Immunology Flashcards
CELLS OF THE ADAPTIVE IMMUNE SYSTEM
Two kinds of cells divide the work of the immune system between them: lymphocytes and phagocytes. Lymphocytes are specialized for the recognition of foreignness and phagocytes are specialized for eating and digestion; that’s what their name means.
SPLEEN ANATOMY
Spleen has red and white pulp; the red pulp roughly corresponds to the medulla in lymph node, containing lots of phagocytic cells and capable of making red cells when necessary. Red pulp makes the spleen the body’s most important filter of particulates, such as bacteria or damaged platelets. The spleen is also the most important store of monocytes. The white pulp consists of islands of cells. The sheath of cells which surrounds the central arteriole is mostly T cells; the more diffuse collection of cells further from the arteriole is mostly B cells, so the spleen is like a huge lymph node, too.
GUT-ASSOCIATED LYMPHOID TISSUE
The gut, with its large and, of necessity, permeable surface, has the largest collection of secondary lymphoid tissue in the body, sometimes called GALT or MALT (gut- or mucosa-associated lymphoid tissue.) Lymph node- like structures called Peyer’s patches underlie the mucosa, especially in the small intestine.
Peyer’s patches
underlie the mucosa, especially in the small intestine. The functional structure of the Peyer’s patches includes specialized mucosal M cells, which are gatekeepers, ingesting proteins and particles as big as a virus and transporting them to the abluminal side. There a rich content of dendritic cells acquire antigens and carry them to the adjacent B cell follicles and T cells zones of the Peyer’s patch. The patches themselves drain to a large collection of mesenteric lymph nodes. It is here where the body has to solve if this foreign stuff (food, normal gut bacteria) harmless, or is it dangerous.
tolerogen
antigen delivered in a form, or by a route, which does not give rise to an immune response, and which furthermore prevents an immune response to subsequently administered immunogen which has the same antigenic determinants
lymphokines
cytokines made by a lymphocyte. These mediators call up a much- augmented inflammatory response by attracting and activating monocytes and macrophages, which are specialized for phagocytosis and destruction.
Type 1 Helper T cells, Th1
recognize antigen and make a lymphokine that attracts thousands of macrophages, the heavy-duty phagocytes, to the area where antigen has been recognized. This intense inflammation can wipe out a serious infection—or a transplanted kidney.
Th17 Helper T cells
similar to Th1 in that their main role is to cause focused inflammation, although they are more powerful than Th1. They help resist some very tough infectious organisms, but they have been implicated in many serious forms of autoimmunity.
Type 2 Helper T cells, Th2
stimulate macrophages to become ‘alternatively activated,’ and then function in walling-off pathogens and promoting healing, a process that usually takes place after the pathogen-killing Th1 response. They are very important in parasite immunity.
Follicular Helper T cells, Tfh
after stimulation by antigen, migrate from T cell areas of lymph nodes into the B cell follicles, where they help B cells get activated to make the IgM, IgG, IgE and IgA antibody subclasses.
Regulatory T cells, Treg
make lymphokines that suppress the activation and function of their sibling T helper cells, so they keep the immune response in check.
CD4
Th1, Th2, Th17, Tfh, and Treg have a molecular marker, called CD4, on their surface, which increases their affinity for antigen, helps get them activated, and also serves us as a convenient tag for their identification. CTL have a related marker, CD8.
Beginning of immune response`
Infection and local damage stimulate the innate immune response; as the affected cells release chemokines and cytokines, inflammation results which helps activate the dendritic cells. Within its phagocytic vacuoles the antigen is partially digested. Peptides derived from it are loaded into special antigen-presenting molecules called MHC Class II and recycled to the cell surface. The dendritic cell now travels via lymphatics to a lymph node or the spleen, where T cells are in abundance. The receptors of helper T cells are designed to recognize antigen that has been eaten, processed by dendritic cells, and loaded onto MHC Class II (‘presented’). The T cells become activated and begin dividing rapidly; in a few days each may give rise to thousands of daughters. They leave the node and travel around the body until they encounter antigen. Inflammation results, and you begin to get better.
Killer T Cells
Cytotoxic T cells also examine the surfaces of incoming dendritic cells for presented antigenic fragments; in this case, they are looking for fragments on a different class of antigen-presenting molecule, called MHC Class I, which is not only on dendritic cells, but on all cells. The appropriate clones of CTL get expanded and the daughters circulate in large numbers throughout the body. When one of the daughters of a stimulated CTL binds a cell showing the same peptide, it delivers a ‘lethal hit,’ signaling the target cell to commit suicide by activating an internal self-destruction process (apoptosis). The activated killer T cell can then kill other infected cells. This is a great way to eliminate infected cells.
complement system
a system of proteins that enhances inflammation and pathogen destruction. The complement system is very important in disease resistance, and its various components can do different things. Some can lyse (burst) a bacterium by making holes in its membrane. Others diffuse away from the site where antibody is interacting with antigen, and attract phagocytic cells. This is useful in disposing of many kinds of antigens (much more on this later).
IgG
is the most abundant antibody in blood. Two adjacent IgG molecules, binding an antigen such as a bacterium, cooperate to activate complement, a system of proteins that enhances inflammation and pathogen destruction. IgG is the only class of antibody that passes the placenta from mother to fetus in humans, and so is critical in protecting the newborn until it can get its own IgG synthesis going.
IgM
a large polymeric immunoglobulin. It’s even better at activating complement than is IgG, and is the first antibody type to appear in the blood after exposure to a new antigen. It is replaced by IgG in a week or two.
IgD
a form of antibody inserted into B cell membranes as their antigen receptor.
IgA
the most important class of antibody in the secretions like saliva, tears, genitourinary and intestinal fluids, and milk. In these secretions it’s associated with another chain called Secretory Component, which it acquires from epithelial cells during the process of being secreted. Secretory Component makes it resistant to digestive enzymes. IgA plays an important role as the first line of defense against microorganisms trying to gain access to the body through the mucous membranes.
IgE
designed to attach to mast cells in tissues. Thus attached, when it encounters antigen, it will cause the mast cell to make prostaglandins, leukotrienes, and cytokines, and release its granules which contain powerful inducers of inflammation like histamine. Together these mediators produce the symptoms of allergy, which range from hay fever and hives to asthma and anaphylactic shock, depending on the site of antigen entry and dose. The real role of IgE is in resistance to parasites, such as worms.
lymphoblast
When a stimulated T cell becomes large and differentiated
KAPPA AND LAMBDA L CHAINS
L chains come in 2 varieties: kappa or lambda (the original light chain gene family duplicated itself). Although each cell that makes an antibody has a choice of using kappa or lambda, it uses only one kind. So, for example, an IgA molecule will be kappa or lambda type, while another IgA might be the other. A single cell may switch from making, say, IgM to making IgA. When this happens, the heavy chain changes (mu replaced by alpha) but the L chain, either kappa or lambda, stays the same during the switch.
ANTIGEN-ANTIBODY INTERACTION
When an IgG or IgM antibody binds antigen with at least one of its (two or ten) binding sites, there is a change in the angle between the Fab parts and the Fc, so that the molecule may be more Y or T shaped than before (this explains why the region between Fabs and Fc is called the Hinge.) This results in a bulging of the structure of the Fc part so that one or two very important biological activities are initiated: 1. Binding to phagocytic cells, especially PMNs, eosinophils, and macrophages, which have receptors (FcR) for this altered Fc of IgG (but not of IgM) and 2. C1q, the first component of the complement system (the 5-branched molecule marked C in the picture below), now binds to the Fc ends of two adjacent IgGs and is activated (the Antibody Function unit is where we’ll have a more complete discussion of complement.) 2 IgGs will have to be binding close together on the same (usually bacterial) surface, but one IgM can do it alone, because it carries 5 Fcs at all times. This makes IgM much better at activating complement.
divalent antibodies
The basic structure of antibodies, 2 L and 2 H chains, is bilaterally symmetrical, so each antibody can bind, in theory, two identical antigenic determinants; we say that such an antibody is divalent.
multivalent antigens
Most real-life antigens, and all immunogens, are bigger than epitopes, and in fact have multiple, usually different, antigenic determinants or epitopes (a bacterium or a cell has hundreds). These antigens are therefore multivalent.
immunodiffusion
f you take a layer of agar gel in a dish, cut two holes in it, and put antibody in one and antigen in the other, they will begin diffusing radially out of their wells. In the area between the two wells, the situation is similar to a quantitative precipitin test; there is antigen excess near the antigen well, and antibody excess near the antibody well, so
somewhere in between, eventually, equivalence must be reached. But: what happens at equivalence? The complex precipitates. We go back next day and look at our agar gel, and see a line of precipitate between the wells
C1 esterase inhibitor
also called C1-inh, an inhibitor of the complement activity. If you don’t have it you are at risk for (hereditary or acquired) angioedema, giant hives (urticaria) that can swell up your face like a balloon or, if you’re very unlucky, can swell your larynx shut and kill you.
Cellular receptors for microbes
Cells express receptors in the plasma membrane (for extracellular microbes), the endosomes (for ingested microbes), and the cytosol (for intracellular microbes) that enable the cells to sense the presence of foreign invaders in any cellular com- partment. The best defined of these receptors belong to the family of Toll-like receptors (TLRs) ; these and other cellular receptors of innate immunity. The receptors are expressed on many cell types, including epithelial cells (through which microbes enter from the external environment), dendritic cells, macrophages, and other leukocytes (which may encounter microbes in various tissues). Engagement of these receptors triggers production of molecules involved in inflammation, including adhesion molecules on endothelial cells, cytokines, and other mediators.
Sensors of cell damage
All cells have cytosolic receptors that recognize a diverse set of molecules that are liberated or altered as a consequence of cell damage. These molecules include uric acid (a product of DNA breakdown), ATP (released from damaged mitochondria), reduced intracellular K+ concentrations (reflecting loss of ions because of plasma membrane injury), even DNA when it is released into the cytoplasm and not sequestered in nuclei, as it should be normally, and many others. These receptors activate a multiprotein cytosolic complex called the inflammasome, which induces the production of the cytokine interleukin-1 (IL-1). IL-1 recruits leukocytes and thus induces inflammation (see later). Gain-of-function mutations in the sensor are the cause of rare diseases known as autoinflammatory syndromes that are characterized by spontaneous inflammation; IL-1 antagonists are effective treatments for these disorders. The inflammasome has also been implicated in inflammatory reactions to urate crystals (the cause of gout ), lipids (in metabolic syndrome), cholesterol crystals (in atherosclerosis), and even amyloid deposits in the brain (in Alzheimer disease). These disorders are discussed later in this and other chapters.
General Features and Causes of Inflammation
Inflammation is a beneficial host response to foreign invaders and necrotic tissue, but it may also cause tissue damage. The main components of inflammation are a vascular reaction and a cellular response; both are activated by mediators that are derived from plasma proteins and various cells. The steps of the inflammatory response can be remembered as the five Rs: (1) recognition of the injurious agent, (2) recruitment of leukocytes, (3) removal of the agent, (4) regulation (control) of the response, and (5) resolution (repair). The causes of inflammation include infections, tissue necrosis, foreign bodies, trauma, and immune responses. Epithelial cells, tissue macrophages and dendritic cells, leukocytes, and other cell types express receptors that sense the presence of microbes and damage. Circulating proteins recognize microbes that have entered the blood. The outcome of acute inflammation is either elimination of the noxious stimulus followed by decline of the reaction and repair of the damaged tissue, or persistent injury resulting in chronic inflammation.
mannose-binding lectin
The complement system reacts against microbes and produces mediators of inflammation. A circulating protein called mannose-binding lectin recognizes microbial sugars and promotes ingestion of the microbes and the activation of the complement system. Other proteins called collectins also bind to and combat microbes.
Edema
denotes an excess of fluid in the interstitial tissue or serous cavities; it can be either an exudate or a transudate.
Pus
a purulent exudate, is an inflammatory exudate rich in leukocytes (mostly neutrophils), the debris of dead cells and, in many cases, microbes.
transcytosis
Increased transport of fluids and proteins through the endothelial cell. This process may involve intracellular channels that may be stimulated by certain factors, such as vascular endothelial growth factor (VEGF), that promote vascular leakage. However, the contribution of this process to the vascular permeability of acute inflammation is uncertain
selectins
There are three types of selectins: one expressed on leukocytes (L-selectin), one on endothelium (E-selectin), and one in platelets and on endothelium (P-selectin). The ligands for selectins are sialylated oligosaccharides bound to mucin-like glycoprotein backbones. The expression of selectins and their ligands is regulated by cytokines produced in response to infection and injury. Tissue macrophages, mast cells, and endothelial cells that encounter microbes and dead tissues respond by secreting several cytokines, including tumor necrosis factor (TNF), IL-1, and chemokines ( chemo attractant cyto kines ). TNF and IL-1 act on the endothelial cells of postcapillary venules adjacent to the infection and induce the coordinate expression of numerous adhesion molecules. Within 1 to 2 hours the endothelial cells begin to express E-selectin and the ligands for L-selectin. Other mediators such as histamine and thrombin, described later, stimulate the redistribution of P-selectin from its normal intracellular stores in endothelial cell granules (called Weibel-Palade bodies ) to the cell surface. Leukocytes express L-selectin at the tips of their microvilli and also express ligands for E- and P-selectins, all of which bind to the complementary molecules on the endothelial cells. These are low-affinity interactions with a fast off-rate, and they are easily disrupted by the flowing blood. As a result, the bound leukocytes bind, detach, and bind again, and thus begin to roll along the endothelial surface.
integrins
TNF and IL-1 induce endothelial expression of ligands for integrins, mainly vascular cell adhesion molecule 1 (VCAM-1, the ligand for the β1 integrin VLA-4) and intercellular adhesion molecule-1 (ICAM-1, the ligand for the β2 integrins LFA-1 and Mac-1). Leukocytes normally express integrins in a low-affinity state. Chemokines that were produced at the site of injury bind to endothelial cell proteoglycans, and are displayed at high concentrations on the endothelial surface. These chemokines bind to and activate the rolling leukocytes. One of the consequences of activation is the conversion of VLA-4 and LFA-1 integrins on the leukocytes to a high-affinity state. The combination of cytokine- induced expression of integrin ligands on the endothelium and increased integrin affinity on the leukocytes results in firm integrin-mediated binding of the leukocytes to the endothelium at the site of inflammation. The leukocytes stop rolling, their cytoskeleton is reorganized, and they spread out on the endothelial surface.
chemotaxis
locomotion along a chemical gradient. Both exogenous and endogenous substances can act as chemoattractants. The most common exogenous agents are bacterial products , including peptides that possess an N -formylmethionine terminal amino acid and some lipids. Endogenous chemoattractants include several chemical mediator: (1) cytokines , particularly those of the chemokine family (e.g., IL-8); (2) components of the complement system, particularly C5a ; and (3) arachidonic acid (AA) metabolites, mainly leukotriene B (LTB ) . All these chemotactic agents bind to specific seven- transmembrane G protein-coupled receptors on the surface of leukocytes. Signals initiated from these receptors result in activation of second messengers that increase cytosolic calcium and activate small guanosine triphosphatases of the Rac/Rho/cdc42 family as well as numerous kinases. These signals induce polymerization of actin, resulting in increased amounts of polymerized actin at the leading edge of the cell and localization of myosin filaments at the back. The leukocyte moves by extending filopodia that pull the back of the cell in the direction of extension, much as an automobile with front-wheel drive is pulled by the wheels in front. The net result is that leukocytes migrate toward the inflammatory stimulus in the direction of the locally produced chemoattractants.
why neutrophils predominate in early inflammation
they are more numerous in the blood than other leukocytes, they respond more rapidly to chemokines, and they may attach more firmly to the adhesion molecules that are rapidly induced on endothelial cells, such as P- and E-selectins. After entering tissues, neutrophils are short-lived; they undergo apoptosis and disappear within 24 to 48 hours. Monocytes not only survive longer but may also proliferate in the tissues, and thus they become the dominant population in prolonged inflammatory reactions. There are, however, exceptions to this stereotypic pattern of cellular infiltration. In certain infections—for example, those produced by Pseudomonas bacteria—the cellular infiltrate is dominated by continuously recruited neutrophils for several days; in viral infections, lymphocytes may be the first cells to arrive; some hypersensitivity reactions are dominated by activated lymphocytes, macrophages, and plasma cells (reflecting the immune response); and in allergic reactions, eosinophils may be the main cell type.
targets for antiinflammtory treatments
The molecular understanding of leukocyte recruitment and migration has provided a large number of potential therapeutic targets for controlling harmful inflammation. Agents that block TNF, one of the major cytokines in leukocyte recruitment, are among the most successful therapeutics ever developed for chronic inflammatory diseases, and antagonists of leukocyte integrins are approved for inflammatory diseases or are being tested in clinical trials. Predictably, these antagonists not only have the desired effect of controlling the inflammation but can also compromise the ability of treated patients to defend themselves against microbes, which, of course, is the physiologic function of the inflammatory response.
Phagocytic Receptors
Mannose receptors, scavenger receptors, and receptors for various opsonins bind and ingest microbes. The macrophage mannose receptor is a lectin that binds terminal mannose and fucose residues of glycoproteins and glycolipids. These sugars are typically part of molecules found on microbial cell walls, whereas mammalian glycoproteins and glycolipids contain terminal sialic acid or N -acetylgalactosamine. Therefore, the mannose receptor recognizes microbes and not host cells. Scavenger receptors were originally defined as molecules that bind and mediate endocytosis of oxidized or acetylated low-density lipoprotein (LDL) particles that can no longer interact with the conventional LDL receptor. Macrophage scavenger receptors bind a variety of microbes in addition to modified LDL particles. Macrophage integrins, notably Mac-1 (CD11b/CD18), may also bind microbes for phagocytosis. The efficiency of phagocytosis is greatly enhanced when microbes are opsonized by specific proteins (opsonins) for which the phagocytes express high-affinity receptors. The major opsonins are IgG antibodies, the C3b breakdown product of complement, and certain plasma lectins, notably mannose-binding lectin, all of which are recognized by specific receptors on leukocytes.
engulfment by leukocyte
After a particle is bound to phagocyte receptors, extensions of the cytoplasm (pseudopods) flow around it, and the plasma membrane pinches off to form a vesicle (phagosome) that encloses the particle. The phagosome then fuses with a lysosomal granule, resulting in discharge of the granule’s contents into the phagolysosome. During this process the phagocyte may also release granule contents into the extracellular space. The process of phagocytosis is complex and involves the integration of many receptor-initiated signals that lead to membrane remodeling and cytoskeletal changes. Phagocytosis is dependent on polymerization of actin filaments; it is, therefore, not surprising that the signals that trigger phagocytosis are many of the same that are involved in chemotaxis.
Intracellular Destruction of Microbes and Debris by Leukocytes
Killing of microbes is accomplished by reactive oxygen species (ROS, also called reactive oxygen intermediates) and reactive nitrogen species, mainly derived from nitric oxide (NO), and these as well as lysosomal enzymes destroy phagocytosed debris. This is the final step in the elimination of infectious agents and necrotic cells. The killing and degradation of microbes and dead cell debris within neutrophils and macrophages occur most efficiently after activation of the phagocytes. All these killing mechanisms are normally sequestered in lysosomes, to which phagocytosed materials are brought. Thus, potentially harmful substances are segregated from the cell’s cytoplasm and nucleus to avoid damage to the phagocyte while it is performing its normal function.
H 2 O 2 -MPO-halide system
oxygen is then converted into hydrogen peroxide (H 2 O 2 ), mostly by spontaneous dismutation. H 2 O 2 is not able to efficiently kill microbes by itself. However, the azurophilic granules of neutrophils contain the enzyme myeloperoxidase (MPO), which, in the presence of a halide such as Cl − , converts H 2 O 2 to hypochlorite ( , the active ingredient in household bleach). The latter is a potent antimicrobial agent that destroys microbes by halogenation (in which the halide is bound covalently to cellular constituents) or by oxidation of proteins and lipids (lipid peroxidation). The H 2 O 2 -MPO-halide system is the most efficient bactericidal system of neutrophils. Nevertheless, inherited deficiency of MPO by itself leads to minimal increase in susceptibility to infection, emphasizing the redundancy of microbicidal mechanisms in leukocytes. H 2 O 2 is also converted to hydroxyl radical ( − OH), another powerful destructive agent. These oxygen-derived free radicals bind to and modify cellular lipids, proteins, and nucleic acids, and thus destroy cells such as microbes.
α 1 -antitrypsin
Because of the destructive effects of lysosomal enzymes, the initial leukocytic infiltration, if unchecked, can potentiate further inflammation by damaging tissues. These harmful proteases, however, are normally controlled by a system of antiproteases in the serum and tissue fluids. Foremost among these is α 1 -antitrypsin, which is the major inhibitor of neutrophil elastase. A deficiency of these inhibitors may lead to sustained action of leukocyte proteases, as is the case in patients with α 1 -antitrypsin deficiency. α 2 -Macroglobulin is another antiprotease found in serum and various secretions.
Neutrophil extracellular traps (NETs)
are extracellular fibrillar networks that provide a high concentration of antimicrobial substances at sites of infection and prevent the spread of the microbes by trapping them in the fibrils. They are produced by neutrophils in response to infectious pathogens (mainly bacteria and fungi) and inflammatory mediators (e.g., chemokines, cytokines [mainly interferons], complement proteins, and ROS). The extracellular traps consist of a viscous meshwork of of nuclear chromatin that binds and concentrates granule proteins such as antimicrobial peptides and enzymes. In the process of NET formation, the nuclei of the neutrophils are lost, leading to death of the cells. NETs have also been detected in the blood during sepsis, and it is believed that their formation in the circulation is dependent on platelet activation. The nuclear chromatin in the NETs, which includes histones and associated DNA, has been postulated to be a source of nuclear antigens in systemic autoimmune diseases, particularly lupus, in which individuals react against their own DNA and nucleoproteins.
T H 17 cells
some T lymphocytes, which are cells of adaptive immunity, also contribute to acute inflammation. The most important of these cells are those that produce the cytokine IL-17 (so-called T H 17 cells). IL-17 induces the secretion of chemokines that recruit other leukocytes. In the absence of effective T H 17 responses, individuals are susceptible to fungal and bacterial infections, and the skin abscesses that develop are “cold abscesses,” lacking the classic features of acute inflammation, such as warmth and redness.
Mediators of Inflammation
The mediators of inflammation are the substances that initiate and regulate inflammatory reactions. The most important mediators of acute inflammation are vasoactive amines, lipid products (prostaglandins and leukotrienes), cytokines (including chemokines), and products of complement activation. These mediators induce various components of the inflammatory response typically by distinct mechanisms, which is why inhibiting each has been therapeutically beneficial. However, there is also some overlap (redundancy) in the actions of the mediators.Mediators are either secreted by cells or generated from plasma proteins. Cell- derived mediators are normally sequestered in intracellular granules and can be rapidly secreted by granule exocytosis (e.g., histamine in mast cell granules) or are synthesized de novo (e.g., prostaglandins and leukotrienes, cytokines) in response to a stimulus. The major cell types that produce mediators of acute inflammation are the sentinels that detect invaders and damage in tissues, that is, macrophages, dendritic cells, and mast cells, but platelets, neutrophils, endothelial cells, and most epithelia can also be induced to elaborate some of the mediators. Active mediators are produced only in response to various stimuli. These stimuli include microbial products and substances released from necrotic cells. Some of the stimuli trigger well-defined receptors and signaling pathways, described earlier, but we still do not know how other stimuli induce the secretion of mediators (e.g., from mast cells in response to cell injury or mechanical irritation). The usual requirement for microbes or dead tissues as the initiating stimulus ensures that inflammation is normally triggered only when and where it is needed. Most of the mediators are short-lived. They quickly decay, or are inactivated by enzymes, or they are otherwise scavenged or inhibited. One mediator can stimulate the release of other mediators. For instance, products of complement activation stimulate the release of histamine, and the cytokine TNF acts on endothelial cells to stimulate the production of another cytokine, IL-1, and many chemokines. The secondary mediators may have the same actions as the initial mediators but may also have different and even opposing activities. Such cascades provide mechanisms for amplifying—or, in certain instances, counteracting—the initial action of a mediator.
Histamine
produced by mast cells, basophils, and platelets. Produces vasodilation, increased vascular permeability, and endothelial activation
Degranulation
a cellular process that releases antimicrobial cytotoxic molecules from secretory vesicles called granules found inside some cells. It is used by several different cells involved in the immune system, including granulocytes (neutrophils, basophils and eosinophils) and mast cells. It is also used by certain lymphocytes such as natural killer (NK) cells and cytotoxic T cells, whose main purpose is to destroy invading microorganisms.
TxA 2 (thromboxane A2
A type of protaglandins, platelets contain the enzyme thromboxane synthase, and hence TxA 2 is the major product in these cells. TxA 2 , a potent platelet-aggregating agent and vasoconstrictor, is itself unstable and rapidly converted to its inactive form TxB 2 .
prostacyclin (PGI 2 )
Vascular endothelium lacks thromboxane synthase but possesses prostacyclin synthase, which is responsible for the formation of prostacyclin (PGI 2 ) and its stable end product PGF 1a . Prostacyclin is a vasodilator and a potent inhibitor of platelet aggregation, and also markedly potentiates the permeability-increasing and chemotactic effects of other mediators. A thromboxane-prostacyclin imbalance has been implicated as an early event in thrombus formation in coronary and cerebral blood vessels.
PGE 2 and PGD 2
PGD 2 is the major prostaglandin made by mast cells; along with PGE 2 (which is more widely distributed), it causes vasodilation and increases the permeability of postcapillary venules, thus potentiating edema formation. PGF 2a stimulates the contraction of uterine and bronchial smooth muscle and small arterioles, and PGD 2 is a chemoattractant for neutrophils.PGE 2 is hyperalgesic and makes the skin hypersensitive to painful stimuli, such as intradermal injection of suboptimal concentrations of histamine and bradykinin. It is involved in cytokine-induced fever during infections
Lipoxins
Lipoxins are also generated from AA by the lipoxygenase pathway, but unlike prostaglandins and leukotrienes, the lipoxins suppress inflammation by inhibiting the recruitment of leukocytes. They inhibit neutrophil chemotaxis and adhesion to endothelium. They are also unusual in that two cell populations are required for the transcellular biosynthesis of these mediators. Leukocytes, particularly neutrophils, produce intermediates in lipoxin synthesis, and these are converted to lipoxins by platelets interacting with the leukocytes.
Cyclooxygenase inhibitors
include aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen. They inhibit both COX-1 and COX-2 and thus inhibit prostaglandin synthesis (hence their efficacy in treating pain and fever); aspirin does this by irreversibly acetylating and inactivating cyclooxygenases. Selective COX-2 inhibitors are a newer class of these drugs; they are 200-300 fold more potent in blocking COX-2 than COX-1. There has been great interest in COX-2 as a therapeutic target because of the possibility that COX-1 is responsible for the production of prostaglandins that are involved in both inflammation and homeostatic functions (e.g., fluid and electrolyte balance in the kidneys, cytoprotection in the gastrointestinal tract), whereas COX-2 generates prostaglandins that are involved only in inflammatory reactions. If this idea is correct, the selective COX-2 inhibitors should be anti- inflammatory without having the toxicities of the nonselective inhibitors, such as gastric ulceration. However, these distinctions are not absolute, as COX-2 also seems to play a role in normal homeostasis. Furthermore, selective COX-2 inhibitors may increase the risk of cardiovascular and cerebrovascular events, possibly because they impair endothelial cell production of prostacyclin (PGI 2 ), a vasodilator and inhibitor of platelet aggregation, but leave intact the COX-1-mediated production by platelets of thromboxane A 2 (TxA 2 ), an important mediator of platelet aggregation and vasoconstriction. Thus, selective COX-2 inhibition may tilt the balance towards thromboxane and promote vascular thrombosis, especially in individuals with other factors that increase the risk of thrombosis. Nevertheless, these drugs are still used in individuals who do not have risk factors for cardiovascular disease when their benefits outweigh their risks.
Lipoxygenase inhibitors
5-lipoxygenase is not affected by NSAIDs, and many new inhibitors of this enzyme pathway have been developed. Pharmacologic agents that inhibit leukotriene production (e.g., Zileuton) are useful in the treatment of asthma.
Corticosteroids
are broad-spectrum antiinflammatory agents that reduce the transcription of genes encoding COX-2, phospholipase A 2 , proinflammatory cytokines (e.g., IL-1 and TNF), and iNOS.
Leukotriene receptor antagonists
block leukotriene receptors and prevent the actions of the leukotrienes. These drugs (e.g., Montelukast) are useful in the treatment of asthma.
TNF antagonists
have been remarkably effective in the treatment of chronic inflammatory diseases, particularly rheumatoid arthritis and also psoriasis and some types of inflammatory bowel disease. One of the complications of this therapy is that patients become susceptible to mycobacterial infection, reflecting the reduced ability of macrophages to kill intracellular microbes. Although many of the actions of TNF and IL-1 seem overlapping, IL-1 antagonists are not as effective, for reasons that remain obscure. Also, blocking either cytokine has no effect on the outcome of sepsis, perhaps because other cytokines contribute to this serious systemic inflammatory reaction.
C-X-C chemokines
have one amino acid residue separating the first two of the four conserved cysteine residues. These chemokines act primarily on neutrophils. IL-8 is typical of this group. It is secreted by activated macrophages, endothelial cells, and other cell types, and causes activation and chemotaxis of neutrophils, with limited activity on monocytes and eosinophils. Its most important inducers are microbial products and other cytokines, mainly IL-1 and TNF.
C-C chemokines
have the first two conserved cysteine residues adjacent. The C-C chemokines, which include monocyte chemoattractant protein (MCP-1), eotaxin , macrophage inflammatory protein-1α (MIP-1α), and RANTES (regulated and normal T-cell expressed and secreted), generally attract monocytes, eosinophils, basophils and lymphocytes, but are not as potent chemoattractants for neutrophils. Although most of the chemokines in this class have overlapping actions, eotaxin selectively recruits eosinophils.
C chemokines
lack the first and third of the four conserved cysteines. The C chemokines (e.g., lymphotactin) are relatively specific for lymphocytes.
CX C chemokines
contain three amino acids between the two cysteines. The only known member of this class is called fractalkine. This chemokine exists in two forms: a cell surface- bound protein induced on endothelial cells by inflammatory cytokines that promotes strong adhesion of monocytes and T cells, and a soluble form, derived by proteolysis of the membrane- bound protein, that has potent chemoattractant activity for the same cells.
C1 inhibitor (C1 INH)
blocks the activation of C1, the first protein of the classical complement pathway. Inherited deficiency of this inhibitor is the cause of hereditary angioedema .
Decay accelerating factor (DAF) and CD59
are two proteins that are linked to plasma membranes by a glycophosphatidyl (GPI) anchor. DAF prevents formation of C3 convertases and CD59 inhibits formation of the membrane attack complex. An acquired deficiency of the enzyme that creates GPI anchors leads to deficiency of these regulators and excessive complement activation and lysis of red cells (which are sensitive to complement-mediated cell lysis) in the disease called paroxysmal nocturnal hemoglobinuria (PNH).
Classical macrophage activation
may be induced by microbial products such as endotoxin, which engage TLRs and other sensors; by T cell–derived signals, importantly the cytokine IFN-γ, in immune responses; or by foreign substances including crystals and particulate matter. Classically activated (also called M1) macrophages produce NO and ROS and upregulate lysosomal enzymes, all of which enhance their ability to kill ingested organisms, and secrete cytokines that stimulate inflammation. These macrophages are important in host defense against microbes and in many inflammatory reactions. As discussed earlier in the context of acute inflammation and leukocyte activation, the same activated cells are capable of injuring normal tissues.
Alternative macrophage activation
is induced by cytokines other than IFN-γ, such as IL-4 and IL-13, produced by T lymphocytes and other cells. These macrophages are not actively microbicidal and the cytokines may actually inhibit the classical activation pathway; instead, the principal function of alternatively activated (M2) macrophages is in tissue repair. They secrete growth factors that promote angiogenesis, activate fibroblasts, and stimulate collagen synthesis. It seems plausible that in response to most injurious stimuli, the first activation pathway is the classical one, designed to destroy the offending agents, and this is followed by alternative activation, which initiates tissue repair. However, such a precise sequence is not well documented in most inflammatory reactions.
tertiary lymphoid organs
In some chronic inflammatory reactions, the accumulated lymphocytes, antigen-presenting cells, and plasma cells cluster together to form lymphoid tissues resembling lymph nodes. These are called tertiary lymphoid organs ; this type of lymphoid organogenesis is often seen in the synovium of patients with long-standing rheumatoid arthritis and in the thyroid in Hashimoto thyroiditis. It has been postulated that the local formation of lymphoid organs may perpetuate the immune reaction, but the significance of these structures is not established.
Foreign body granulomas
are incited by relatively inert foreign bodies, in the absence of T cell–mediated immune responses. Typically, foreign body granulomas form around materials such as talc (associated with intravenous drug abuse), sutures, or other fibers that are large enough to preclude phagocytosis by a macrophage and do not incite any specific inflammatory or immune response. Epithelioid cells and giant cells are apposed to the surface of the foreign body. The foreign material can usually be identified in the center of the granuloma, particularly if viewed with polarized light, in which it appears refractile.
Immune granulomas
are caused by a variety of agents that are capable of inducing a persistent T cell–mediated immune response. This type of immune response produces granulomas usually when the inciting agent is difficult to eradicate, such as a persistent microbe or a self antigen. In such responses, macrophages activate T cells to produce cytokines, such as IL-2, which activates other T cells, perpetuating the response, and IFN-γ, which activates the macrophages. It is not established which macrophage-activating cytokines (IL-4 or IFN-γ) transform the cells into epithelioid cells and multinucleate giant cells.
spesis
In severe bacterial infections (sepsis), the large amounts of bacteria and their products in the blood stimulate the production of enormous quantities of several cytokines, notably TNF and IL- 1. High blood levels of cytokines cause various widespread clinical manifestations such as disseminated intravascular coagulation, hypotensive shock, and metabolic disturbances including insulin resistance and hyperglycemia. This clinical triad is known as septic shock
fibrosis
is most often used to describe the extensive deposition of collagen that occurs in the lungs, liver, kidney, and other organs as a consequence of chronic inflammation, or in the myocardium after extensive ischemic necrosis (infarction). If fibrosis develops in a tissue space occupied by an inflammatory exudate, it is called organization (as in organizing pneumonia affecting the lung).
Fibroblast growth factors (FGFs)
mainly FGF-2, stimulates the proliferation of endothelial cells. It also promotes the migration of macrophages and fibroblasts to the damaged area, and stimulates epithelial cell migration to cover epidermal wounds.
Angiopoietins 1 and 2 (Ang 1 and Ang 2)
are growth factors that play a role in angiogenesis and the structural maturation of new vessels. Newly formed vessels need to be stabilized by the recruitment of pericytes and smooth muscle cells and by the deposition of connective tissue. Ang1 interacts with a tyrosine kinase receptor on endothelial cells called Tie2. The growth factors PDGF and TGF-β also participate in the stabilization process: PDGF recruits smooth muscle cells and TGF-β suppresses endothelial proliferation and migration, and enhances the production of ECM proteins.
matrix metalloproteinases (MMPs)
After its deposition, the connective tissue in the scar continues to be modified and remodeled. The degradation of collagens and other ECM components is accomplished by a family of matrix metalloproteinases (MMPs). MMPs are produced by a variety of cell types (fibroblasts, macrophages, neutrophils, synovial cells, and some epithelial cells), and their synthesis and secretion are regulated by growth factors, cytokines, and other agents. The activity of the MMPs is tightly controlled. They are produced as inactive precursors (zymogens) that must be first activated; this is accomplished by proteases (e.g., plasmin) likely to be present only at sites of injury. In addition, activated collagenases can be rapidly inhibited by specific tissue inhibitors of metalloproteinases (TIMPs), produced by most mesenchymal cells. Thus, during scar formation, MMPs are activated to remodel the deposited ECM and then their activity is shut down by the TIMPs.
Chediak-Higashi
defect in chemotaxis and lysosomal degranulation into phagosomes
fibrinopurulent exudate (suppurative/ purulent exudate)
pus, composed of neutrophils, infecions (bacteria and fungal)
abscess
contained within parenchyma/ confined space the cavity that exists is newly formed. Contains neutrophils, caused by infections.
empyema
located within an anatomic space or cavity (pleural, subdural space, within appendix. Gallbladder) composed of neutrophils, later on macrophages and lymphocytes. Caused by infection
cellulitis
located within skin, fascia, or deep connective tissue. Caused by infections or inflammatory. Often occurs in setting of cut.
granuloma
usually within parenchyma, rounded/nodular appearance. Composed of macrophages, lymphocytes, and plasma cells. Caused by infections or inflammatory.
cholelithiasis
gallstone within the gallbladder
choledocholithiasis
gall stone within the common bile duct.
Hypertrophy
the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number.
Atrophy
the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, excessive amount of apoptosis of cells, and disuse or lack of exercise or disease intrinsic to the tissue itself.
Metaplasia
the reversible replacement of one differentiated cell type with another mature differentiated cell type. The change from one type of cell to another may generally be a part of normal maturation process or caused by some sort of abnormal stimulus. In simplistic terms, it is as if the original cells are not robust enough to withstand the new environment, and so they change into another type more suited to the new environment. If the stimulus that caused metaplasia is removed or ceases, tissues return to their normal pattern of differentiation. Metaplasia is not synonymous with dysplasia and is not directly considered carcinogenic.
Hyperplasia
an increase in the amount of organic tissue that results from cell proliferation. It may lead to the gross enlargement of an organ and the term is sometimes confused with benign neoplasia or benign tumor.
Karyorrhexis
the destructive fragmentation of the nucleus of a dying cell
Pyknosis
the irreversible condensation of chromatin in the nucleus of a cell undergoing necrosis or apoptosis. It is followed by karyorrhexis, or fragmentation of the nucleus.
Karyolysis
the complete dissolution of the chromatin of a dying cell due to the enzymatic degradation by endonucleases. The whole cell will eventually stain uniformly with eosin after karyolysis. It is usually preceded by karyorrhexis and occurs mainly as a result of necrosis, while in apoptosis after karyorrhexis the nucleus usually dissolves into apoptotic bodies.
Coagulative necrosis
a type of accidental cell death typically caused by ischemia or infarction.
Liquefactive necrosis
a type of necrosis which results in a transformation of the tissue into a liquid viscous mass. Often it is associated with focal bacterial or fungal infections. In liquefactive necrosis, the affected cell is completely digested by hydrolytic enzymes, resulting in a soft, circumscribed lesion consisting of pus and the fluid remains of necrotic tissue. Dead leukocytes will remain as a creamy yellow pus. After the removal of cell debris by white blood cells, a fluid filled space is left. It is generally associated with abscess formation and is commonly found in the central nervous system.
Caseous necrosis
a form of cell death in which the tissue maintains a cheese-like appearance. The dead tissue appears as a soft and white proteinaceous dead cell mass. Frequently, caseous necrosis is encountered in the foci of tuberculous infections. It can also be caused by syphilis and certain fungi. A similar appearance can be associated with histoplasmosis, cryptococcosis, and coccidioidomycosis.[
Fat necrosis
a form of necrosis characterized by the action upon fat by digestive enzymes. It is usually associated with trauma of the pancreas or acute pancreatitis.
Ischemia
a restriction in blood supply to tissues, causing a shortage of oxygen and glucose needed for cellular metabolism (to keep tissue alive).
Hypoxia
a condition in which the body or a region of the body is deprived of adequate oxygen supply. Hypoxia may be classified as either generalized, affecting the whole body, or local, affecting a region of the body.
Superoxide dismutase
are enzymes that alternately catalyze the dismutation (or partitioning) of the toxic superoxide (O2−) radical into either ordinary molecular oxygen (O2) or hydrogen peroxide (H2O2). Can protect against ROS
Catalase
It catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in protecting the cell from oxidative damage by reactive oxygen species (ROS).
Glutathione peroxidase
the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage. The biochemical function of glutathione peroxidase is to reduce lipid hydroperoxides to their corresponding alcohols and to reduce free hydrogen peroxide to water.
Xanthine oxidase
a form of xanthine oxidoreductase, a type of enzyme that generates reactive oxygen species. These enzymes catalyze the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to uric acid. These enzymes play an important role in the catabolism of purines in some species, including humans
acute tubular necrosis
a medical condition involving the death of tubular epithelial cells that form the renal tubules of the kidneys. ATN presents with acute kidney injury (AKI) and is one of the most common causes of AKI. Common causes of ATN include hypotension and use of nephrotoxic drugs.
disseminated intravascular coagulation
a pathological process characterized by the widespread activation of the clotting cascade that results in the formation of blood clots in the small blood vessels throughout the body. This leads to compromise of tissue blood flow and can ultimately lead to multiple organ damage. In addition, as the coagulation process consumes clotting factors and platelets, normal clotting is disrupted and severe bleeding can occur from various sites. DIC does not occur by itself but only as a complicating factor from another underlying condition, usually in those with a critical illness. The combination of widespread tissue ischemia and simultaneous bleeding carry an increased risk of death in addition to that posed by the underlying disease.
hemdynamics
Hydrostatic pressure “pushes” fluid from the capillary into the interstitial space on the arterial end. This loss of fluid then increases the plasma protein concentration (oncotic pressure), so fluid is “pulled” back into the capillary on the venous end to balance the protein concentration. Increased hydrostatic pressure and decreased plasma oncotic pressure each can lead to fluid movement out of the capillaries and into the adjacent tissue (edema) or body cavity (effusion). Damage to capillary walls allows non-regulated movement of fluid and proteins into tissue. Inadequate drainage of fluid from the tissues via the lymphatic system can also lead to fluid accumulation.
increased hydrostatic pressure
heart failure, fluid overload (infusion, renal failure), venous obstruction or compression, arteriolar dilation
decreased oncotiv pressure
due to liver disease: protein loss (kidney, GI tract), low protein production (liver disease, malnutrition)
lymphatic obstruction
inflammation infection, neoplasm, post surgery irradiation
Increased vascular permeability
Increased blood volume in a tissue may or may not lead to edema and effusions. Hyperemia is an active increase in blood flow due to arteriolar dilation. It serves normal physiologic purposes such as bringing inflammatory and repair mediators into areas of tissue damage or infection, and it provides increased oxygen to exercising skeletal muscle. Hyperemia causes a red coloration (erythema) to the tissue due to the increased mass of oxygenated red blood cells. Congestion is a pathologic accumulation of blood due impaired outflow of venous blood. Congested tissue has a red-blue color due to accumulation of deoxygenated blood, and may have increased hydrostatic pressure.
Hyperemia
Physiologic: Active, Arteriolar dilation, Oxygenated blood: red
Congestion
Pathologic: Passive, Impaired venous outflow, Deoxygenated blood: pale or red/blue
risk factors for Deep Vein Thrombosis
Immobility, recent surgery, Above the age of 40, Estrogen, Pregnancy or post-partum, Previous or current cancer, Limb trauma and/or orthopedic procedures, Coagulation abnormalities, Obesity. All of these effect vircho triad (endothelial injury, hypercoagulability, abnormal blood flow)
atheroemboli
athersclerotic plaque of aorta, iliac, or carotid arteries, effects legs, brain, GI tract, and kidney causing stroke, tissue necrosis in the leg, GI pain and bleeding, acute kidney injury.
amniotic fluid emboli
caused by Torn placental membranes, uterine vein rupture. Affects Lungs, brain, vasculature causing During labor or immediately postpartum onset of respiratory insufficiency, shock, seizures, DIC. 10% of maternal deaths
arterial thromboemboli
caused by Heart (vegetations or mural thrombi), aorta, carotid artery, affecting Legs (75%), brain (10%), causing stroke, tissu necrosis in the legs.
epithelia neoplasm classification
adenoma, papilloma
mesechymal neoplastic
osteoma, chondroma, fibroma
Carcinoma
epithelial, Adenocarcinoma (carcinoma with formation of glandular structures)
sarcoma
mesenchymal: Eg: osteosarcoma, chondrosarcoma, fibrosarcoma
Hematopoietic
mesechymal, Lymphoma (lymph node origin) and Leukemia (bone marrow origin)
pediatric neoplasms
Since childhood neoplasms arise in context of developing tissues/organs, they tend to be quite different from adult neoplasms. Origin in developmental precursors. Tendency to recapitulate aspects of developmental program of tissue of origin. Short latency and early metastasis. Fewer mutations; prominent role for oncogenic fusions and epigenetic dysregulation. Relative chemosensitivity (at a price)
the four types of tissue in the body
the human body contains >200 different cell types. These arise by differentiation from totipotent/multipotent stem cells during embryogenesis. The different types of cells are organized into four basic tissues: epithelium (surface/internal), muscle (cardiac, smooth, skeletal), nerve (CNS, PNS), and connective tissue (bone, joint, fat, blood, bone marrow, lymph glands, etc).
Acute tubular necrosis (ATN)
a medical condition involving the death of tubular epithelial cells that form the renal tubules of the kidneys. ATN presents with acute kidney injury (AKI) and is one of the most common causes of AKI. Common causes of ATN include hypotension and use of nephrotoxic drugs. The presence of “muddy brown casts” of epithelial cells found in the urine during urinalysis is pathognomonic for ATN. Management relies on aggressive treatment of the factors that precipitated ATN (e.g. hydration and cessation of the offending drug). Because the tubular cells continually replace themselves, the overall prognosis for ATN is quite good if the cause is corrected, and recovery is likely within 7 to 21 days. ATN may be classified as either toxic or ischemic. Toxic ATN occurs when the tubular cells are exposed to a toxic substance (nephrotoxic ATN). Ischemic ATN occurs when the tubular cells do not get enough oxygen, a condition that they are highly sensitive and susceptible to, due to their very high metabolism.
Discuss major causes (etiologies) of cell injury.
Physical agents - trauma, extreme temperatures (burns, hyperthermia, hypothermia, Humans must maintain a temperature no lower than about 30°C, nor higher than about 42°C), etc. Chemical and drugs - drug toxicity, poisoning, etc. Infection - pathogenic bacteria, virus, fungi, protozoa, etc. Immunologic insults - anaphylaxis, autoimmunity, etc. Genetic derangement-phenylketonuria, cystic fibrosis, etc. Nutritional imbalance - atherosclerosis, protein and vitamin deficiency, etc. Hypoxia - cells receive too little 02. Multiple causes - primary lung disease, heart failure, shock, arterial or venous thrombosis, etc.
Hypoxia
different cells vary in the ability to tolerate hypoxia. Neurons can tolerate only 3 to 5 min while fat cells and skeletal muscle cells survive for many hours. There is a second type of injury that stems from the production of oxygen radicals that follow 02 therapy, acute inflammation and reperfusion of hypoxic tissues.
