Ritu Dawes
Edward Jenner Institute for Vaccine Research
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Featured researches published by Ritu Dawes.
AIDS | 2001
Elma Z. Tchilian; Diana L. Wallace; Ritu Dawes; Nesrina Imami; Catherine Burton; Frances Gotch; Peter C. L. Beverley
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.
Proceedings of the National Academy of Sciences of the United States of America | 2003
Tara Stanton; Sally Boxall; Kouzo Hirai; Ritu Dawes; Susan Tonks; Tomoyo Yasui; Yasushi Kanaoka; Nadira Yuldasheva; Osamu Ishiko; Walter F. Bodmer; Peter C. L. Beverley; Elma Z. Tchilian
CD45 (leukocyte common) antigen is a hemopoietic cell-specific tyrosine phosphatase essential for antigen receptor-mediated signaling in lymphocytes. The molecule undergoes complex alternative splicing in the extracellular domain, and different patterns of CD45 splicing are associated with distinct functions. Lack of CD45 leads to severe combined immunodeficiency, and alterations of CD45 splicing, because of a polymorphism in exon 4, have been associated with altered immune function. Here we describe a polymorphism in exon 6 (A138G) of the gene encoding CD45 that interferes with alternative splicing. The polymorphism results in an amino acid substitution of Thr-47 to Ala in exon 6, a potential O- and N-linked glycosylation site. This exon 6 A138G variant is present at a frequency of 23.7% in the Japanese population but is absent in Caucasoids. Peripheral blood T cells from individuals carrying the A138G variant show a significant decrease in the proportion of cells expressing the A, B, and C CD45 isoforms and a high frequency of CD45R0+ cells. These phenotypic alterations in the A138G carriers may lead to changes in ligand binding, homodimerization of CD45, and altered immune responses, suggesting the involvement of natural selection in controlling the A138G carrier frequency.
Journal of Immunology | 2006
Ritu Dawes; Svetla Petrova; Zhe Liu; David C. Wraith; Peter C. L. Beverley; Elma Z. Tchilian
Expression of the CD45 Ag in hemopoietic cells is essential for normal development and function of lymphocytes, and both mice and humans lacking expression exhibit SCID. Human genetic variants of CD45, the exon 4 C77G and exon 6 A138G alleles, which alter the pattern of CD45 isoform expression, are associated with autoimmune and infectious diseases. We constructed transgenic mice expressing either an altered level or combination of CD45 isoforms. We show that the total level of CD45 expressed is crucial for normal TCR signaling, lymphocyte proliferation, and cytokine production. Most importantly, transgenic lines with a normal level, but altered combinations of CD45 isoforms, CD45RABC/+ and CD45RO/+ mice, which mimic variant CD45 expression in C77G and A138G humans, show more rapid onset and increased severity of experimental autoimmune encephalomyelitis. CD45RO/+ cells produce more TNF-α and IFN-γ. Thus, for the first time, we have shown experimentally that it is the combination of CD45 isoforms that affects immune function and disease.
Immunogenetics | 2002
Elma Z. Tchilian; Ritu Dawes; Patricia A. Ramaley; Jimmy Whitworth; Nadira Yuldasheva; R. S. Wells; Christine Watera; Neil French; Charles F. Gilks; Warunee Kunachiwa; Ruslan Ruzibakiev; Nipapan Leetrakool; Christine V. F. Carrington; D. Dan Ramdath; Frances Gotch; Henry A. F. Stephens; Adrian V. S. Hill; Peter C. L. Beverley
Abstract. 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. Abnormal CD45 splicing has been recognized in humans, caused by a C77G transversion in the gene encoding CD45 (PTPRC). Recently the C77G polymorphism has been associated with multiple sclerosis and increased susceptibility to HIV-1 infection. These studies suggest that the regulation of CD45 splicing may be critical for the proper function of the immune system. Because of these data we examined the frequency of the C77G allele in African and Asian populations from countries with high or low prevalence of HIV infection. Here we report that the variant CD45 C77G allele is absent in African populations. We further show that populations living in the Pamir mountains of Central Asia have a very high prevalence of the C77G variant.
Journal of Medical Genetics | 2006
Ritu Dawes; Branwen J. Hennig; William L. Irving; Svetla Petrova; Sally Boxall; Victoria Ward; Diana L. Wallace; Derek C. Macallan; Mark Thursz; Adrian V. S. Hill; Walter F. Bodmer; Peter C. L. Beverley; Elma Z. Tchilian
Background: A polymorphism in exon 4 (C77G) of CD45 that alters CD45 splicing has been associated with autoimmune and infectious diseases in humans. Objective: To investigate the effect of C77G in hepatitis C virus (HCV) infected individuals and study the phenotype and function of peripheral blood mononuclear cells (PBMC) from healthy and hepatitis C infected C77G carriers. Results: C77G individuals showed an increased proportion of primed CD45RA and effector memory CD8 T cells and more rapid activation of the lymphocyte specific protein tyrosine kinase (Lck) following CD3 stimulation. Transgenic mice with CD45 expression mimicking that in human C77G variants had more activated/memory T cells, more rapid proliferative responses, and activation of Lck. Conclusions: Changes in CD45 isoform expression can alter immune function in human C77G variants and CD45 transgenic mice. The C77G allele may influence the outcome of HCV infection.
European Journal of Immunology | 2006
Maria Montoya; Ritu Dawes; Delyth M. Reid; Lian Ni Lee; Jenny Piercy; Persephone Borrow; Elma Z. Tchilian; Peter C. L. Beverley
CD45 is a leukocyte tyrosine phosphatase, essential for normal immune responses. We have studied the function of splenic dendritic cells of CD45+/+, CD45–/–, CD45RABC and CD45RO transgenic mice. We show that there are increased numbers of plasmacytoid dendritic cells in CD45–/– mice. DC of all mice are capable of responding to lymphocytic choriomeningitis virus (LCMV) infection by up‐regulation of MHC and costimulatory molecules. DC of CD45–/– mice have an impaired capacity to produce type I interferons in response to LCMV infection in vivo. These data indicate that lack of CD45 expression in DC has a profound effect on their function. This is largely restored by CD45RABC or CD45RO transgenes.
Pediatric Research | 2004
Sally Boxall; James McCormick; Peter C. L. Beverley; Stephan Strobel; Paola De Filippi; Ritu Dawes; Catherine Klersy; Rita Clementi; Emanuella De Juli; Alina Ferster; Diana L. Wallace; Maurizio Aricò; Cezare Danesino; Elma Z. Tchilian
Hemophagocytic lymphohistiocytosis (HLH) and Langerhans cell histiocytosis (LCH) are members of a group of rare heterogenous disorders, the histiocytoses, characterized by uncontrolled accumulation of pleomorphic infiltrates of leukocytes. The etiology of these diseases is mainly unknown. CD45 is a hemopoietic cell specific tyrosine phosphatase essential for antigen receptor mediated signaling in lymphocytes and different patterns of CD45 splicing are associated with distinct functions. Recently a polymorphism (C77G) in exon 4 of CD45 causing abnormal CD45 splicing and a point mutation affecting CD45 dimerization were implicated in multiple sclerosis in humans and lymphoproliferation and autoimmunity in mice respectively. Here we show that two patients with HLH exhibited abnormal CD45 splicing caused by the C77G variant allele, while a further 21 HLH patients have normal CD45. We have also examined 62 LCH patients and found three to have the C77G mutation. Peripheral blood thymus-derived (T) CD8+ cells from normal individuals carrying the C77G mutation show a significant decrease in the proportion of cells expressing L-selectin and increased frequency of cells with LFA-1hi expression. It remains to be established whether C77G is a contributing factor in these histiocytic disorders.
Immunogenetics | 2004
Tara Stanton; Sally Boxall; Andrea R. Bennett; Pontiano Kaleebu; Christine Watera; Jimmy Whitworth; Neil French; Ritu Dawes; Adrian V. S. Hill; Walter F. Bodmer; Peter C. L. Beverley; Elma Z. Tchilian
The CD45 (leucocyte common) antigen is a haemopoietic cell specific tyrosine phosphatase essential for antigen receptor signalling in lymphocytes, and expression of different CD45 isoforms is associated with distinct functions. Here we describe a novel polymorphism in exon 4 (A54G) of the gene encoding CD45 (PTPRC) that results in an amino acid substitution of Thr-19 to Ala in exon 4. The 54G allele was identified in African Ugandan populations and was found with a suggestive but not statistically significant increase in frequency amongst HIV-seropositive Ugandans. This suggests that the 54G variant and CD45 splicing abnormalities might be associated with HIV infection.
Immunogenetics | 2006
Victoria Ward; Branwen J. Hennig; Kouzo Hirai; Hideki Tahara; Akihiro Tamori; Ritu Dawes; Mineki Saito; Charles R. M. Bangham; Henry A. F. Stephens; Anne E. Goldfeld; Warunee Kunachiwa; Nipapan Leetrakool; Julian M. Hopkin; Sarah J. Dunstan; Adrian V. S. Hill; Walter F. Bodmer; Peter C. L. Beverley; Elma Z. Tchilian
CD45 is crucial for normal lymphocyte signalling, and altered CD45 expression has major effects on immune function. Both mice and humans lacking CD45 expression are severely immunodeficient, and single-nucleotide polymorphisms in the CD45 gene that cause altered splicing have been associated with autoimmune and infectious diseases. Recently, we identified an exon 6 A138G polymorphism resulting in an increased proportion of activated CD45RO T cells and altered immune function. Here we report a significantly reduced frequency of the 138G allele in hepatitis C Japanese patients and a possibly reduced frequency in type I diabetes. The allele is widely distributed in the Far East and India, indicating that it may have a significant effect on disease burden in a large part of the human population.
Human Molecular Genetics | 2004
Sally Boxall; Tara Stanton; Kouzo Hirai; Victoria Ward; Tomoyo Yasui; Hideki Tahara; Akihiro Tamori; Shuhei Nishiguchi; Susumu Shiomi; Osamu Ishiko; Masaaki Inaba; Yoshiki Nishizawa; Ritu Dawes; Walter F. Bodmer; Peter C. L. Beverley; Elma Z. Tchilian