My research team applies immunological-, genetic-, protein-, and cell-engineering together with a functional proteomics based approach to study the molecular mechanisms that operate in allergic disease. Work is in progress in the following areas:
Following the identification of residues in human immunoglobulin E (IgE) which influence the interaction of the mediator of the allergic response with high-and low-affinity receptors (1,2,3), we aim at the development of rational, small molecule antagonist of the allergic response (4).
In parallel, investigations are ongoing into the molecular basis of signal transduction and target cell activation via the high-affinity receptor complex for IgE in cells of mast cell lineage. An investigation of changes in gene expression in these cells following allergen provocation has yielded surprising insight into the aetiology of class-specific immune responses which may have important consequences for the design of vaccination procedures to prevent IgE-mediated allergies (5,6,7).
To investigate mast cell activation and downstream signalling via the high-affinity receptor for IgE, which culminates in the release of mediators of the allergic response responsible for the clinical symptoms of allergic disease, we are using a functional proteomics based approach (8) to study signalling events culminating in regulated exocytosis which involve small molecular weight G-proteins (9,10). The identification of positive and negative regulatory control mechanisms of mast cell degranulation has important implications for the design therapeutic interventions, preventing cell degranulation.
Figure legend Response of immune system to polyvalent antigen
Selected Publications
[1] Sayers, I., Housden J.E., Spivey AC, and Helm, BA. (2004) The Importance of Lys-352 of human IgE in FceRII/CD23 recognition. J. Biol. Chem. 279, 35320-5.
[2] Sayers, I. and B.A. Helm (1999) Structural basis of human IgE-Fc receptor interactions. Clin Exp Allergy 29: 585-94
[3] I. Sayers, S.A. Cain, J.R.M. Swan, M.A. Pickett, P.J. Watt, S.A. Holgate, E.A. Padlan, P. Schuck and B.A. Helm (1998) Amino acid residues that influence FcRI mediated effector functions of human immunoglobulin E. Biochemistry 37, 16152-16164
[4] Spivey, AC, McKendrick, J., Srikaran, R., Helm, BA (2003) Solid phase synthesis of an A-B loop mimetic of the Ce3 domain of human IgE by Sonogashira coupling. J. Org. Chem., 68, 1843-51.
[5] Smyth, L.J., Machado, D.C., Good, S., Upton, A., Aufderheide M., and Helm, B.A. (2000) Assessment of the molecular basis of pro-allergenic effects of cigarette smoke. Environmental Science and Technology, 34, 1370-74.
[6] Machado, D.C., Horton, D., Harrop, R., Peachell, P.T. and Helm, B.A. (1996) Potential Allergens stimulate mediator release and interleukin-4 synthesis from cells of mast cell lineage in the absence of sensitisation with antigen-specific IgE. Eur. J. Immunol. 26:2972-2980.
[7] Dudler, T., Machado, D.C., Kolbe, L., Annand, R, Rhodes, N., Gelb, M., Koelsch, E., Suter, M. and Helm, B.A. (1995) A link between catalytic activity, IgE-independent mast cell activation and allergenicity of bee venom phospholipase A 2. J. Immunol. 155: 2505-2513.
[8] Carroll, K., Carey E., Helm, B. (2002) Protein mapping in rat basophilic leukaemia cells. J. Chromatography 771, 289-301. Carroll, K., Ray, K., Helm, B. and Carey E. (2001) Differential expression of Rab3 isoforms in high- and low-secreting mast cell lines. Eur. J Cell Biol. 80, 295-302).
[9] Carroll, K., Ray, K., Helm, B. and Carey E. (2001) Differential expression of Rab3 isoforms in high- and low-secreting mast cell lines. Eur. J Cell Biol. 80, 295-302.
[10] Carroll, K., Ray, K., Helm, B. and Carey E. (2000) Two-dimensional electrophoresis reveals differential protein expression in high-and low-secreting variants of the rat basophilic leukaemia cell line. Electrophoresis, 12, 2476-86.
