IMMUUNIJÄRJESTELMÄ AVAINASEMASSA TULEHDUKSISSA

[Bb]

Lähettäjä: Soijuv Lähetetty: 27.3.2006 7:53

Taudinaiheuttajien päästyä elimistöön, immuunijärjestelmässä aktivoituu esim. TNF (tuumorinekroositekijä). Mikrobit ovat kuitenkin oppineet erilaisia menetelmiä joilla ne suojautuvat TNF:n vaikutuksilta esim. muuntamalla TNF-vastetta. TNF:llä on merkittävä rooli erilaisissa tulehduksellisissa sairauksissa, esim. reuma, MS, insuliiniresistenssi, suoliston tulehdukselliset sairaudet esim. Crohn. Tutkimuksissa keskitytään TNF:n liiallisen aktivoitumisen estämiseen.


Modulation of Tumor Necrosis Factor by Microbial Pathogens

Masmudur M. Rahman, Grant McFadden*

In response to invasion by microbial pathogens, host defense mechanisms get activated by both the innate and adaptive arms of the immune responses. TNF (tumor necrosis factor) is a potent proinflammatory cytokine expressed by activated macrophages and lymphocytes that induces diverse cellular responses that can vary from apoptosis to the expression of genes involved in both early inflammatory and acquired immune responses. A wide spectrum of microbes has acquired elegant mechanisms to overcome or deflect the host responses mediated by TNF. For example, modulatory proteins encoded by multiple families of viruses can block TNF and TNF-mediated responses at multiple levels, such as the inhibition of the TNF ligand or its receptors, or by modulating key transduction molecules of the TNF signaling pathway. Bacteria, on the other hand, tend to modify TNF-mediated responses specifically by regulating components of the TNF signaling pathway. Investigation of these diverse strategies employed by viral and bacterial pathogens has significantly advanced our understanding of both host TNF responses and microbial pathogenesis. This review summarizes the diverse microbial strategies to regulate TNF and how such insights into TNF modulation could benefit the treatment of inflammatory or autoimmune diseases.
...Anti-TNF Therapy: Clues from Pathogens?

Although TNF plays a major role in growth regulation, cell differentiation, and response to microbial infections, its inappropriate overexpression has been implicated in the pathogenesis of a wide spectrum of human disorders, such as autoimmunity (e.g., multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease), allergy, septic shock, allograft rejection, and insulin resistance. TNF derived from mast cells also plays a crucial role in initiation of inflammation, particularly in the case of rheumatoid arthritis [123]. TNF may also exert tumor-promoting activity [124]. A recent study has demonstrated that the PLAD domain of TNFR1 is critical in TNF response, because mutations in PLAD reduce NF-κB activation and cause TNFR-associated periodic syndrome, an autoinflammatory syndrome [125]. Protein therapeutics containing only the PLAD domain can effectively prevent TNFR signaling and potently inhibit arthritis [126].

Many approaches have been investigated to inhibit TNF activity for the treatment of various inflammatory/autoimmune diseases (e.g., rheumatoid arthritis, Crohn disease, and inflammatory bowel disease). The currently commercially available TNF antagonists are infliximab (a chimeric mouse/human monoclonal anti-TNF antibody), etanercept (a soluble fusion protein combining two p75 TNFRs with an Fc fragment of human IgG1), and adalimumab (a humanized monoclonal anti-TNF antibody). Although they have shown to be partially effective in clinical trails, still more needs to be learned in terms of the biology of TNF. These current inhibitors need to be delivered at high doses, and some adverse events have been reported, so that the long-term safety of all these molecules is not thoroughly understood [127]. The investigation of TNF inhibition mechanisms by pathogens may provide novel therapeutic insights. In particular, TNF inhibitors derived from viral pathogens, which operate at relatively low concentration within the infected host, offer new therapeutic strategies for reducing the pathologic consequences of excessive TNF expression in inflammatory disorders.