Inflammatory bowel disease
Professor AW Segal
Inflammatory Bowel Disease (IBD)
IBD, which affects approximately 1 in 500 of the population, is a generic term that includes Crohn’s diseae (CD) and ulcerative colitis (UC). However, some very significant differences in the inflammatory response in these two conditions seem to reflect the underlying mechanisms of the two diseases.
Recently we have shown major abnormalities in the inflammatory response to bacteria in these two conditions1, 2, 3. Whereas, UC is characterised by prolonged inflammation due to a defective resolution phase, CD results from impaired acute inflammation (review4). Macrophages are grossly abnormal in these two conditions and play a central role in disease progression. We are currently investigating the precise mechanisms that fail in CD and UC. In CD it appears to involve the secretory machinery required for pro-inflammatory cytokine release. In UC the problem appears to involve a signaling system that switches on the production and release of resolving mediators. Acute inflammation is normally only switched on for about 24 hours. This suppression does not occur, or is delayed, in UC. We are currently investigating the signaling pathways normally activated in macrophages by bacteria and then determine where they are defective in UC cells. These approaches should greatly increase our knowledge of these two chronic inflammatory diseases and facilitate the development of rational treatment.
1. Marks DJ, Harbord MW, MacAllister R, Rahman FZ, Young J, Al-Lazikani B, Lees W, Novelli M, Bloom S, Segal AW. Defective acute inflammation in Crohn's disease: a clinical investigation. Lancet 2006;367:668-678.
2. Smith AM, Rahman FZ, Hayee B, Graham SJ, Marks DJ, Sewell GW, Palmer CD, Wilde J, Foxwell BM, Gloger IS, Sweeting T, Marsh M, Walker AP, Bloom SL, Segal AW. Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease. J Exp Med 2009;206:1883-1897.
3. Faculty of 1000 Biology: evaluations for Smith AM et al J Exp Med 2009 Aug 31 206 (9) :1883-97 http://f1000biology.com/article/id/1165996/evaluation.
4. Sewell GW, Marks DJ, Segal AW. The immunopathogenesis of Crohn's disease: a three-stage model. Curr Opin Immunol 2009.
Cell biology of phagocytes
NADPH oxidase, cytoskeleton, oxygen radicals, killing/digestion of microbes.
Phagocytes and in particular neutrophils constitute the first line of defence of the innate immune system against invading pathogens. These white blood cells are able to chase, bind and finally engulf bacteria in a sealed phagocytic vacuole formed by invagination of the plasma membrane. Within this specialised organelle, pathogens are exposed to proteolytic enzymes that are downloaded from cytoplasmic granules. Setting ionic conditions within the vacuole that are optimal for the activity of these enzymes is critical for an efficient killing and digestion of the pathogen. To this contribute the NADPH oxidase, as well as a range of ion channels, ion exchangers and ion pumps. As it generates some reactive oxygen species in the vacuole, the NADPH oxidase has also been considered as bactericidal by itself. We use a range of electrophysiological, imaging and spectroscopy techniques to delineate the respective role of proteases and reactive oxygen species in the killing process.
Erythrocyte cytoskeleton and Na/K transport
Red Cell Membranes and Sodium-Potassium Leaks
The work in this lab concerns the movements of salt atoms, sodium and potassium, across the red cell membrane. As in all other human cells, the membrane of the red cell encloses a concentrated solution of proteins and metabolites which attracts water into the cell by osmosis. If not countered, this osmotic force will make the cell swell and burst. The cell offsets this osmotic effect by pumping sodium out of the cell, maintaining a small net deficit of sodium+potassium inside the cell that keeps it stable. The pump that does this works against a ‘leak’ process which cannot be too big, or else the pump cannot cope and the cell bursts.
There is a series of human diseases, known as the ‘hereditary stomatocytoses’, in which the leaks are abnormally large, such that the red cells rupture prematurely, causing ‘haemolytic anaemia’. In our work we seek to understand the nature of these conditions.
Among many others, we collaborate with Dr Lesley Bruce at the Bristol Institute for Transfusion Sciences, Bristol.
1. Bruce, LJ, H Guizouarn, NM Burton, N Gabillat, J Poole, JF Flatt, RL Brady, F Borgese, J Delaunay, and GW Stewart, The monovalent cation leak in overhydrated stomatocytic red blood cells results from amino acid substitutions in the Rh-associated glycoprotein. Blood, 2009. 113(6): p. 1350-7.
2. Bruce, LJ, H Robinson, H Guizouarn, P Harrison, M-J King, JS Goede, SE Coles, DM Gore, H Lutz, R Ficarella, M Layton, A Iolascon, JC Ellory, and GW Stewart, Monovalent cation leaks in human red cells caused by single amino-acid substitutions in the transport domain of the band 3 chloride-bicarbonate exchanger, AE1. Nature Genetics, 2005. 37: p. 1258-63.