MicrobiologyBytes

The responses of the immune system can be divided into two broad types – innate and adaptive immunity. Adaptive immune responses depend on clones of B and T lymphocytes which are specific for particular antigens. This is a powerful system and one of the main mechanisms the body uses to fight disease, but it has the limitation that these clones of cells take time to develop and respond to infections, typically something like four to seven days. In many infections, that would give an invading pathogen enough time to take over the entire body and inflict fatal damage, so to control infections during vital the first few days, the body relies on the evolutionarily ancient and more universal innate immune system. These innate immune responses include opsonization, phagocytosis, activation of complement and apoptosis.

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The adaptive immune system recognizes foreign attackers through T and B cell receptors on the surface of white blood cells which allow them to respond to individual antigens. In contrast, innate immunity works through a more general set of recognition molecules called pattern recognition receptors (PRRs). These are evolutionarily ancient proteins, which seem to have evolved originally to allow the body to distinguish “self” from “non-self” during development, but are also important in fighting diseases. There are various groups of pattern recognition receptors, some of which are secreted from cells, while others expressed on the cell surface or in intracellular compartments.
The Toll protein was first identified in the fruit fly Drosophila melanogaster, where it was shown to play a role in embryonic development. In 1996, Toll was also found play an essential part in the fly’s immunity to fungal infections, which it does by activating the synthesis of antimicrobial peptides. Similar proteins known as Toll-like receptors (TLRs) are present in all vertebrates as well as in invertebrates all the way back to nematodes. TLRs seem to be one of the most ancient and conserved parts of the immune system. It has been estimated that most mammalian species have between ten and fifteen types of Toll-like receptor.
So how do they work?
Unlike B and T cell receptors which are constantly changing, pattern recognition receptors such as Toll do not alter, so they are directed against key pathogen associated molecules which are evolutionarily conserved. Such features in pathogens include bacterial cell-surface lipopolysaccharides (LPS), proteins such as flagellin from bacterial flagella, double-stranded RNA of virus genomes, and the unmethylated CpG islands found in bacterial and viral DNA. Each TLR respond to a small set of different but unchanging targets.
When the molecule (or ligand in immunology jargon) to which they respond binds to the receptor, this causes intracelluar signals to be sent through a complicated cascade reaction which alters the pattern of gene expression in the cell. Adjuvants are substances which stimulate the effect an antigen such as a vaccine component by stimulating the immune system to respond to the vaccine. Many adjuvants are believed to work by mimics of TLR targets, so TLRs turn out to be important in vaccine development as well as in fighting disease directly.

Ten different TLRs have been identified in humans and the overlap between them allows recognition of a diverse range of pathogens. The functional molecules work in pairs known as dimers. Sometimes these pairs consist of two identical TLR molecules (these are called homodimers), and sometimes two different TLRs (known as heterodimers) join together to form a working receptor. This further extends the range of targets the limited number of proteins is able to recognize and respond to.
Because it is not possible to demonstrate direct biochemical interactions between them, it has been suggested that mammalian TLRs do not bind to pathogen-associated molecular patterns directly, but instead recognize the more basic building blocks from which their targets are constructed. For example, TLR4 recognizes lipid A, a core component of bacterial lipopolysaccharide (LPS). This makes sense as this makes it even harder for pathogens to evolve in order to avoid recognition.
Generally, the number of TLR molecules on the cell surface is rather low, varying from a few hundred to a few thousand molecules per cell. Some TLRs such as TLR1 are found on a wide range of different cell types, whereas others are only found in certain places, e.g. TLR3 is mostly found on immature dendritic cells. The amount of TLR present on a cell does seem to respond to stimulation by the presence of the targets they can detect, but TLR expression is also extremely variable between different individuals, which might correlate with individual differences in susceptibility to different pathogens. Sadly for me, TLR expression declines with age, which is a possible partial explanation for the increased susceptibility of elderly people to infections. In spite of this, as our understanding of how TLRs work continues to develop, we will find new ways to advance the fight against infectious diseases

• Wikipedia: TLRs
• Role of Toll-like receptors in pathogen recognition. Clin Microbiol Rev. 2003 16: 637-646
• Toll like receptors and viruses. Rev Med Virol. 2007 17: 35-43
• Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol. 2007 7: 179-190

This entry was posted on Monday, March 12th, 2007 at 10:19 am and is filed under Biology, Genetics, Health, Immunology, Medicine, Microbiology, Podcast, Science. You can follow any responses to this entry through the RSS 2.0 feed. Both comments and pings are currently closed.