the MHC region for a total of 18,405 individuals with Crohn’s disease, 14,308 individuals with ulcerative colitis and 34,241 control subjects. Using these SNP data, we imputed and benchmarked the genetic variation within the class I ( HLA-B , HLA-C and HLA-A ) and class II ( HLA-DRB1 , HLA-DRB3 , HLA-DRB4 ,

Roberts, Rebecca L; Wallace, Mary C; Seinen, Margien L; Krishnaprasad, Krupa; Chew, Angela; Lawrance, Ian; Prosser, Ruth; Bampton, Peter; Grafton, Rachel; Simms, Lisa; Radford-Smith, Graham; Andrews, Jane M; Barclay, Murray L

Basic science S17 influencing the development of inflammatory and immune responses.Aim of the present study is to evaluate the expression and function of uPA-uPAR system in experimental models of colitis.Methods: The dextran sulfate sodium (DSS) and trinitrobenzene sulfonic acid (TNBS) were used as models of colitis.Expression of uPAR and uPA in healthy and colitic mice was assessed by Real-time.uPAR expression changes were further confirmed by western-blot analyses.Specificity of uPAR expression was investigated by both confocal microscopy and flow cytometry.The functional role of uPAR was examined in uPAR knock out (KO) mice.Colitis disease activity index (DAI) was calculated and intestinal damage evaluated by both endoscopy and histology.Results: The expression levels of uPA and uPAR increased during both DSS and TNBS treatment, as measured by Real-Time (4 6 fold increase for uPAR, p < 0.01 and 2 6 fold increase for uPA, p < 0.01).Western Blot studies confirmed uPAR changes in colitic mice (6 fold increase, p < 0.01).Confocal microscopy and FACS analysis identified CD68+ cells as the major cell type expressing high levels of uPAR.KO mice displayed higher weight loss and increased DAI (p < 0.01, at day 8 and 9 for DSS model; p < 0.05 at day 3 and 4 for TNBS model), compared to wild-type littermates.Histological and endoscopic score were significantly higher in KO mice (p < 0.05).Conclusions: Our findings reveal the uPA-uPAR system as a new component involved in controlling inflammation.In particular, uPAR expression is up-regulated during colitis by CD68+ macrophage and its genetic deletion leads to detrimental inflammation.uPAR seems to play a protective role in the development of experimental colitis and modulation of the uPA-uPAR system could offer a new pathway to control intestinal inflammation.

Background SPARC is a matricellular protein involved in tissue remodelling, cell migration and angiogenesis, while forkhead box P3 (FOXP3) protein functions as a transcription factor involved in immune cell regulation. Both SPARC and FOXP3 can play an anti-tumorigenic role in cancer progression. The aim was to determine if SPARC, FOXP3, CD8 and CD45RO expression levels are associated with colorectal cancer (CRC) stage, disease outcome and long-term cancer-specific survival (CSS) in stage II and III CRC. Methods and Findings SPARC expression was initially assessed in 120 paired normal and stage I-IV CRCs. Subsequently, approximately 1000 paired patient samples of stage II or III CRCs in tissue microarrays were stained for SPARC, FOXP3, CD8 or CD45RO. Proportional hazards modelling assessed correlations between these markers and clinicopathological data, including disease outcome and cancer specific survival (CSS). Both SPARC and FOXP3 expression were significantly greater in CRC than normal colon (p<0.0001). High SPARC expression correlated with good disease outcome (≥60 mths without disease recurrence, p = 0.0039) and better long-term CSS in stage II CRC (<0.0001). In stage III CRC, high SPARC expression correlated with better long-term CSS (p<0.0001) and less adjuvant chemotherapy use (p = 0.01). High FOXP3 correlated with a good disease outcome, better long-term CSS and less adjuvant chemotherapy use in stage II (p<0.0037, <0.0001 and p = 0.04 respectively), but not in stage III CRC. High CD8 and CD45RO expression correlated with better disease outcome in stage II CRC, and better CSS, but the differences were not as marked as for SPARC and FOXP3. Conclusions These data suggest that high SPARC and FOXP3 are associated with better disease outcome in stage II CRC and may be prognostic indicators of CSS. Further assessment of whether these markers predict patients at high risk of recurrence with stage II CRC and functional studies of these effects are underway