The Pirbright Institute publication directory contains details of selected publications written by our researchers.

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The CD45 antigen is essential for normal antigen receptor-mediated signalling in lymphocytes, and different patterns of splicing of CD45 are associated with distinct functions in lymphocytes. Here we show that abnormal CD45 splicing caused by a C77G transversion in exon A of the gene encoding CD45 (PTPRC) is associated with increased susceptibility to HIV-1 infection.
Tchilian E Z, Wallace D L, Imami N, Liao H X, Burton C, Gotch F, Martinson J, Haynes B F, Beverley P C L (2001)

The Exon A (C77G) mutation is a common cause of abnormal CD45 splicing in humans

Journal of Immunology 166 (10), 6144-6148


The leukocyte common (CD45) Ag is essential for normal T lymphocyte function and alternative splicing at the N terminus of the gene is associated with changes in T cell maturation and differentiation. Recently, a statistically significant association was reported in a large series of human thymus samples between phenotypically abnormal CD45 splicing and the presence of the CC chemokine receptor 5 deletion 32 (CCR5del32) allele, which confers resistance to HIV infection in homozygotes. We show here that abnormal splicing in these thymus samples is associated with the presence of the only established cause of CD45 abnormal splicing, a C77G transversion in exon A. In addition we have examined 227 DNA samples from peripheral blood of healthy donors and find no association between the exon A (C77G) and CCR5del32 mutations. Among 135 PBMC samples, tested by flow cytometric analysis, all those exhibiting abnormal splicing of CD45 also showed the exon A C77G transversion. We conclude that the exon A (C77G) mutation is a common cause of abnormal CD45 splicing and that further disease association studies of this mutation are warranted.
Tchilian E Z, Wallace D L, Wells R S, Flower D R, Morgan G, Beverley P C L (2001)

A deletion in the gene encoding the CD45 antigen in a patient with SCID

Journal of Immunology 166 (2), 1308-1313


SCID is a heterogeneous group of hereditary diseases. Mutations in the common gamma -chain (gamma (c)) of cytokine receptors, including those for IL-2, IL-4, IL-7, IL-9, and IL-15, are responsible for an X-linked form of the disease, while mutations of several other genes, including Janus-associated kinase-3, may cause autosomal recessive forms of SCID. We investigated the first SCID patient to be described with minimal cell surface expression of the leukocyte common (CD45) Ag. CD45 is an abundant transmembrane tyrosine phosphatase, expressed on all leukocytes, and is required for efficient lymphocyte signaling. CD45-deficient mice are severely immunodeficient and have very few peripheral T lymphocytes. We report here that a homozygous 6-bp deletion in the gene encoding CD45 (PTPRC, gene map locus 1q31-32), which results in a loss of glutamic acid 339 and tyrosine 340 in the first fibronectin type III module of the extracellular domain of CD45, is associated with failure of surface expression of CD45 and SCID. Molecular modeling suggests that tyrosine 340 is crucial for the structural integrity of CD45 protein. This is the second description of a clinically relevant CD45 mutation, provides direct evidence for the importance of CD45 in immune function in humans, and suggests that abnormalities in CD45 expression are a possible cause of SCID in humans.
Vorechovsky I, Kralovicova J, Tchilian E, Masterman T, Zhang Z P, Ferry B, Misbah S, Chapel H, Webster D, Hellgren D, Anvret M, Hillert J, Hammarstrom L, Beverley P C (2001)

Does 77 -> G in PTPRC modify autoimmune disorders linked to the major histocompatibility locus?

Nature Genetics 29 (1), 22-23
Publisher’s version:


A 77G allele of the gene encoding CD45, also known as the protein tyrosine phosphatase receptor-type C gene (PTPRC), has been associated with multiple sclerosis (MS). Here we determine allele frequencies in large numbers of MS patients, primary immunodeficiencies linked to the major histocompatability complex (MHC) locus and over 1,000 controls to assess whether aberrant splicing of PTPRC caused by the 77C-->G polymorphism results in increased susceptibility to these diseases. Our results show no difference in the frequency of the 77G allele in patients and controls and thus do not support a causative role for the polymorphism in the development of disorders with a strong autoimmune component in etiology.


The subcellular localization of transmissible gastroenteritis virus (TGEV) and mouse hepatitis virus (MHV) (group I and group II coronaviruses, respectively) nucleoproteins (N proteins) were examined by confocal microscopy. The proteins were shown to localize either to the cytoplasm alone or to the cytoplasm and a structure in the nucleus. This feature was confirmed to be the nucleolus by using specific antibodies to nucleolin, a major component of the nucleolus, and by confocal microscopy to image sections through a cell expressing N protein. These findings are consistent with our previous report for infectious bronchitis virus (group III coronavirus) (J. A. Hiscox et al., J. Virol. 75:506-512, 2001), indicating that nucleolar localization of the N protein is a common feature of the coronavirus family and is possibly of functional significance. Nucleolar localization signals were identified in the domain III region of the N protein from all three coronavirus groups, and this suggested that transport of N protein to the nucleus might be an active process. In addition, our results suggest that the N protein might function to disrupt cell division. Thus, we observed that approximately 30%. of cells transfected with the N protein appeared to be undergoing cell division. The most likely explanation for this is that the N protein induced a cell cycle delay or arrest, most likely in the G(2)/M phase. In a fraction of transfected cells expressing coronavirus N proteins, we observed multinucleate cells and dividing cells with nucleoli (which are only present during interphase). These findings are consistent with the possible inhibition of cytokinesis in these cells.
Wyde P R, Guzman E, Gilbert B E, Couch R B (2001)

Immunogenicity and protection in mice given inactivated influenza vaccine, MPL, QS-21 or QS-7

4th World Congress on Options for the Control of Influenza, Crete, Greece. 1219, 999-1005


Background: Monophosphoryl lipid A (MPL), QS-21 and QS-7 were evaluated in mice for their ability to increase the immunogenicity and protective efficacy of formalin-inactivated (FI) influenza A/Texas/91 virus vaccine. Freund's incomplete adjuvant (FIA) was used as a positive control. Methods: Mice were inoculated twice, 28 days apart, either intramuscularly (I.M.) with vaccine mixed with phosphate buffered saline, FIA, MPL or QS21, or intranasally J.N.) with vaccine containing QS-21 or QS-7. The mice were bled on days 0, 28 and 49 and challenged I.N. on this last day with live virus. Four days later, the lungs from each animal were assessed for influenza virus. All sera were tested for virus-specific neutralizing (Nt), hemagglutination inhibiting (HI) and ELISA antibodies. Studies to account for the mechanism(s) of adjuvant activity have been initiated. Results: FIA, MPL and QS-21 all enhanced the production of virus-specific antibodies and increased protection from pulmonary virus infection following I.M. administration. Maximal adjuvanticity occurred in groups inoculated with "low" doses of vaccine and in groups administered vaccine mixed with QS-21. Both QS adjuvants exhibited significant adjuvant activity following IN inoculation. Protection correlated best with levels of virus-specific serum Nt and HI antibodies. Conclusions: The present studies support continued development of adjuvants for inactivated influenza virus vaccines.
Beard P M, Rhind S M, Sinclair M C, Wildblood L A, Stevenson K, McKendrick I J, Sharp J M, Jones D G (2000)

Modulation of gamma delta T cells and CD1 in Mycobacterium avium subsp paratuberculosis infection

Veterinary Immunology and Immunopathology 77 (3-4), 311-319


M.a. paratuberculosis is the causal agent of paratuberculosis (Johne's disease). Recent work has suggested that gamma delta T cells may play an important role in the early immunological response to mycobacterial diseases, and that CD1 may act as a non-classical MHC molecule in antigen presentation to these gamma delta T cells. Experimental infection of neonatal lambs with M.a. paratuberculosis was used to investigate the changes in gamma delta T cells and CD1 molecules in the gut associated lymphoid tissue 4 weeks after inoculation. Immunohistochemistry was used to label the gamma delta lymphocytes and CD1 molecules. An increase in the number of gamma delta T cells was noted in both the jejunal and ileal Peyer's patches in the gut of infected lambs, but no statistically significant change was found in the mesenteric lymph nodes. There were no obvious changes in the CD1 molecules in any tissue. This work suggests that gamma delta T cells may play a role in the initial immunological events of paratuberculosis infection.


Activation of the nuclear factor κB plays a key role in viral pathogenesis, resulting in inflammation and modulation of the immune response. We have previously shown that A238L, an open reading frame from African swine fever virus (ASFV), encoding a protein with 40% homology to porcine IκBα exerts a potent anti-inflammatory effect in host macrophages, where it down-regulates NF-κB-dependent gene transcription and proinflammatory cytokine production. This paper reveals the mechanism of suppression of NF-κB activity by A238Lp. A238Lp is synthesized throughout infection as two molecular mass forms of 28 and 32 kDa, and vaccinia-mediated expression of A238L demonstrated that both proteins are produced from a single gene. Significantly, the higher 32-kDa form of A238L, but not the 28-kDa form, interacts directly with RelA, the 65-kDa subunit of NF-κB, indicating that the binding is dependent on a post-translational modification. Immunoprecipitation analysis shows the NF-κB p65-A238L p32 heterodimer is a separate complex from NF-κB-IκBα, and it resides in the cytoplasm. Moreover, we show that ASFV infection stimulates the NFκB signal transduction pathway, which results in the rapid degradation of endogenous IκBα, although both forms of A238Lp are resistant to stimulus-induced degradation. Using the proteasome inhibitor MG132, we show that when degradation of IκBα is inhibited, A238Lp binding to NF-κB p65 is reduced. The results suggest that the virus exploits its activation of the NF-κB pathway to enable its own IκB homologue to bind to NF-κB p65. Last, we show that synthesis of IκBα is increased during ASFV infection, indicating RelA-independent transcription of the IκBα gene.


The tick-borne rickettsia Cowdria ruminantium has been propagated continuously for over 500 days in the Ixodes scapularis tick cell line IDES by using the Gardel isolate from bovine endothelial cells as an inoculum, Infection of the tick cells was confirmed by PCR, karyotyping, electron microscopy, and reinfection of bovine cells.


Recombinant E(rns) glycoprotein of bovine viral diarrhoea virus (BVDV) has been tagged with a marker epitope or linked to an immunoglobulin Fc tail and expressed in insect and mammalian cell lines. The product was shown to be functional, both having ribonuclease activity and binding to a variety of cells that were permissive and non-permissive for replication of BVDV. Addition of soluble E(rns) to the medium blocked replication of BVDV in permissive cells. Binding of epitope-tagged E(rns) to permissive calf testes (CTe) cells was abolished and virus infection was reduced when cells were treated with heparinases I or III. E(rns) failed to bind to mutant Chinese hamster ovary (CHO) cells that lacked glycosaminoglycans (pgsA-745 cells) or heparan sulphate (pgsD-677 cells) but bound to normal CHO cells. E(rns) also bound to heparin immobilized on agarose and could be eluted by heparin and by a high concentration of salt. Flow cytometric analysis of E(rns) binding to CTe cell cultures showed that glycosaminoglycans such as heparin, fucoidan and dermatan sulphate all inhibit binding but dextran sulphate, keratan sulphate, chondroitin sulphate and mannan fail to inhibit binding. The low molecular mass polysulphonated inhibitor suramin also inhibited binding to CTe cells but poly-L-lysine did not. Furthermore, suramin, the suramin analogue CPD14, fucoidan and pentosan polysulphate inhibited the infectivity of virus. It is proposed that binding of E(rns) to cells is through an interaction with glycosaminoglycans and that BVDV may bind to cells initially through this interaction.


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