The Disease-promoting Role Of Complement Activation In The Pathogenesis Of IBD

Inflammatory Bowel Disease (IBD) is a chronic and relapsing non-specific intestinal inflammatory disease. The incidence of IBD is higher in the west, however, at present its incidence has been increasing gradually in China. To date, the aetiology and pathogenesis of IBD is still not completely understood, although it has been proposed that their pathogenesis is characterized by an exaggerated immune response in genetically susceptible individuals. Currently, it is urgent to uncover the pathogenesis thereby develop potential effective agents.The innate immune system is a part of host defense against pathogens; it responds immediately after challenge. Complement system is a key component of innate immune system. The activation of complement system prompt the inflammatory cells to produce lots of in?ammatory mediators (e.g. TNF-α, IL-βand IL-6), that results in the loss of immune balance, finally leads to IBD. It demonstrates that complement system may have an impotant role in the pathogenesis of IBD. Three pathways can activate complement system: the classical, alternative and lectin binding pathways, resulting in the production of C3a, C5a and the membrane attack complex (MAC), C5b-9. C5a is one of the most potent in?ammatory peptides. It is a strong chemoattractant for neutrophils and monocytes, through the interaction with its receptors (C5aR or C5L2), C5a can recruit neutrophils and monocytes to imflamed tissues, and push them secret large amounts of inflammatory mediators. Based on the critical role of C5a in inflammatory responses, some chemical agents were developed to block C5a-C5aR interaction. Although they are effective in animal models at a certain extent, their application in human is limited due to the toxicity. Therefore, the involvement of C5a in the pathogenesis of IBD need to be further elucidated. Blockage of C5a bioactivity by antibody specific to C5a maybe become a new regimen for the treatment of IBD in the clinic. The overviews of the experiment designs and results are shown as following:Objective: To investigate whether the excessive activation of complement system is an important factor in the pathogenesis of IBD.Methods: Collect the samples of IBD patients, and utilize TNBS induced IBD model to detect the activation of complement system; then evaluate the therapeutic effect of polyclonal antibody to C5a on TNBS induced colitis; Furthermore, investigate the mechanisms underlying the therapeutic effect of polyclonal antibody to C5a in IBD. Results: Complement system is obviously activated in IBD patients and TNBS colitis, including: the increased expression of C3a and C5a, the enhancement of the haemolytic activity of complement system; destructive infiltration in colon tissues; anti-C5a treatment have preventive and therapeutic effects on TNBS-induced colitis. its mechanisms include: reduced infiltration of proin?ammatory cells into colon tissues; down regulation of the expression of proin?ammatory cytokines, meanwhile up regulation the expression of anti-in?ammatory cytokines; inhibition of polarization of Th1 and Th17 responses and enhanced Th2 response.Conclusions: C5a plays a disease-promoting role in the development of IBD. Blockade of C5a activiy has preventive and therapeutic effects on TNBS-induced colitis. These data indicate the potentials of complement-based therapy, especially C5a, in the clinical application for the treatment of IBD.