Recognition of Grampositive bacteria

Peptidoglycan was once believed to be the major component of Gram-positive bacteria involved in the onset of inflammatory responses mediated by TLRs. It was thought to activate TLR2, initiating a signaling cascade via the MyD88 Mal pathway, and independently, to activate the intracellular Nodi and Nod2 pathways, leading to activation of NF-kB 51 . The TLR2 activating potential of peptidogly-can, however, has been under scrutiny since recent evidence has shown that the bioactivity for TLR2,...

Tolllike receptor TLR signaling in the gut

The surface epithelium serves a critical function in the gastrointestinal (GI) tract as the front line of the mucosal innate immune system against luminal pathogens. The recognition of intestinal pathogens is one of the most important functions of intestinal epithelial cells and is at least partially dependent on TLR signaling. TLRs are members of a conserved interleukin-1 (IL-1) superfamily of transmembrane receptors that recognize pathogen-associated molecular patterns (PAMPs) and are a...

Known mutations in human IRAK4

Within two years of the first report of IRAK-4 deficiency, mutations in the human IRAK-4 gene were identified in 13 patients within nine unrelated families suffering from repeated, life-threatening bacterial infections early in life who also exhibit hyporesponsiveness to LPS, IL-1, and IL-18 87, 100, 101 . These individuals are highly susceptible to Gram-positive infections, although one patient had a documented N. meningitidis infection 101 , show no developmental abnormalities, and manifest...

TLRs as drug targets

Stimulation of TLRs leads to interaction with MyD88 or other members of the MyD88 family of adaptors. This family includes the TIR containing adaptor protein (TIRAP or MAL), the TIR-domain-containing adaptor protein inducing interferon-P (TRIF), the TRIF-related adaptor molecule (TRAM) and the sterile a- and armadillo motif-containing protein (SARM). The MyD88 transduction pathway ultimately leads to the activation of the nuclear factor kB (NF-kB) via the sequential recruitment activation of...

How does atherosclerosis develop

A comprehensive description of the sequence of events in atherogenesis is beyond the focus of this review, but has been well described in several review papers 4-7 . The hallmark feature of atherosclerosis is focal and chronic inflammation in the arterial wall. Inflammation constitutes the first response of innate immunity after a threat is detected, indicating that atherosclerosis is first and foremost an immune-based disease 4 . Virtually all major and minor cellular effectors of the immune...

TLR and common inhaled environmental toxins

Ligands of TLRs are ubiquitous in the environment and are therefore frequently inhaled. For example, endotoxin, which is a component of the Gram-negative bacterial cell wall, is commonly found in dust from domestic and occupational environments 34 , and contributes to the response to bioaerosols 13 . Detectable lev els of endotoxin have been found in dust from the home environment, tobacco smoke, indoor ventilation systems, particulate matter in air pollution and in a wide variety of workplace...

Innate immune responses to commensal bacteria in inflammatory bowel disease

Crohn's disease and ulcerative colitis are the two major forms of IBD characterized by acute and chronic inflammation in the absence of a known pathogen. These inflammatory disorders are distinguished by the depth and location of inflammation with ulcerative colitis being limited to the mucosa of the colon and Crohn's disease involving both the small intestine and the colon in a transmural fashion. The patho-genesis of Crohn's disease and ulcerative colitis is multifactorial, resulting from the...

TLR polymorphisms and association studies of allergic disease

Given the opposing effects of endotoxin, it is perhaps not unexpected that some studies have not revealed an effect of the common TLR4 polymorphism (D299G) on the overall incidence of asthma 116-118 . Individuals having this polymorphism have a blunted airway response 21 and reduced systemic inflammation 119 in response to inhaled endotoxin. Consistent with these observations, a study of asthma specifically associated with endotoxin in house dust showed that people with the TLR4 polymorphism...

Conclusion

Multiple lines of investigation have revealed the importance of TLRs in the development and progression of asthma. By signaling in response to inhaled pathogens or endogenous ligands, TLRs regulate both innate and adaptive immune responses Mechanisms associated with TLR-dependent regulation of inflammation TLR receptors are expressed on both antigen presenting cells as well as T-regulatory cells. Activation of TLRs can result in production of both proinflammatory or anti-inflammatory cytokines,...

Exogenous TLR ligands implicated in the progression of atherosclerosis

A number of infectious agents have been associated with atherosclerotic cardiovascular disorders, including Chlamydia pneumoniae 47 , Helicobacter pylori 48 , cytomegalovirus (CMV) 49 , Epstein-Barr virus 50 , human immunodeficiency virus 51 , herpes simplex viruses (HSV)1 52 , HSV2 53 , and hepatitis B 54 and C 55 . More recent models emphasize the relationship of atherosclerosis to total infectious burden rather than specific pathogens 56 . The above mentioned infectious agents or derived...

Endogenous TLR ligands and products of tissue destruction

It is now recognised that in addition to binding PAMPs, TLR's can also recognise endogenous signals released from injured tissue and cells undergoing necrotic cell death, such as HSP60. There are already examples of endogenous molecules signalling through TLR2, TLR3, TLR4 and TLR9. HSPs are recognised by TLR2 and TLR4, in particular HSP60 69 , HSP70 70 and gp96 71 , which are released by cells undergoing necrosis. HSP-peptide complexes are able to elicit peptide specific CD8+ T cell responses...

List of contributors

Abreu, Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA e-mail maria.abreu mssm.edu Moshe Arditi, Division of Pediatric Infectious Diseases and Immunology, Department of Pediatrics, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Room 4220, Los Angeles, CA 90048, USA e-mail moshe.arditi cshs.org Tamas Bartfai, Department of Neuropharmacology, The Harold L. Dorris Neurological Research...

TLR ligands during allergic sensitization

On the surface, findings related to the actions of TLRs in allergic asthma appear highly contradictory as endotoxin has been reported to both exacerbate asthma and diminish its incidence. Multiple epidemiologic studies have shown that exposure to TLR ligands in childhood is protective against developing asthma later in life. Examples of this include individuals living on farms who have a reduced risk of developing hay fever or asthma 66-68 , the inverse relationship shown between prior measles...

Targeting TLRs with specific ligands

Herpes Genitalis Discharge

Several synthetic TLRs ligands are available. Most of them are specific for one TLR and are being tested in different applications (Fig. 2). Novel therapeutic vaccinations are being developed to activate tumor antigen-specific T cells and prolong their activity in the host. Adjuvants based on dsRNA directly stimulate TLR3, present on myeloid dendritic cells and T cells in humans 28 . Poly I C was the first dsRNA to be used clinically in leukemia and HIV patients for its ability to stimulate...