الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
The immune response is mediated via two parallel immune components, innate and adaptive, whose effector functions are highly integrated and coordinated for the protection of the human body against invading pathogens and transformed cells. The discovery of pathogen recognition receptors (PRRs), most not ably toll-like receptors (TLRs), in innate immunity has evoked increased interest in the therapeutic handling of the innate immune system. TLRs are germ line-encoded receptors that play a potent role in the recognition of a diverse variety of ligands ranging from hydrophilic nucleic acids to lipopolysaccharide (LPS) or peptidoglycan (PGN) structures in pathogens.
The past decade has seen a rebirth of interest in innate immunity and in the regulation of subsequent adaptive responses. The foot soldiers of the innate immune system, namely, dendritic cells and macrophages, ingest pathogens and release cytokines drawing secondary, active and defensive cells from the blood. These active immune cells, mainly antigen-specific T and B-cell clones, are selected during an adaptive immune response and the subsets of these clonal cells become long living memory cells that can be readily reactivated on re-exposure to antigens. Since being first described in the fruitfly, Drosophila melanogaster, the toll-like receptor (TLR) family of pathogen recognition receptors (PRRs) has become a major component in innate immunity, innate-adaptive crosstalk, infectious diseases and inflammatory conditions. In 1997, Medzhitov et al. were the first to report the cloning of a mammalian TLR homologue (now identified as TLR4). More than a decade has passed since the discovery of the first human TLR. During this period, this field of research has exploded so rapidly that all TLRs (i.e., 10 human TLRs) have now been cloned, many of their ligands discovered and their associated main species.
Innate immune responses begin with TLR recognition of specific microbial components that are widely expressed by bacteria, fungi, protozoa and viruses.
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Pathogen-encoded TLR ligands fall into three broad categories: lipids and lipopeptides (TLR2/1; TLR2/6 and TLR4), proteins (TLR5 and TLR11) and nucleic acids (TLR3, 7, 8 and 9). Thus, different TLRs are amenable to targeting by different types of agents.
TLRs are type 1 integral membrane glycoproteins comprising leucine-rich repeat motifs (ectodomain) which mediate the recognition of PAMPs and a conserved cytoplasmic toll/ IL-1 receptor (TIR) endodomain which is required for downstream signal transduction that are joined by a single transmembrane helix .
A mammalian homologue of Drosophila Toll receptor (now termed TLR4) was shown to induce the expression of genes involved in inflammatory responses. In addition, a mutation in the Tlr4 gene was identified in mouse strains that were hyporesponsive to lipopolysaccharide. Since then, Toll receptors in mammals have been a major focus in the immunology field. First, several proteins that are structurally similar to TLR4 were identified and named TLRs. The TLR family now consists of 10 members (TLR1–TLR10). The cytoplasmic portion of TLRs shows high similarity to that of the interleukin (IL)-1 receptor family, and is now called the Toll/IL-1 receptor (TIR) domain. Despite of this similarity, the extracellular portions of both types of receptors are structurally unrelated. The IL-1 receptors possess an Ig-like domain, whereas TLRs bear leucine-rich repeats (LRRs) in the extracellular domain. Genetic approaches have mainly been conducted to analyze the physiological function of TLRs, and have revealed essential roles for TLRs in the recognition of pathogens. Each TLR has been shown to recognize specific components of pathogens, thus demonstrating that the mammalian immune system detects invasion by pathogens via the recognition of microbial components by TLRs.
Individual TLRs are differentially distributed within the cell. TLR1, TLR2 and TLR4 are expressed on the cell surface, as demonstrated by positive staining of the cell surface by specific antibodies. In contrast, TLR3, TLR7, TLR8 and TLR9
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have been shown to be expressed in intracellular compartments such as endosomes . TLR3-, TLR7- or TLR9- mediated recognition of their ligands has been shown to require endosomal maturation. The TLR9 ligand CpG DNA is first non-specifically captured into endosomes, where TLR9 is recruited from the endoplasmic reticulum upon non-specific uptake of CpG DNA . Thus, it can be hypothesized that in the case of bacterial infection, macrophages and dendritic cells engulf bacteria by phagocytosis.
Individual TLR signaling pathways are divergent, it has also become clear that there are MyD88-dependent and MyD88-independent pathways.
MyD88-dependent pathway:
A MyD88-dependent pathway is analogous to signaling pathways through the IL-1 receptors.
MyD88-independent/TRIF-dependent pathway:
MyD88-independent component exists in TLR4 signaling. Subsequent studies have demonstrated that TLR4 stimulation leads to activation of the transcription factor IRF-3, as well as the late phase of NF-kB activation in a MyD88-independent manner.
Several lines of evidence indicate that TLRs are implicated in inflammatory and immune disorders. For example, constitutive activation of innate immune cells caused by defective IL-10 signaling results in development of chronic enterocolitis . Introduction of TLR4 deficiency into these mutant mice results in improvement of intestinal inflammation, indicating that TLR-mediated microbial recognition in the intestine triggers development of chronic enterocolitis. The MyD88- dependent pathway is seemingly involved in allograft rejection. Development of atherosclerosis observed in apolipoprotein E-deficient mice is rescued by introduction of MyD88 deficiency, indicating that the TLR-mediated pathway is responsible for the development of atherosclerosis. Involvement of the TLR9–MyD88-dependent pathway in the induction of auto-antibodies in SLE and rheumatoid arthritis was
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also demonstrated, as described above. In addition to these immune-related disorders, TLR recognition of commensal bacteria has been shown to play a crucial role in the maintenance of intestinal epithelial homeostasis. Thus, TLR-mediated pathways are probably involved in many Aspects of immune responses, even in the absence of infection.
Many attempts to use TLR manipulation for the treatment of infectious, allergic and autoimmune diseases, as well as cancer, are in the early clinical phases, and results have not been always positive. One successful TLR candidate is Ampligen, a mismatched, double-stranded RNA which activates TLR3 and is currently awaiting registration in the US for the treatment of chronic fatigue syndrome (CFS), an illness that is not fully understood, but often seems to be associated with viral infection. Ampligen new drug application (NDA) was filed, but marketing for the treatment of CFS has not yet been approved.
Their ability to initiate and propagate inflammation makes them attractive therapeutic targets. By understanding TLR-induced mechanisms, we can design more targeted therapeutic interventions for inflammatory disorders in the future. The ancient system of host defense of our cells is an outstanding target for intervention in the relentless efforts in finding cures. Pharmacological intervention in TLR pathways may potentially hold great therapeutic promise. Although for the past decades corticosteroids and in some instances antibodies were the mainstay of anti-inflammatory treatment, we are now at the stage of evaluating TLR pathway modifying molecules in human diseases.