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Immunology

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Description

Toll-like receptors (TLRs) type I transmembrane proteins that recognize pathogens and activate immune cell responses as a key part of the innate immune system. In vertebrates, they can help activate the adaptive immune system, linking innate and acquired immune responses. TLR are pattern recognition receptors (PRRs), binding to pathogen-associated molecular patterns (PAMPs), small molecular sequences consistently found on pathogens.

TLRs (or TLR-like genes) are present in mammals and many other animals (including goldfish and chickens), as well as plants and are thus believed to have an ancient evolutionary origin. After defensins, they may be the oldest components of the human immune system.

Their name derives from sequence homology to the fruit fly Drosophila melanogaster gene Toll. ("Toll" is German for "amazing" or "mad".) In flies, Toll was first identified as a gene important in embryogenesis in establishing the dorsal-ventral axis. In 1996, Toll was found to have a role in the fly's immunity to fungal infections. Toll-like receptors in mammals were identified in 1997.

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Receptors

It has been estimated that most mammalian species have between ten and fifteen types of Toll-like receptors. Ten TLRs (named simply TLR1 to TLR10) have been identified in humans, and equivalent forms of many of these have been found in other mammalian species. However, equivalents of certain TLR found in humans are not present in all mammals. For example, a gene coding for a protein analogous to TLR10 in humans is present in mice, but appears to have been damaged at some point in the past by a retrovirus. Other mammals may express TLR which are not found in humans. This may complicate the process of using experimental animals as models of human innate immunity. Additionally, there are proteins that share similarities with certain regions of TLRs and not others, such as RP105. Whether these are to be called Toll-like Receptors is mainly a matter of semantics.

TLRs function as a dimer. Though most TLRs appear to function as homodimers, TLR2 forms heterodimers with TLR1 or TLR6, each dimer having a different ligand specificity.

TLRs may also depend on other co-receptors for full ligand sensitivity, such as in the case of TLR4's recognition of LPS, which requires MD-2. CD14 and LPS Binding Protein (LBP) are known to facilitate the presentation of LPS to MD-2.

The function of TLRs in all organisms appears to be similar enough to use a single model of action. Each Toll-like receptor forms either a homodimer or heterodimer in the recognition of a specific or set of specific molecular determinants present on microorganisms.

Because the specificity of Toll-like receptors (and other innate immune receptors) cannot be changed, these receptors must recognize patterns that are constantly present on threats, not subject to mutation, and highly specific to threats (i.e. not normally found in the host where the TLR is present.) Patterns that meet this requirement are usually critical to the pathogen's function and cannot be eliminated or changed through mutation; they are said to be [evolutionarily conserved]?. Well conserved features in pathogens include bacterial cell-surface lipopolysaccharides (LPS), lipoproteins, lipopeptides and lipoarabinomannan; proteins such as flagellin from bacterial flagella; double-stranded RNA of viruses or the unmethylated CpG islands of bacterial and viral DNA; and certain other RNA and DNA. See the table below for a summary of known TLR activity.

Activation and effects

Following activation by the bound pathogenic factor, several reactions are possible. Immune cells can produce signalling factors called cytokines which trigger inflammation. In the case of a bacterial factor, the pathogen might be phagocytosed and digested, and its antigens presented to CD4+ T cells. In the case of a viral factor, the infected cell may shut off its protein synthesis and may undergo programmed cell death (apoptosis). Immune cells that have detected a virus may also release anti-viral factors such as interferons?.

Summary of Known Mammalian Toll-like Receptors
Receptor Ligand PAMP(s) Activation Cascade(s)
[TLR 1]? triacyl lipoproteins? unknown
[TLR 2]? lipoproteins? [gram positive bacteria]? peptidoglycan; [lipoteichoic acid]?; fungi?MyD88? dependent TIRAP
[TLR 3]? double-stranded RNA (as found in certain viruses?), poly I:C MyD88 independent TRIF/TICAM
[TLR 4]? lipopolysaccharide? MyD88 dependent TIRAP; MyD88 independent TRIF/TICAM/TRAM
[TLR 5]? flagellin MyD88 dependent IRAK
[TLR 6]? diacyl lipoproteins unknown
[TLR 7]? small synthetic compounds; single-stranded RNA MyD88 dependent IRAK
[TLR 8]? small synthetic compounds MyD88 dependent IRAK
[TLR 9]? unmethylated [CpG site? CpG] DNA MyD88 dependent IRAK
[TLR 10]? unknown unknown
[TLR 11]? unknown, but present in uropathogenic bacteria MyD88 dependent IRAK

The discovery of the Toll-like receptors finally identified the innate immune receptors that were responsible for many of the innate immune functions that had been studied for many years. Interestingly, TLRs seem only to be involved in the cytokine production and cellular activation in response to microbes, and do not play a significant role in the adhesion and phagocytosis of microorganisms.

Danger model

More recently TLRs have been suspected of binding to non-pathogen associated factors produced during disease, stress, and trauma; including molecules such as fibrinogen (involved in blood clotting post-trauma) and heat shock proteins (HSPs) (generated in heat stress, including pathogen response fevers). This is based upon Polly Matzinger's "Danger Model" of immunity, which suggests that these molecular signatures are recognised as associated with either an increased risk of disease, or disease itself ("danger!"), and put the immune system on alert through TLR activation. However, this model is controversial.

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Attribution

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