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26 Cards in this Set
- Front
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What is immunology? |
The study of how the body defends itself against infection by micro-organisms, including bacteria, virus, fungi and parasites |
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What is innate immunity? |
Natural immune response - prevents or limits infection • resistance - unaltered on repeated infection • specificity - generally effective against all organisms • effector cells - phagocytes, macrophages, and neutrophils. NK cells, mast cells, eosinophils • effector molecules - lysozyme, complement, interferons alpha, beta and gamma, defensins, lactoferrin |
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What is adaptive immunity? |
An acquired response - eradicates infection • resistance - improved by repeated infection (memory) • specificity - specific for stimulating organism • effector cells - lymphocytes, T-cells and B-cells • effector molecules - antibodies and cytokines |
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Surface epithelia - a natural barrier to infection |
Epithelial cells line and protect surfaces of the body in contact with the environment • Mechanical; > cells joined by tight junctions, flow of air or fluid across the epithelium, mucus production and movement by cilia • Chemical; > fatty acids and salty sweat in skin > lysozyme in saliva, sweat and tears > low pH and pepsin in the stomach > defensins in the airway and GI tract > acidity of urine, vaginal lactic acid • Microbiological; > symbiotic bacteria compete for nutrients |
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Innate immunity cells - PHAGOCYTES |
The phagocytes engulf, digest, and destroy bacteria • Macrophages - large mononuclear cells found in tissues. Circulate in blood as monocytes. Monocytes are recruited into tissue sites of infection where they mature into macrophages. • Neutrophils - multi-lobed nucleus, polymorphonuclear (PMN) cells, many granules in the cytoplasm, circulate in the blood. Most abundant white blood cell (account for 50-70% of all wbc). > neutrophils are produced in the bone marrow at a rate of 7 million/min. They are short-lived and circulate in the blood for about 6 hours and are removed in the spleen if not needed |
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Innate immunity cells - SECRETORY |
• Eosinophils - granulocytic leukocytes. bi-lobed nucleus and prominent granules released on contact with parasites and ticks. Found mainly in tissue and low level in circulation. The number increases following infection and during the late phase of an allergic reaction. > they contain highly toxic proteins; major basic protein (MBP), eosinophil cationic protein (ECP), and eosinophil derived neurotoxin (EDN) • Mast cells - reside in tissues alongside blood vessels and under epithelial layers. They are mediators stored in granules. Protect mucosal surfaces. Activated mast cells release histamine in the allergic reaction. • NK cells - large granular cytotoxic lymphocyte, releases lytic granules to kill virus-infected cells and some tumour cells. Found in blood. Activated by Type-I interferons alpha and beta (IFNa, IFNb), produced by virally infected cells. |
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Adaptive immunity cells - LYMPHOCYTES |
B-cells and T-cells are also called lymphocytes, account for 20-40% of WBC. (NK cells ~15% of lymphocytes but have no B-cell or T-cell receptors) > formed in the bone marrow and carry immunoglobulins (antibodies) on the cell surface. This is the B-cell antigen receptor, and each B-cell carries receptors that bind to one specific antigen. Antigens are Antibody generators. They are foreign proteins or peptides. > B-cells are activated during the adaptive immune response to mature into active plasma cells that produce large quantities of specific antibody. The antibodies are secreted into body fluids, both blood and lymph fluid. "Antibody-mediated immunity" T-cells are produced in the bone marrow but mature in the thymus gland. The antigen receptor is known as the T-cell receptor (TCR). During the adaptive immune response, T-cells divide and proliferate and become activated. T-cells must come into close physical contact with their target cell to destroy it. "Cell-mediated immunity" |
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Stages of innate response |
1. Adherence of bacteria to epithelium. Specific factors on surface enable attachment, e.g. specific sugar residues on glycoprotein molecules. This determines the tissue specificity of the organism. 2. Penetration of epithelium, e.g. Cut or burn. 0-4 hours after exposure to infection 3. Local infection of tissues leads to activation of macrophages. Macrophages resident within tissues recognise the bacteria by non-specific mechanisms and limit infection by engulfing and destroying bacteria. Epithelial cells also produce anti-bacterial proteins and peptides, e.g. defensins and the process of wound healing and epithelial repair closes site of infection. 4. Macrophages overwhelmed - recruitment of neutrophils. 4-96 hours after infection exposure. Macrophages become activated and produce pro-inflammatory cytokines which recruit second wave of phagocytes - neutrophils |
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Stages of the adaptive response |
1. Bacterial peptides (antigens) spread to the lymph nodes. This occurs after 96 hours, if the early host response fails to clear the infection. Antigens are either spread to lymphoid tissue as free antigen or as antigen engulfed in macrophages 2. Antigens trapped in lymph nodes activate T-cells and B-cells. They increase in number (clonal expansion) and induce adaptive immune response at site of infection 3. Specific antibodies and active T-cells mediate adaptive immunity. T-cells produce cytokines to further activate the macrophages and mature B-cells that produce specific antibodies to neutralise bacterial antigens and activate complement. |
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Phagocytosis of bacteria by macrophages |
Phagocytosis is central to all stages of host defence against infection. > receptors on phagocytes recognise and bind to bacterial cell wall components. The bacterium is bound by these receptors to the macrophage and this stimulates receptor-mediated endocytosis. 1: Once ingestion starts, a phagosome forms around bacterium, and the bacterium becomes completely isolated inside a phagosome inside the macrophage. > lysosomes contain enzymes that are capable of destroying bacterial cell wall to kill it. Also, the formation of reactive free oxygen radicals helps kill bacteria. Lysosome fuse with the phagosome to form a phagolysosome inside the cell, in which the bacterium is killed. This is usually an effective process. However, when there is a massive infection the system becomes leaky and can lead to tissue damage as the fusion of lysosomes occurs before the phagosome has fully formed. In this case, phagocytes can damage the tissue they are trying to protect. Phagocytosis is greatly enhanced by opsonisation of bacteria with complement components, especially C3b. |
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Toll like receptors and phagocytosis |
Recognise pathogen associated molecular patterns (PAMPS) > PAMPs are sequences found on pathogens but not on human cells > They tell the phagocyte that 'non-self' is present and provide information on the type of pathogen present > There are 10 Toll like receptors found on human cells which recognise things such as lipopolysaccharide (TLR4), peptidoglycan (TLR2) and viral DNA (TLR9) • gateway to the immune system • TLR on surface = 2,4,6 • TLR intracellular = 3,7,8,9 |
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Opsonisation by C3b |
Alters the surface of a pathogen and facilitates phagocytosis This occurs by the recognition of complement components by complement receptors on the phagocytotic cell (both macrophages and neutrophils). Complement refers to a family of 30 different plasma proteins, many are proteases that generate a number of active components. Opsonisation is a major function of C3b. C3b is recognised by complement receptor-1 (CR1). Macrophages and neutrophils phagocytose bacteria more efficiently when the bacteria have been opsonised by C3b. |
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Activation of complement component C3 to form the opsonin C3b by the alternative pathway |
Complement component C3 is present in high concentrations in plasma and this is the start point for complement activation. Operates immediately after bacteria cross the epithelia and are present in tissues. • C3 is hydrolysed spontaneously (tick over) to form C3b and C3a • C3b is stabilised by binding to microbial cell surfaces. Here it is protected from further hydrolysis which would otherwise inactivate it • Factor B (another complement component present in plasma) binds to C3b bound to cell surface and is then hydrolysed into Bb and Ba by Factor D (another complement component) • This leaves a complex of C3b, Bb on the cell surface. This complex is itself a C3 convertase and can cleave more C3 and thereby amplify the cleavage of C3 by several orders of magnitude above 'tick over' |
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C3b opsonises bacteria, but not host cells - explain |
The alternate pathway of complement activation opsonises bacteria but spares host cells as host cells have regulatory pathways that are not present on the bacterial cell surface. This mechanism can allow phagocytes to distinguish 'self' from 'non-self' On bacterial cell surface - Factor P (properdin) increases activation and conversion of C3 by binding and stabilising C3bBb complex. It converts large numbers of free C3 to C3b which coats the surface of the bacterium. This is opsonisation. Host cells - express complementary regulatory proteins which inactivate C3bBb thus CR-1, decay accelerating factor (DAF), factor H and membrane cofactor of proteolysis (MCP) bind to C3bBb to displace Bb from the complex preventing further formation of complexes by C3 convertase (C3bBb). Also, they all make C3b sensitive to Factor-I which cleaves C3b to its inactive form iC3b. Therefore protected from phagocytes. |
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Additional results of complement activation |
C3b binds to and opsonises bacteria to enhance phagocytosis. • C3b also initiates a series of reactions that bring about bacterial cytolysis. First, C3b splits C5. The C5b fragment then binds to C6 and C7, which attach to the plasma membrane of a microbe. Then C8 and C9 proteins join the other proteins to form a cylinder shaped membrane attack complex that inserts into the bacterial membrane. • The membrane attack complex creates channels or pores in the membrane that results in cytolysis, and bacteria bursts due to inflow of fluid through the channels. • C3a and C5a bind to mast cells and cause them to release histamine, which increases the permeability of blood vessels and C5a attracts phagocytes to the site of inflammation. C3a and C5a are also known as anaphylatoxins and are involved in anaphylactic allergic reactions |
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Activated macrophages produce cytokines |
Macrophages are stimulated by soluble products of bacteria such as toxins which are found in high concentrations at the site of infection. This activated macrophage directs the early host response to infection which is to bring in the neutrophil from the blood to the infection. > neutrophils are present in the blood in large numbers and have a short half life of 6hrs, so many are made an lost each day. The macrophage synthesises and release cytokines, which are chemical signals that communicate between cells. Cytokines stimulate neutrophil recruitment from the blood. • IL-1 and TNF alpha activate endothelial cells that line blood vessels. They stimulate the expression of adhesion molecules and neutrophil chemoattractants such as IL-8. • IL-8; is a neutrophil chemoattractant that is expressed by macrophages as well as activated endothelium. Enhances binding of neutrophils to adhesion molecules and direct neutrophils to site of infection • Systemic effects - cytokines have long range systemic effects when they enter the bloodstream. IL-1, TNF-alpha and IL-6 are endogenous pyrogens (increase body temp) which decreases bacterial replication. • IL-6 and IL-12 - enhance the adaptive immune response by activating lymphocytes. |
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Neutrophil recruitment and inflammation |
> rubor (redness), calor (heat), donor (pain), tumor (swelling) Neutrophils leave the blood vessels during the early inflammatory response; > neutrophils are normally restricted to the centre of the vessel where blood flow is greatest. > during the inflammatory response, vessels dilate (diameter increases), bringing more blood to that area. > permeability of the blood vessel increases, leading to the accumulation of fluid in the tissue causing swelling and pain. • due to the change of blood flow, neutrophils interact with the blood vessel wall and start to migrate. The movement of cells across the blood vessel wall is regulated by cytokines produced by the macrophage |
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Migration of neutrophil across endothelium - 1: ROLLING ADHESION |
• Lectins are molecules that recognise carbohydrates; E-selectin is an endothelial cell surface selectin molecule. They recognise carbohydrate residues on the neutrophil surface. These residues belong to glycoproteins on the neutrophil surface. > this is a weak and reversible interaction that causes the neutrophil to slow down and roll along the endothelial surface. > it also enhances the interaction of adhesion molecules in the second step • E-selectin expression is increased by TNF-alpha which is released by activated macrophages at tissue sites of infection. Therefore neutrophil recruitment occurs at tissue-specific sites |
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Neutrophil recruitment to site of infection - 2: ADHESION MOLECULES |
Adhesion molecules such as lymphocyte function associated antigen (LFA-1) on neutrophils bind to the intercellular adhesion molecule-1 (ICAM-1) on the endothelium. > the chemokines are a family of proteins that attract WBC. > IL-8 is a chemokine and very potent. It interacts with specific receptors on the neutrophil to direct them to site of infection. In addition, when bound to its receptor, IL-8 makes the binding between adhesions molecules on the neutrophil and endothelium stronger, hence rolling stops. > expression of both ICAM-1 and IL-8 on endothelium is increased by TFN-alpha. |
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Neutrophil recruitment to site of infection - 2: ADHESION MOLECULES |
Adhesion molecules such as lymphocyte function associated antigen (LFA-1) on neutrophils bind to the intercellular adhesion molecule-1 (ICAM-1) on the endothelium. > the chemokines are a family of proteins that attract WBC. > IL-8 is a chemokine and very potent. It interacts with specific receptors on the neutrophil to direct them to site of infection. In addition, when bound to its receptor, IL-8 makes the binding between adhesions molecules on the neutrophil and endothelium stronger, hence rolling stops. > expression of both ICAM-1 and IL-8 on endothelium is increased by TFN-alpha. |
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Recruitment of neutrophil to site of infection - 3: DIAPEDESIS |
Neutrophils respond to concentration gradients of IL-8 and move across the blood vessel wall into the tissue where IL-8 is present at higher concentrations than in the blood. > the neutrophil squeezes between endothelial cells and penetrates the basement membrane to reach site of infection |
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Neutrophil recruitment to site of infection - 2: ADHESION MOLECULES |
Adhesion molecules such as lymphocyte function associated antigen (LFA-1) on neutrophils bind to the intercellular adhesion molecule-1 (ICAM-1) on the endothelium. > the chemokines are a family of proteins that attract WBC. > IL-8 is a chemokine and very potent. It interacts with specific receptors on the neutrophil to direct them to site of infection. In addition, when bound to its receptor, IL-8 makes the binding between adhesions molecules on the neutrophil and endothelium stronger, hence rolling stops. > expression of both ICAM-1 and IL-8 on endothelium is increased by TFN-alpha. |
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Recruitment of neutrophil to site of infection - 3: DIAPEDESIS |
Neutrophils respond to concentration gradients of IL-8 and move across the blood vessel wall into the tissue where IL-8 is present at higher concentrations than in the blood. > the neutrophil squeezes between endothelial cells and penetrates the basement membrane to reach site of infection |
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Neutrophil recruitment to site of infection - 4: MIGRATION |
The migration of neutrophils through the tissue matrix under the influence of concentration gradients of IL-8. Migration involves the interaction of the neutrophil with components of the matrix, and the neutrophil releases proteolytic enzymes that degrade the matrix and increases the rate of migration. > at the site of the infection, the neutrophil phagocytoses and kills bacteria, supporting the role of the macrophage. |
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Neutrophil recruitment through tissue |
Neutrophils migrate into tissues by a process called haptotaxis - they move up a gradient of chemoattractants that are bound to the tissue matrix or stroma. Chemoattractants are produced by the bacteria and by stromal cells in the tissue matrix such as fibroblasts and epithelial cells. > cells crawl over the surface of the matrix towards high concentrations of chemoattractants > stromal cells release chemokines such as IL-8 and also two lipid mediators leukotriene B4 (LTB4) and platelet activating factor (PAF). • neutrophils initially respond to these chemoattractants but their ultimate goal is the bacterial infection. Bacteria release peptides with a formyl group (formyl peptide) attached that are not made by human cells and they activate complement. |
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Phagocytosis and bacterial killing |
The neutrophil has a multi-lobed nucleus and is often called a polymorphonuclear cell (PMN). The cytoplasm is packed with many dense granules that fall into 3 categories; primary (azurophil) granules, secondary (specific) granules, and tertiary granules. > Each contains a different anti-microbial protein > there are also small secretory vesicles that contain plasma proteins such as albumin • neutrophil phagocytosis involves two different receptor classes, those that recognise activated complement such as CR1 and CR3 and those that recognise immunoglobulins (FcgR). • Immunoglobulins (antibodies) also opsonise bacteria as well as complement components. Once bound, the target bacteria are ingested into a phagosome. Once in the phagosome, primary and secondary granules fuse with the phagosome and release their contents onto the bacteria to kill them. (See notes on proteases, defensins, BPI, reactive oxygen) |
