note: i switched from janeway's "immunobiology" to parham's "the immune system" for its conciseness (30 pages per chapter vs. 50 pages)
this chapter introduces b cells and antibodies and the way that they are produced before encountering antigen, and the way that they are modified after encountering antigen. antibodies are y-shaped molecules which are made up of 2 "heavy" chains and 2 "light chains". each of these chains has a constant region, all 4 of which make up the stem of the y, and a variable region, which make up the two arms of the y (one light chain variable region and one heavy chain variable region per arm). the variable region at the arms of the y contain 3 hypervariable regions that are the binding sites for antigen. antibodies are expressed either on the surface of b cells, where they are bound with a hydrophobic anchor at the carboxy terminus of the constant region, or as free floating molecules.
the production of antibodies in naive b cells is designed to make an incredible diversity of structure in the variable regions of the antibody. the more diverse the antibody repertoire is, the more likely it will bind to a antigen, and thus the process of producing variability is introduced in the production of antibodies in several different places: initially during random recombination of gene segments, also in junctional diversity, then through somatic hypermutation.
while genes for other proteins are transcribed from continuous sections of DNA (loci) from which DNA might be spliced out, the DNA for antibody molecules is represented in gene segments, in which there are multiple varied choices for each section of the gene. for example, for each light chain there are two gene segments required to make the variable region; a V segment and a J segment. there are 30 such V segments and 5 J segments to choose from, resulting in 180 possible combinations of the variable region for the light chain. the heavy chain has more possible segments and yet another segment, D, which adds more variability and results in about 10,000 possible configurations. furthermore, the unique combination of light chain plus heavy chain variable regions represent another source for variability.
when the junctions between these gene segments are formed during recombination, further variability is added by enzymes that add palindromic sequences as well as random nucleotides between the gene segments. the antibody can then be produced and expressed on the b cell surface. the first antibodies that are produced are IgG and IgM- classifications of antibodies based on their constant region.
somatic hypermutation occurs after the b cell has encountered antigen- this involves both a proliferation of b cells, and random mutation / nucleotide substitution in the variable region of the antibody. this produces large quantities of b cells with slightly different variable regions, some of which have a higher affinity for the antigen than the original b cell antibody. this b cell is positively selected for in a process called affinity maturation and the higher affinity antibody is produced in greater quantities.
a b cell can receive signals from cytokines to "class switch" its antibodies, which refers to changing the "constant" region of the antibody (the stem of the y). the variable region is the same, which means the antibody still has the same antigen specificity; however the effector actions and role in the body can be different. for example, IgM is the first antibody produced, is relatively inflexible and forms a pentameric ring. IgA is present in epithelial linings and secretions and the lumen of the gut. IgG is the most common antibody present in the blood and acts directly on antigens to neutralize or opsonize for phagocytosis. IgE is specialized to stimulate mast cells during inflammation or infection.
questions
1. what are the five classes of antibodies?
2. what is the most common antibody?
3. the chains in immunoglobulins are linked by...
4. describe the middle portion of an IgG molecule.
5. what are the kappa and lambda isotypes?
6. what are hypervariable regions?
7. how many hypervariable regions are there per variable domain?
8. what is the antigen binding site composed of? what else are they called?
9. what is an antigenic determinant or epitope?
10. what is a multivalent antigen?
11. what is the difference between a linear and discontinuous epitope?
12. what sort of forces does binding of antigen to antibody depend on?
13. where and when in a b cell's development does rearrangment of gene segments for antibody production occur?
14. what are the types of gene segments that encode the variable regions of the light and heavy chains?
15. what are the main differences between the gene segments that code for the variable sections of the antibody?
16. what is somatic recombination?
17. describe the difference between somatic recombination of a light chain vs. a heavy chain.
18. approximately how many different arrangements of gene segments are possible for light vs. heavy chains?
19. what are RSS's?
20. what is the 12/23 rule for RSS's?
21. what is the RAG?
22. what is the difference between the coding joint and the signal joint?
23. what is meant by "junctional diversity"?
24. what is unique about IgM and IgD?
25. what is allelic exclusion?
26. what are Ig-alpha and Ig-beta?
27. what happens to IgM and IgD upon the b cell's encounter with antigen?
28. what is the main difference between membrane bound and secreted immunoglobulins?
29. what is somatic hypermutation?
30. what is the frequency of mutation/nucelotide substitution in somatic hypermutation?
31. what is affinity maturation?
32. what are the characteristics of IgM?
33. what are the characteristics of IgG?
34. what are the characteristics of IgA?
35. what are the characteristics of IgE?
answers
1. IgA, IgD, IgE, IgG, IgM
2. IgG
3. disulfide bonds.
4. it is a relatively flexible "hinge" region that can be cleaved proteolytically.
5. a the class of immunoglobulin based on the light chain classification in the constant region.
6. regions on the exposed tip of variable domains that have a particularly diverse expression of amino acids.
7. 3
8. the combining of the hypervariable region from the variable domains of both the light and heavy chains. also called complementary determining regions (CDR).
9. the part of an antigen that the antibody binds to
10. an antigen that has more than one epitope.
11. linear is when the CDR binds to adjacent amino acids and discontinuous is when the CDR binds to amino acids that have been brought together by the antigen's chain folding.
12. noncovalent bonds such as hydrogen bonding, van der waal's forces, salt bridges, etc
13. in the bone marrow, early in b cell development.
14. for light chain: variable and joining gene segments. for heavy chain: variable, joining, and diversity gene segments.
15. the sequences that encode the first and second hypervariable regions.
16. the joining of gene segments to form the heavy or light chains.
17. for a light chain only one recombination is required; between the V and the J segments. for a heavy chain two recombinations are required: between the J and D, then the J/D to the V segment.
18. about 300 for light and 10,000 for heavy.
19. recombinant signal sequences, the gene sequences that flank the gene segments.
20. an RSS has either a 12 or 23 long base pair spacer in its middle; a 12 RSS can only be combined with a 23 RSS- this allows the different gene segments to be joined correctly to each other, in the right order and sequence.
21. the recombinant activating genes
22. after recombination, the coding joint is the joint between the adjoined gene segments whereas the signal joint is the loop of base pairs that was excised out between the gene segments.
23. junctional diversity is introduced in the "hairpin" that is formed when gene segments are combined by the RAG complex. the hairpin is then spliced and P (palindromic) and N nucleotides (added randomly) are added in, increasing the diversity of gene sequence in the third hypervariable region.
24. these are immunoglobulins that are produced and expressed first and simultaenously by the naive b cell before encountering antigen.
25. every B cell has two copies, or alleles, of the heavy or light chain locus which can be rearranged to produce a particular immunoglobulin. instead of drawing from both alleles, each B cell only uses one.
26. the transmembrane proteins that freshly produced immunoglobulins associate with in the endoplasmic reticulum which form a complex that bind to the b cell membrane surface. the Ig-alpha and beta proteins have longer tails which extend into the cytoplasm which are involved in intracellular signalling during antigen binding.
27. they are expressed in the secreted form instead of the membrane bound form.
28. the membrane bound form has a hydrophobic anchor on the carboxy terminus of the heavy chains, allowing it to stay on the cell membrane.
29. a process that the b cells undergo after encountering antigen where random nucleotide mutations occur in the variable regions of both the light and heavy chains, producing a great diversity of "mutant" immunoglobulin molecules, some of which have an even higher affinity for antigen than the original.
30. one mutation per cell division, more than a million times the normal mutation rate for a gene.
31. the process by which the b cells which bear mutant immunoglobulins produced by hypermutation which have a higher affinity for antigen are selected for and proliferate.
32. IgM is the first antibody produced by the b cells in response to pathogen and is often in the pentameric form, where it has less flexibility but more binding sites for antigen.
33. IgG is the most common antibody found in circulation and tissues. it is smaller than IgM and has a flexible hinge region, allowing the Fab regions to move indepently. it also has more effector actions than IgM, such as opsonization and activating the complement system. it can also pass through the placenta.
34. IgA is the principal antibody secreted by the lymph tissue into the lumen of the gut, as well as other secretions such as tears and sweat. it is often in the dimeric form.
35. IgE is the antibody which is highly specialized to stimulate mast cells during inflammation, causing it to release its histamine and heparine granules.
Showing posts with label antigen. Show all posts
Showing posts with label antigen. Show all posts
Thursday, February 5, 2009
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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