Tumour Necrosis Factor Alpha in Segmental Colitis Associated with Diverticula

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Slide 1 : UNIVERSITY OF FOGGIA School of Medicine Tumour Necrosis Factor Alpha in Segmental Colitis Associated with Diverticula Enzo Ierardi Associate Professor of Gastroenterology
Slide 2 : Segmental Colitis Associated with Diverticula DefinitionSegmental colitis associated with diverticula (SCAD) is an inflammatory bowel disease confined to a colonic tract involving diverticular disorder Incidence: ~ 0.3-1.4%, more frequent in males aged more than 60 yrs living in developed countries Site: in most cases the disease is located in descending and sigmoid colon and the rectum is not affected Pathology: the inflammation may mimic the aspects of inlammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis and is usually confined to the mucosa
Slide 3 : Diagnosis Diagnosis is performed by clinical symptoms, endoscopy and histology The main symptom is intestinal bleeding associated to abdominal pain, alterations in bowel movement habits and incomplete defecation At endoscopy, peridiverticular mucosa shows hyperaemia, oedema, with superficial erosions and ulcers Histology shows mononucler cell infiltration of the lamina propria, lymphoid aggregates, cript abscessess and loss of glandular parallelism. In the long term, Paneth cell metaplasia may occur. Therapeutic approach is based on antibiotics, mesalazine, and steroids, expecially with a low systmic effect such as beclometasone
Slide 4 : IBD aetiopathogenesis is unknown.A series of antigenic esogenous and endogenous stimulations in genetically predisposed subjects may provoke the loss of physiologic control of inflammation with an abnormal production of pro-inflammatory cytokines and the alteration of the balance of inflammatory mediators at intestinal level Aetiopathogenetic aspetcs of IBD Genetic factors Infectious factors Environmental factors Psycologic factors Alterations of immune system function Alterations of intestinal bareer Intestinal wall disorder
Slide 5 : TNFa TNFa is a pro-inflammatory cytokine which plays a pivotal role in the inflammatory response of the acute phase It acts in the regulation of immune cell function It is produced after the exposition to lipopolysaccarides of Gram negative bacteria by: Mononuclear phagocytes T lymphocytes after antigenuic activation Stimulated NK cells Stimulated mastocytes
Slide 6 : APC CD4+ IL-12 IL-15 IL-1 TNF? CD4+ Th 0 IL-2 TNF? IFN ? IL-4 IL-5 IL-6 IL-10 IL-13 IFN? IL-10 CELLULAR IMMUNITY CIRCULATING IMMUNITY IL-12 IL- 4 IL-2 Th 1 Th 2 Elson CO: The immunology of IBD, 1999
Slide 7 : AIM OF THE WORK In a previous report we described an impressive improvement in a patient affected by SCAD refractory to convenional treatments with the use of anti-TNFa (infliximab), associated to a marked reduction of this cytokine in intestinal mucosa thus suggesting a possible role of TNFa even in the pathogenesis of SCAD On these bases we performed the present study with the aim of confirming TNFa involvement in SCAD and designed a “post hoc” study in order to evaluate both TNFa expression in intestinal mucosa and mucosal inflammation and damage in a series of patients affected by SCAD enclosed in a previous follow-up report (Imperiali et al, Am J Gastroenterol 1999)
Slide 8 : MATERIAL AND METHODS The study involved 14 patients ( 8 M, 6 F, mean age 66.5 yrs and range 49-80 yrs) with an endoscopic diagnosis of SCAD Control group was represented by a matched group of patients with irritable bowel syndrome (IBS) undergoing endoscopy for rcurrent abdominal pain Both groups underwent colonoscopy and biopsy samples were taken at sigmoid level
Slide 9 : Mucosal damage was evaluated by a score represented by the mean value of the single scores of the following alterations: Polymorphonuclear inflitration of the epithelium and the lamina propria Crypt abscesses Loss of glandular parallelism Crypt ramification and/or shortening Epithelial mucus depletion Extension of inflammation towards muscularis mucosae and submucosa MATERIAL AND METHODS(histological damage evaluation: Ierardi et al 2007; Digest Liver Dis) A score ranging from 0 to 3 was assigned to each parameter, as follows: 0 absence of alterations (normal picture) 1 mild alterations 2 moderate alterations 3 severe alterations
Slide 10 : Inflammation activity was established by the number of plymorphonuclear cells in the lamina propria Cell count was performed in five randomized fields with a magnification of 400 x and expressed as polymorphs/mm² using a dedicated software (Leica Q Winn Softare program, Cambridge – UK). MATERIAL AND METHODS(inflammation activity: Ierardi et al 2007; Digest Liver Dis) Inlammation activity was considered as: Mild: ? 5 and < 10 plymorphs/mm² Moderate: ? 10 and < 15 plymorphs/mm² severe: ? 15 polymorphs/mm²
Slide 11 : TNFa was revealed by immunohistochemistry after incubation with a polyclonal rabbit antibody (PromoCell, Heidelberg, Germany). The reaction was revealed by a peroxidase/anti-peroxidase (PAP) technique (Dako, Copenhagen, Denmark). Diaminobenzidine was used as chromogen and haematoxylin as counterstain MATERIAL AND METHODS(TNFa labelling index - LI: Ierardi et al 2001; J Clin Pathol) STATISTICAL ANALYSIS Student’s t test for unpaired data TNFa LI was represented by the percentage of stromal positive cells when at least 1000 cells were counted in randomized fields at a magnification of 400 x
Slide 12 : RESULTS Damage score in SCAD patients was higher compared to control group (2.05± 0.5 versus 0.1± 0.2; P< 0.001) Mucosal damage was strongly related to a high activity score expressed as polymorphs/mm2 in SCAD group compared to controls (16.3 ± 3 versus 2.2± 1.4/ mm²; P<0.001) A high activity of inflammation was strongly related to a high TNFa LI
Slide 13 : TNFa LI was higher than 25 in all patients with SCAD, whilst it was always under this value in controls MUCOSAL EXPRESSION OF TNFa
Slide 14 : TNFa expression was higher in SCAD patients showing a severe mucosal damage score (>2) compared to patients with moderate damage (46.4± 6 versus 32 ± 8.8; P = 0.003). SCAD patients with severe inflammation (? 15 polymorphs/mm²) showed a high TNFa LI compared to patients with moderate activity score (44.1 ± 8% versus 32.3 ± 9.6 %; P = 0.016). MUCOSAL EXPRESSION OF TNFa
Slide 15 : CONCLUSIONS SCAD presence is strongly associated to an immunohistochemical overexpression of TNFa simlarly to conventional IBD such as Crohn’s disease and ulcerative colitis Therefore, SCAD may be considered as a clinical autonomous entity, different from bacterial diverticulitis, with an etiopathogenesis presumably due to an altered immunoregulation Our study supports the possibility to treat with anti TNFa the few cases of SCAD clinically severe and refractory to conventional therapies

 


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