Toll like receptors and their therapeutic potential Essay -- essays re

Cellular Basis Of Disease: Why has the discovery of Toll-like receptors revolutionised our understanding of how the innate immune system works, and what is the therapeutic potential? The body has two immune systems: the innate immune system and the adaptive immune system. Adaptive, or acquired, immunity refers to antigen-specific defence mechanisms that take several days to become protective and are designed to react with and remove a specific antigen. This is immunity develops throughout life. Innate immunity refers to antigen-nonspecific defence mechanisms that a host uses immediately or within several hours after exposure to an antigen. This is the immunity that you are born with, and is the initial response by the body to eliminate microbes and prevent infection. It is in the innate immune system that Toll-like receptors are important in helping our understanding. The most important role of the innate immune system is to react rapidly to infectious agents with the initiation an inflammatory response, and to shape the subsequent adaptive immune responses. There are currently two different models for immune system induction. The first model predicts the recognition of non-self determinants on pathogens, and the other, more controvertial, model predicts that there is recognition of damage or danger to self-tissues. In the first model, pathogens are recognised by either specific or general components of their structure. A system referring to the patterns that are recognised are the pathogen associated molecular patterns (PAMPs) and the receptors recognising them are pattern recognition receptors (PRRs). The second model, put forward by Matzinger, is that it is the danger itself that is sensed. It is argued that it is tissue damage or cellular debris from necrotic cells that sends the signal for the immune system to initiate a response. The presence of DNA or RNA, that shouldn't be outside of the cell, may cause an alarm signal. Heat shock proteins released from the cell, or mannose that is normally cleaved off, may also serve as an alarm signal. It is suggested that the PRRs are there to recognise these endogenous signals from ruptured cells, and not to recognise pathogens as proposed in the first model. It is the first model that is most widely accepted in the scientific community, and it is this model of events that I shall describe. Activation of the ... ...77(9):7059-65 9. Horng T. et al., 2002. The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature. 420(6913):329-33 Takatsuna H., et al. 2003. Identification of TIFA as an adapter protein that links TRAF6 to IRAK-1 in IL-1 receptor signaling. J Biol Chem. 2003 Yang L, Blumbergs PC, Jones NR, Manavis J, Sarvestani GT and Ghabriel MN (2004). Early expression and cellular localization of proinflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in human traumatic spinal cord injury. Spine. 29: 966-71 Therapeutic targeting of Toll-like receptors for inflammatory and infectious diseases. O'Neill LA. Nat Rev Drug Discov. 2002 Oct;1(10):797-807 Role of toll-like receptors and their adaptors in adjuvant immunotherapy for cancer. Seya T, Akazawa T, Uehori J, Matsumoto M, Azuma I, Toyoshima K. Anticancer Res. 2003 Nov-Dec;23(6a):4369-76 Toll-like receptor signaling in anti-cancer immunity. Okamoto M, Sato M. J Med Invest. 2003 Feb;50(1-2):9-24 H. Hemmi, et al., "A toll-like receptor recognizes bacterial DNA," Nature, 408(6813):740-5, 7 December 2000. bst.portlandpress.com/ bst/031/0637/bst0310637.htm