this chapter talked about t-cell receptors and the ligand that they bind, MHC molecules. MHC's are surface molecules expressed on host cells that display peptide fragments derived from antigen. MHC's are differentiated by two classes: class 1 MHC's bind to intracellular peptide fragments, from antigen which has been degraded by proteosomes in the cytosol. class 2 MHC's bind to peptides in extracellular vescicles which have been degraded by lysosomes or acidification.
t cells are also divided into two families based on the type of antigen they are responding to. CD8 t cells respond to intracellular antigen (such as viral infection) and accordingly bind to MHC class 1 molecules, which trap intracellular antigen. CD4 t cells respond to extracellular antigen (such as bacterial infection) and therefore bind to MHC class 2 molecules. within CD4 t cells, TH1 cells stimulate macrophages to release cytokines and TH2 cells stimulate b cells to release antibodies.
the t cell receptor is similar in structure to one Fab arm of the b cell immunoglobulin, in that it is made out of two chains with 4 domains and an antigen binding site on the extended end. the diversity of the variable domain is also created in a similar way to the immunoglobulins in that it uses somatic recombination of varied gene segments. one main difference between t cell receptors and immunoglobulins is that while immunoglobulins are modified after contact with antigen, either to class switch to a different effector function or to enhance binding specificity for the antigen, t cell receptors remain the same.
MHC molecules, as mentioned above, bind to peptides in host cells and present them to t cells to provoke an immune response. whereas all host cells have class 1 MHC's, only professional antigen presenting cells have class 2 MHC's: dendritic cells, macrophages, and b-cells. although MHC's are binding a diverse array of peptide from antigen, the source of diversity of the binding site is much different than that of immunoglobulins or t cell receptors. instead of random rearrangement of gene segments, MHC binding sites achieve high diversity by the polymorphism present in the genes that encode them.
questions
1. what are the similarities between immunoglobulins and t cell receptors?
2. what are the two chains in a t cell receptor?
3. what are CDR's and how many does each t cell receptor have?
4. what is the context in which antigen binds to t cell receptors?
5. why are t cell receptors not further modified after encountering antigen, as immunoglobulins are?
6. what gene segments do the alpha and beta chain locuses contain?
7. where does t cell receptor gene rearrangment occur?
8. what is SCID?
9. what is Omenn syndrome?
10. what is the CD3 complex?
11. what are gamma-mu t-cells?
12. what type of t cell receptor do t cells that reside in epithelial tissue have?
13. what are the different subdivisions of t cells?
14. HIV exploits which receptor on t cells?
15. what are the divisions within MHC molecules and what type of T cells do they bind to?
16. describe the structure of MHC class 1 and class 2 molecules.
17. how does the structure of MHC molecules allow for simultaneous binding of t cell receptors and coreceptors?
18. compare the length of peptides pinned down by MHC class 1 and class 2's.
19. what are TAP's?
20. what are chaperones?
21. the MHC class I molecules cannot leave the endoplasmic reticulum unless..
22. how do MHC's relate to autoimmunity?
23. describe the intracellular path by which MHC class II molecules bind to peptides in extracellular vesicles.
24. what are the two functions of invariant chains?
25. what is HLA-DM and what does it do?
26. what is a common cell that lacks MHC class I molecules?
27. describe the difference between the body's expression of MHC class I and II molecules.
28. what are professional antigen presenting cells?
29. what effect does the cytokine IFN-gamma have on professional antigen presenting cells?
30. what is it that makes MHC's highly polymorphic?
31. what are the class 1 MHC isotypes?
32. what are the class 2 MHC isotypes?
33. what are anchor residues?
answers
1. t cell receptors are like the Fab portion of an immunoglobulin in that they are made up of two different chains and have a variable region on the outside. t cell receptors are also formed by somatic recombination of gene segments just like immunoglobulins as well.
2. TCR-alpha and TCR-beta.
3. complementarity determining regions, each chain has three; each t cell receptor has 6.
4. only via opposing cell surfaces when binding to antigen peptides presented by MHC's on the surface of other cell (as opposed to soluble immunoglobulins binding to antigen in solution).
5. because immunoglobulins act as effectors which need to increase their efficiency of binding to the particular antigen; whereas t cell receptors are simply receptors.
6. the alpha chain contains V and J gene segments and thus is analogous to the immunoglobulin's light chain whereas the beta chain contains V,J, and D, and is analogous to the heavy chain.
7. in the thymus
8. severe combined immunodeficiency disease, in which the RAG gene complex is dysfunctional, leading to absence of functional B and T (hence the "combined") cells.
9. immunodeficiency syndrome caused from a partially defective RAG gene.
10. the four invariant membrane proteins that t cell receptors associate with in the ER, which facilitate expression of the receptor on the cell surface.
11. a set of t cells that express t cell receptors with gamma-mu chains instead of alpha-beta chains.
12. mostly the gamma-mu t cell receptors.
13. CD4 and CD8 t cells, based on a specific glycoprotein present on the t cell's surface. CD4 t cells are cytotoxic, killing infected cells. CD8 t cells are further subdivided into TH1 cells, which activate macrophages, and TH2 cells, which stimulate antibody release from b cells.
14. the CD4 receptor.
15. MHC class 1 molecules bind intracellular antigens and therefore to the cytotoxic CD8 cells, and MHC class 2 molecules bind antigen in extracellular vescicles, therefore binding to CD4 helper cells.
16. MHC class 1 is made up of 4 extracellular units, 2 layers of 2 domains. the closest layer has one transmembrane alpha domain and a beta protein (which is not encoded by the MHC), while the outer layer has two alpha domains that make up the peptide binding site. MHC class 2 is made up of 4 extracellular units as well, where the first layer is made up of an alpha and beta domain, and the outer layer is made up of another alpha and beta domain.
17. the t cell receptor and peptide binds to the outer domains and the coreceptors bind to the inner layer.
18. the length is limited in class 1 MHC to about 9 amino acid long peptides, because both sides of the peptide are pinned down to the peptide binding pocket, whereas in class 2 MHC's the can extend beyond the pocket and can thus be longer.
19. TAP's are "transporters associated with antigen presentation" which transport peptides that result from antigen breakdown in proteosomes, into the ER to meet with MHC class 1 molecules.
20. chaperones are proteins that aid in the folding and the binding of peptides for MHC class 1 molecules.
21. they have bound a peptide.
22. in the absence of an infection, MHC's present peptides derived from the host rather than from antigens. if the t cells respond to these self antigens, this produces autoimmunity.
23. in this pathway, antigen is phagocytosed/endocytosed into phagosomes, which combine with lysosomes to form phagolysosomes, which degrade the antigen into peptides. the MHC class II molecules then travel to these vesicles and bind to peptide, and then are expressed on the cell surface.
24. invariant chains bind to MHC class II's in the ER, preventing them from binding to the peptides destined for class II MHC's. they also aid in transport to the extracellular vesicles which contain peptides that they will eventually bind to.
25. HLA-DM is the molecule that removes the CLIP (the last bit of the invariant chain that is not removed by proteases in the extracellular vesicles) from the MHC class II, allowing it to bind peptide.
26. erythrocytes.
27. all cells have MHC class I molecules and are thus under total surveillance via t cells for viral infection. only certain cells have MHC class II molecules, and are called professional antigen presenting cells.
28. macrophages, dendritic cells, b cells; can present peptide derived from extracellular vesicles to the CD4 T cells.
29. it upregulates the MHC class II molecules and therefore aids in response to infection or inflammation.
30. the presence of many alleles within the gene families that code for MHC's.
31. the class 1 MHC isotypes are HLA-A,B,C,E,F,G
32. HLA-DM, DO, DP, DQ, DR
33. residues on the peptide that have side chains that bind to pockets within the binding groove of MHC's
main ideas:
t cell receptor structure and synthesis
subdivisions of function among t cells
differences in MHC classes between:
structure of molecule
function
peptides bound
cells which express them
invariant chains
source of MHC polymorphism
Showing posts with label mhc. Show all posts
Showing posts with label mhc. Show all posts
Saturday, February 7, 2009
Saturday, January 24, 2009
immunology: janeway's immunobiology chapter 2
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.
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.
Sunday, January 11, 2009
immunology: janeway's immunobiology chapter 1
bear with me while i try a few different formats for this class... my usual question/answer/summary format didn't work for me for this chapter for some reason.
this chapter introduced the innate and adaptive immune systems and introduced the dynamics of the cells involved, as well as the interaction between the two systems.
the history of immunology
edward jenner discovered smallpox vaccination in 1796. robert koch discovered that microorganisms are the source of pathologies. louis pasteur devised a vaccine against chickens. antibodies discovered 1890.
cells involved
all cells derived from pluripotent, hematopoetic stem cells. these differentiate into two lineages, myeloid and lymphoid. the myeloid lineage creates red blood cells, platelets, dendritic cells, macrophages and granulocytes (the key players in the innate immune system). the lymphoid lineage creates lymphocytes, which are the main players in the adaptive immune system.
lymphoid organs and tissues
primary/central lymphoid organs such as bone marrow and thymus produce lymphocytes and peripheral/secondary lymphoid organs such as the spleen and lymph nodes maintain lymphocytes. in the peripheral lymph organs, antigen-bearing cells from infected tissues meet naive lymphocytes and initiate the adaptive immune response.
innate immune system
the innate immune system is the body's first defense which is non specific and uses mainly the phagocytic cells such as the macrophage and the dendritic cell which reside in the peripheral tissues.
inflammation response
macrophages that encounter antigens in tissues secrete chemokines and cytokines, which vasodilate the nearby blood vessels and cause fluid leakage, allowing lymphocytes to enter the tissues and fight the infection. this is accompanied by redness, swelling, heating.
clonal selection theory
each lymphocyte in the adaptive immune system has a different specificity for a particular antigen- resulting in a portfolio of millions of potential antigens it can guard against. this diversity is created during the production of lymphocytes via a random recombination of varied "gene segments" which rearranges and recombines the sections of DNA that code for the antigen specific proteins.
the so called "naive" lymphocytes then go through a selection process where if they encounter antigen on a regular basis, they will survive (the cells need regular "survival signals from peripheral lymphatic tissues in order to halt apoptosis). if they are receptive to too much antigen (meaning, sensitive to self), they will be deleted, and likewise if they do not bind to any antigen.
antibodies- structure and strategies
antibodies are y shaped molecules found on b and t lymphocytes. the stem of the y is called the constant region of the antibody and is representative of the functional class of antibody. the branched tip of the antibody is called the variable region and differs from antibody to antibody.
free antibodies can bind directly to toxins, preventing them from infecting cells- called neutralization. they can also bind to infected cells and be better recognized by macrophages and other phagocytic cells, called opsonization. finally, they can initiate a "complement" system which aids in phagocytosis and also creates membrane complexes on infected cells which facilitates their destruction.
b cells vs t cells
b and t lymphocytes are the main cells in the adaptive immune system. b cells' sole contribution is the antibody, while t cells have a variety of effector actions. t cells can be further differentiated into cytotoxic t cells, which bind to and destroy virus infected cells, and t-helper cells. within t-helper cells, there are two subclasses: first is TH1 cells, which fight cells infected by pathogens residing in vesicles (thereby remaining undetected) by causing fusion of lysosomes and the vesicles. second is TH2 cells, which signal B-cells to become mature effector cells, as a sort of confirmation of infection.
MHC's
MHC's (major histocompatibility complex) are membrane protein complexes that bind to antigen during their formation in the cytosol and mount themselves on the outside of the plasma membrane, displaying peptide fragments from the particular antigen that the cell has encountered.
there are two classes of MHC molecules based on what they bind to. MHC class 1 molecules bind to viral peptides and therefore are involved in recognition from cytotoxic t cells (see above) and MHC class 2 molecules bind to intracellular vesicles and therefore are involved in recognition from t-helper cells.
allergies and autoimmune diseases
allergies are caused when the immune system mounts a response against a foreign, but innocuous substance. autoimmune diseases are when the immune system begins to recognize itself as an antigen.
page by page summaries:
p. 1
the beginning of immunology lie in the discovery of the smallpox vaccine by edward jenner in 1796. robert koch discovered that pathologies are caused by microorganisms, of four types: bacteria, viruses, fungi, and parasites.
based on these two discoveries, louis pasteur devised a vaccine against cholera in chickens. emil von behring and shibasaburo kitasato discovered antibodies, substances that bind to pathogens.
p.2
the innate immune system was discovered mainly by elie metchnikoff, who observed the microorganism-consuming properties of macrophages and how the body comes pre-prepared to combat a wide variety of pathogens. contrast this with adaptive immunity, which is the body's specific response against an unknown antigen. the term antigen is used to describe any substance that produces an immune response (which might or might not involve antibody production). both immune systems involve the leukocyte, or white blood cells. the innate immune system involves granulocytes (most importantly, neutrophils) and macrophages. the adaptive immune system uses mainly leukocytes. both systems complement each other and work together to provide a remarkably effective form of defense against antigens.
this book will mostly talk about the adaptive immune system, but the innate immune system often participates in adaptive immune responses as well.
p.3
all the cellular elements of blood are formed by pluripotent hematopoetic stem cells in the bone marrow. these produce two lineages: myeloid and lymphoid. the myeloid "progenitor" gives rise to granulocytes, dendritic cells, and macrophages. macrophages are huge phagocytic cells which reside in tissues and are derived from monocytes that circulate in the blood. dendritic cells also migrate from the blood to tissues; immature cells are phagocytic cells that reside in the tissues and upon encountering an antigen, mature and travel to the lymph, where they present the antigen to lymphocytes. mast cells also differentiate in the tissues and involved in both allergic responses and also some immune functions.
three types of granulocytes: neutrophils, eosinophils, basophils. neutrophils are phagocytic cells that play the most important role in the immune response of granulocytes. eosinophils are thought to be involved in protection against parasitic infection. the function of basophils is complementary and similar to eosinophils and mast cells.
the lymphoid progenitor produces two types of lymphocytes- b cells and t cells. b cells differentiate into plasma cells when activated, which secrete antibodies. t cells differentiate into two types: cytotoxic t cells which combats virus infection, and another type that activates other B cells and macrophages.
p.4
lymphocytes appear to be inactive because of the lack of cytoplasm, ER, and condensed chromatin- and in fact they are inactive until encountering an antigen. lymphocytes have a huge portfolio of antigen receptors which enables them to ward off attacks from virtually any foreign antigen. natural killer cells are the third cell from the lymphoid lineage and are non-specific, and part of the innate immune system.
p.5
the lymphoid organs are masses of tissue where lymphocytes are created and maintained. the primary/central lymphoid organs produce lymphocytes, including the bone marrow and thymus, and the secondary/peripheral lymphoid organs maintain the lymphocytes, such as the spleen and lymph nodes. t and b cells both originate in bone marrow, but t cells then migrate to the thymus for maturation. both then enter the bloodstream.
peripheral lymphoid organs are the places where antigens and lymphocytes meet.
p.6
lymph is extracellular fluid that is collected from tissues and recirculated into the blood. on the way, they are filtered into lymph nodes, where antigens are trapped and where b and t cells congregate. b cells are mainly in the follicles, sometimes with germinal centers, and t cells are mainly in the paracortical areas.
p.8
the spleen is a large lymph organ which is made up of mainly "red pulp", which is responsible for disposing of old red blood cells. the white pulp is the section that deals with antigens; through which antigen containing blood flows from trabecular arteries, through a "periarteriolar lymphoid sheath" made up of T cells, and a B cell "follicle" made up of germinal centers and a "corona", then back out to the trabecular veins. the interactions between the b and t cells in an immune response will be discussed later.
p.9
the gut associated lymphatic tissues: tonsils, appendix, adenoid, and peyer's patches, collect antigen from epithelial surfaces of the GI tract. the peyer's patch in the gut is the most highly organized and dense; they are formed from aggregations of mainly b cells into follicles, surrounded by smaller numbers of T cells.
p.10
all of these lymphoid organs have the same basic formula: trap antigen from site of infection and initiate an immune response. also, they provide signals to circulating lymph which sustain them and keep them prepared to fight off antigens.
lymphocytes circulate back and forth between the blood and lymph. during infection, lymphocytes are trapped in the lymphoid tissues and differentiate into effector cells that can combat the infection.
p.11
lymphoid organs are dynamic and ever adapting in response to infection; for example, in lymph nodes, expanding b cell germinal centers during infection can cause the entire lymph node to enlarge. also, the diffuse mucus associated lymphoid tissue can appear and reappear according to local need.
p.12
the innate immune system is the body's front line, general defense against antigens via phagocytic macrophages and neutrophils. when the infectious microorganism can not be overcome, or if the pathogen is not recognized, the adaptive immune system is then enlisted.
when macrophages encounter bacteria, they release molecules known as chemokines and cytokines, which initiate the inflammation response. part of the inflammation response involves vasodilation, which increases blood flow to the area, causing swelling, fluid leakage, and heating. the cytokines act on the endothelial walls, causing circulating leukocyte to adhere and squeeze out into the tissues, where they are attracted to the chemokines that have been secreted. the transport and actions of the leukocytes account for the pain during inflammation.
p.13
neutrophils and macrophages are the main cells involved in the inflammatory response. they are both phagocytic and both have surface receptor molecules specific to certain common constituents of bacteria.
dendritic cells are the cells that initiate the adaptive immune response. they are created in bone marrow and sent to peripheral tissues, where they reside in preparation for encountering pathogens. during infection, they phagocytose pathogens and travel to the lymph system and interact with naive lymphocytes.
although dendritic cells have the same mechanism for recognizing and phagocytosis, their primary job is to circulate to the peripheral lymphoid tissues and interact with T-lymphocytes. they employ a second strategy to take up antigens which is not receptor dependent- macropinocytosis.
p.14
the receptors of the cells in the innate immune system are designed to sense certain bacterial components that have been constant over the course of evolution. in this way they are limited and are unable to recognize new strains or bacteria that have evolved with a protective shell which hides those molecules. furthermore, viruses have no such common markers. however, dendritic cells are constantly taking in extracellular fluid via macropinocytosis, where any viruses or cloaked bacteria will be unmasked and the immune response will be activated.
lymphocytes, in contrast to the innate immune system cells, each have receptors with a specificity for only one particular pathogen.
p.15
the wide variety of lymphocytes undergoes a sort of natural selection in which the cells that encounter antigen proliferate and differentiate.
clonal selection theory is the theory that elucidates this idea which explains why we only produce antibodies for antigens that we have been exposed to: the body has a huge diversity of potentially anti-body producing cells, with different specificities. a lymphocyte's encounter and successful recognition with a particular antigen via a membrane bound version of the antibody causes it to clone itself and produce many antibodies of the same type.
james gowans discovered that lymphocytes are directly related to the adaptive immune response by removing them in mice and observing that the adaptive immune response disappeared.
clonal deletion is the idea that the immature lymphocytes that have receptors for the self are destroyed before maturation.
p.16
four postulates of the clonal selection hypothesis:
each lymphocyte has a receptor of unique specificity
when a foreign molecule binds to the receptor of a lymphocyte, it is activated
the differentiated effector cells from an activated lymphocyte will have the same receptor specificity as the parent
lymphocytes with receptors specific to the self will be deleted in early stages of lymphocyte development
antibodies are the free form of the receptors on lymphocytes. they have two portions; the constant region which is the same for all antibodies, and the variable region which has a unique structure. both regions are made up of two identical light chains and two heavy chains.
p.17
the diversity of lymphocyte receptors is produced by recombination of "gene segments" that code for the variable region of the antibody.
b cell receptors are detachable and have two different variable regions, whereas t cell receptors are bound to the membrane and have only one variable region.
p.18
the pool of maturing lymphocytes with the huge diversity of receptors is then selected for based upon the signals that the receptors receive. in order to proliferate, naive lymphocytes need to receive signals periodically. if they receive too many signals this indicates that they are self-reactive and if they don't receive any, that means that the receptors are not useful for sensing commonly encountered antigens.
this maintenance of useful lymphocytes depends on a system of "survival-signalling", where the body provides periodic signals to useful lymphocytes, for them to continue to proliferate by inhibiting apoptosis. the implication here is that if the lymphocyte dies, the particular specificity that its receptor had is now removed from the receptor portfolio of the immune system.
p.19
when the naive lymphocyte encounters the particular antigen it is receptive for in the peripheral lymph tissues, it stops circulating and enlarges, forming a lymphoblast. a lymphoblast has a larger cytoplasm and nucleus, visible chromatin, and new RNA's and proteins are synthesized. the lymphoblast then divide, creating thousands of copies of themselves within a few days. the lymphoblasts then differentiate into b cells and t cells- b cells secrete antibodies and t cells can destroy infected cells. the whole process takes 4-5 days.
after the infection has been cleared, most of the effector cells undergo apoptosis; the ones that don't are memory cells and allow the body to be better prepared against a recurrent attack from that particular antigen, an idea called immunological memory.
p.20
peripheral lymphoid tissues, in particular the spleen and lymph nodes, are organized to both trap antigen presenting cells / naive lymphocytes, and also designed to allow them to interact efficiently.
p.21
in order to be fully activated, lymphocytes need to be signalled twice; once by the antigen itself and once by a cell in the immune system which confirms the presence of the antigen. in the case of t-lymphocytes, the second signal is from the antigen presenting dendritic cell. for the b-lymphocytes, the second signal is from an activated t-cell.
p.23
the receptors on b cells are adapted to detect antigen from outside the body; ie bacteria. the receptors on t cells are adapted to detect antigen generated inside infected cells; ie from viruses.
p.24
as described before, antibodies have two parts, the constant region and the variable region, and are y-shaped. the "stem" of the y determines the class of the antibody, which corresponds to the type of effector action that will be produced.
the simplest strategy for antibodies is to bind to the pathogens, preventing them from entering cells they are trying to infect. this is called neutralization.
another strategy that antibodies are used for is opsonization, where they bind to pathogens and allow macrophages to phagocytose the pathogen (after recognizing the constant region of the antibody)
a third strategy that antibodies are used for is called "complementing"; where antibodies can initiate a series of complement proteins on the pathogen's surface which allow phagocytic cells to recognize and aid in the attack against the pathogen.
p.25
all of the cells marked by antibodies have the same fate; digestion and removal via phagocytes.
the complement system and phagocytes are non-specific and depend on antibodies for recognizing antigens.
b cell's only contribution to the immune system is the antibody, whereas t cells have a variety of effector actions.
p.26
t-cells are involved in the "cell mediated immune response" where pathogens are generated intracellularly (mostly via viruses).
a virally infected cell has antigens on its surface which cytotoxic t-cells can recognize, enabling them to destroy the cell before the virus uses the cell's machinery to replicate itself.
p.27
the second class of t-cells are called CD-4 t cells because of a particular molecule (co-receptor) that is present on the membrane. there are two subclasses of CD-4 t cells; first is TH1 cells. these cells stimulate macrophages to destroy intracellular pathogens, oftentimes from bacteria, by fusing the pathogen-destroying lysosomes with the intracellular vesicles in which the pathogens are being protected.
the second class is TH2 cells, cells which activate b-cells. b-cells in general need a confirmation signal from a helper t-cell in order to mature into an effector cell.
p.28
MHC's are membrane glycoprotein complexes that hold ("present") antigen for recognition by t-cells.
there are two classes of MHC based on the type of antigen peptide that they capture and present. MHC class 1 molecules collect intracellular peptides and thus are able to display antigens from virus infected cells. MHC class 2 molecules collect peptides that are contained within the intracellular vescicles and therefore are able to display antigens from infected macrophages.
p.29
accordingly, class 1 MHC's are recognized by cytotoxic T cells, which combat virus-infected cells, and class 2 MHC's are recognized by TH1 cells, which combat infected macrophages.
p.30
when recognizing the infected cells, t cells can either release various effector molecules or enlist the help of other cells.
AIDS is an autoimmune disease in which the TH1 cells are destroyed, leaving macrophages susceptible to infection.
p.31
allergic reactions manifest when the immune system responds against an innocuous foreign substance.
immuosuppresants are used in some auto-immune diseases or grafting procedures to stop the immune system's response against the body or the transplanted tissue. these immunosuppresants are not antigen specific and therefore suppress more lymphocytes than needed.
this chapter introduced the innate and adaptive immune systems and introduced the dynamics of the cells involved, as well as the interaction between the two systems.
the history of immunology
edward jenner discovered smallpox vaccination in 1796. robert koch discovered that microorganisms are the source of pathologies. louis pasteur devised a vaccine against chickens. antibodies discovered 1890.
cells involved
all cells derived from pluripotent, hematopoetic stem cells. these differentiate into two lineages, myeloid and lymphoid. the myeloid lineage creates red blood cells, platelets, dendritic cells, macrophages and granulocytes (the key players in the innate immune system). the lymphoid lineage creates lymphocytes, which are the main players in the adaptive immune system.
lymphoid organs and tissues
primary/central lymphoid organs such as bone marrow and thymus produce lymphocytes and peripheral/secondary lymphoid organs such as the spleen and lymph nodes maintain lymphocytes. in the peripheral lymph organs, antigen-bearing cells from infected tissues meet naive lymphocytes and initiate the adaptive immune response.
innate immune system
the innate immune system is the body's first defense which is non specific and uses mainly the phagocytic cells such as the macrophage and the dendritic cell which reside in the peripheral tissues.
inflammation response
macrophages that encounter antigens in tissues secrete chemokines and cytokines, which vasodilate the nearby blood vessels and cause fluid leakage, allowing lymphocytes to enter the tissues and fight the infection. this is accompanied by redness, swelling, heating.
clonal selection theory
each lymphocyte in the adaptive immune system has a different specificity for a particular antigen- resulting in a portfolio of millions of potential antigens it can guard against. this diversity is created during the production of lymphocytes via a random recombination of varied "gene segments" which rearranges and recombines the sections of DNA that code for the antigen specific proteins.
the so called "naive" lymphocytes then go through a selection process where if they encounter antigen on a regular basis, they will survive (the cells need regular "survival signals from peripheral lymphatic tissues in order to halt apoptosis). if they are receptive to too much antigen (meaning, sensitive to self), they will be deleted, and likewise if they do not bind to any antigen.
antibodies- structure and strategies
antibodies are y shaped molecules found on b and t lymphocytes. the stem of the y is called the constant region of the antibody and is representative of the functional class of antibody. the branched tip of the antibody is called the variable region and differs from antibody to antibody.
free antibodies can bind directly to toxins, preventing them from infecting cells- called neutralization. they can also bind to infected cells and be better recognized by macrophages and other phagocytic cells, called opsonization. finally, they can initiate a "complement" system which aids in phagocytosis and also creates membrane complexes on infected cells which facilitates their destruction.
b cells vs t cells
b and t lymphocytes are the main cells in the adaptive immune system. b cells' sole contribution is the antibody, while t cells have a variety of effector actions. t cells can be further differentiated into cytotoxic t cells, which bind to and destroy virus infected cells, and t-helper cells. within t-helper cells, there are two subclasses: first is TH1 cells, which fight cells infected by pathogens residing in vesicles (thereby remaining undetected) by causing fusion of lysosomes and the vesicles. second is TH2 cells, which signal B-cells to become mature effector cells, as a sort of confirmation of infection.
MHC's
MHC's (major histocompatibility complex) are membrane protein complexes that bind to antigen during their formation in the cytosol and mount themselves on the outside of the plasma membrane, displaying peptide fragments from the particular antigen that the cell has encountered.
there are two classes of MHC molecules based on what they bind to. MHC class 1 molecules bind to viral peptides and therefore are involved in recognition from cytotoxic t cells (see above) and MHC class 2 molecules bind to intracellular vesicles and therefore are involved in recognition from t-helper cells.
allergies and autoimmune diseases
allergies are caused when the immune system mounts a response against a foreign, but innocuous substance. autoimmune diseases are when the immune system begins to recognize itself as an antigen.
page by page summaries:
p. 1
the beginning of immunology lie in the discovery of the smallpox vaccine by edward jenner in 1796. robert koch discovered that pathologies are caused by microorganisms, of four types: bacteria, viruses, fungi, and parasites.
based on these two discoveries, louis pasteur devised a vaccine against cholera in chickens. emil von behring and shibasaburo kitasato discovered antibodies, substances that bind to pathogens.
p.2
the innate immune system was discovered mainly by elie metchnikoff, who observed the microorganism-consuming properties of macrophages and how the body comes pre-prepared to combat a wide variety of pathogens. contrast this with adaptive immunity, which is the body's specific response against an unknown antigen. the term antigen is used to describe any substance that produces an immune response (which might or might not involve antibody production). both immune systems involve the leukocyte, or white blood cells. the innate immune system involves granulocytes (most importantly, neutrophils) and macrophages. the adaptive immune system uses mainly leukocytes. both systems complement each other and work together to provide a remarkably effective form of defense against antigens.
this book will mostly talk about the adaptive immune system, but the innate immune system often participates in adaptive immune responses as well.
p.3
all the cellular elements of blood are formed by pluripotent hematopoetic stem cells in the bone marrow. these produce two lineages: myeloid and lymphoid. the myeloid "progenitor" gives rise to granulocytes, dendritic cells, and macrophages. macrophages are huge phagocytic cells which reside in tissues and are derived from monocytes that circulate in the blood. dendritic cells also migrate from the blood to tissues; immature cells are phagocytic cells that reside in the tissues and upon encountering an antigen, mature and travel to the lymph, where they present the antigen to lymphocytes. mast cells also differentiate in the tissues and involved in both allergic responses and also some immune functions.
three types of granulocytes: neutrophils, eosinophils, basophils. neutrophils are phagocytic cells that play the most important role in the immune response of granulocytes. eosinophils are thought to be involved in protection against parasitic infection. the function of basophils is complementary and similar to eosinophils and mast cells.
the lymphoid progenitor produces two types of lymphocytes- b cells and t cells. b cells differentiate into plasma cells when activated, which secrete antibodies. t cells differentiate into two types: cytotoxic t cells which combats virus infection, and another type that activates other B cells and macrophages.
p.4
lymphocytes appear to be inactive because of the lack of cytoplasm, ER, and condensed chromatin- and in fact they are inactive until encountering an antigen. lymphocytes have a huge portfolio of antigen receptors which enables them to ward off attacks from virtually any foreign antigen. natural killer cells are the third cell from the lymphoid lineage and are non-specific, and part of the innate immune system.
p.5
the lymphoid organs are masses of tissue where lymphocytes are created and maintained. the primary/central lymphoid organs produce lymphocytes, including the bone marrow and thymus, and the secondary/peripheral lymphoid organs maintain the lymphocytes, such as the spleen and lymph nodes. t and b cells both originate in bone marrow, but t cells then migrate to the thymus for maturation. both then enter the bloodstream.
peripheral lymphoid organs are the places where antigens and lymphocytes meet.
p.6
lymph is extracellular fluid that is collected from tissues and recirculated into the blood. on the way, they are filtered into lymph nodes, where antigens are trapped and where b and t cells congregate. b cells are mainly in the follicles, sometimes with germinal centers, and t cells are mainly in the paracortical areas.
p.8
the spleen is a large lymph organ which is made up of mainly "red pulp", which is responsible for disposing of old red blood cells. the white pulp is the section that deals with antigens; through which antigen containing blood flows from trabecular arteries, through a "periarteriolar lymphoid sheath" made up of T cells, and a B cell "follicle" made up of germinal centers and a "corona", then back out to the trabecular veins. the interactions between the b and t cells in an immune response will be discussed later.
p.9
the gut associated lymphatic tissues: tonsils, appendix, adenoid, and peyer's patches, collect antigen from epithelial surfaces of the GI tract. the peyer's patch in the gut is the most highly organized and dense; they are formed from aggregations of mainly b cells into follicles, surrounded by smaller numbers of T cells.
p.10
all of these lymphoid organs have the same basic formula: trap antigen from site of infection and initiate an immune response. also, they provide signals to circulating lymph which sustain them and keep them prepared to fight off antigens.
lymphocytes circulate back and forth between the blood and lymph. during infection, lymphocytes are trapped in the lymphoid tissues and differentiate into effector cells that can combat the infection.
p.11
lymphoid organs are dynamic and ever adapting in response to infection; for example, in lymph nodes, expanding b cell germinal centers during infection can cause the entire lymph node to enlarge. also, the diffuse mucus associated lymphoid tissue can appear and reappear according to local need.
p.12
the innate immune system is the body's front line, general defense against antigens via phagocytic macrophages and neutrophils. when the infectious microorganism can not be overcome, or if the pathogen is not recognized, the adaptive immune system is then enlisted.
when macrophages encounter bacteria, they release molecules known as chemokines and cytokines, which initiate the inflammation response. part of the inflammation response involves vasodilation, which increases blood flow to the area, causing swelling, fluid leakage, and heating. the cytokines act on the endothelial walls, causing circulating leukocyte to adhere and squeeze out into the tissues, where they are attracted to the chemokines that have been secreted. the transport and actions of the leukocytes account for the pain during inflammation.
p.13
neutrophils and macrophages are the main cells involved in the inflammatory response. they are both phagocytic and both have surface receptor molecules specific to certain common constituents of bacteria.
dendritic cells are the cells that initiate the adaptive immune response. they are created in bone marrow and sent to peripheral tissues, where they reside in preparation for encountering pathogens. during infection, they phagocytose pathogens and travel to the lymph system and interact with naive lymphocytes.
although dendritic cells have the same mechanism for recognizing and phagocytosis, their primary job is to circulate to the peripheral lymphoid tissues and interact with T-lymphocytes. they employ a second strategy to take up antigens which is not receptor dependent- macropinocytosis.
p.14
the receptors of the cells in the innate immune system are designed to sense certain bacterial components that have been constant over the course of evolution. in this way they are limited and are unable to recognize new strains or bacteria that have evolved with a protective shell which hides those molecules. furthermore, viruses have no such common markers. however, dendritic cells are constantly taking in extracellular fluid via macropinocytosis, where any viruses or cloaked bacteria will be unmasked and the immune response will be activated.
lymphocytes, in contrast to the innate immune system cells, each have receptors with a specificity for only one particular pathogen.
p.15
the wide variety of lymphocytes undergoes a sort of natural selection in which the cells that encounter antigen proliferate and differentiate.
clonal selection theory is the theory that elucidates this idea which explains why we only produce antibodies for antigens that we have been exposed to: the body has a huge diversity of potentially anti-body producing cells, with different specificities. a lymphocyte's encounter and successful recognition with a particular antigen via a membrane bound version of the antibody causes it to clone itself and produce many antibodies of the same type.
james gowans discovered that lymphocytes are directly related to the adaptive immune response by removing them in mice and observing that the adaptive immune response disappeared.
clonal deletion is the idea that the immature lymphocytes that have receptors for the self are destroyed before maturation.
p.16
four postulates of the clonal selection hypothesis:
each lymphocyte has a receptor of unique specificity
when a foreign molecule binds to the receptor of a lymphocyte, it is activated
the differentiated effector cells from an activated lymphocyte will have the same receptor specificity as the parent
lymphocytes with receptors specific to the self will be deleted in early stages of lymphocyte development
antibodies are the free form of the receptors on lymphocytes. they have two portions; the constant region which is the same for all antibodies, and the variable region which has a unique structure. both regions are made up of two identical light chains and two heavy chains.
p.17
the diversity of lymphocyte receptors is produced by recombination of "gene segments" that code for the variable region of the antibody.
b cell receptors are detachable and have two different variable regions, whereas t cell receptors are bound to the membrane and have only one variable region.
p.18
the pool of maturing lymphocytes with the huge diversity of receptors is then selected for based upon the signals that the receptors receive. in order to proliferate, naive lymphocytes need to receive signals periodically. if they receive too many signals this indicates that they are self-reactive and if they don't receive any, that means that the receptors are not useful for sensing commonly encountered antigens.
this maintenance of useful lymphocytes depends on a system of "survival-signalling", where the body provides periodic signals to useful lymphocytes, for them to continue to proliferate by inhibiting apoptosis. the implication here is that if the lymphocyte dies, the particular specificity that its receptor had is now removed from the receptor portfolio of the immune system.
p.19
when the naive lymphocyte encounters the particular antigen it is receptive for in the peripheral lymph tissues, it stops circulating and enlarges, forming a lymphoblast. a lymphoblast has a larger cytoplasm and nucleus, visible chromatin, and new RNA's and proteins are synthesized. the lymphoblast then divide, creating thousands of copies of themselves within a few days. the lymphoblasts then differentiate into b cells and t cells- b cells secrete antibodies and t cells can destroy infected cells. the whole process takes 4-5 days.
after the infection has been cleared, most of the effector cells undergo apoptosis; the ones that don't are memory cells and allow the body to be better prepared against a recurrent attack from that particular antigen, an idea called immunological memory.
p.20
peripheral lymphoid tissues, in particular the spleen and lymph nodes, are organized to both trap antigen presenting cells / naive lymphocytes, and also designed to allow them to interact efficiently.
p.21
in order to be fully activated, lymphocytes need to be signalled twice; once by the antigen itself and once by a cell in the immune system which confirms the presence of the antigen. in the case of t-lymphocytes, the second signal is from the antigen presenting dendritic cell. for the b-lymphocytes, the second signal is from an activated t-cell.
p.23
the receptors on b cells are adapted to detect antigen from outside the body; ie bacteria. the receptors on t cells are adapted to detect antigen generated inside infected cells; ie from viruses.
p.24
as described before, antibodies have two parts, the constant region and the variable region, and are y-shaped. the "stem" of the y determines the class of the antibody, which corresponds to the type of effector action that will be produced.
the simplest strategy for antibodies is to bind to the pathogens, preventing them from entering cells they are trying to infect. this is called neutralization.
another strategy that antibodies are used for is opsonization, where they bind to pathogens and allow macrophages to phagocytose the pathogen (after recognizing the constant region of the antibody)
a third strategy that antibodies are used for is called "complementing"; where antibodies can initiate a series of complement proteins on the pathogen's surface which allow phagocytic cells to recognize and aid in the attack against the pathogen.
p.25
all of the cells marked by antibodies have the same fate; digestion and removal via phagocytes.
the complement system and phagocytes are non-specific and depend on antibodies for recognizing antigens.
b cell's only contribution to the immune system is the antibody, whereas t cells have a variety of effector actions.
p.26
t-cells are involved in the "cell mediated immune response" where pathogens are generated intracellularly (mostly via viruses).
a virally infected cell has antigens on its surface which cytotoxic t-cells can recognize, enabling them to destroy the cell before the virus uses the cell's machinery to replicate itself.
p.27
the second class of t-cells are called CD-4 t cells because of a particular molecule (co-receptor) that is present on the membrane. there are two subclasses of CD-4 t cells; first is TH1 cells. these cells stimulate macrophages to destroy intracellular pathogens, oftentimes from bacteria, by fusing the pathogen-destroying lysosomes with the intracellular vesicles in which the pathogens are being protected.
the second class is TH2 cells, cells which activate b-cells. b-cells in general need a confirmation signal from a helper t-cell in order to mature into an effector cell.
p.28
MHC's are membrane glycoprotein complexes that hold ("present") antigen for recognition by t-cells.
there are two classes of MHC based on the type of antigen peptide that they capture and present. MHC class 1 molecules collect intracellular peptides and thus are able to display antigens from virus infected cells. MHC class 2 molecules collect peptides that are contained within the intracellular vescicles and therefore are able to display antigens from infected macrophages.
p.29
accordingly, class 1 MHC's are recognized by cytotoxic T cells, which combat virus-infected cells, and class 2 MHC's are recognized by TH1 cells, which combat infected macrophages.
p.30
when recognizing the infected cells, t cells can either release various effector molecules or enlist the help of other cells.
AIDS is an autoimmune disease in which the TH1 cells are destroyed, leaving macrophages susceptible to infection.
p.31
allergic reactions manifest when the immune system responds against an innocuous foreign substance.
immuosuppresants are used in some auto-immune diseases or grafting procedures to stop the immune system's response against the body or the transplanted tissue. these immunosuppresants are not antigen specific and therefore suppress more lymphocytes than needed.
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