this chapter introduced the mechanisms used by the innate immune system to ward off early infection and also trigger an adaptive immune response.
the first means of defense employed by the innate immune system are in the epithelial surfaces. this includes the tight junctions and thick layers in the epithelia that prevent microorganisms from entering, the mucosal layers and cilia in the lungs that constantly trap and remove microorganisms, antimicrobial agents in tears, and the chemically hazardous environment in the GI tract from gastric and pancreatic enzymes.
if pathogens penetrate this epithelial layer, they then encounter the cells of the innate immune system: macrophages and neutrophils. macrophages are derived from monocytes that circulate in the blood that reside in tissues, and are long lived. neutrophils circulate in the blood and are called into the tissues in large numbers in response to infection and are short lived. both cells have "germline-encoded" receptors that have evolved to recognize common membrane constituents of bacteria. some common receptors on the cells of the innate immune system are mannose binding lectin and scavenger receptors.
pathogen binding to these receptors can stimulate phagocytosis: the pathogen is enveloped in the cell membrane and forms an intracellular vesicle called a phagosome which can then become acidic or fuse with a lysosome, killing the pathogen via lysosomal enzymes. secondly, it can trigger the release of cytokines and chemokines, which can mediate the inflammatory response.
the inflammatory response is a local vasodilation, redness, pain, and heating, caused by release of cytokines and chemokines. it can also trigger blood clotting, which prevents the infection from spreading systemically. these changes promote recruitment of leukocytes from the bloodstream to aid in infection: cytokines act on the endothelium of the nearby blood vessels, causing vasodilation, while chemokines act on the cell-adhesion molecules (CAM) of the endothelium, changing their conformation and affinity for the integrins on the circulating leukocytes. this causes the leukocytes in circulation to bind with selectins, then ICAM's, arresting their flow. they then bore holes through the basement membrane via enzymes that break down the extracellular matrix and enter into peripheral tissues. here, they are guided by increasing concentration gradients of chemokines to the site of infection.
toll like receptors are another pathogen binding receptor on innate immunity cells that also trigger the release of chemokines and cytokines, as well as stimulating the surface expression of co-stimulatory molecules, which trigger the maturation of naive lymphocytes and thus help initiate the adaptive immune response. this is an example of how the innate immune system triggers the adaptive immune response.
the complement system is also used by the innate immune system to aid in the phagocytosis of pathogens. there are three pathways, the classical, MB-lectin, and alternative, all of which are zymogenic cascades which are initiated by protein complexes in the plasma. the classical pathway is initiated by pathogen binding, which triggers a cascade which creates a C3 convertase, which opsonizes the pathogen's surface with C3b, leaving it susceptible to phagocytosis. the MB-lectin pathway is similar except is initiated by a different protein complex. the alternative pathway is initiated by spontaneous cleavage of a complement protein C3, as opposed to pathogen binding, which then also forms a C3 convertase. the alternative pathway can be used by the other two pathways to greatly amplify the complement process, since C3b created by the convertase can then be used to initiate another alternative pathway.
the complement pathway also releases small protein fragments (denoted by the small "a" after the protein as opposed to the membrane bound "b") which are weak mediators of inflammation or can signal other molecules. another mechanism that the complement pathway uses to destroy pathogens is the membrane attack complex, which is the formation of membrane pores on a pathogen's surface that disrupt the concentration gradients and kill the cells. however this is a relatively limited mechanism and only used against certain pathogens.
interferons are used in the innate immune system to fight off against infection. cells infected with viruses release interferons, which then act on itself and its uninfected neighbors, triggering transcription of proteins which act intracellularly to destroy viral RNA and halt transcription. they also induce expression of class 1 MHC molecules, which signal natural killer cells to release cytotoxic granules which trigger cell death in these infected cells.
questions
1. how quickly can the innate immune system respond to infection?
2. what are some of the mechanisms that the innate immune system uses?
3. what are some of the microorganisms that cause disease?
4. what are obligate vs. facultative intracellular pathogens?
5. what is a zoonotic infection?
6. what is the first barrier which prevents infection?
7. what goes on in the epithelial layer of the lung to prevent infection?
8. what goes on in the epithelial layer of the gut to prevent infection?
9. what is secreted in the tears that prevents infection?
10. what are commensal bacteria and how do they aid in preventing infection?
11. what are the two types of phagocytic cells in the innate immune system?
12. describe how a macrophage can use phagocytosis to kill a pathogen.
13. what are some of the toxic chemicals that the macrophages and neutrophils can produce?
14. what is the respiratory burst?
15. major differences between neutrophils and macrophages...
16. what are two strategies that bacteria have evolved to evade the innate immune system?
17. what do cytokines and chemokines do?
18. what is the inflammation response?
19. what two enzymatic cascades can be triggered by activated endothelium during the inflammation response?
20. what is the difference between the receptors on the cells of the innate immune system vs. that of the adaptive immune system?
21. what are some common molecular patterns of bacteria and viruses that can be recognized by the cells of the innate immune system?
22. what is the mannose binding lectin and the macrophage mannose receptor?
23. what are scavenger receptors?
24. what are toll like receptors and what do they do?
25. describe the recognition of bacterial LPS and how it relates to toll like receptors.
complement...
26. what is the complement system?
27. what are the three pathways to the complement system?
28. describe the main differences between the three pathways.
29. the complement fragments C3a, C4a, and C5a acts as...
30. what can the terminal fragments of the complement system also do?
31. what are the two families of cytokines released from phagocytic cells in the innate immune system?
32. what are the ways in which chemokines help fight infection?
33. what are selectins?
34. what are ICAM's?
35. what is p-selectin and what is it expressed in response to?
36. describe the first step in extravasation.
37. describe the second step in extravasation.
38. what is diapedesis?
39. what is the fourth and final step in extravasation?
40. how does TNF-alpha help contain infection to a local area?
41. what is septic shock and what role does TNF-alpha play in it?
42. what are endogenous pyrogens and what are some examples?
43. what is the "acute phase response?"
44. what are the acute phase proteins and how do they work?
45. what is leukocytosis?
46. what are interferons and what do they do?
47. what is the signalling system that interferons use to recruit natural killer cells?
48. what are natural killer cells? what do they do? what are they activated by?
answers
1. within minutes/hours
2. physical barrier of the epithelia, phacocytic cells beneath epithelia, inflammation response, recruiting other leukocytes from the blood stream, the complement system, chemokines/cytokines, natural killer cells.
3. viruses, bacteria, fungus, protozoa, worms
4. obligate intracellular pathogens can only proliferate inside of a host cell, whereas facultative intracellular pathogens can proliferate outside as well.
5. when an infection migrates from animals to humans.
6. tight junctions of the epithelial layer
7. the respiratory airways secrete mucus and have cilia which are constantly moving trapped particulates and pathogens out of the body cavity.
8. the gut has mucus as well, as well as a corrosive chemical environment, as well as peristaltic action which constantly moves microorganisms outward.
9. anti microbial chemicals such as lyzozyme and phospholipase A.
10. the bacteria that lives symbiotically in the gut, which competes with harmful microorganisms for nutrients and space.
11. macrophages and neutrophils.
12. pathogens that bind to the receptors on the macrophage are then enveloped in the membrane of the macrophage and ingested into the cell, where it forms a phagosome. it then fuses with a lysosome to form a phagolysosome, which exposes the pathogen to the harmful lysomal enzymes and kills it. alternatively, the phagosome can turn acidic, which also kills pathogens.
13. hydrogen peroxide, nitric oxide, superoxide anion .
14. the process of forming superoxide anion from hydrogen peroxide; so called because it demands an extra burst of oxygen consumption.
15. macrophages are long lived, reside in tissues (after differentiation from monocytes), while neutrophils reside in the circulatory system and are called upon to fight infection in the tissues, after which they die.
16. forming a thick polysaccharide capsule covering the molecules that would be recognized by the receptors on macrophages and neutrophils. also, inhibiting acidification in phagosomes after phagocytosis, or preventing fusion with lysosomes.
17. cytokines act to produce different changes in other cells or tissues, and chemokines are chemical attractants that cause chemotaxis in effector cells. they also help mediate the inflammation response.
18. a series of local events triggered by release of cytokines and chemokines that includes swelling, redness, pain, vasodilation, recruitment of effector cells such as neutrophils.
19. the kinin system and the blood clotting cascade.
20. on the cells of the innate immune system, each cell has a variety of "germline- coded" receptors that have evolved to recognize common bacterial membrane components. on the cells of the adaptive, each cell has only one type of receptor on its membrane which was created by the clonal selection mechanism described in the previous chapter.
21. bacteria have unmethylated repeats of the dinucelotide CpG, viruses express double stranded RNA.
22. the mannose binding lectin is a free floating molecule receptor that binds to the a particular arrangement and spacing of mannose molecules on bacteria. the macrophage mannose receptor is the membrane bound version of this receptor.
23. another type of phagocytic receptor that binds various anionic polymers and acetylated (modified) LDL's.
24. another type of receptor that acts as a "danger signal" and produces several effects such as release of cytokines, chemokines, and display of co-stimulatory molecules which activate naive lymphocytes.
25. LPS is recognized by the phagocytic cell's CD14 surface receptor, which then associates with the toll like receptor 4, which is then activated to produce cytokines, chemokines, and display costimulatory molecules.
26. the complement system is a system of proteins (activated using a zymogenic cascade) that opsinizes pathogens and aids in their phagocytosis.
27. the classical, MB-lectin, and alternative
28. the classical pathway is activated by binding to pathogen and the pivotal step is the production of C3 convertase which coats the pathogen with C3b molecules, aiding phagocytes' destruction of the pathogen. the MB-lectin pathway is similar but uses a different pathogen-binding complex to initiate the zymogenic cascade. the alternative pathway is initiated by spontaneous hydrolysis of C3 as opposed to pathogen binding, and it can be amplified (the pathway produces C3b, which can be used to initiate a new cycle)
29. weak mediators of inflammation, causing vasodilation, upregulation of CAM's in endothelium, and inducing smooth muscle contraction.
30. form a membrane attack complex, which creates pores in the pathogen and disrupts concentration gradients, ultimately killing the pathogen.
31. hematopoeitin and TNF
32. they work to recruit effector cells from the circulation by causing conformation change in the CAM's and also by attracting effector cells to places of infection in the tissue by means of increasing concentration gradients. finally, they can also activate the macrophages and neutrophils to fight the infection; producing the respiratory burst or releasing lysosomal contents.
33. selectins are a family of CAM's that initiate leukocyte-endothelium interaction.
34. intercellular cell adhesion molecules are the second CAM that cause extravasation of effector cells
35. p-selectin is a CAM that is expressed in response to the complement protein C5a, leukotriene B4, or histamine from mast cells. it can also be induced by bacterial LPS or the cytokine TNF-alpha.
36. rolling adhesion is the first step of extravasation in which effector cells are loosely bound to p-selectins and e-selectins on the endothelial surface.
37. chemokines induce upregulation of integrins on leukocytes, which then bind to ICAM's on the endothelium, arresting their movement
38. the process in extravasation by which leukocytes cross through the basement membrane of the endothelium by way of enzymes that break down the extracellular matrix.
39. migration of the effector cell towards the site of infection by means of a extracellular matrix-bound concentration gradient of chemokines which were produced by phagocytic cells.
40. by stimulating vasodilation (decreased perfusion) and blood clotting in the endothelium, it prevents the spread of the pathogen to other parts of the body.
41. in an infection reaches the bloodstream ("sepsis"), TNF-alpha is released by macrophages in the bloodstream, which causes systemic vasodilation (and therefore systemic edema) and clotting, which causes multiple organ failure, the eventual loss of blood clotting ability, and a high mortality rate.
42. molecules produced by the host that stimulate an increase in body temperature, such as TNF-alpha, IL-1beta, and IL-6.
43. the stimulation of hepatocytes by cytokines to produce acute phase proteins.
44. SP-A, SP-D, MB-lectin, C-reactive protein. these are all molecular receptors for common components on bacterial membranes.
45. the stimulation by cytokines of increased production of leukocytes, either by release from the bone marrow or from endothelial walls
46. interferons are molecules that are secreted from host cells that have been infected with a virus. they have autocrine and paracrine actions, acting on the infected cell itself and the neighboring uninfected cells. the receptors that they bind to signal intracellular pathways that block viral RNA transcription and destroy RNA fragments.
47. interferons also upregulate expression of MHC class I molecules, which are then used to signal natural killer cells, which destroy the infected cell.
48. natural killer cells are derived from the lymphoid lineage and resides in circulation. they release cytotoxic granules which induce cell death, and are stimulated in response to cytokines or interferons.
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