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Showing posts with label Organ. Show all posts

Wednesday, May 5, 2021

Circulatory System: Blood Vessels

Circulatory System: Blood Vessels


Circulatory System: Blood Vessels
Time period: day 18 to birth
Vasculogenesis
Vasculogenesis is the formation of new blood vessels from cells that were not blood vessels before. As if by magic, blood cells and vessels appear in the early embryo. In fact, mesodermal cells are induced to differentiate into haemangioblasts, which further differentiate into both haematopoietic stem cells and angioblasts.
Haematopoietic stem cells will form all the blood cell types, and angioblasts will build the blood vessels. Separate sites of vasculogenesis may merge to form a network of blood vessels, or new vessels may grow from existing vessels by angiogenesis. When the liver forms it will be the primary source of new haematopoietic stem cells during development.

Angiogenesis
Angiogenesis is the development of new blood vessels from existing vessels. Endothelial cells detach and proliferate to form new capillaries. This process is under the influence of various chemical and mechanical factors. Although important in growth this also occurs in wound healing and tumour growth, and as such angiogenesis has become a target for anti‐cancer drugs.
Circulatory System: Blood Vessels, Angiogenesis, Primitive circulation, Aortic arches, Ductus arteriosus, Coronary arteries

Primitive circulation
Near the end of the third week blood islands form through vasculogenesis on either side of the cardiogenic field and the notochord (see Chapter 27). They merge, creating two lateral vessels called the dorsal aortae (Figure 29.1). These blood vessels receive blood from three pairs of veins, including the vitelline veins of the yolk sac (a site of blood vessel formation external to the embryo), the cardinal veins and the umbilical veins (Figure 29.1).
Circulation System: Changes At Birth

Circulation System: Changes At Birth


Circulation System: Changes At Birth
Time period: birth (38 weeks)
Foetal blood circulation
Dramatic and clinically significant changes occur to the circulatory and respiratory systems at birth. Here, we look at changes primarily of the circulatory system and how these changes prepare the baby for life outside the uterus.
If we were to follow the flow of oxygenated blood in the foetus from the placenta (Figure 31.1), we would start in the umbilical vein and track the blood moving towards the liver. Here, half the blood enters the liver itself and half is redirected by the ductus venosus directly into the inferior vena cava, bypassing the liver.
The blood remains well oxygenated and continues to the right atrium, from which it may pass into the right ventricle in the expected manner or directly into the left atrium via the foramen ovale (Figure 31.2). Blood within the left atrium passes to the left ventricle and then into the aorta.
Blood entering the right atrium from the superior vena cava and the coronary sinus is relatively poorly oxygenated. The small amount of blood that returns from the lungs to the left atrium is also poorly oxygenated. Mixing of this blood with the well‐oxygenated blood from the ductus venosus reduces the oxygen saturation somewhat.
Blood within the right ventricle will leave the heart within the pulmonary artery, but most of that blood will pass through the ductus arteriosus and into the descending aorta. Almost all of the well‐oxygenated blood that entered the right side of the heart has avoided entering the pulmonary circulation of the lungs, and has instead passed to the developing brain and other parts of the body (Figure 31.3).
Circulation System: Changes At Birth, Foetal blood circulation, Ductus venosus, Ductus arteriosus, Foramen ovale,

Ductus venosus
The umbilical arteries constrict after birth, preventing blood loss from the neonate. The umbilical cord is not cut and clipped immediately after birth, however, allowing blood to pass from the placenta back to the neonatal circulation through the umbilical vein.
Respiratory System

Respiratory System


Respiratory System
Time period: day 28 to childhood
Introduction
The development of the respiratory system is continuous from the fourth week, when the respiratory diverticulum appears, to term. The 24‐week potential viability of a foetus (approximately 50% chance of survival) is partly because at this stage the lungs have developed enough to oxygenate the blood. Limiters to oxygenation include the surface area available to gaseous exchange, the vascularisation of those tissues of gaseous exchange and the action of surfactant in reducing the surface tension of fluids within the lungs.
Development of the respiratory system includes not only the lungs, but also the conducting pathways, including the trachea, bronchi and bronchioles. Lung development can be described in five stages: embryonic, pseudoglandular, canalicular, saccular and alveolar.
Although not in use as gas exchange organs in utero, the lungs have a role in the production of some amniotic fluid.
Respiratory System, Lung bud, Respiratory tree, Alveoli,

Lung bud
The development of the respiratory system begins with the growth of an endodermal bud from the ventral wall of the developing gut tube in the fourth week (Figure 32.1).
Digestive System: Gastrointestinal Tract

Digestive System: Gastrointestinal Tract


Digestive System: Gastrointestinal Tract
Time period: days 21–50
Induction of the tube
The gut tube forms when the yolk sac is pulled into the embryo and pinched off (see Figure 20.2) as the flat germ layers of the early embryo fold laterally and cephalocaudally (head to tail). Consequently, it has an endodermal lining throughout with a minor exception towards the caudal end. Epithelium forms from the endoderm layer and other structures are derived from the mesoderm.
Initially, the tube is closed at both ends, although the middle remains in contact with the yolk sac through the vitelline duct (or stalk) even as the yolk sac shrinks (Figure 33.1).
The cranial end will become the mouth and is sealed by the buccopharyngeal membrane, which will break in the fourth week, opening the gut tube to the amniotic cavity. The caudal end will become the anus and is sealed by the cloacal membrane, which will break during the seventh week.
Buds develop along the length of the tube that will form a variety of gastrointestinal and respiratory structures (see Chapter 34).
Digestive System: Gastrointestinal Tract, Mesenteries, Story of the hindgut and the cloaca, Twists of the midgut

Divisions of the gut tube
The gut is divided into foregut, midgut and hindgut sections by the region of the gut tube that remains linked to the yolk sac and by the anterior branches from the aorta that supply blood to each part (Figure 33.2).
INNERVATION OF THE LUNGS AND TRACHEOBRONCHIAL TREE

INNERVATION OF THE LUNGS AND TRACHEOBRONCHIAL TREE


INNERVATION OF THE LUNGS AND TRACHEOBRONCHIAL TREE
The tracheobronchial tree and lungs are innervated by the autonomic nervous system. Three types of pathways are involved: autonomic afferent, parasympathetic efferent, and sympathetic efferent. Each type of fiber is discussed here; the neurochemical control of respiration is covered later in the section on physiology (see Plates 2-25 and 2-26).
 
INNERVATION OF TRACHEOBRONCHIAL TREE: SCHEMA
INNERVATION OF TRACHEOBRONCHIAL TREE: SCHEMA
Autonomic Afferent Fibers
Afferent fibers from stretch receptors in the alveoli and from irritant receptors in the airways travel via the pulmonary plexus (located around the tracheal bifurcation and hila of the lungs) to the vagus nerve. Similarly, fibers from irritant receptors in the trachea and from cough receptors in the larynx reach the central nervous system via the vagus nerve. Chemoreceptors in the carotid and aortic bodies and pressor receptors in the carotid sinus and aortic arch also give rise to afferent autonomic fibers. Whereas the fibers from the carotid sinus and carotid body travel via the glossopharyngeal nerve, those from the aortic body and aortic arch travel via the vagus nerve. Other receptors in the nose and nasal sinuses give rise to afferent fibers that form parts of the trigeminal and glossopharyngeal nerves. In addition, the respiratory centers are controlled to some extent by impulses from the hypothalamus and higher centers as well as from the reticular activating system.
STRUCTURE OF THE TRACHEA AND MAJOR BRONCHI

STRUCTURE OF THE TRACHEA AND MAJOR BRONCHI


STRUCTURE OF THE TRACHEA AND MAJOR BRONCHI
The trachea or windpipe passes from the larynx to the level of the upper border of the fifth thoracic vertebra, where it divides into the two main bronchi that enter the right and left lungs. About 20 C-shaped plates of cartilage support the anterior and lateral walls of the trachea and main bronchi. The posterior wall, or membranous trachea, is free of cartilage but does have interlacing bundles of muscle fibers that insert into the posterior ends of the cartilage plates. The external diameter of the trachea is approximately 2.0 cm in men and 1.5 cm in women. The tracheal length is approxi- mately 10 to 11 cm.

STRUCTURE OF THE TRACHEA AND MAJOR BRONCHI

Mucous glands are particularly numerous in the posterior aspect of the tracheal mucosa. Throughout the trachea and large airways, some of these glands lie between the cartilage plates, and others are external to the muscle layers with ducts that penetrate this layer to open on the mucosal surface. Posteriorly, elastic fibers are grouped in longitudinal bundles immediately beneath the basement membrane of the tracheal epithelium, and these appear to the naked eye as broad, flat bands that give a rigid effect to the inner lining of the trachea; they are not so obvious anteriorly. More distally, the bands of elastic fibers are thinner and surround the entire circumference of the airways.

Monday, May 3, 2021

INTRAPULMONARY AIRWAYS

INTRAPULMONARY AIRWAYS


INTRAPULMONARY AIRWAYS
According to the distribution of cartilage, airways are divided into bronchi and bronchioles. Bronchi have cartilage plates as discussed earlier. Bronchioles are distal to the bronchi beyond the last plate of cartilage and proximal to the alveolar region. Cartilage plates become sparser toward the periphery of the lung, and in the last generations of bronchi, plates are found only at the points of branching. The large bronchi have enough inherent rigidity to sustain patency even during massive lung collapse; the small bronchi collapse along with the bronchioles and alveoli. Small and large bronchi have submucosal mucous glands within their walls.

INTRAPULMONARY AIRWAYS

When any airway is pursued to its distal limit, the terminal bronchiole is reached. Three to five terminal bronchioles make up a lobule. The acinus, or respiratory unit, of the lung is defined as the lung tissue supplied by a terminal bronchiole. Acini vary in size and shape. In adults, the acinus may be up to 1 cm in diameter. Within the acinus, three to eight generations of respiratory bronchioles may be found. Respiratory bronchioles have the structure of bronchioles in part of their walls but have alveoli opening directly to their lumina as well. Beyond these lie the alveolar ducts and alveolar sacs before the alveoli proper are reached.
STRUCTURE OF BRONCHI AND BRONCHIOLES LIGHT MICROSCOPY

STRUCTURE OF BRONCHI AND BRONCHIOLES LIGHT MICROSCOPY


STRUCTURE OF BRONCHI AND BRONCHIOLES LIGHT MICROSCOPY
The airways are the hollow tubes that conduct air to the respiratory regions of the lung. They are lined throughout their length by pseudostratified, ciliated, columnar epithelium (also referred to as respiratory epithelium) supported by a basement membrane (see Plate 1-24 for details of cell types and their arrangement). The remainder of the wall includes a muscle coat and accessory structures such as submucosal glands, together with connective tissue. In the bronchi, cartilage provides additional support.
In adults, the diameter of the main bronchus is similar to that of the trachea (-2 cm), and the diameter of a terminal bronchiole is about 1 mm. These measurements vary with age and the size of the individual and with the functional state of the airway. For reference purposes, it is helpful to designate airways by their order or generation along an axial pathway. The epithelium is thicker in the larger airways and gradually thins toward the periphery of the lung.
Immediately beneath the basement membrane, elastic  fibers are collected into fine  bands that form longitudinal ridges. In cross-section, the fiber bundles are at the apices of the bronchial folds. The rest of the wall is made up of loose connective tissue containing blood vessels, nerves, capillaries, and lymphatics.

STRUCTURE OF BRONCHI AND BRONCHIOLES LIGHT MICROSCOPY

Blood Supply
The bronchial arteries supply the capillary bed in the airway wall, forming one plexus internal and another external to the muscle layer (see also Plate 1-26).
ULTRASTRUCTURE OF THE TRACHEAL, BRONCHIAL, AND BRONCHIOLAR EPITHELIUM

ULTRASTRUCTURE OF THE TRACHEAL, BRONCHIAL, AND BRONCHIOLAR EPITHELIUM


ULTRASTRUCTURE OF THE TRACHEAL, BRONCHIAL, AND BRONCHIOLAR EPITHELIUM
The lining of the respiratory airways is predominantly a pseudostratified, ciliated, columnar epithelium in which all cells are attached to the basement membrane but not all reach the lumen. In the smaller peripheral airways, the epithelium may be only a single layer thick and cuboidal rather than columnar because basal cells are absent at this level.
Ciliated cells are present in even the smallest airways and respiratory bronchioles, where they are adjacent to alveolar lining cells. The “ciliary escalator” starts at the most distal point of the airway epithelium. In smaller airways, the cilia are not as tall as in the more central airways. Eight epithelial cell types can be identified in humans, although ultrastructural features and cell kinetics have been studied mainly in animals. The following classification is based on studies in the rat: the (1) basal and (2) pulmonary neuroendocrine cells are attached to the basement membrane but do not reach the lumen; (3) the intermediate cell is probably the precursor that differentiates into (4) the ciliated cell, (5) the brush cell, or one of the secretory cells (6) the mucous (goblet) cell, (7) the serous cell, or (8) the Clara cell.
The Clara cell, The mucous (goblet) cell, The brush cell,  The ciliated cell, The basal cell

The basal cell divides and daughter cells pass to the superficial layer.
The pulmonary neuroendocrine cell (PNEC), previously referred to as the Kulchitsky cell, contains numerous neurosecretory granules and is a rare, but likely important, functional cell of the airway epithelium. The PNEC neurosecretory granules contain serotonin and other bioactive peptides such as gastrin-releasing peptide (GRP). PNECs are more numerous before birth and may play a role in the innate immune system. The intermediate cell is columnar. It has electronlucent cytoplasm and no special features. It is probably the cell that differentiates into the others.
BRONCHIAL SUBMUCOSAL GLANDS

BRONCHIAL SUBMUCOSAL GLANDS


BRONCHIAL SUBMUCOSAL GLANDS
The submucosal glands of the human airways are of the branched tubuloacinar type: tubulo refers to the main part of the secretory tubule and acinar to the blind end of such a tubule.
Three-dimensional reconstruction of the gland reveals its various zones:
1.  The origin is referred to as the ciliated duct and is lined by bronchial epithelium with its mixed population of cells. With the naked eye, the origin of the gland is seen as a hole of pinpoint size in the surface epithelium of the bronchus.
2.  The second part of the duct expands to form the collecting duct and is lined by a columnar epithelium in which the cells are eosinophilic after staining with hematoxylin and eosin. Ultrastructural examination shows these cells to be packed with mitochondria, resembling the cells of the striated duct of the salivary gland (except that they lack the folds of membrane responsible for the appearance of striation). The collecting duct may be up to 0.25 mm in diameter and 1 mm long. It passes obliquely from the airway lumen, so the usual macroscopic section does not include the full length of the duct. It is usually seen as a rather large “acinus” composed of cells without secretory granules.
3.  About 13 tubules rise from each collecting duct. These may branch several times and are closely intertwined with each other. The secretory cells lining these tubules are of two types: mucous and serous. Mucous cells line the central or proximal part of a tubule; serous cells line the distal part. Outpouchings or short-sided tubules may arise from the sides of the mucous tubules, and these are lined by serous cells. The peripheral portion of a tubule usually branches several times, and each of the final blind endings is lined with serous cells.

BRONCHIAL SUBMUCOSAL GLANDS

The gland tissue is internal to a basement membrane. In addition to the cell types described above, the following are found: (1) myoepithelial cells; (2) “clear” cells; and (3) nerve fibers, including motor fibers. Outside the basement membrane, there are rich vascular and lymphatic networks and the nerve plexus.
The B‐Cell Surface Receptor For Antigen (BCR)

The B‐Cell Surface Receptor For Antigen (BCR)


The B‐Cell Surface Receptor For Antigen (BCR)
The B‐cell displays a transmembrane immunoglobulin on its surface
In Chapter 2 we discussed the cunning system by which an antigen can be led inexorably to its doom by activating B‐cells that are capable of making antibodies complementary in shape to itself through interacting with a copy of the antibody molecule on the lymphocyte surface. It will be recalled that binding of antigen to membrane antibody can activate the B‐cell and cause it to proliferate, followed by maturation into a clone of plasma cells secreting antibody specific for the inciting antigen (Figure 4.1a).
B‐cells and T‐cells “see” antigen in fundamentally different ways

Figure 4.1 B‐cells and T‐cells “see” antigen in fundamentally different ways. (a) In the case of B‐cells, membrane‐bound immunoglobulin serves as the B‐cell receptor (BCR) for antigen. (b) T‐cells use distinct antigen receptors, which are also expressed at the plasma membrane, but T‐cell receptors (TCRs) cannot recognize free antigen as immunoglobulin can. The majority of T‐cells can only recognize antigen when presented within the peptide‐binding groove of an MHC molecule. Productive stimulation of the BCR or TCR results in activation of the receptor‐bearing lymphocyte, followed by clonal expansion and differentiation to effector cells.

Immunofluorescence staining of live B‐cells with labeled anti‐immunoglobulin (anti‐Ig) (e.g., Figure 2.8c) reveals the earliest membrane Ig to be of the IgM class. Each individual B‐cell is committed to the production of just one antibody specificity and so transcribes its individual rearranged VJCk (or λ) and VDJCμ genes. Ig can be either secreted or displayed on the B‐cell surface through differential splicing of the pre‐mRNA transcript encoding a particular immunoglobulin. The initial nuclear μ chain RNA transcript includes sequences coding for hydrophobic transmembrane regions that enable the IgM to sit in the membrane where it acts as the BCR, but if these are spliced out, the antibody molecules can be secreted in a soluble form (Figure 4.2).
The T‐Cell Surface Receptor For Antigen (TCR)

The T‐Cell Surface Receptor For Antigen (TCR)


The T‐Cell Surface Receptor For Antigen (TCR)
As alluded to earlier, T‐cells interact with antigen in a manner that is quite distinct from the way in which B‐cells do; the receptors that most T‐cells are equipped with cannot directly engage soluble antigens but instead “see” fragments of antigen that are immobilized within a narrow groove on the surface of MHC molecules (Figure 4.1b). 

As we shall discuss in detail in Chapter 5, MHC molecules bind to short 8–20 amino acid long peptide fragments that represent “quality control” samples of the proteins a cell is expressing at any given time, or what it has internalized through phagocytosis, depending on the type of MHC molecule. In this way, T‐cells can effectively inspect what is going on, antigenically speaking, within a cell at any given moment by surveying the range of peptides being presented within MHC molecules. Another major difference between B‐ and T‐cell receptors is that T‐cells cannot secrete their receptor molecules in the way that B‐cells can switch production of Ig from a membrane‐bound form to a secreted form. These differences aside, T‐cell receptors are structurally quite similar to antibody as they are also built from modules that are based upon the immunoglobulin fold.
The Generation Of Diversity For Antigen Recognition

The Generation Of Diversity For Antigen Recognition


The Generation Of Diversity For Antigen Recognition
We know that the immune system has to be capable of recognizing virtually any pathogen that has arisen or might arise. The awesome genetic solution to this problem of anticipating an unpredictable future involves the generation of millions of different specific antigen receptors, probably vastly more than the lifetime needs of the individual. As this greatly exceeds the estimated number of 25 000–30 000 genes in the human body, there are some clever ways to generate all this diversity, particularly as the total number of V, D, J, and C genes in an individual human coding for antibodies and TCRs is only around 400. Let’s revisit the genetics of antibody diversity, and explore the enormous similarities, and occasional differences, seen with the mechanisms employed to generate TCR diversity.


Intrachain amplification of diversity
Random VDJ combination increases diversity geometrically
We saw in Chapter 3 that, just as we can use a relatively small number of different building units in a child’s construction set such as LEGO® to create a rich variety of architectural masterpieces, so the individual receptor gene segments can be viewed as building blocks to fashion a multiplicity of antigen specific receptors for both B‐ and T‐cells. The immunoglobulin light chain variable regions are created from V and J segments, and the heavy chain variable regions from V, D, and J segments. Likewise, for both the αβ and γδ T‐cell receptors the variable region of one of the chains (α or γ) is encoded by a V and a J segment, whereas the variable region of the other chain (β or δ) is additionally encoded by a D segment. As for immunoglobulin genes, the enzymes RAG‐1 and RAG‐2 recognize recombination signal sequences (RSSs) adjacent to the coding sequences of the TCR V, D, and J gene segments. The RSSs again consist of conserved heptamers and nonamers separated by spacers of either 12 or 23 base‐pairs and are found at the 3′ side of each V segment, on both the 5′ and 3′ sides of each D segment, and at the 5′ of each J segment. Incorporation of a D segment is always included in the rearrangement; Vβ cannot join directly to Jβ, nor Vδ directly to Jδ. To see how sequence diversity is generated for TCR, let us take the αβ TCR as an example (Table 4.2). Although the precise number of gene segments varies from one individual to another, there are typically around 75 gene segments and 60 Jα gene segments. If there were entirely random joining of any one V to any one J segment, we would have the possibility of generating 4500 VJ combinations (75 × 60). Regarding the TCR β‐chain, there are approximately 50 Vβ genes that lie upstream of two clusters of DβJβ genes, each of which is associated with a Cβ gene (Figure 4.11). The first cluster, associated with Cβ1, has a single Dβ1 gene and 6 Jβ1 genes, whereas the second cluster associated with Cβ2 again has a single Dβ gene (Dβ2) with 7 Jβ2.

Thursday, April 29, 2021

Invariant Natural Killer T‐Cell Receptors Bridge Innate and Adaptive Immunity

Invariant Natural Killer T‐Cell Receptors Bridge Innate and Adaptive Immunity


Invariant Natural Killer T‐Cell Receptors Bridge Innate and Adaptive Immunity
The highly variable nature of the TCR confers on the conventional T‐cell population the ability to respond to an immense array of different antigens, with individual T‐cells specific for a single antigen. Invariant natural killer T‐cells (iNKT) are a unique subset of T‐cells that display a semi‐variant TCR that equips individual iNKT cells with the ability to detect a broad array of microbial lipid antigens, presented on CD1d antigen‐presenting molecules on antigen‐presenting cells (APCs). Although conventional T‐cells are activated by APCs that have first been activated by microbial antigen (in a process that takes some time), iNKTs can respond directly to PAMPs, secreting cytokines and presenting co‐stimulatory molecules in a manner more reminiscent of innate immune cell PRR activation than T‐cell stimulation.

Natural killer T‐cells

Figure 4.15 Natural killer T‐cells. (a) Schematic representation of type I and type II natural killer T (NKT) cells. These two subsets use different variable (V) region gene segments in the α and β chains of their T‐cell receptors (TCRs), and they recognize different CD1d‐ restricted antigens. (b) The αβTCR is composed of two chains, with the V domains containing the complementarity determining region (CDR) loops. The CDR3 loops are encoded by multiple gene segments and also contain nontemplated (N) regions, which add further diversity to the TCR repertoire. The color coding is the same as that used for the type I NKT TCR in (a). APC, antigen‐presenting cell; C, constant; D, diversity; J, joining. (Reproduced with permis­ sion from the authors Rossjohn et al., (2012) Nature Reviews Immunology 12, 845–857 © Nature Publishing Group.)

Although conventional CD4+ T‐cells provide help to B‐ cells as part of an adaptive immune response, iNKTs are unique in that they can provide help to B‐cells in an innate and adaptive manner, with differing outcomes. iNKTs that are activated by antigen presented on B‐cell C1d can directly license B‐cell activation in a cognate, innate‐like manner, through co‐stimulation with CD40L and the production of various cytokines, such as IFNγ and IL‐21. This leads to a restricted form of B‐ cell activation, with plasmablast expansion, early germinal center development, modest affinity maturation, and primary class‐switched antibody production, but lacking the development of plasma cells and B‐cell memory responses. Alternatively, iNKTs that have been activated by DCs presenting antigen can drive full B‐cell activation in a noncognate, or adaptive fashion, by enlisting the help of CD4+ T‐cells to license B‐cells, driving the generation of mature germinal centers, robust affinity maturation, the development of antibody‐producing plasma cells, and a B‐cell memory response.
NK Receptors

NK Receptors


NK Receptors
Natural killer (NK) cells are a population of leukocytes that, like T‐ and B‐cells, employ receptors that can provoke their activation, the consequences of which are the secretion of cytokines, most notably IFNγ, and the delivery of signals to their target cells via Fas ligand or cytotoxic granules that are capable of kill­ ing the cell that provided the activation signal (Figure 1.40 and Figure 1.41; see also Videoclip 3). 
However, in addition to activating NK receptors, NK cells also possess receptors that can inhibit their function. As we shall see, inhibitory NK cell receptors are critical to the correct functioning of these cells as these receptors are what prevent NK cells from indiscriminately attacking healthy host tissue. Let us dwell on this for a moment because this is quite a different set‐up to the one that prevails with T‐ and B‐cells. A T‐ or B‐lymphocyte has a single type of receptor that either recognizes antigen or it doesn’t. NK cells have two types of receptor: activating receptors that trigger cytotoxic activity upon recognition of ligands that should not be present on the target cell, and inhibitory receptors that restrain NK killing by recognizing ligands that ought to be present. Thus, NK cell killing can be triggered by two different situations: either the appearance of ligands for the activating receptors or the disappearance of ligands for the inhibitory receptors. Of course, both things can happen at once, but one is sufficient.
We have already discussed NK cell‐mediated killing in some detail in Chapter 1, here we will focus on how these cells select their targets as a consequence of alterations to the normal pattern of expression of cell surface molecules, such as classical MHC class I molecules, that can occur during viral infection. NK cells can also attack cells that have normal expression levels of classical MHC class I but have upregulated nonclassical MHC class I‐related molecules because of cell stress or DNA damage.

NK cells express diverse “hard‐wired” receptors
Unlike the antigen receptors of T‐ and B‐lymphocytes, NK receptors are “hard‐wired” and do not undergo V(D)J recombination to generate diversity. As a consequence, NK cell receptor diversity is achieved through gene duplication and divergence and, in this respect, resembles the pattern recognition receptors we discussed in Chapter 1. Thus, NK receptors are a somewhat confusing ragbag of structurally disparate molecules that share the common functional property of being able to survey cells for normal patterns of expression of MHC and MHC‐related molecules. NK cells, unlike αβ T‐cells, are not MHC‐restricted in the sense that they do not see antigen only when presented within the groove of MHC class I or MHC class II molecules. On the contrary, one of the main functions of NK cells is to patrol the body looking for cells that have lost expression of the normally ubiquitous classical MHC class I molecules; a situation that is known as “missing‐self ” recognition (Figure 4.17). Such abnormal cells are usually either malignant or infected with a microorganism that interferes with class I expression.
We saw in Chapter 1 that many pathogens activate PRRs such as Toll‐like receptors that induce transcription of inter­feron‐regulated factors, which subsequently direct the transcription of type I interferons (IFNα and IFNβ). PRRs, such as TLR3, TLR7–9 and the RIG‐like helicases, that reside within intracellular compartments are particularly attuned to inducing the expression of type I interferons (see Figure 1.16). Such PRRs typically detect long single or double‐stranded RNA molecules that are characteristically produced by many viruses. One of the downstream consequences of interferon secretion is the cessation of protein synthesis and consequent downregulation of, among other things, MHC class I molecules. Thus, detection of PAMPs from intracellular viruses or other intracellular pathogens can render such cells vulnerable to NK cell‐mediated attack. Which is exactly the point? Many intracellular pathogens also directly interfere with the expression or surface exposure of MHC class I molecules as a strategy to evade detection by CD8+ T‐cells that survey such molecules for the presence of nonself peptides.
Natural killer (NK) cell‐mediated killing and the “missing‐self” hypothesis

Figure 4.17 Natural killer (NK) cell‐mediated killing and the “missing‐self” hypothesis. (a) Upon encounter with a normal autologous MHC class I‐expressing cell, NK inhibitory receptors are engaged and activating NK receptors remain unoccupied because no activating ligands are expressed on the target cell. The NK cell does not become activated in this situation. (b) Loss of MHC class I expression (“missing‐self”), as well as expression of one or more ligands for activating NK receptors, provokes NK‐mediated attack of the cell via NK cytotoxic granules. (c) Upon encountering a target cell expressing MHC class I, but also expressing one or more ligands for activating NK receptors (“induced‐self”), the outcome will be determined by the relative strength of the inhibitory and activating signals received by the NK cell. (d) In some cases, cells may not express MHC class I molecules or activating ligands and may be ignored by NK cells, possibly owing to expression of alternative ligands for inhibitory NK receptors.

Because of the central role that MHC class I molecules play in presenting peptides derived from intracellular pathogens to the immune system, it is relatively easy to understand why these molecules may attract the unwelcome attentions of viruses or other uninvited guests planning to gatecrash their cellular hosts. It is probably for this reason that NK cells coevolved alongside MHC‐restricted T‐cells to ensure that pathogens, or other conditions that may interfere with MHC class I expression and hence antigen presentation to αβ T‐cells, are given short shrift. Cells that end up in this unfortunate position are likely to soon find themselves looking down the barrel of an activated NK cell. Such an encounter typically results in death of the errant cell as a result of attack by cytotoxic granules containing a battery of proteases and other destructive enzymes released by the activated NK cell.
The Major Histocompatibility Complex (MHC)

The Major Histocompatibility Complex (MHC)


The Major Histocompatibility Complex (MHC)
Molecules within this complex were originally defined by their ability to provoke vigorous rejection of grafts exchanged between different members of a species (Milestone 4.2). We have already referred to the necessity for antigens to be associated with class I or class II MHC molecules in order that they may be recognized by T‐lymphocytes (Figure 4.8). How antigenic peptides are processed and selected for presentation within MHC molecules and how the TCR sees this complex are discussed in detail in Chapter 5, but let us run through the major points briefly here so that reader will appreciate why these molecules are of huge importance within the immune system.
MHC molecules assemble within the cell, where they associate with short peptide fragments derived either from proteins being made by the cell (MHC class I molecules bind to peptides derived from proteins being synthesized within the cell) or proteins that have been internalized by the cell through phagocytosis or pinocytosis (MHC class II molecules bind to peptides derived from proteins made external to the cell). There are some exceptions to these general rules, which we deal with in Chapter 5. We have already made the analogy that this process represents a type of “quality control” checking system where a fraction of proteins present in the cell at any given moment are presented to T‐cells for inspection to ensure that none of these is derived from nonself. Of course, if a cell happens to harbor a nonself peptide, we want the immune system to know about this as quickly as possible, so that the appropri­ ate course of action can be taken. Thus, MHC class I molecules display peptides that are either self, or that are being made by an intracellular virus or bacterium. MHC class II molecules display peptides that are either extracellular self proteins or proteins being made by extracellular microorganisms. The whole point is to enable a T‐cell to inspect what is going on, antigenically speaking, within the cell.
As we shall see, MHC class I molecules serve an important role presenting peptides for inspection by CD8 T‐cells that are mainly preoccupied with finding virally infected or “abnormal” cells to kill. Should a TCR‐bearing CD8 T‐cell recognize a class I MHC–peptide combination that is a good “fit” for its TCR, it will attack and kill that cell. MHC class II molecules, on the other hand, are not expressed on the general cell population but are restricted to cells of the immune system, such as DCs, that have an antigen‐presenting function as we already outlined in Chapter 1. Upon recognition of an appropriate MHC class II–peptide combination by a CD4 T‐cell, this will result in activation of the latter and maturation to an effector T‐cell that can give help to B‐cells to make antibody for example. Although this is an oversimplification, as we will learn in later chapters, please keep in mind the general idea that MHC class I and II molecules present peptides to CD8‐ and CD4‐ restricted T‐cells, respectively, for the purposes of allowing these cells to determine whether they should become “activated” and differentiate to effector cells. Let us now look at these molecules in greater detail.
 
Figure M4.2.1 Main genetic regions of the major histocompatibility complex (MHC).

 


Class I and Class II Molecules Are Membrane Bound Heterodimers
MHC class I
Class I molecules consist of a heavy polypeptide chain of 44 kDa noncovalently linked to a smaller 12 kDa polypep­ tide called β2‐microglobulin. The largest part of the heavy chain is organized into three globular domains (α1, α2, and α3) that protrude from the cell surface, a hydrophobic section anchors the molecule in the membrane, and a short hydrophilic sequence carries the C‐terminus into the cytoplasm (Figure 4.19).

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