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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).
HUMERAL SHAFT FRACTURES

HUMERAL SHAFT FRACTURES


HUMERAL SHAFT FRACTURES
Injury To The Upper Arm
Whenever a patient presents with a possible humeral fracture, inspect the upper arm for swelling, ecchymosis, deformity, and open wounds. Palpate the area of maximal tenderness, and assess the joint above (shoulder) and below (elbow) for injury. Always perform a thorough distal neurovascular examination. After a fracture of the humeral shaft, the arm should be supported and immobilized.
When gross fracture angulation occurs, emergency care personnel should restore overall alignment of the arm by applying longitudinal traction. This is best accomplished with conscious sedation of the patient to avoid patient guarding and muscle spasm that may prevent adequate reduction of the fracture. Once the fracture is reduced, someone must maintain alignment of the fracture manually while a well-padded splint is applied to the arm to provide stability and maintain the reduction. For humeral shaft fractures, a coaptation splint typically works best. The entire injured limb can then be placed in a sling for added comfort.


HUMERAL SHAFT FRACTURES

Fracture Of Shaft Of Humerus
Fractures of the humeral shaft are generally due to direct trauma and can present as different fracture patterns, such as transverse, spiral or oblique, and comminuted. Nonsurgical treatment is acceptable in most instances, but the choice of treatment is based on the type and location of the fracture, concomitant injuries, and age and condition of the patient. For closed fractures, a coaptation splint or a collar and a lightweight, hanging arm cast may be placed initially. About 10 days after injury, when the initial swelling has subsided, the patient is fitted with a fracture brace, which allows the patient to exercise the hand, wrist, elbow, and shoulder while maintaining fracture alignment.
INJURY TO THE ELBOW

INJURY TO THE ELBOW


INJURY TO THE ELBOW
Injuries of the elbow range from nondisplaced fractures to complex fracture-dislocations. When a patient presents with an elbow injury, inspect the elbow and forearm for swelling, ecchymosis, deformity, and wounds such as abrasions or lacerations that could raise concern for an open injury. Palpate the area of maximal tenderness, and assess the joint above (shoulder) and below (wrist) for additional areas of tenderness that could suggest other injuries.
INJURY TO THE ELBOW

Palpation can also be utilized to detect for the presence of a joint effusion associated with the injury. An effusion is, again, most easily noted by palpation over the posterolateral “soft spot” of the elbow. Elbow range of motion may be limited after an acute injury owing to pain or because of the presence of a fracture or dislocation. A thorough distal neurovascular examination is mandatory to determine if damage has occurred to any neurovascular structures from the injury. After an elbow fracture, the elbow show be supported and immobilized with a well-padded posterior elbow splint incorporating both the upper arm and forearm. The entire injured limb can then be placed in a sling for added comfort.
FRACTURE OF DISTAL HUMERUS

FRACTURE OF DISTAL HUMERUS


FRACTURE OF DISTAL HUMERUS
In adults, fractures of the distal humerus often require surgical fixation because they are usually caused by a high-energy injury and frequently are comminuted and/or intra-articular in location. Fracture patterns include supracondylar, transcondylar, intercondylar (T or Y), lateral or medial condyle, or epicondyle and isolated capitellar or trochlear fractures. Intra-articular fractures may be difficult to adequately assess on plain radiographs; therefore, CT scans may be needed.
Surgical fixation can be with plates and screws, or screws alone, depending on the particular fracture pattern. Joint replacement has also become an option for distal humerus fractures that may be too comminuted to be stabilized with plates and screws.
FRACTURE OF DISTAL HUMERUS

Complex Intra-articular Fractures
Comminuted intra-articular fractures of the distal humerus are among the more challenging orthopedic injuries, and their reconstruction requires considerable surgical skill (see Plate 2-21). The major complications include restricted elbow motion and early degenerative joint disease.
FRACTURE OF HEAD AND NECK OF RADIUS

FRACTURE OF HEAD AND NECK OF RADIUS


FRACTURE OF HEAD AND NECK OF RADIUS
Fractures of the radial head occur primarily in adults, whereas fractures of the radial neck are more common in children. The usual causes of these injuries are indirect trauma, such as a fall on the outstretched hand, and, less commonly, a direct blow to the elbow. Radial head and neck fractures are generally classified into four groups. In type I fractures, the fracture is nondisplaced or minimally displaced. Type II fractures refer to displaced fractures of the joint margin or neck with a single fracture line. Type III fractures are comminuted fractures of the head or neck. Type IV fractures are associated with dislocation of the elbow.
RADIAL HEAD AND NECK FRACTURES

Diagnosis of a radial or neck head fracture may be difficult. Pain, effusion in the elbow, and tenderness to palpation directly over the radial head or neck are the typical manifestations. If the fracture is displaced, a “click” or crepitus over the radial head or neck is detected during forearm supination or pronation. Radiographic findings in nondisplaced fractures are minimal, and the radiograph often shows only swelling in the elbow with a fat pad sign. Any radiographic evidence of fat pad displacement accompanied by tenderness over the radial head or neck strongly suggests a fracture.
FRACTURE OF OLECRANON

FRACTURE OF OLECRANON


FRACTURE OF OLECRANON
Olecranon fractures are caused by a direct blow to the elbow or an indirect avulsion injury, such as a fall on an outstretched hand while the triceps is contracting. Nondisplaced fractures of the olecranon can be treated with posterior splinting or a cast, but displaced fractures are best stabilized with open reduction and internal fixation. 
FRACTURE OF OLECRANON

These fractures are typically intra-articular; therefore, care should be taken to appropriately reduce and align the joint surface during surgical fixation, regardless of technique utilized. Fixation with a tension band wire using screws or Kirschner wires is common in more simple fracture patterns. The tension band technique acts to convert the tensile forces through the fracture that are causing displacement into compressive forces that will allow fracture reduction and healing. If the fracture is too comminuted or too distal (extends to the coronoid or proximal ulnar shaft), a tension band technique is typically not adequate for fracture stability. Interfragmentary compression utilizing plate fixation is the preferred method of treatment in this situation. Precontoured plates that match the anatomy of the olecranon are now available and routinely used. The plate is positioned along the subcutaneous border of the ulna, however, and may require removal after fracture healing owing to its very superficial location.
DISLOCATION OF ELBOW JOINT

DISLOCATION OF ELBOW JOINT


DISLOCATION OF ELBOW JOINT
Dislocations of the elbow joint are the most common dislocations after those of the shoulder and finger joints. Swelling, pain, and pseudoparalysis of the arm are acute signs and symptoms of dislocation, and elbow deformity is visible on both clinical and radiographic examinations.
DISLOCATION OF ELBOW JOINT

Acute elbow dislocations are classified as anterior or posterior, with the direction determined by the position of the radius and ulna relative to the humerus. In addition to the anterior or posterior direction of dislocation, the forearm bones can also be displaced medially or laterally. Posterior elbow dislocations are by far the most common type and usually result from a fall on an outstretched hand. The rare, but extensively studied, anterior dislocation of the elbow is usually an open injury and may lacerate the brachial artery. Rarely, the radius and ulna dislocate in different directions, an injury called a “divergent” dislocation.
SEBACEOUS CARCINOMA

SEBACEOUS CARCINOMA


SEBACEOUS CARCINOMA
Sebaceous carcinoma is a rare malignant tumor of the sebaceous gland. These tumors are most frequently seen on the eyelids. They are most commonly found as solitary tumors but may be seen as a part of the Muir-Torre syndrome. The Muir-Torre syndrome is caused by a genetic abnormality in the tumor suppressor genes MSH2 and MLH1 and is associated with multiple sebaceous tumors, both benign and malignant. The syndrome is also associated with a high incidence of internal gastrointestinal and genitourinary malignancies.
SEBACEOUS CARCINOMA

Clinical Findings: These tumors are most commonly found on the eyelid skin and the eyelid margin. The reason is that the periocular skin contains many types of modified sebaceous glands, including the meibomian glands and the glands of Zeis. Many other, less common modified sebaceous glands exist, including the caruncle glands and the multiple sebaceous glands associated with the hairs of the periocular skin. It is believed that most sebaceous carcinomas arise from the meibomian glands, with the glands of Zeis the second most common site of origin. The meibomian glands are modified sebaceous glands that are located within the tarsal plate of the upper and lower eyelid.

ANATOMY PHYSIOLOGY

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