Antibodies from IMGENEX: Toll-like Receptors

Date Added: december 16, 2010

Author: Stephen Jones

The guardians of innate immunity

Innate immunity as the first line of defense
The innate immune system is an ancient mechanism of host defense in almost all multicellular organisms from plants to humans. In invertebrates, it is the only mechanism of defense against pathogens but in higher vertebrates it is the first line of defense. The role of the innate immune system is to distinct between self and non-self and between pathogenic and nonpathogenic microbes, it also plays an important role in triggering and optimization of the adaptive immune response. This remarkable system allows an immediate nonspecific response against micro-organisms while the adaptive immune system mounts a specific response against the invading pathogen during the late phase of infection.

Pattern Recognition Receptors

The cornerstone of the innate immune system is composed of germline-encoded receptors called pattern recognition receptors (PRR), in which the Toll-like receptors belong. These PRRs are activated upon recognition of “pathogen-associated molecular patterns’ or PAMPs. PAMPs are molecular structures shared by large groups of pathogens not normally present in the host.

1. Molecular model system must be shared by large groups of pathogens and therefore should represent general trends rather than specific structures.
2. They must be retained products of microbial metabolism that are not subject to antigenic variability. Although the immune system selects against these models, the pathogens can not “change” because they are essential to the survival or pathogenicity of microorganisms. Any attempt to change them could be lethal to the microbe or render it non-pathogenic.
3. The structures recognized must be absolutely distinct from self-antigens. The major consequence of this requirement is the ability of the innate immune system distinguish between self and non-self.

Characterized PAMPS particular cell wall constituents such as lipopolysaccharide (LPS), peptidoglycan (PGN), lipoteichoic acid (LTA) or lipoarabinomannan (LAM), but also single or double stranded RNA and unmethylated CpG DNA .

Overview of Toll-like receptors
The TLRs owe their name to a receptor called Toll closely related, first identified in Drosophila. The first member of the Toll family was identified in Drosophila in 1988 during a screen for embryonic polarity genes. Drosophila Toll receptors cause an induction of innate immune responses of a first link to a tube adapter, which is a functional homologue of mammalian MyD88. This tube is connected to the kinase Pelle, a homologue of IRAK, and after a cascade of reactions leading to the transcription of genes that modulate and mediate the activation of antimicrobial pathways that directly kill the pathogen.

Toll and its mammalian homologs are type I transmembrane protein characterized by an extracellular leucine-rich domain and a cytoplasmic domain referred to as Toll/IL-1R or TIR domain because of its homology with the cytoplasmic domain of interleukin a mammalian receptor (IL-1R). Upon binding of extracellular ligand recognition domain of PAMPs, changes in the intracellular domain result in the initiation of signaling events, including translocation of transcription factors, modulation of cytokines and interferon-stimulated gene regulation leading to inflammatory responses and / or release of antimicrobial agent.

The first member of the mammalian TLR family characterized was TLR4, which has been shown to trigger the way proinflammatory NF-kB upon binding to LPS. The completion of the Human Genome Project has identified many putative TLRs in the genome. These TLRs differ from each other in ligand specificities, expression profiles, and target genes they induce.

At least 11 TLRs have been identified in humans and 13 in mice. While they are expressed primarily in the treatment of antigen presenting cells and such as macrophages, neutrophils and dendritic cells, expression of TLRs is not limited to these cell types. Although research is ongoing, TLR expression at least at the mRNA level, appears to be detectable in a wide range of tissues, including adrenal gland, liver, lungs, spinal cord, spleen, testis , thymus, and trachea, suggesting that subsets of TLR are expressed in most cells of the body.

TLR signaling
Stimulation of TLRs by pathogens leads to the expression of several genes involved in immune response by a number of signaling pathways. Pathways activated include the NF-kB (IkBa phosphorylation, translocation of NF-kB p65 in the nucleus), the p38 mitogen activated protein kinases, Jun N-terminal-kinase (JNK), and the path of interferon .

Although TLR-mediated signaling pathways are still unclear, a number of specific molecules are known to be involved. These include adapter molecules such as MyD88, MyD88 adapter-like (Mal), also known as Toll/IL-1R (TIR) domain containing adapter protein (TIRAP) and TIR domain-containing adapter inducing interferon (TRIF), also known as TICAM1. Other key signaling proteins include IL-1 receptor associated kinase (IRAK) such as IRAK1, 2 and 4, transforming growth factor kinase (TAK-1), IkB kinase (IKK) and TRAF (TNF receptor factors Associates).