Profile: Dr Ken Smith

Principal investigators

Negative regulation of the immune response in health and disease
The immune response is controlled by cell surface molecules which act as negative regulators or brakes, preventing or turning off cellular activation. Knockout mice with defects in these negative regulatory systems develop immune hyperactivity and autoimmunity. Our group aims to understand how these molecules regulate the normal immune response, and how defects in their action cause autoimmune disease.

1. Negative regulation and the normal immune response.

We have shown that interleukin-4 reduces expression of negative regulators on B cells, suggesting that IL-4 may enhance the B cell immune response by releasing the B cell from inhibition, rather than by directly activating it. We are investigating the functional consequences of this reduced expression, and whether IL-4 has a similar effect in other cell types. In addition, we are studying the role played by the inhibitory Fc receptor FcγRII in feedback control of the B cell response and on affinity maturation.

2. Defective negative regulation and autoimmune disease.

Systemic lupus erythematosus (SLE) is an autoimmune disease arising from the combined effects of multiple susceptibility genes. Fcg RIIb inhibits activation of cells including B cells and macrophages. We have identified reduced expression and function of Fcg RII in all major SLE-prone mouse strains. The resulting immune hyperactivity is likely to make a fundamental contribution to disease. We are examining how reduced Fcg RII causes autoimmunity, and how such genetic "defects" have evolved in the wild mouse population.

3. The B cell immune response and viral immune modulators.

We are analysing how murine γ-herpesvirus 68 (related to human Epstein Barr virus) influences B cell gene expression using microarray technology and viruses deficient in potential immmunomodulatory genes [with Dr Paul Lyons (profile), DIL, and Dr Stacey Efstathiou, Virology].This should provide insight not only into mechanisms of viral pathogenesis, but may also identify novel B cell signalling pathways.

Funding

• The Wellcome Trust
• Medical Research Council

Group members:

• Menna Clatworthy
• Tony Cutler
• Gisela Gamba Fernandez
• Andres Floto
• Jim Hair
• Karen Heilbronn
• Nick Pritchard
• Liz Rudge 

Key publications

• Rudge E.R., Cutler A.J., Pritchard N.R. & Smith K.G.C. (2002) "Interleukin -4 reduces expression of inhibitory receptors on B cells and abolishes CD22 and FcgRII-mediated B cell suppression" Journal of Experimental Medicine. 195, 1079-1085.

• Pritchard, N.R., Cutler, A.J., Uribe, S., Chadban, S.J., Morley, B.J. & Smith, K.G.C.(2000). "Autoimmune-prone mice share an Fcgr2 promoter haplotype associated with reduced expression and function of the negative regulatory Fc receptor FcγRII." Current Biology 10, 227-230.
  
  
• Smith, K.G.C., Light, A., O’Reilly, L.A., Ang, S.M., Strasser, A. & Tarlinton, D.M. (2000). "bcl-2 transgene expression inhibits apoptosis in the germinal center and reveals differences in the selection of memory B cells and bone marrow antibody forming cells." Journal of Experimental Medicine 191, 475-484.
  
  
• Tarlinton, D.M. & Smith, K.G.C. (2000). "Dissecting affinity maturation — a model explaining selection of antibody forming cells and memory B cells in the germinal centre." Immunology Today 21, 436-441.
  
  
• Smith, K.G.C., Tarlinton, D.M., Doody, G.M., Hibbs, M.L. & Fearon, D.T (1998). "Inhibition of the B cell by CD22: a requirement for Lyn" Journal of Experimental Medicine. 187, 807-811.

Publications

• Pritchard NR, Cutler AJ, Uribe S, Chadban SJ, Morley BJ and Smith KGC. "Autoimmune-prone mice share an Fcgr2 promoter haplotype associated with reduced expression and function of the negative regulatory Fc receptor FcRII." Current Biology 2000;10:227-230.
  
  
• Smith KGC, Light A, O’Reilly LA, Ang SM, Strasser A and Tarlinton DM "bcl-2 transgene expression inhibits apoptosis in the germinal center and reveals differences in the selection of memory B cells and bone marrow antibody forming cells." Journal of Experimental Medicine 2000; 191: 475-484.
  
  
• Calne RY, Moffatt SD, Friend PJ, Jamieson NV, Bradley JA, Hale G, Firth JD, Bradley JR, Smith KGC and Waldmann H. "Prope tolerance with induction using campath 1H and low-dose cyclosporin monotherapy in 31 cadaveric renal allograft recipients." Nippon Geka Gakkai Zasshi 2000; 101: 301-306.
  
  
• Cozzi E, Bhatti FNK, Schmoeckel M, Chavez G, Smith KGC, Zaidi A, Bradley JR, Thiru S, Goddard M, Vial C, Morgan P, White DJG and Friend PJ. "Long-term survival of non-human primates receiving life-supporting transgenic porcine kidney xenografts." Transplantation 2000;70:15-21.
  
  
• Tarlinton DM and Smith KGC. "Dissecting affinity maturation — a model explaining selection of antibody forming cells and memory B cells in the germinal centre." Immunology Today 2000; 21: 436-441.
  
  
• Masroor S, Cozzi E, Soin B, Vial C, Chavez G, Smith KGC, Bradley JR, White DJ and Friend PJ "Absence of hyperacute rejection and preservation of function in HDAF transgenic pig kidneys exposed to prolonged cold ischaemia." Transplantation Proceedings 2000;32:965-966.
  
  
• Chadban SJ, Bradley JR and Smith KGC. "Clinical Immunosuppression in Renal Transplantation" in Thiru S and Waldmann H (editors) "Pathology and Immunology of Transplantation" Blackwell Science, London 2000;180-215.
  
  
• Soin B, Cozzi E, Ostlie D, Smith KGC, Bradley JR, White DJG and Friend PJ "Growth of porcine kidneys in the normal and xenotransplant environment" Xenotransplantation 2000;7:96-100.
  
  
• Tarlinton DM, Light A, Smith KGC and Nossal GJV "Affinity maturation in the B cell response to antigen". The Immunologist 2001; 8:9-11
  
  
• Reed MJ, Alexander GJM, Thiru S and Smith KGC. "Hepatitis C-associated glomerulonephritis: a novel therapeutic approach." Nephrology Dialysis Transplantation 2001;16:869-871.
  
  
• Soin B, Smith KGC, Zaidi A, Cozzi E, Bradley JR, Ostlie D, Lockhart A, White DJG and Friend PJ "Physiological aspects of pig-to-primate renal xenotransplantation" Kidney International 2001;60:1592-1597.
  
  
• Clatworthy MR and Smith KGC "B cells and autoimmune disease" in Lightstone EB and Friedland JS (eds) Postgraduate Medical Sciences Series "Infection and Immunity", Harwood Academic 2001: in press.
  
  
• Rudge ER, Cutler AJ, Pritchard NR and Smith KGC. "Interleukin -4 reduces expression of inhibitory receptors on B cells and abolishes CD22 and FcgRII-mediated B cell suppression" Journal of Experimental Medicine 2002:195;1079-1085.

• Pritchard NR and Smith KGC "B cell inhibitory receptors and autoimmunity" Immunology 2003:263-273

• Floto RA and Smith KGC "The vagus, macrophages and nicotine". The Lancet 2003:361;1069-1070

• Willcocks L and Smith KGC "Renal Transplantation". Medicine, 2003: in press

• Marques S, Efstathiou S, Smith KGC, Haury M and Simas JP. "Selective Gene Expression of Latent Murine Gammaherpesvirus 68 in B Lymphocytes." 2003: Journal of Virology 2003: in press

Last updated: 8 May 2003

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