"An investigation of Macrophage Biology in Crohn's Disease and other Inflammatory Diseases"
Prof Tony Segal
Description of Project:
Crohn's disease is a chronic inflammatory disorder primarily affecting the gut. The cause of the chronic inflammation is unknown, although most theories emphasise oan overly exuberant immune reaction as the initiating event. By contrast, we have found that the acute inflammatory response in Crohn's patients is in fact weak. neutrophil recruitment was markedly impaired in Crohn's patients following traum to either skin or bowel. This appeared to be secondary to defective chemotactic production by macrophages. We postulated that a weak acute inflammatory response might rpredispose to accumulation of bacteria an their products with the bowel wall, which would subsequently drive chronic inflammation. Consistent with this idea, we were able to demonstrate that subcutaneous injection of killed E coli into the forearm eleicuted a weak early local response in patients but subsequently engendered a systemic proinflammatory response.
Marks,D.J., Harbord,M.W., MacAllister,R., Rahman,F.Z., Young,J., Al Lazikani,B., Lees,W., Novelli,M., Bloom,S., & Segal,A.W. (2006a) Defective acute inflammation in Crohn's disease: a clinical investigation. Lancet., 367, 668-678.
Harbord,M.W., Marks,D.J., Forbes,A., Bloom,S.L., Day,R.M., & Segal,A.W. (2006) Impaired neutrophil chemotaxis in Crohn's disease relates to reduced production of chemokines and can be augmented by granulocyte-colony stimulating factor. Aliment.Pharmacol Ther., 24 , 651-660.
Marks,D.J ., Rahman,F.Z., Novelli,M., Yu,R.C., McCartney,S., Bloom,S., & Segal,A.W. (2006) An exuberant inflammatory response to E coli: implications for the pathogenesis of ulcerative colitis and pyoderma gangrenosum. Gut., 55, 1662-1663.
Marks,D.J. , Mitchison,N.A., Segal,A.W., & Sieper,J. (2006) Can unresolved infection precipitate autoimmune disease? Curr.Top.Microbiol.Immunol., 305:105-25., 105-125.
Marks,D.J. , Harbord,M.W., MacAllister,R., Rahman,F.Z., Young,J., Al Lazikani,B., Lees,W., Novelli,M., Bloom,S., & Segal,A.W. (2006) Defective acute inflammation in Crohn's disease: a clinical investigation. Lancet., 367, 668-678.
Marks,D.J. , Radulovic,M., McCartney,S., Bloom,S., & Segal,A.W. (2007) Modified skin window technique for the extended characterisation of acute inflammation in humans. Inflamm.Res., 56, 168-174.