个人简介
I did a BSc at King’s College (formerly Queen Elizabeth College, London), MSc at Brunel University (London) and PhD (Immunology) at the Royal London Hospital (London). I worked for several years in the field of transplantation immunology with the late Professor Hilliard Festenstein at the Royal London supported by the MRC. In 1990 I was appointed as a lecturer at the Department of Biological Sciences (University of Essex).
研究领域
My main research interest resides in the investigation of the factors that control the cell-surface organization of immunoreceptors encoded by the Major Histocompatibility Complex (MHC). The MHC molecules are critical for the regulation of the immune response because they capture and display peptides, mainly those derived from pathogens to T lymphocytes. The MHC molecules are loaded with peptides in the cytoplasm and display these at the cell surface of subpopulations of cells, primarily antigen presenting cells. At the cell surface the MHC-peptide complex exist as non-covalently associated pair of sub-units. A subunit with a bound peptide functions as a ligand for antigen-specific T cell receptors on T lymphocytes. These are the cells, which control the specific adaptive responses of the immune system.
As integral membrane proteins the MHC molecules have the capacity to ‘redistribute’ in the membrane. Such redistribution is under the influence of constraints imposed by the cytoskeleton and the modulatory activity exerted upon receptor-density by, for example cytokines and other factors. Because of the lipid environment and the fluidity of the cell membrane the MHC molecules are potentially mobile (by lateral diffusion). They can enter into associations with each other (i.e., they can dimerize) or they can associate with other co-stimulatory molecules.
A fundamental problem in immunobiology is to understand how MHC immunoreceptors and their corresponding subunits and associated structures interact at the cell surface. Further questions concern the nature of the changes that may be triggered, for example, in viral and bacterial infections and in autoimmunity.
A hypothesis to be tested is that the MHC molecules are displayed in ‘functional domains’ comprising single pairs or more than one pair of MHC subunits in close association. This pattern of cell-surface associations may reflect degrees of cellular activation or inhibition such as occur in anergy.
We have been interested in testing these ideas by establishing novel and sensitive techniques that would allow us to study the behaviour (mobility and receptor associations) of the MHC molecules at the cell-surface on single living cells. Our aim is to eventually relate this to the function of these molecules in normal and disease satates.
We are currently using molecular probes (e.g., Fab fragment of an antibody coupled to a fluorescent particle) and a single particle imaging system on a cooled slow-scan coupled charged device (CCD) digital camera. The system permits the resolution of immunological receptors at a nanometer-scale on single living cells in tissue culture. Thus, in essence, this technique permits the study of receptors in their native configuration. This approach obviates the use of conventional biochemical extraction procedures, traditionally used in immunology, such as the use of non-ionic or zwitterionic detergents that disrupt the cell membrane and hence affect protein-protein interactions.
Using this experimental approach we have recently shown that a subset of the human MHC molecules, known as HLA DR, redistribute at the cell surface in a temperature-dependent equilibrium between single HLA DR heterodimers and dimers of heterodimers. The biological role of such ‘dimer of dimers’ has not yet been established and is currently the subject of collaborative research with other groups in other universities.
Interestingly the spatial resolution of receptor expression using the above approach has wider applicability in membrane immunology. It can provide information on the pattern of cell-surface organization of virtually any immunoreceptor in the normal and disease state.
One such application has been found our current studies on the function of the MHC in development and differentiation. The hypothesis here is that the expression of MHC subsets is developmentally regulated, with selective sets of these molecules playing a role in embryo compaction and polarization. This hypothesis can be directly tested using single particle imaging on embryonic cells kept in vivo under culture conditions. In previous work here at Essex, has shown that in the mouse the mRNA MHC transcripts are expressed from one-cell after conception and prior to implantation of the embryo in the maternal uterus. Both maternally encoded and paternally encoded genes of the MHC are expressed in the one-cell embryo. The role of these molecules in the actual process of embryonic development remains to be elucidated.
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Manos Mavrakos, Minnie O’Farrell and Nelson Fernández (2008). Regulation of the CD14 complex by the nuclear enzyme poly ADP-ribose polymerase-1 in the response against bacterial LPS (manuscript in progress)
Valerie Shaikly, Ayesha Shakhawat, Anna Withey, Ian Morrison, James Cooper, Vladimir Ovsyankin, Mohamed Taranissi, Gillian B. Dealtry, Richard Cherry, and Nelson Fernández (2008). Single cell bio-imaging reveals spatial and temporal co-expression of major histocompatibility Class Ib molecules HLA-G and HLA-E in human preimplantation embryos.(manuscript in progress)
Ioannis Karakikes, Ian E G Morrison, Peter O’Toole, Cristina V Navarrete, Jesus Gomez, Richard J Cherry, and Nelson Fernández (2008). Interaction between the HLA Class II -associated molecule CD74 and HLA-DR (manuscript in progress)
V.R. Shaikly, I.E.G. Morrison, M. Taranissi, C.V. Noble, A.D. Withey, R.J. Cherry, S.M. Blois, N. Fernández (2008). Analysis of HLA-G in Maternal Plasma, Follicular Fluid, and Preimplantation Embryos Reveal an Asymmetric Pattern of Expression. J Immunol 180:4330-4337.
Sandra M. Blois, Gabriela Barrientos, Mariana G. Garcia, Arif S. Orsal, Mareike Tometten, Rosalia I. Cordo-Russo, Burghard F. Klapp, Angela Santoni, Nelson Fernández, Peter Terness and Petra C. Arck (2008). Interaction between dendritic cells and natural killer cells during pregnancy in mice. J Mol Med 86:837–852.
Joanne C. Cooper, Gillian B. Dealtry, Mohamed Abdelrahman Ahmed, Petra C. Arck, Burghard F. Klapp, Sandra M. Blois and Nelson Fernández (2007). An Impaired Breeding Phenotype in Mice with a Genetic Deletion of Beta-2 Microglobulin and Diminished MHC Class I Expression: Role in Reproductive Fitness. Biology of Reproduction 77:274–279.
Laskarin G, Kammerer U, Rukavina D,Thomson AW, Fernández N, Blois SM (2007). Antigen-presenting cells and materno-fetal tolerance: an emerging role for dendritic cells. American Journal of Reproductive Immunology 58:255–267.
SM Blois, U Kammerer, C Alba Soto, M Tometten, V Shaikhly, R Jurd, D Rukavina, AW Thomson, N Fernández, PC Arck. (2007). Dendritic cells: key to foetal tolerance? Biology of Reproduction 77:590–598.
Mariana G. Garcia, Irene Tirado-González, Bori Handjiski, Mareike Tometten, Arif S. Orsal, Silvia E. Hajos, Nelson Fernández, Petra C. Arck and Sandra M. Blois (2007). High Expression of Survivin and Down-Regulation of Stat-3 characterize the Feto-Maternal Interface in Failing Murine Pregnancies During the Implantation Period. Placenta. 28(7):650-657.
D'Arcy V, Abdullaev ZK, Pore N, Docquier F, Torrano V, Chernukhin I, Smart M, Farrar D, Metodiev M, Fernández N, Richard C, Delgado MD, Lobanenkov V, Klenova E. (2006) The potential of BORIS detected in the leukocytes of breast cancer patients as an early marker of tumorigenesis. Clin Cancer Res 12:5978-86.
IEG Morrison, I Karakikes, RE Barber, N Fernández and RJ Cherry (2003). Detecting and quantifying colocalisation of cell surface molecules by single particle fluorescence imaging. Biophys J 85, 4110-4121.
Eva M. Fernández, Peter J. O'Toole, Ian E.G. Morrison, Richard J. Cherry and Nelson Fernández (2003) Interaction of HLA DR with actin microfilaments Hum Immunol 64:827-837
R J Cherry, IEG Morrison, I Karakikes, RE Barber, G Silkstone and N Fernández (2003). Measurements of associations of cell surface receptors by single particle fluorescence imaging. Biochem Soc Trans 31 (5), 1028–1031.
I Karakikes, RE Barber, IEG Morrison, N Fernández and RJ Cherry (2003). Colocalisation of cell surface receptors at high spatial resolution by single particle fluorescence imaging. Bioch. Soc. Trans. 31 (6), 1453-1455
J.M. Sutton, O.J. Clarke, N. Fernández and R.W. Boyle (2002) Porphyrin, Chlorin and Bacteriochlorin Isothiocyanates Useful Reagents for the Synthesis of Photoactive Bioconjugates. Bioconjugate Chemistry.
George Georgiou, Sukhvinder S. Bahra, Alan R. Mackie, Caroline A. Wolfe, Paul O'Shea, Shab Ladha, Nelson Fernández and Richard J. Cherry (2002) Measurements of the lateral diffusion of human MHC Class I molecules on HELA cells by fluorescence recovery after photobleaching using phycoerythrin Biophysical Journal 82 (4): 1828-1834
Triantafilou, K., Triantafilou, M., Ladha, S., Dedrick, R., Fernández, N. and Cherry, R. (2001) Fluorescence recovery after photobleaching reveals that lipopolysaccharide rapidly transfers from CD14 to heat shock proteins 70 and 90 on the cell membrane J Cell Sci 114 (17): 3072-3072
Kathy Triantafilou, Martha Triantafilou and Nelson Fernández (2000) Molecular associations and microdomains involved in APC-T cell interactions Critical Reviews in Immunol 20:359-373.
Kathy Triantafilou, Martha Triantafilou, Keith M. Wilson and Nelson Fernández (2000) Human major histocompatibility molecules have the intrinsic ability to form homotypic associations Hum Immunol 61(6): 585-598
Martha Triantafilou, Kathy Triantafilou, and Nelson Fernández (2000) Rough and smooth forms of fluorescein-labelled bacterial endotoxin exhibit CD14/LBP dependent and independent binding that is influenced by endotoxin concentration Eur. J. Bioch. 267 (8): 2218-2226
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