The GateKeepers of Innate Immunity

Innate immunity as the first line of defense
The innate immune system is an ancient host defense mechanism found in almost every multicellular organism from plants to humans. In invertebrates it is the sole mechanism of defense against pathogens but in higher vertebrates constitutes the first line of defense. The role of the innate immune system is not an insignificant one; not only must it discriminate between self and non-self as well as distinguish between pathogenic and non-pathogenic microbes, it also plays an important role in triggering and optimizing the adaptive immune response. This remarkable system allows an immediate non-specific response against microorganisms whereas the adaptive immunity mounts a specific response against the invading pathogen during the late phase of the infection.

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Pattern Recognition Receptors
The cornerstone of the innate immune system is comprised of germline-encoded receptors referred to as pattern-recognition receptors (PRRs), to which the Toll-like receptors belong.  These PRRs are activated upon recognition of “Pathogen-Associated Molecular Patterns” or PAMPs.  PAMPs are molecular patterns shared by large groups of pathogens not usually present in the host. 
 
1. Molecular patterns system must be shared by large groups of pathogens and thus must represent general patterns rather then specific structures.
2. They must be conserved products of microbial metabolism which are not subject to antigenic variability.  Although the immune system selects against these patterns, pathogens cannot "change" them because they are essential for the survival or pathogenicity of the microorganisms.  Any attempts to change them could be lethal to the microbe or render it nonpathogenic.
3. The recognized structures must be absolutely distinct from self-antigens. The major consequence of this requirement is the ability of the innate immune system to discriminate between self and non-self.

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

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

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

The first characterized member of the mammalian family of TLRs was TLR4 which was shown to trigger the pro-inflammatory NF-kB pathway upon binding to LPS. The completion of the human genome project led to the identification of numerous putative TLRs in the genome. These TLRs differ from each other in ligand specificities, expression patterns, and target genes they induce.

At least 11 TLRs have been identified in humans and 13 in mice. While they are expressed predominantly in antigen processing and presentation cells such as macrophages, neutrophils, and dendritic cells, TLR expression is not restricted 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, lung, spinal cord, spleen, testis, thymus, and trachea suggesting that subsets of TLRs are expressed in the majority of cells in the body.

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

While TLR-mediated signaling pathways are still being elucidated, 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 adaptor protein (TIRAP), and TIR domain-containing adapter inducing interferon (TRIF), also known as TICAM1. Other key signaling proteins include IL-1 receptor associated kinases (IRAKs) such as IRAK1, 2, and 4, transforming growth factor kinase (TAK-1), IkB kinases (IKKs), and TRAFs (TNF receptor associated factors). 

Summary of Toll-like Receptors & their Ligands