Monday, June 27, 2005

Toll-like Receptors and You

One of the things that first got me interested in immunology was the concept that when our bodies are invaded by a pathogen, we go through a sort of 'molecular' war. Antigen presenting cells, such as Macrophages and Dendritic cells make up the scouts of our immune 'armies' detecting the initial enemy incursion. From here they report their findings to the T-cells and B-cells which employ the destructive molecular weaponry we possess to remove the pathogen. With such power however, I often wondered what mechanisms existed to prevent the immune system from recognising self tissues as an enemy. More importantly still, I wondered where these mechanisms evolved from and how they learnt to differentiate the enemy from us. At first I considered the innate immune system relatively unimportant in this process- just something to delay a pathogens replication until the big guns of the adaptive immune system could come into play. Essentially that the adaptive immune system was the one that did all the important decisions regarding the ensuing molecular battle.

Of course, now I realise that the innate immune system is more important than just a mere mecahnism for delaying replication of a pathogen, until the adaptive immune system can decide what to do about the invader. In fact, it turns out that the innate immune system is essentially responsible for restricting the pathogen and orchestrating the resulting adaptive immune response to follow. This is all coordinated by the immune systems recognition of pathogens through membrane bound receptors called Toll-like receptors, or TLRs for short. These receptors recognise different parts of microbial invaders, such as lipopolysaccharide, bacterial DNA (CpG motifs) and double stranded RNA (signature of viruses). Most importantly, depending on where the microbial product was detected in the body and what that molecule was, will dictate the entire immune response to follow.

This gives TLRs two key functions in the mammalian immune system. The first is that after recognition of a pathogen it activates the transcription of appropriate immune genes and regulators (such as cytokines). This promotes the initial response and gears up local lymphocytes such as macrophages, neutrophils and cells involved in the start of an immune response. Secondly, depending on the initial genes that were transcribed it biases the resulting adaptive immune response, producing antibodies to destroy extracellular pathogens such as bacteria or a cytotoxic (cell killing) response to destroy intracellular pathogens like viruses.

As a paper that was recently published in the Proceedings of the National Academy of Sciences (PNAS) shows, the TLRs of vertebrates are closely related in evolutionary terms, with most vertebrate receptors belonging to six specific families. They hypothesised that these general TLR families are continually present due to the inability of microbes to easily mutate or change the components they recognise. Additionally, they found that many of these TLR families have been specifically adapted to the patterns of pathogens that each animal has encountered. For example, although TLR 11 is functional in other animals, in humans it's nothing more than a useless pseudogene and is non-functional.

Additionally, some animals such as Rainbow Trout, express a soluble form of some of their membrane bound TLRs which consists of the LRR. These soluble mediators may be the precursors of mammalian LPS binding proteins. Additional hints of the origin of the immune system comes from analogous systems in Lampreys, which have been demonstrated to have variable lymphocyte receptors (VLRs). These have membrane bound receptors and soluble forms containing LRRs similar to the above TLRs. It's worth pointing out that VLRs are similar to TLRs in basic function, VLRs do not have the same function in coordination of an adaptive immune response which is not present in these animals.

In terms of evolution, TLRs have been highly conserved in function throughout many different animals, probably indicating the significance that microbial pathogens have imposed upon their hosts over evolution. Additionally, although the general function of TLRs has remained relatively conserved in their signalling function, they have taken on a new level of importance in mammals by coordinating a resulting adaptive immune response, which invertebrates like Drosophila lack. TLRs are a magnificent example of a system from 'simpler' animals that has been conserved throughout evolution and its functions altered later down the track to enable new uses.


Roach J.C., G. Glusman, L. Rowen, A. Kaur, M.K. Purcell, K.D. Smith, L.E. Hood and A. Aderem (2005). The evolution of vertebrate Toll-like receptors. Proceedings of the National Academy of Sciences, 102,27;9577-9582.