economic globalization. beyond the traditional risks of diarrhoeal disease and respiratory infections in the urban poor and the adaptation of various vector-borne infections to urbanization, the urban environment poses various physicochemical hazards. these include exposure to lead, air pollution, traffic hazards, and the ??urban heat island?? amplification of heatwaves. as the number of urban consumers and their material expectations rise and as the use of fossil fuels increases, cities contribute to the large-scale pressures on the biosphere including climate change. we must develop policies that ameliorate the existing, and usually unequally distributed, urban environmental health hazards and larger-scale environmental problems.
Debate on the paper by David Waltner-Toews
McMichael Anthony J.
Cadernos de Saúde Pública , 2001,
Abstract:
Impediments to Comprehensive Research on Climate Change and Health
Anthony J. McMichael
International Journal of Environmental Research and Public Health , 2013, DOI: 10.3390/ijerph10116096
Abstract: During every climatic era Life on Earth is constrained by a limited range of climatic conditions, outside which thriving and then surviving becomes difficult. This applies at both planetary and organism (species) levels. Further, many causal influences of climate change on human health entail changes—often disruptive, sometimes irreversible—in complex system functioning. Understanding the diverse health risks from climate change, and their influence pathways, presents a challenge to environmental health researchers whose prior work has been in a more definable, specific and quantitative milieu. Extension of the research agenda and conceptual framework to assess present and future health risks from climate change may be constrained by three factors: (i) lack of historically-informed understanding of population-health sensitivity to climatic changes; (ii) an instinctual ‘epidemiologising’ tendency to choose research topics amenable to conventional epidemiological analysis and risk estimation; and (iii) under-confidence in relation to interdisciplinary collaborative scenario-based modeling of future health risks. These constraints must be recognized and remedied. And environmental researchers must argue for heightened public attention to today’s macro-environmental threats to present and future population health—emphasising the ecological dimension of these determinants of long-term health that apply to whole populations and communities, not just to individuals and social groupings.
Magnitude of Alloresponses to MHC Class I/II Expressing Human Cardiac Myocytes Is Limited by Their Intrinsic Ability to Process and Present Antigenic Peptides
J. Bruce Sundstrom,Kimberley C. Jollow,Veronique Braud,Francois Villinger,Andrew J. McMichael,E. Clinton Lawrence,Edwin W. Ades,Aftab A. Ansari
Clinical and Developmental Immunology , 2003, DOI: 10.1080/10446670310001642410
Abstract: In this investigation we have explored the relationship between the weak allogenicity of cardiac myocytes and their capacity to present allo-antigens by examining the ability of a human cardiac myocyte cell line (W-1) to process and present nominal antigens. W-1 cells (HLA-A*0201 and HLA-DR β1*0301) pulsed with the influenza A matrix 1 (58-66) peptide (M1) were able to serve as targets for the HLA-A*0201 restricted CTL line PG, specific for M1-peptide. However, PG-CTLs were unable to lyse W-1 target cells infected with a recombinant vaccinia virus expressing the M1 protein (M1-VAC). Pretreatment of these M1-VAC targets with IFN-γ partially restored their ability to process and present the M1 peptide. However, parallel studies demonstrated that IFN-γ pretreated W-1's could not process tetanus toxin (TT) or present the TT(830-843) peptide to HLA-DR3 restricted TT-primed T cells. Semi-quantitative RT-PCR measurements revealed significantly lower constitutive levels of expression for MHC class I, TAP-1/2, and LMP-2/7 genes in W-1s that could be elevated by pretreatment with IFN-γ to values equal to or greater than those expressed in EBV-PBLs. However, mRNA levels for the genes encoding MHC class II, Ii, CIITA, and DMA/B were markedly lower in both untreated and IFN-γ pretreated W-1s relative to EBV-PBLs. Furthermore, pulse-chase analysis of the corresponding genes revealed significantly lower protein levels and longer half-life expression in W-1s relative to EBV-PBLs. These results suggest that weak allogenicity of cardiac myocytes may be governed by their limited expression of MHC genes and gene products critical for antigen processing and presentation.
Sequential Broadening of CTL Responses in Early HIV-1 Infection Is Associated with Viral Escape
Annika C. Karlsson, Astrid K.N. Iversen, Joan M. Chapman, Tulio de Oliveira, Gerald Spotts, Andrew J. McMichael, Miles P. Davenport, Frederick M. Hecht, Douglas F. Nixon
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0000225
Abstract: Background Antigen-specific CTL responses are thought to play a central role in containment of HIV-1 infection, but no consistent correlation has been found between the magnitude and/or breadth of response and viral load changes during disease progression. Methods and Findings We undertook a detailed investigation of longitudinal CTL responses and HIV-1 evolution beginning with primary infection in 11 untreated HLA-A2 positive individuals. A subset of patients developed broad responses, which selected for consensus B epitope variants in Gag, Pol, and Nef, suggesting CTL-induced adaptation of HIV-1 at the population level. The patients who developed viral escape mutations and broad autologous CTL responses over time had a significantly higher increase in viral load during the first year of infection compared to those who did not develop viral escape mutations. Conclusions A continuous dynamic development of CTL responses was associated with viral escape from temporarily effective immune responses. Our results suggest that broad CTL responses often represent footprints left by viral CTL escape rather than effective immune control, and help explain earlier findings that fail to show an association between breadth of CTL responses and viral load. Our results also demonstrate that CTL pressures help to maintain certain elements of consensus viral sequence, which likely represent viral escape from common HLA-restricted CTL responses. The ability of HIV to evolve to escape CTL responses restricted by a common HLA type highlights the challenges posed to development of an effective CTL-based vaccine.
Design and Pre-Clinical Evaluation of a Universal HIV-1 Vaccine
Sven Létourneau, Eung-Jun Im, Tumelo Mashishi, Choechoe Brereton, Anne Bridgeman, Hongbing Yang, Lucy Dorrell, Tao Dong, Bette Korber, Andrew J. McMichael, Tomá? Hanke
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0000984
Abstract: Background One of the big roadblocks in development of HIV-1/AIDS vaccines is the enormous diversity of HIV-1, which could limit the value of any HIV-1 vaccine candidate currently under test. Methodology and Findings To address the HIV-1 variation, we designed a novel T cell immunogen, designated HIVCONSV, by assembling the 14 most conserved regions of the HIV-1 proteome into one chimaeric protein. Each segment is a consensus sequence from one of the four major HIV-1 clades A, B, C and D, which alternate to ensure equal clade coverage. The gene coding for the HIVCONSV protein was inserted into the three most studied vaccine vectors, plasmid DNA, human adenovirus serotype 5 and modified vaccine virus Ankara (MVA), and induced HIV-1-specific T cell responses in mice. We also demonstrated that these conserved regions prime CD8+ and CD4+ T cell to highly conserved epitopes in humans and that these epitopes, although usually subdominant, generate memory T cells in patients during natural HIV-1 infection. Significance Therefore, this vaccine approach provides an attractive and testable alternative for overcoming the HIV-1 variability, while focusing T cell responses on regions of the virus that are less likely to mutate and escape. Furthermore, this approach has merit in the simplicity of design and delivery, requiring only a single immunogen to provide extensive coverage of global HIV-1 population diversity.
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