- •Sensing the microbial universe
- •The toll receptor in Drosophila
- •Lipopolysaccharides: shield and signal
- •Signalling through the TLR4 receptor
- •The TIRAP/MyD88 pathway
- •From TRAF6 to activation of IRF-3
- •The TRAM, TRIF pathway
- •The IRF family of transcription factors
- •Negative feedback control of the TLR4 pathway
- •Some consequences of TLR4-induced gene transcription
- •Essay: ubiquitylation and SUMOylation
- •Ubiquitylation
- •Ubiquitylation: a process involving three activities (but not necessarily three proteins)
- •63K or 48K conjugation
- •Two classes of E3-ubiquitin ligases
- •Ubiquitin-binding proteins
- •SUMO and sumoylation
- •Essay: the proteasome complex
- •The proteasome
- •20S particle
- •Proteasome activator (PA) subunits
- •List of abbreviations
- •References
Chapter 15
Activation of the Innate immune System: the Toll-like Receptor 4 and Signalling through Ubiquitylation
Host defence in mammals is provided by innate and adaptive (or acquired) mechanisms of immunity, both able to discriminate between the self
and non-self. In innate immunity, invading microbes are sensed either directly, through the release of cellular components, or indirectly through the deposition of lectins, C-reactive protein, or complement (C3b) on their outer membranes.1,2 This first line of defence, though not always fully protective, buys time and is required to establish the much more potent processes
of adaptive immunity by which invading microbes are sensed by specific immunoglobulins (Ig) and then destroyed. This occurs directly by means of cytolytic antibodies that activate the complement system. Or it may occur indirectly by means of cytotoxic T cells that recognize virus-infected cells, or through stimulation of phagocytosis by granulocytes and macrophages.
In an evolutionary perspective, innate immunity predated adaptive immunity, dendritic cells constituting the primary cellular link between the two processes. The establishment of adaptive immunity depends on antigen
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Signal Transduction
The many abbreviations used in this chapter are collected together at the end of the chapter.
presentation by dendritic cells, macrophages and B cells. There follows the expansion of antigen-specific clones of T cells (both CD4 T-helper cells and CD8 cytolytic T cells) and immunoglobulin-producing B cells. These processes are dependent on the creation of an inflammatory environment; effectively, the production of inflammatory mediators such as interleukin
IL-1 , IL-6, IL-12, IFN- / / or TNF- , and chemotactic factors such as RANTES, MIP1 / , IL-8, or MCP-1. These play important roles in the recruitment of leukocytes by regulating the expression of adhesion molecules (see Chapters 13 and 16). They also participate in the maturation of dendritic cells, preparing them to initiate the differentiation of effector T cells and of memory cells. Further down the line, the inflammatory mediators also play a role in the maturation of B cells into plasma cells, and thus stimulate the production of microbe-specific immunoglobulins.
Metchnikov and Ehrlich
The foundations for the understanding of immunity, both innate and adaptive, were laid by Ilya Metchnikov and Paul Ehrlich, who, in 1908, shared the Nobel prize ‘in recognition of their work on immunity’. We can regard Metchnikov as an early developmental biologist. He detected a population of highly motile cells associated with the larvae of starfish (echinoderms) and postulated
that these could somehow be implicated in defence. Putting this idea to the test, he added crusted thorns from a tangerine tree which had served as
Christmas decorations for his children, and found the next morning that they were surrounded by these mobile cells. The scene reminded him of white blood cells accumulating at sites of infection and he suggested that the two phenomena represent the mobilization of specialized cells in order to destroy invaders. His friend Professor Claus suggested the name ‘phagocytes’ (from the Greek phagein, eating) to describe the mobile cells. His first paper on ‘phagocytosis’ appeared in 1884.3
Ehrlich, around 1895, was investigating the protective effect of serum passive immunization against bacterial toxins. He found that it contained ‘antitoxins’ that disabled the bacterial products. He was one of the first to recognize the importance of specific molecular interactions or, as he stated it, ‘corpora non agunt nisi fixate’, meaning, ‘substances do not act if they are not bound’. The antitoxins we now recognize as antibodies (immunoglobulins). A similar principle of molecular recognition was also elaborated by John
Newport Langley who, in 1906, postulated that ‘receptive substances’ transmit physiological effects (see page 16).
Sensing the microbial universe
To initiate an immunological response, the invading microbes must first be recognized. This occurs through a family of pattern-recognition receptors (PRRs). These have a limited diversity, are expressed in all cells,
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