35,555 research outputs found
NEW ROLES FOR FC RECEPTORS IN NEURODEGENERATION-THE IMPACT ON IMMUNOTHERAPY FOR ALZHEIMER’S DISEASE
No full textThere are an estimated 18 million Alzheimer’s disease (AD) sufferers worldwide and with no disease modifying treatment currently available, development of new therapies represents an enormous unmet clinical need. AD is characterised by episodic memory loss followed by severe cognitive decline and is associated with many neuropathological changes. AD is characterised by deposits of amyloid beta (Aβ), neurofibrillary tangles, and neuroinflammation. Active immunisation or passive immunisation against Aβ leads to the clearance of deposits in transgenic mice expressing human Aβ. This clearance is associated with reversal of associated cognitive deficits, but these results have failed to translate to humans, with both active and passive immunotherapy failing to improve memory loss. One explanation for these observations is that certain anti-Aβ antibodies mediate damage to the cerebral vasculature limiting the top dose and potentially reducing efficacy. Fc gamma receptors (Fcγ) are a family of immunoglobulin like receptors which bind to the Fc portion of IgG, and mediate the response of effector cells to immune complexes. Data from both mouse and human studies suggest that cross-linking Fc receptors by therapeutic antibodies and the subsequent pro-inflammatory response mediates the vascular side effects seen following immunotherapy. Increasing evidence is emerging that Fc receptor expression on CNS resident cells, including microglia and neurons, is increased during aging and functionally involved in the pathogenesis of age-related neurodegenerative diseases. We propose that increased expression and ligation of Fc receptors in the CNS, either by endogenous IgG or therapeutic antibodies, has the potential to induce vascular damage and exacerbate neurodegeneration. To produce safe and effective immunotherapies for AD and other neurodegenerative diseases it will be vital to understand the role of Fc receptors in the healthy and diseased brain
Identification and expression of a murine cytomegalovirus early gene coding for an Fc receptor
No full textSeveral herpesviruses, including cytomegalovirus, induce receptors for the Fc domain of murine immunoglobulin G (IgG) molecules. Viral genes coding for these receptors have been characterized only for alphaherpesviruses. In this report, we describe a new approach that led to the identification of an Fc receptor (FcR) of murine cytomegalovirus (MCMV). The Fc fragment of IgG precipitated glycoproteins (gp) of 86 to 88 and 105 kDa from MCMV-infected cells. Deglycosylation by endoglycosidase F resulted in a protein with a molecular mass of 64 kDa. Injection of complete MCMV DNA or of DNA fragments, and the subsequent testing of cytoplasmic binding of IgG by immunofluorescence microscopy, was used to search for the coding region in the MCMV genome. The gene was located in the HindIII J fragment, map units 0.838 to 0.846, where an open reading frame of 1,707 nucleotides predicts a gp of 569 amino acids with a calculated molecular mass of 65 kDa. The sequence of this gp is related to those of the gE proteins of herpes simplex virus type 1 and varicella-zoster virus. The defined length of the mRNA, 1,838 nucleotides, was in agreement with that of a 1.9-kb RNA expressed throughout the replication cycle, starting at the early stages of infection. Expression of the gene fcr1 by recombinant vaccinia virus resulted in the synthesis of gp86/88 and gp105, each with FcR properties, and the correct identification of the gene encoding the FcR was confirmed by the DNA injection method
Studies investigating peripheral blood derived cells that express the high affinity receptor for immunoglobulin E (Fc?RI) In Allergic Disorders
No full textIt is just forty years since the identification of immunoglobulin E (IgE) as the reagin responsible for allergen induced immediate hypersensitivity reactions. IgE exerts its biological actions through the binding of its Fc fragment to specific Fc receptors on effector cells. There are two predominant Fc receptors for IgE – Fc?RI, which has a very high affinity for IgE and Fc?RII, which shows less avid binding. For much of the first two decades after the identification of IgE, it was thought that Fc?RI expression was limited to mast cells and basophils and that IgE binding to other cell types such as Blymphocytes and antigen presenting cells (APCs) was mainly due to Fc?RII. However with major advances in characterisation and functional knowledge of Fc?RI, particularly in the last fifteen years, it has become apparent that Fc?RI can be expressed on several more cell types that may be involved in initiation and maintenance of allergic inflammation – including APCs (monocytes and dendritic cells)and possibly eosinophils.The research described in the four papers forming this thesis was completed during this period and evaluated Fc?RI expression on different cell types, their potential roles in allergen induced inflammatory responses and whether successful therapeutic strategies for allergic disorders may involve actions on Fc?RI+ cells. The relative expression of Fc?RI on peripheral blood basophils, monocytes and eosinophils from atopic and non-atopic subjects and any relationship with serum IgE concentrations was assessed in the first paper. The second study examined a potentially important role for basophils as a cellular source of rapidly releasable IL-4 which may help initiate allergen induced TH2 responses. The next study investigated the possible effects on allergen induced early and late asthmatic responses of the immunosuppressive drug cyclosporin A which had been shown both to inhibit mast cell and basophil degranulation and cytokine secretion (particularly by CD4+ T-cells). The final study evaluated Fc?RI expression on these cell types as well humoral factors (e.g. seasonal changes in allergen specific IgG and IgE) in subjects who, after 3 to 4 years of grass pollen immunotherapy, had continued on either active or placebo immunotherapy for a further 3 years. A historical perspective explaining some of the reasons the studies were done is provided in the introductory chapter whilst the discussion chapter at the end reviews how many of the findings of the study have evolved in subsequent years right up to the present day and finishes off with a brief synopsis of how rapidly increasing knowledge of the regulatory functions of dendritic cells (expressing Fc?RI and often monocyte derived) has resulted in better understanding of the mechanisms of allergen specific immunotherapy and is leading to more effective treatment modalities
A new method of calculation of Franck-Condon factors which includes allowance for anharmonicity and the Duschinsky effect: Simulation of the HeI photoelectron spectrum of ClO2
No full textA new method of Franck-Condon (FC) factor calculation for nonlinear polyatomics, which includes anharmonicity and Duschinsky rotation, is reported. Watson's Hamiltonian is employed in this method with multidimensional ab initio potential energy functions. The anharmonic vibrational wave functions are expressed as linear combinations of the products of harmonic oscillator functions. The Duschinsky effect, which arises from the rotation of the normal modes of the two electronic states involved in the electronic transition, is formulated in Cartesian coordinates, as was done previously in an earlier harmonic FC model. This new anharmonic FC method was applied to the simulation of the bands in the He I photoelectron (PE) spectrum of ClO2. For the first band, the harmonic FC model was shown to be inadequate but the anharmonic FC simulation gave a much-improved agreement with the observed spectrum. The experimentally derived geometry of the (X) over tilde (1)A(1) state of ClO2+ was obtained, for the first time, via the iterative FC analysis procedure {R(Cl-O)=1.414 +/- 0.002 Angstrom, angle O-Cl-O=121.8 +/- 0.1 degrees}. The heavily overlapped second PE band of ClO2, corresponding to ionization to five cationic states, was simulated using the anharmonic FC code. The main vibrational features observed in the experimental spectrum were adequately accounted for in the simulated spectrum. The spectral simulation reported here supports one of the two sets of published assignments for this band, which was based on multireference configuration interaction (MRCI) calculations. In addition, with the aid of the simulated envelopes, a set of adiabatic (and vertical) ionization energies to all five cationic states involved in this PE band, more reliable than previously reported, has been derived. This led also to a reanalysis of the photoabsorption spectrum of ClO2
Fc gamma receptors: glycobiology and therapeutic prospects
No full textJerrard M Hayes,1 Mark R Wormald,2 Pauline M Rudd,3 Gavin P Davey1 1School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland; 2Department of Biochemistry, Oxford Glycobiology Institute, University of Oxford, Oxford, UK; 3NIBRT Glycoscience Group, National Institute for Bioprocessing, Research and Training, Dublin, Ireland Abstract: Therapeutic antibodies hold great promise for the treatment of cancer and autoimmune diseases, and developments in antibody–drug conjugates and bispecific antibodies continue to enhance treatment options for patients. Immunoglobulin (Ig) G antibodies are proteins with complex modifications, which have a significant impact on their function. The most important of these modifications is glycosylation, the addition of conserved glycans to the antibody Fc region, which is critical for its interaction with the immune system and induction of effector activities such as antibody-dependent cell cytotoxicity, complement activation and phagocytosis. Communication of IgG antibodies with the immune system is controlled and mediated by Fc gamma receptors (FcγRs), membrane-bound proteins, which relay the information sensed and gathered by antibodies to the immune system. These receptors are also glycoproteins and provide a link between the innate and adaptive immune systems. Recent information suggests that this receptor glycan modification is also important for the interaction with antibodies and downstream immune response. In this study, the current knowledge on FcγR glycosylation is discussed, and some insight into its role and influence on the interaction properties with IgG, particularly in the context of biotherapeutics, is provided. For the purpose of this study, other Fc receptors such as FcαR, FcεR or FcRn are not discussed extensively, as IgG-based antibodies are currently the only therapeutic antibody-based products on the market. In addition, FcγRs as therapeutics and therapeutic targets are discussed, and insight into and comment on the therapeutic aspects of receptor glycosylation are provided. Keywords: glycosylation, IgG, Fc gamma receptor, therapeutic monoclonal antibod
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Adjuvant-free immunization with hemagglutinin-Fc fusion proteins as an approach to influenza vaccines
No full textThe hemagglutinins (HAs) of human H1 and H3 influenza viruses and avian H5 influenza virus were produced as recombinant fusion proteins with the human immunoglobulin Fc domain. Recombinant HA-human immunoglobulin Fc domain (HA-HuFc) proteins were secreted from baculovirus-infected insect cells as glycosylated oligomer HAs of the anticipated molecular mass, agglutinated red blood cells, were purified on protein A, and were used to immunize mice in the absence of adjuvant. Immunogenicity was demonstrated for all subtypes, with the serum samples demonstrating subtype-specific hemagglutination inhibition, epitope specificity similar to that seen with virus infection, and neutralization. HuFc-tagged HAs are potential candidates for gene-to-vaccine approaches to influenza vaccination
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