Tlr 2 And Tlr 4 Signal Ling example essay topic

Cellular Basis Of Disease: Why has the discovery of Toll-like receptors revolutionized 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 controversial, 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 Mat zinger, 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 innate immune system is mediated by pattern recognition receptors (PRRs) on dendritic cells, macrophages and polymorphonuclear granulocytes, that recognise pathogen-associated molecular proteins (PAMPs). PRRs recognise molecules that are not associated to human cells (PAMPs). The best characterised signal ling PRRs are the Toll-like receptors (TLRs).

They are present in plants, invertebrates and vertebrates, and represent a primitive host defence mechanism against bacteria, fungi and viruses. There are 13 TLRs that have been discovered in mammals so far, named TLR-1 to TLR-13. TLRs are primary trans membrane proteins of immune cells, that contain leucine repeats in their extracellular domains and a cytoplasmic tail that contains a conserved region called the Toll / IL 1 receptor (TIR) domain. The Toll gene was first discovered in the fruit fly Drosophila, but has close homologue's in mammalian immune cells. This is where the name Toll-like receptor is derived. Different combinations of TLRs appear in pairs in different cell types.

Different TLRs bind directly or indirectly to different microbial molecules. TLRs found on cell surfaces: a. TLR-1/TLR-2 pairs bind uniquely bacterial and GPI-anchored proteins in parasites b. TLR-2/TL 6 pairs bind acid from gram-positive cell walls and from fungi. TLR-4/TLR-4 pairs bind from gram-negative cell walls; d.

TLR-5 binds bacterial flagellinTLRs found in the membranes of the used to degrade pathogens: a. TLR-3 binds double-stranded viral Rna. TLR-7 binds uracil-rich single-stranded viral RNA such as in Hiv. TLR-8 binds single-stranded viral Rna. TLR-9 binds un methylated cytosine-guanine di nucleotide sequences (CpG DNA) found in bacterial and viral genomes.

Those TLRs shown above without a pair are those that have not yet had their pairing discovered. The binding of a microbial molecule to its TLR sends a signal to the nucleus of the cell, therefore inducing the expression of genes that code for. The then bind to cytosine receptors on other defence cells. The trigger innate immune defences such as inflammation, fever and phagocytosis to provide an immediate response against the invading microorganism. Put pic here.

TLR signal ling consists of two different pathways: a MyD 88-dependent pathway that leads to the production of inflammatory, and a MyD 88-independent pathway that is associated with the stimulation of Interferons (I FNs) and the maturation of dendritic cells. MyD 88 is a cytoplasmic protein with a TIR domain similar to that of TLRs'. The MyD 88-dependent pathway is present in all TLRs. TLRs induce the recruitment of MyD 88 via its TIR domain which activates Interleukin-1 Receptor Kinase 1 (IRAK 1) by. Irak are serine / threonine kinase's that act as signal transduction mediators for the TIR family.

The IRAK family consists of two active kinase's, IRAK 1 and IRAK 4, and two inactive kinase's, IRAK 2 and IRAK-M. IRAK 1 is by IRAK 4 and leaves the MyD 88-TLR receptor complex and associates with Tumor Necrosis Factor Receptor-associated factor 6 (TRAF 6) through an adaptor called TIFA. TRAF 6, then induces downstream signal ling, causing the activation of NF kB (a transcription factor) which, in turn induces the production of pro-inflammatory and effector that direct the adaptive immune response, such as IL 1 and IL 12. In the absence of IRAK 1, IL 1 signal ling is reduced but not completely stopped. There is only a partial loss of function because of the existence of the two homologue's to IRAK 1, IRAK 2 and IRAK-M, that are able to compensate a little for the loss of IRAK 1. Evidence suggests that IRAK 1 activity is negatively regulated by IRAK-M and a separate molecule called Tollip (Toll-interacting protein).

The over expression of Tollip has been shown to inhibit NF-kB activation in response to TLR 2 and TLR 4 signal ling. Inhibition by Tollip is mediated through its ability to suppress the activity of IRAK. Tollip, therefore, may act as moderator of the inflammatory response following TLR activation. Cells lacking IRAK-M were shown to produce higher levels of pro-inflammatory in response to various TLR-activating molecular patterns and knockout mice exhibited increased inflammatory responses to bacterial infections. Endotoxin tolerance was also found to be significantly reduced in cells lacking IRAK-M. Therefore, IRAK-M acts as a negative regulator of inflammatory signal ling. Differences between signal ling pathways induced by different TLRs are beginning to emerge.

The second pathway is activated by TLR 3 and TLR 4 and leads to activation of both NF-kappaB and another transcription factor interferon regulatory factor 3 (IRF 3), allowing for an additional set of genes to be induced, including antiviral genes such as interferon-B (IFN-B). In this way, TLRs can tailor the innate response to pathogens. TLR 2 and TLR 4 signal ling requires the adaptor TIR domain-containing adapter protein, (TIRAP) which is involved in the MyD 88-dependent pathway, however, TLR 3 triggers the production of IFN beta in response to double-stranded RNA, in a MyD 88-independent manner. This response is mediated by the adaptor TIR-containing adaptor molecule 1 (TICAM-1) TRAM / TICAM 2 is another adaptor molecule involved in the MyD 88-independent pathway whose function is restricted to the TLR 4 pathway. Many TLRs have been shown to respond to very specific pathogenic signatures. For example, TLR 2 responds to the that characterise the cell walls of Gram-positive bacteria; TLR 4 is triggered by the of Gram-negative bacteria, and TLR 5 responds exclusively to, a protein found only in the flagellae that some bacteria use to move about.

Blocking TLR function as a potential therapeutic strategy is obvious when bacteria and bacterial products, through over expressed TLR responses, activate a network of host-derived mediators. This is seen in sepsis or in the heightening of pathogen-induced diseases. Allergic asthma is an example of a chronic, T-helper type 2 cell-driven inflammatory disease demonstrating how TLR agonists or antagonists might offer possibilities for therapeutic intervention. It is proposed that the relatively sterile environment and increased use of antibiotics for childhood infections has contributed to the recent epidemic of asthma. TLR-activating bacterial vaccines or selective TLR agonists that mimic host-defence-induced responses might have therapeutic benefit in a topic diseases. There is increasing evidence that atherosclerosis is an inflammatory disease.

Rheumatoid arthritis and atherosclerosis share many common features, such as the production of inflammatory mediators, (Maps) and activation of inflammatory signal ling pathways NF kappaB. Patients with rheumatoid arthritis have an increased prevalence of atherosclerosis and of myocardial infarction compared to the general population. Recently, observation of TLR expression in atherosclerotic lesions and genetic deletion studies in mice models of atherosclerosis suggest a role of TLR signal ling as an important pathway in atherosclerosis. A detailed analysis of the TLR pathway components, including the role of intracellular adaptor's in human atherosclerosis is needed before TLR signal ling blockade can be thought of as a therapeutic approach in patients. In addition to the development of new therapies for diseases such as septic shock or disease-modifying therapies that result in immune deviation in asthma, agents that enhance TLR-signal ling pathways can be powerful in assisting in the fight against pathogens or cancer. An important issue is determining the therapeutic implications and opportunities that arise from an understanding of how TLRs and viruses interact.

Viral proteins, directed against TLRs or their derivatives, could potentially be used to suppress inappropriate TLR signal ling in a number of clinical contexts. Viral-TLR interactions have recently been suggested to be beneficial in cancer immunotherapy. In mouse models, vaccines and vectors could break CD 8 tolerance in the presence of regulatory T cells, while other cell-based vaccines could not, due to virus-induced TLR activation. The ability of tumours to evade the immune system is thought to result from the inability of T-lymphocytes to recognise and respond to tumour antigens. The lack of T-cell response may depend on the failure of dendritic cells to present antigen, causing the T-cells to become tolerant to tumour antigens rather than prepare for an immune response.

The inability of tumour-associated dendritic cells to effectively present antigen may depend on inhibitory factors in the tumour. Recent experiments suggest that the administration of TLR ligands stimulate dendritic cell activation and maturation and may therefore help overcome T-cell tolerance to tumour antigens. The discovery of the Toll-like receptors has finally identified the innate immune receptors that are responsible for many of the innate immune functions that had been studied for many years. Interestingly, TLRs seem only to be involved in the cytosine production and cellular activation in response to microbes, and do not play a significant role in the adhesion and phagocytosis of microorganisms. The recent and ongoing studies surrounding the roles of TLRs in the innate immune system, have revolutionized the subject, and there have been huge strides taken towards finding cures for two of the most prominent diseases present in the world today: cancer and atherosclerosis. The findings have enormous implications for therapy and have turned the innate immune system into a hot topic for investigation.

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