By Mark J. Soloski, Ph.D.
- Introduction
- Pattern Recognition Molecules: Down the Toll Road!
- Impact on Rheumatological Disease
- Suggested Reading
When most of us studied immunology for the first time we were taught that when antigen is introduced into the host, it takes some 5-7 days before anything interesting happens. Thus our focus was on the generation of the adaptive immune response involving the production of specific antibody or the generation of cytotoxic T cells. Very little attention was given events from day 0-5 except perhaps to acknowledge that antigen was being processed and presented to T cells and both T and B cells were undergoing an activation process. But there is much more to responding to a foreign pathogen than the “acquired” immune response, as we shall see.
The problem: microbes can divide as frequently as every 10 to 15 minutes. Acquired immunity requires several days to mount an antigen specific response. How does the host keep potential pathogens at bay until then? It is clear that the immune system evolved to respond to an array of life threatening infectious microorganisms. As a result of this pressure, multicellular organisms have developed varied defense mechanisms that are triggered by infection to protect the host by destroying the invading microbes and neutralizing their virulence factors. This phylogenetically ancient defense mechanism, also known as the innate immune system, uses germline-encoded receptors for the recognition of microbial pathogens. This feature distinguishes the innate immune system from the other component of immunity, the adaptive immune system, found only in vertebrates.
Many microbial pathogens synthesize unique molecular structures (LPS, teichoic acid, etc), many of which are essential for survival. The innate immune system has evolved a series of receptors (Pattern Recognition Receptors, PRRs) which have the property of recognizing microbe unique structures (PAMPS, Pathogen Associated Molecular Patterns). These PRRs, when they bind their ligands (PAMPS), transmit signals into the immune cell which can lead to inhibition of microbial growth and/or the release of biological mediators that can instruct the adaptive arm of the immune response. Therefore, the innate immune response represent a “first line” of defense that in and of itself, can limit microbe growth but, perhaps more importantly, can transmit information to the adaptive immune response, whose role is to facilitate the complete clearance of the microbe.
We will focus on the innate immune system and discuss one of three molecular recognition systems that have evolved. The system we will focus on includes a series of receptors (Toll receptors) on phagocytes that recognize microbial products. The second system involving serum proteins (complement, etc) that can chemically modify bacterial cell walls and mediate their clearance and a third system involving unique lineages of bone marrow derived cells (NK and NK T cells) that bear receptors allowing the recognition of pathogen induced cellular changes will be the subject of future articles.
Pattern Recognition Molecules: Down the Toll Road!
This area of study got started in Drosophila with the definition of a set of genes (Toll and 18-wheeler, both PRRs) affecting early development. Through the use of genetics, multiple components of this system were defined including a potential ligand, and intracellular associated signaling components that mediate the activation of the Drosophila transcriptional activator NFkB. Later, through additional genetic and expression studies it was discovered that these receptor signaling complexes also play a role in the adult in insect immunity to microbial pathogens. Drosophilia that have defects in Toll have increased susceptibility to infection with fungi, while defects in 18-wheeler are susceptible to bacteria infection. Based on this it was subsequently shown that this receptor”signaling complex leads to the activation of NFkB regulated genes such as dorsomycin, cecropin, diptercin, etc, all which have anti-microbial properties.
The novel features of this receptor complex prompted work on the identification of a similar complex in higher vertebrates. Indeed this was the case and several Toll-like Receptors (TLR1 -9) have been defined in mouse and man. Studies on the definition of TLR function have taken two avenues. First, TLR deficient cells have been transfected with TLR genes and their ability to respond to exogenous stimuli tested. For example, human TLR-2 expression confers the ability to produce cytokines following stimulation with either LPS (a component of the cell wall of gram negative bacteria) or a lipoprotein purified from Mycobacteria tuberculosis (Mtb). The other approach is to generate mice deficient in one or more TLRs using homologous recombination. To date, mice deficient in TLR-2 or TLR-4 have been generated. Cells from mice deficient in TLR-4 fail to generate cytokines in response to LPS (gram-negative bacteria) while mice deficient in TLR-2 fail to respond to components of gram-positive bacteria. This work indicated that there are subtle differences in human and mouse Tolls but more importantly implies that there may be a “division of labor” among TLRs with some specializing in the recognition of specific classes of pathogens. One possibly is that differential engagement of TLRs expressed on the same cell may lead to a unique cellular response that can impact on both the survival of the pathogen and be instructive to subsequent adaptive (T and B cell mediated) response.
One important issue that is unresolved is the lack of evidence that these microbial products directly bind to TLRs. One possibility is that other proteins are involved. For example, TLR4 may associate with the GPI-anchored molecule CD14 and form a binding complex.
In addition to the TLRs, there are other protein receptors that have been demonstrated to interact with microbial structures. For example, the mannose-binding protein (MBP), a member of the collectin family, is synthesized in the liver and is secreted in response to infection. This molecule uniquely binds to microbial carbohydrate (CHO) patterns that decorate microorganisms yet does not bind self CHOs. MBP recognizes a hydroxyl (OH) micropattern only found in the hexoses N-actylglucosamine, glucose, fucose and mannose that make up cell wall structures and is not found in the configuration of OH groups in galactose and sialic acid, the penultimate and ultimate sugars that are present in “self” glycoproteins/glycolipids.
Impact on Rheumatological Disease
What does all of this have to do with rheumatological disease! Likely quite a bit. It is becoming increasingly apparent that early events in the immune process (days 0-5?) influence the eventual response. It is likely that early events, possibly mediated by pattern recognition molecules, will have profound influence on how antigens are cleared, processed and recognized by the immune system and how cells are activated and/or functionally programmed. There is no information to date as to the genetic variation within this pattern recognition system but given our knowledge base, it is likely that some elements may prove to be susceptibility factors that predispose to the generation of autoimmunity. The Toll road is an exciting new field of investigation, the speed limit is high – dont blink, keep posted for details.
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