Roitt's Essential Immunology - the textbook of choice for students and instructors of Ivan M. Roitt MA, DSc(Oxon), FRCPath, Hon FRCP (Lond), FRS Centre for. Get this from a library! Roitt's essential immunology. [Peter J Delves; Seamus J Martin; Dennis R Burton; Ivan M Roitt]. Roitt's Essential Immunology Peter J. Delves Professor Delves obtained When Ivan wrote the first edition some 40 years Abbreviations AAV.
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Preceded by Roitt's essential immunology / Peter J. Delves [et al.]. 12th ed. | ISBN (pdf) | ISBN (epub). Subjects: | MESH: University College London (with Ivan Roitt) and The La Jolla. Institute for. Peter J. Delves, Seamus J. Martin, Dennis R. Burton, Ivan M. Roitt 15 Transplantation · Chapter 16 Tumour immunology · Chapter 17 Autoimmune diseases. Peter J. Delves, Seamus J. Martin, Dennis R. Burton, Ivan M. Roitt Roitt's Essential Immunology - the textbook of choice for students and instructors of.
Burton, Ivan M. Ivan M. Skickas inom vardagar. All rights reserved. Many exhibit remarkable selectivity for prokaryo- tic and eukaryotic microbes relative to host cells, partly dependent upon differential membrane lipid composition. Recognition of nonself entities is achieved by means of an array of pattern recogni- tion receptors and proteins collectively called pattern recog- nition molecules that have evolved to detect conserved i. The abundant glycogen stores can be utilized by glycolysis enabling the cells to function under anerobic conditions.
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Cytokines are commonly released by cells of the immune system in response to PAMPs and DAMPs, and this has the effect of altering the activation state and behaviour of other cells to galvanise them into joining the fight. Both types of messenger proteins act by dif- fusing away from the cells secreting them and binding to cells equipped with the appropriate plasma membrane recep- tors to receive such signals.
Cytokines, chemokines and their respective receptors are discussed at length in Chapter 9.
Innate versus adaptive immunity Three levels of immune defense Before we get into the details, we will first take a look at how the immune system works in broad brushstrokes. The verte- brate immune system comprises three levels of defense Figure 1. First, there is a physical barrier to infection that is pro- vided by the skin on the outer surfaces of the body, along with the mucous secretions covering the epidermal layers of the The vertebrate immune system comprises three levels of defense.
Infectious agents that successfully penetrate the physical barriers are then engaged by the cells and soluble factors of the innate immune system.
The innate immune system is also responsible for triggering activation of the adaptive immune system, as we will discuss later in this chapter. The cells and products of the adaptive immune system reinforce the defense mounted by the innate immune system. Any infectious agent attempting to gain entry to the body must first breach these surfaces that are largely imperme- able to microorganisms; this is why cuts and scrapes that breach these physical barriers are often followed by infection.
The second level of defense is provided by the innate immune system, a relatively broad-acting but highly effective defense layer that is largely preoccupied with trying to kill infectious agents from the moment they enter the body.
The actions of the innate immune system are also responsible for alerting the cells that operate the third level of defense: The latter cells represent the elite troops of the immune system and can launch an attack that has been specifically adapted to the nature of the infectious agent using sophisticated weapons such as antibodies.
Innate immune responses are immediate and relatively broad acting Upon entry of a foreign entity into the body, the innate immune response occurs almost immediately.
Innate immune responses do not improve upon frequent encounter with the same infectious agent. The innate immune system recognizes broadly conserved components of infectious agents, the afore- mentioned PAMPs, that are not normally present in the body. Upon detecting a PAMP, the innate immune system mounts an immediate attack on anything displaying such molecules by either engulfing such entities or through attacking them with destructive enzymes, such as proteases or membrane attacking proteins Figure 1.
The clear intent is to bludgeon the unwanted intruder into submission as quickly as possible. This makes sense when one considers the prodigious rates of prolif- eration that bacteria can achieve—many bacterial species are capable of dividing every 20 minutes or so—particularly in the nutrient-rich environment our bodies provide. Key players in the innate immune response include macrophages, neu- trophils and soluble bactericidal i.
Although highly effective, innate immune responses are not always sufficient to com- pletely deal with the threat, particularly if the infectious agent is well adapted to avoid the initial attack.
Importantly, adaptive immune responses improve upon each encounter with a particular infectious agent, a feature called immunological memory, which underpins the concept of vaccination. The adaptive immune response is mediated primarily by T- and B-lymphocytes and these cells display specific receptors on their plasma membranes that can be tailored to recognize an almost limitless range of structures. By definition, molecules that are recognized by T- and B-lymphocytes are called antigens.
Recognition of antigen by a lymphocyte triggers proliferation and differentiation of such cells and this has the effect of greatly increasing the numbers of lymphocytes capable of recognizing the particular antigen that triggered the response in the first place. This rapidly swells the ranks of lymphocytes capable of dealing with the infectious agent bearing the specific antigen and results in a memory response if the same antigen is encountered at some time in the future.
We will look in detail at the receptors used by T- and B-cells to see antigen in Chapter 4. Innate and adaptive immune responses are interdependent The innate and adaptive immune systems work in tandem to identify and kill infectious agents Figure 1. The innate immune system uses hard-wired i. PAMPs that are commonly expressed on microorganisms. Because the recep- tors of the innate immune system are encoded by the germline, innate immune responses are quite similar between individuals of the same species.
In contrast, the adaptive immune system uses randomly generated receptors that are highly specific for each infectious agent that the immune system comes into Physical barriers Innate immune system Adaptive immune system Therefore, adaptive immune responses are highly variable between individuals within a species and reflect the range of pathogens a particular individual has encountered.
Thus, when an infection occurs, the innate immune system serves as a rapid reaction force that deploys a range of relatively nonspecific weapons to eradicate the infectious agent, or at the very least to keep the infection contained. This gives time for the initially sluggish adaptive immune system to select and clonally expand cells with receptors that are capable of making a much more specific response that is uniquely tailored to the infectious agent. The adaptive immune response to an infectious agent reinforces and adds new weapons to the attack mounted by the innate immune system.
While it was once fashionable to view the innate immune system as somewhat crude and clumsy when compared to the relative sophistication of the adaptive immune system, an explosion of new discoveries over the past 5—10 years has revealed that the innate immune system is just as highly adapted and sophisticated as the adaptive immune system. Moreover, it has also become abundantly clear that the adaptive immune system is highly dependent on cells of the innate immune system for the purposes of knowing when to respond, how to respond and for how long.
Exactly why this is so will be discussed later in this chapter, but for now let us consider the external barriers to infection in a little more detail.
External barriers against infection As mentioned above, the simplest way to avoid infection is to prevent the microorganisms from gaining access to the body Figure 1. When intact, the skin is impermeable to most infectious agents; when there is skin loss, as for example in burns, infection becomes a major problem. Additionally, most bacteria fail to survive for long on the skin because of the direct inhibitory effects of lactic acid and fatty acids in sweat and sebaceous secretions and the low pH that they generate.
An exception is Staphylococcus aureus, which often infects the relatively vulnerable hair follicles and glands. Mucus, secreted by the membranes lining the inner sur- faces of the body, acts as a protective barrier to block the adherence of bacteria to epithelial cells.
Microbial and other foreign particles trapped within the adhesive mucus are removed by mechanical stratagems such as ciliary movement, coughing and sneezing. Among other mechanical factors that help protect the epithelial surfaces, one should also include the washing action of tears, saliva and urine. Many of the secreted body fluids contain bactericidal components, such as acid in gastric juice, spermine and zinc in semen, lactoperoxidase in milk and lysozyme in tears, nasal secretions and saliva.
A totally different mechanism is that of microbial antago- nism associated with the normal bacterial flora of the body i. This suppresses the growth of many potentially pathogenic bacteria and fungi at superficial sites by competition for essential nutrients or by production of inhibitory substances.
To give one example, pathogen invasion is limited by lactic acid produced by particular species of commensal bacteria that metabolize glycogen secreted by the vaginal epithelium. When protective commensals are disturbed by antibiotics, susceptibility to opportunistic infections by Candida and Clostridium difficile is increased.
Even at this level, survival is a tough game. If microorganisms do penetrate the body, the innate immune system comes into play. Innate immunity involves two main defensive strategies to deal with a nascent infection: Before we discuss these strategies in more detail, let us first consider the stereotypical order of events that occur upon infection. The beginnings of an immune response A major player in the initiation of immune responses is the macrophage. Tissue macrophages are relatively quiescent cells, biding their time sampling the environment around them through continuous phagocytosis.
However, upon entry of a microorganism that engages one or more of their PRRs such as a Toll-like receptor or a NOD-like receptor , a startling transition occurs. Engagement of the PRR on the macrophage switches on a battery of genes that equip it to carry out a number of new functions. A year later, in , he observed that fungal spores can be attacked by the blood cells of Daphnia, a tiny metazoan that, also being transparent, can be studied directly under the microscope.
He went on to extend his investigations to mammalian leukocytes, showing their ability to engulf microorganisms, a process that he termed phagocytosis. Because he found this process to be even more effective in animals recovering from infection, he came to a somewhat polarized view that phagocytosis provided the main, if not the only, defense against infection. Caricature of Professor Metchnikoff. From Chanteclair, , No. Figure M1. Second, the macrophage begins to secrete cytokines and chemokines that have effects on nearby endothelial cells lining the blood capillaries; this makes the capillaries in this area more permeable than they would nor- mally be.
In turn, the increased vascular permeability permits two other things to happen. Plasma proteins that are normally largely restricted to blood can now invade the tissue at the point of infection and many of these proteins have microbi- cidal properties.
A second consequence of increased vascular permeability is that another type of innate immune cell, the neutrophil, can now gain access to the site of infection. Neutrophils, like macrophages, are also adept at phagocytosis but are normally not permitted to enter tissues due to their potentially destructive behavior.
Upon entry into an infected tissue, activated neutrophils proceed to attack and engulf any microorganisms they encounter with gusto. We will now deal with some of these events in more detail. Pattern recognition receptors PRRs on phagocytic cells recognize and are activated by pathogen-associated molecular patterns PAMPs Because the ability to discriminate friend from foe is of para- mount importance for any self-respecting phagocyte, these cells are fairly bristling with receptors capable of recognizing diverse PAMPs.
Several of these pattern recognition receptors are lectin-like and bind multivalently with considerable spe- cificity to exposed microbial surface sugars with their charac- teristic rigid three-dimensional geometric configurations.
They do not bind appreciably to the array of galactose or sialic acid groups that are commonly the penultimate and ultimate sugars that decorate mammalian surface polysaccharides so providing the molecular basis for discriminating between self and nonself microbial cells. Other PRRs detect nucleic acids derived from bacterial and viral genomes by virtue of modifications not commonly found within vertebrate nucleic acids or conforma- tions not normally found in the cytoplasm e.
Multiple receptors also exist in each class with the result that in excess of 50 distinct PRRs may be expressed by a phagocyte at any given time. Because this topic is an area of active investigation at present, it is likely that many additional PRRs will be identified in the near future. Let us now look at the five known families of PRRs in more detail.
Toll-like receptors TLRs A major subset of the PRRs belong to the class of so-called Toll-like receptors TLRs because of their similarity to the Toll receptor in the fruit fly, Drosophila, which in the adult triggers an intracellular cascade generating the expression of antimicrobial peptides in response to microbial infection.
A series of cell surface TLRs acting as sensors for extracellular infections have been identified Figure 1. TLRs reside within plasma membrane or endosomal membrane compartments, as shown. Toll-like receptor TLR structure. TLR3 ectodomain structure. The N-linked glycans are shown as green ball-and-stick. Reproduced from Bell J. C-type lectin receptors CTLRs Phagocytes also display another set of PRRs, the cell-bound C-type calcium-dependent lectins, of which the macro- phage mannose receptor is an example.
These transmembrane proteins possess multiple carbohydrate recognition domains whose engagement with their cognate microbial PAMPs gener- ates an intracellular activation signal. The CTLR family is highly diverse and the ligands for many receptors in this category remain the subject of ongoing research. NOD-like receptors NLRs Turning now to the sensing of infectious agents that have suc- ceeded in gaining access to the interior of a cell, microbial products can be recognized by the so-called NOD-like recep- tors.
Unlike TLRs and CTLRs that reside within the plasma membrane or intracellular membrane compartments, NLRs are soluble proteins that reside in the cytoplasm where they also act as receptors for pathogen-derived molecular patterns. Although a diverse family of receptors, NLRs typically contain an N-terminal protein—protein interaction motif that enables these proteins to recruit proteases or kinases upon activation, followed by a central oligomerization domain and C-terminal leucine-rich repeats LRRs that appear to act as the sensor for pathogen products.
NLRs are thought to exist in an autoin- hibited state with their N-terminal domains folded back upon their C-terminal LRRs, a conformation that prevents the N-terminal region from interacting with its binding partners in the cytoplasm. RIG-like helicase receptors RLRs The RIG-like helicases are a very recently discovered group of proteins that act as intracellular sensors for viral-derived prod- ucts.
Scavenger receptors Scavenger receptors represent yet a further class of phagocytic receptors that recognize a variety of anionic polymers and acetylated low-density proteins. The role of the CD14 scaven- ger molecule in the handling of Gram-negative LPS lipopoly- saccharide endotoxin merits some attention, as failure to do so can result in septic shock.
Activated macrophages and neutrophils are capable of phagocytosing particles that engage their PRRs and in this state they also release a range of cytokines and chemokines that amplify the immune response further. Other transcription factor cascades, involving most notably the interferon-regulated factors IRFs , are also activated downstream of the PRRs Figure 1. Some of the most important inflammatory mediators synthesized and released in response to PRR engagement include the antiviral interferons cf.
Collectively, these molecules amplify the immune response further and have effects on the local blood capillaries that permit extravasation of neutrophils which come rushing into the tissue to assist the macrophage in dealing with the situation.
Dying cells also release molecules capable of engaging PRRs As we have mentioned earlier, cells undergoing necrosis but not apoptosis are also capable of releasing molecules i. DAMPs are involved in amplifying immune responses to infectious agents that provoke cell death and also play a role in the phenomenon of sterile injury, where an immune response occurs in the absence of any discernable infectious agent e.
Indeed, Polly Matzinger has pro- posed that robust immune responses are only seen when nonself is detected in combination with tissue damage i. The thinking here is that the immune system does not need to respond if an infectious agent is not causing any harm. The macrophage These cells derive from bone marrow promonocytes that, after differentiation to blood monocytes Figure 1. They are present throughout the connective tissue and around the base- ment membrane of small blood vessels and are particularly concentrated in the lung Figure 1.
Other examples are mesangial cells in the kidney glomerulus, brain microglia and osteoclasts in bone. Unlike neutrophils, macrophages are long-lived cells with significant rough-surfaced endoplasmic reticulum and mitochondria and, whereas neutrophils provide the major defense against pyogenic pus-forming bacteria, as a rough generalization it may be said that macrophages are at their best in combating those bacteria Figure 1.
The polymorphonuclear neutrophil This cell, the smaller of the two, shares a common hematopoietic stem cell precursor with the other formed elements of the blood and is the dominant white cell in the bloodstream.
It is a non- dividing short-lived cell with a multilobed nucleus and an array of granules Figure 1. These neutrophil granules are of two main types: The abundant glycogen stores can be utilized by glycolysis enabling the cells to function under anerobic conditions.
Microbes are engulfed by activated phagocytic cells After adherence of the microbe to the surface of the neutrophil or macrophage through recognition of a PAMP Figure 1. Events are now moving smartly and, within 1 minute, the cytoplasmic granules fuse with the phagosome and discharge their contents around the imprisoned microorganism Figures 1.
There is an array of killing mechanisms Killing by reactive oxygen intermediates Trouble starts for the invader from the moment phagocytosis is initiated. There is a dramatic increase in activity of the hexose monophosphate shunt generating reduced nicotinamide adenine dinucleotide phosphate NADPH. Electrons pass from the NADPH to a flavine adenine dinucleotide FAD - containing membrane flavoprotein and thence to a unique plasma membrane cytochrome cyt b Furthermore, the combination of peroxide, myeloperoxidase and halide ions constitutes a potent halogenating system capable of killing both bacteria and viruses Figure 1.
Although H2O2 and the halogenated compounds are not as active as the free radicals, they are more stable and therefore diffuse further, making them toxic to microorganisms in the extracellular vicinity. Killing by reactive nitrogen intermediates Nitric oxide surfaced prominently as a physiologic mediator when it was shown to be identical with endothelium-derived relaxing factor.
This has proved to be just one of its many roles including the mediation of penile erection, would you believe it! Note the three multilobed polymorphonuclear neutrophils and the small lymphocyte bottom left. Romanowsky stain.
Note the vacuolated cytoplasm. The small cell with focal staining at the top is a T-lymphocyte. The multilobed nuclei and the cytoplasmic granules are clearly shown, those of the eosinophil being heavily stained. The nucleus gradually becomes lobular LN. To the right is a monocyte with horseshoe- Figure 1. Cells involved in innate immunity. Several multilobed neutrophils are clearly delineated.
Carbol-fuchsin counterstained with malachite green. Round central nucleus surrounded by large darkly staining granules. Two small red cell precursors are shown at the bottom. The intracellular granules are metachromatic and stain reddish purple. Note the clustering in relation to dermal capillaries.
The slides from which illustrations a , b , d—f , i and j were reproduced were very kindly provided by Mr. The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by health science practitioners for any particular patient.
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Delves, Peter J. Martin, Seamus J. Burton, Dennis R. Roitt, Ivan M. Ivan Maurice , author. Other titles: Essential immunology Description: Includes bibliographical references and index. Immune System Immunity Classification: Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.