MICR 461 Immunology Study Guide PDF

MICR 461 Immunology Study Guide Chapter 1 What is the functional definition of a pathogen? o A biological entity that has the potential to invade and colonize the human body, causing disease. List the four...

MICR 461 Immunology Study Guide Chapter 1 What is the functional definition of a pathogen? o A biological entity that has the potential to invade and colonize the human body, causing disease. List the four main categories of pathogens o Bacteria, Viruses, Fungi, Parasites What are commensal bacteria, and how do we benefit from them? o Commensal bacteria are bacteria that live on the skin, or in the human body, that do not harm human health. We benefit from them since they supply human with essential nutriments, ones we can’t get from food or make, and defend us from opportunistic pathogens. What are some things that pathogens are seeking to find in a host? o Nutriments, Water, Favorable pH, Structural support, physical protection Why do we say that microbes don’t have malicious intent to harm their host? o Microbes don’t have malicious intent to harm their host since they carry out their genetic program of survival and production as long as the host’s ressources support them. Damage is just a consequence. (They did what they had to do and were programmed to do without thinking of others) Understand the distinction between “inside” and “outside” our body o ”Inside” our body refers to the actual action of being inside tissue, “outside” can be anywhere no in tissues, such as the GI tract, our skin, etc. Think of it as a tunnel, are we actually in a mountain or are we passing through without contacting dirt or rocks that make the mountain What are some features of skin and mucosa that serve as barriers to infection? o Features of skin that serve as barriers to infection is that it is an impenetrable barrier of epithelium which is protected by keratinized cells and mucosa secretes mucus which makes it hard for pathogens to move around. What is meant by infection? o Infection means that pathogens have broken through the barrier and entered our bodies Understand that our innate response involves pathogen recognition and effector mechanism? o Our innate immune system can recognize typical everyday pathogen profiles (just regular clowns), this response is highly localized and can be extinguished without illness. The effector mechanisms kill and eliminate by engulfing pathogens and creating complement proteins. What is phagocytosis? Can you name two immune cells that are phagocytic? o Phagocytosis is the ingestion of smaller molecules. Immune cells that are phagocytic are monocytes, macrophages, and neutrophils Why is innate immunity called “innate”? o The innate immune system is called “innate” because it is the part of the immune system that humans are born with and that is generalized to common threats Understand why we say innate immunity is concerned with “typical” pathogen profiles  o We stay that innate immunity is concerned with “typical” pathogen profiles because they are broadly sensitivity to a number of pathogens and their enforcers are not specialized Compare/contrast the pros vs. cons of innate vs. adaptive immunity o preset, quick response vs slow, more powerful response o modest cost to maintain vs expensive maintenance o general response vs specialized response What are the concepts behind adaptive response? o The adaptive immune response uses specialized proteins (B-cells immunoglobulin and T-cells receptors) to build a effective specialized response to new pathogens. They also use these same proteins to create an immunological memory. What is an antigen? o An antigen is a molecule recognized by an antibody (protein that is created by the immune system to recognize pathogens), which creates an immune response. What are immunoglobulins? o Immunoglobulins are proteins that act as antibodies, they are B-cells surface receptors that are soluble and found in blood. What are T cell receptors? o T cell receptors are the the cells that target only one pathogen, they are the “swat” team. They are not soluble and not floating in blood. Understand why B-cells and T-cells are involved in adaptive training and specialized attack* o B-cells and T-cells are involved in adaptive training and specialized attacks because B-cells have the ability to identify pathogens and notify the other immune cells, and T-cells are able to learn how to identify pathogens and attacks them. Compare/contrast the effector mechanisms of innate vs. adaptive immunity. o Effector mechanisms of innate immunity look for typical proteins that have been programmed into our genes after years of battling with them. The adaptive immune system only create the proteins that they have encountered after never seeing them. Understand why both innate and adaptive immunity are required for our health o Both innate and adaptive immunity are required for our health because the innate immune system are responsible for everyday pathogens, they protect against generic and common pathogens and don’t have the strength or the capability to fight an big and unknown infection. While the adaptive immune system is responsible for those big and unknown infections, but it takes time to build up the response and to build the defenses against them, but they are always watching for those same infection afterwards. List the five types of circulating leukocytes and their relative proportion in blood (hint: Never Let Monkeys Eat Bananas) o N - Neutrophils (40-75%) o L - Lymphocytes (20-50%) o M - Monocytes (2-10%) o E - Eosinophil (1-6%) o B - Basophil (>1%) Review the cell lineages of hematopoietic cells and whether they are adaptive or innate effector cells  What is a cytokine? Realize it is not one specific molecule, but a term that functionally describes a type of molecule. o Cytokines are signaling proteins. They are released when macrophages digest pathogens. They cause inflammation due to signalling for immune cells. Understand the phagocytic AND cytokine signaling role of macrophages o Cytokine are released from macrophages after they have using phagocytosis to ingest and kill pathogens. What is the main functional distinction between “primary” versus “secondary” lymphoid (immune) tissues in the body? o The main functional distinction between “primary” and “secondary” lymphoid tissue in the body is that “primary” tissue are where immune cells are made and “secondary” tissue is where those cells encounter antigen and activate. Is bone marrow an example of primary or secondary immune tissue? What about a lymph node? Why? o Bone marrow is an example of primary immune tissue because that us where immune cells are being made. Lymph nodes are an example of secondary immune tissue because the lymphatic system is where the immune cells travel the body looking for pathogens. MICR 461 Immunology Study Guide Chapter 2 Understand that the innate response has two parts: immediate and induced  o Immediate response: The induce response is when macrophages that are already there detect and destroy bacteria by phagocytosis. o Induced response: The induced response is when the macrophages produce signaling molecules (cytokines) and recruits other immune cells (monocytes and neutrophils - innate immune cells) to help fight off infection What surface features of some bacteria make them hard to bind by macrophages? o The surface features of some bacteria make them hard to bind by macrophages is the polysaccharide. What are the 3 main functions of complement proteins? o To make phagocytosis more efficient o Sending signal that attract macrophage o Disrupting microbe membrane Understand the significance of C3 cleavage leading to C3b and C3a o C3 cleaving leads to activation of the C3b and C3b. What are the three pathways of complement activation? o The three pathways of complement activation are alternative pathway, lectin pathway, and classical pathway. What is common, what differs among the three pathways? o All three pathways leads to C3 activation, they all differ in how they do so, alternative pathways uses the pathogen surface, the lectin pathways uses mannose-binding lectin, and classical pathway uses C-reactive protein/antibody bond to antigen specific. What is opsonization? o Opsonization is when the pathogen gets covered by immune cells. Be comfortable describing how C3 activation, Factor B and D, lead to iC3Bb creation / C3bBb creation, and C3b fixation on pathogen surfaces o The first step of the pathway is that C3 reacts with H2O. This makes iC3 which activates the complex, changing the shape so that iC3 can bind to factor B, which activates and creates a new active site where factor D can bind. The binding between factor D and the iC3 and Factor B, fragments factor B into Bb and Ba, Ba gets released, while Bb and iC3 to create iC3Bb which is a protease (protein breakdown). Describe in general terms how C3b fixation is regulated up/down by Complement Control Proteins (CCP) such as Factor H, P, DAF, MCP o Factor P: Stabilize C3b, protects C3b from proteolysis, up regulated C3b o Factor H: Changes C3b shape, can’t cut anymore C3, down regulated o Factor I: Binds to H factor altered C3b and cleaves C3b into inactive iC3b o DAF: downregulates C3b as removes Bb from C3b slowing down the cutting of C3 and opsonization process o MCP: Increases Factor I action Explain why complement fixation greatly increases phagocyte efficiency o Complement fixation greatly increases phagocyte efficiency since they “tag” the pathogen. Understand how complement C5 activation leads to Membrane Attack Complex (MAC) formation o Complement C5 activation leads to C6, C7, and C8 binding together and then recruiting multiple C9 creating a MAC. Explain the function of the MAC in targeting pathogens o MAC is used since C3 activates C5 to create MAC and is blocked by CD59 near human cells, and creates tunnels in pathogens.  Understand that opsonization and MAC happen in parallel o MAC needs the beginning of opsonization (C3 activation) to be able to proceed Understand why/how we prevent MAC attack of our normal body cells o Human bodies use CD59 to block the recruitment of C9 which prevents MAC attack Explain the function of the C3a and C5a fragments as anaphylatoxins o C3a and C5a are anaphylatoxins, these functions help recruit immune cells by relaxing capillary and increasing blood flow. Describe the function of macroglobulins o Macroglobulins are like a mouse trap, they trap protease inhibitor Describe the function of defensins – where are they typically secreted and why? o Defensin are immediate lysing pathogens, they are typically secreted in sweat, tears, gut lumen because they are vulnerable and sensitive tissues Immunology 461 Study Guide Chapter 3 Compare/contrast immediate vs. induced innate immune response o Immediate Response: ▪ 0-4 hours ▪ pathogen invades tissue and proliferates ▪ pathogen is recognized by preformed soluble effector molecules and resident effector cells in the infected tissue ▪ pathogen is eliminated and the infection ends ▪ very minor to no tissue damage is repaired o Induced Response: ▪ 4 hours - 4 days ▪ activation of cells resident in infected tissue, recruitment of effector cells to infected tissue. Inflammation, fever, acute-phase response ▪ soluble effector molecules and effector cells recruited to the tissue and attack pathogens. ▪ pathogen is eliminated and infection ends ▪ minor tissue damage is repaired. Explain why inflammation, pain, fatigue and fever are normal components of the induced response – why do they happen? o These things happen as a result of the induced response. ▪ Inflammation happens as fluid in the infected tissue gets built up and is not moved, fluid is brought to the infected tissue with immune cells, and the fluid is not dispersed to prevent infection spreading.  ▪ Pain happens to make your body aware of the infection ▪ Fatigue happens because the immune response take energy, and your body wants to conserve the energy it has to fight the infection ▪ Fever happens since most pathogens have an ideal temperature of about 37oC and if it's hotter, it's easier to get rid of the infection. Explain how having a variety of cell membrane receptors helps macrophages detect pathogens o Having a variety of cell membranes receptors helps the immune system recognize pathogens. Understand the role of lectins binding carbohydrates such as mannose o Lectins are receptors for carbohydrates. Macrophages use lectin to bind to mannose on pathogens, since it is abundant on the surface of many pathogens. This facilitates phagocytosis. Understand the concept of induced response slowly activating in response to cytokine signaling, and why this means a successful immediate response will “cancel” an induced response. o Induced response is slowly activated in response to cytokine signaling because as macrophages phagocytize pathogens, they release cytokines. However, if the pathogen “out-runs” the macrophages they will keep releasing cytokines until the pathogen is eliminated, but the cytokines will go and recruit neutrophils and start the induced response. If the macrophages successfully eliminate the infection, then they will stop releasing cytokine, “canceling” an induced response. What are Toll-like receptors (TLRs)? o Toll-like receptors (TLR) are a series of proteins receptors that bind to lipopolysaccharides (LPS), which are not made by human cells, and activate a series of conformational changes in proteins, starting with MyD88, and activating transcription factors, which code for cytokines. Understand that TLRs signal through MyD88 resulting in NFkB activation and cytokine expression – a VERY important part of innate immune response. You do NOT need to memorize the other intermediate proteins in the chain (TRAFs, IRAK, etc.) Explain what an interleukin is and know the general functions of IL1β, TNF-α, IL-6, CXCL8, and IL-12. (General functions in Fig. 3.9 are fine)  o Interleukins are cytokines that are associated with inflammation ▪ IL-6: induces fat and muscle cells to metabolize, making heat and raises temperature in infected tissue ▪ CXCL8: recruits neutrophils from blood and guides them to infected tissue (road signs) ▪ IL-1β and TNF-α: induce blood vessels to become more permeable , allowing effector cells and fluid containing soluble effector molecules to enter infected tissue. ▪ IL-12: recruits and activates natural killer cells (NK) and that secretes cytokines that strengthen the macrophage' response to infection. Understand the role of the 4 main neutrophil / endothelium adhesion molecules: CD34, L-selectin, LFA-1, ICAM-1. o L-Selectin: they are expressed on the surface of endothelial cells in response to infection in tissue (road signs) o CD34: they are expressed on neutrophils and bind to L-selectin to slow down neutrophils o ICAM-1: helps take recruited neutrophils out of vessel o LFA-1: binds to ICAM-1 and stimulates a response Explain how a neutrophil flowing past infected tissue is slowed/stopped at the site o Using the proteins that bind on the surface of epithelial cells and neutrophils, this slows down the neutrophils and then as the neutrophils is slowing down, more receptors (ICAM-1 and LFA-1) are bringing the neutrophils into the infected issue. Understand the role of CXCL8 in attracting neutrophils. What cell makes the CXCL8? In response to what? o CXCL8 is a homing signal for neutrophils, it stimulates chemotaxis, which is directed movement of neutrophils toward infected tissue. Understand the process by which the respiratory burst phenomenon is involved in neutrophils destroying pathogen o Respiratory bursts lead to a sudden increase in pH, which activates the enzymes in neutrophils, once the enzyme is activated (very potent pro-enzyme) the pathogens are quickly digested, however so is the neutrophil. Explain how/why neutrophils can typically only destroy one or two bacteria by phagocytosis, but several by Neutrophil Extracellular Traps (NETs) o Neutrophils enzyme is so potent that once it is activated, there isn’t much time before the neutrophils also gets digested by the enzyme, therefore while alive it can only destroy one or two bacteria by phagocytosis, but once the neutrophil is dying, it will use NET, which is when the nucleus explodes and releases the sticky chromatin strand and covers surrounding pathogens with the same digestive enzyme, which destroys them. What is the role of interleukin 6 (IL-6)? o IL-6 induces fat and muscle cells to metabolize, making heat and raises temperature in infected tissue (fever). Explain what the acute-phase response of the liver represents o The acute-phase response represents the release of multiple different plasma proteins  ▪ C-reactive protein: binds to C1 complets to cleave C4 ▪ Mannose-binding lectin: binds to sugars on pathogens Be familiar with the signaling of mannose-binding lectin (MBL) and C-reactive protein as they relate to C4b fixation o MBL and C-reactive protein act in a very similar way to the alternative pathway, except they are using different proteins, MBL and C-reactive that are only produced when the immediate innate system couldn’t fight off infection. They bind to specific pathogen surface characteristics, such as mannose, and cut C4 protein to make complexes that are more effective than C3Bb. How do MBL and C-reactive protein fit into our discussion of the three C3 complement fixation pathways (Alternative, Lectin, Classical) o All complement fixation pathways are meant to induce complement activation. However, since both MBL and C-reactive protein are made during the acute-phase response in the liver, it means that the alternative pathway has not been effective in eliminating the infection. Understand how the “switch” from immediate to induced innate response should more appropriately be thought of as a “shift” rather than “switch”? o The immediate innate response happens right away, macrophages are already in the tissues scavenging for potential pathogens, however if the pathogen “out runs” this first response, the cytokine levels being released by the macrophages will keep increasing. While this is happening, the cytokine levels are building up a response, recruiting neutrophils and starting alternative pathways, with MBL and C-reactive proteins. Understand the distinction between extracellular and intracellular infection. o Extracellular infections do not enter a host to reproduce, intracellular infections do, which makes them harder to catch. Explain the roles of interferons as a sub-set of cytokines o Interferons are a special cytokine that is made by all cells in response to viral infection to interfere with progression of infection and cause cells to be more vulnerable to activated NK cells. Distinguish between roles of Type I (IFN α/β) and Type II (IFN γ) interferons in terms of what cells produce them, what stimulates production, and their function. o Type I (IFN α/β): are made by virus-infected cells, they are secreted by cells and bind to receptors to induce intracellular signaling, changing behavior of cells to prevent further infection. o Type II (IFN γ): made by NK cells to stimulate macrophages for efficient phagocytosis and inflammatory cytokine secretion. Understand IFN signaling is both autocrine and paracrine – what does this accomplish? o Autocrine signaling: IFNβ binds to interferon receptors on the surface of infected cells to mobilize other interferon-response factors and change patterns of gene expression. o Paracrine signaling: IFNβ binds to interferon receptors on the surface of nearby cells to mobilize other interferon-response factors and change  Understand the functions of the RLR receptors RIG-I and MDA5, and how they involve the MAVS proteins on mitochondria to regulate IFN gene expression o RLR: receptor proteins that recognize viral RNAs in cytoplasm (ex: RIG-I and MDA5) o MAVs proteins are on the mitochondrial membrane, where RLR bring viral RNA to further initiate interferon regulatory factors for type I interferons. What are some parts of the “interferon response”? o Change in cellular gene expression induced by interferons, resulting in different antiviral responses, such as resistance to viral replication, increased expression for ligands on NK cells ,and activation of NK cells. What is the role of NK cells? Where are NK cells found? o They originate from precursors to T cells, found in the bone marrow and lymph nodes. They are lymphocytes that are quick to respond to viral infection by destroying infected cells, increasing inflammation. How are NK cells activated? o Activated in response to type I interferons. Understand the function of the NK-synapse – why is this important? What is happening back/forth in the synapse that helps the NK cell “decide” what to do? o NK cells form synapse to induce apoptosis by forming with target cells receptors and ligands to exchange directly with target cells, transferring enzymes and protein that will induce apoptosis. Explain the relationship between NK cells and macrophages in infected tissue o They activate each other. Macrophages secrete IL-23 that activates NK and NL cells secrete IFN types II that stimulate macrophages. Explain the relationship between NK cells and dendritic cells – how might this determine whether the adaptive immune response is activated? o Dendritic cells sample their environment to determine if infection is present, they then stimulate lymphocytes to respond to the infectious agent. NK cell receptors detect the pathogen-induced changes on the dendritic cells, and interact to form synapse. If NK cells outnumber the dendritic cell, it kills the dendritic cell. Immunology 461 Study Guide Chapter 4 List some reasons why we needed to evolve an adaptive immune system on top of our innate immune system (hint: consider evolution of pathogens) o As pathogens got « smarter » compared to other life forms, invertebrates developed an immune system that will combat the adapting pathogens. Understand the general structure of immunoglobulins o The general structure of an immunoglobulin is 4 polypeptide proteins, 2 large heavy ones and 2 light and short ones. There is a N termini, or the variable region, that is where the epitope binds, and the C termini, or the constant region, that remains consistent from every immunoglobulin. Explain what is meant by the heavy vs. light chains, variable vs. constant regions, and Fab / Fc fragments of an Ig o Heavy vs light chains refer to whether they are apart of the C termini (heavy chains) or not (light chains)  o Variable region is the region that bind partially to the epitome, while the constant region remains constant for every immunoglobulin. o Fab is the antigen-binding fragment (antigen bind), and Fc crystallizing fragment (Fc) is what remains constant is is blinded to the immune cell (B cells) How do the hypervariable regions (HV or CDR) of Ig peptide sequences accomplish diverse binding affinities? o They have so many different variable regions, which allows for a “close enough fit” Understand how the jigsaw puzzle example in lecture demonstrates the concept of “close enough” fit as the basis for immunoglobulin selection o Because jigsaw puzzle pieces will « fit in » with other pieces but not actually be perfect, it is the same as antigen and immunoglobulin. What are the definitions of antigen and epitope? o Antigen is the molecule that is recognized by the antibody to start an immune response o Epitope is the region on the surface of the pathogen that the antibody binds to. How does our immune system use the hypervariable regions of Ig to compensate for not possibly being able to predict every pathogen it encounters? (Hint: since our immune system is not “psychic”, what must it to anticipate an unknown threat?) o The solution is to produce millions of different variable domains that are « close enough fit » Why is important that novel Ig is first confined to the surface of a B-cell and not immediately allowed to circulate in soluble form (think: the in-class cookie demo) o It is important that novel Ig is the first confined to the surface of a B-cell and not immediately allowed to circulate in soluble form because it allows our immune system to know which B-cell the Ig originated from, since they are all different it is important to know which genetic code is used. Be comfortable with the concepts of V(D)J recombination, including the principles of recombinase proteins such as RAG 1 and 2 using RSS sequences flanking immunoglobulin genes (the “12/23 Rule”) to increase antigen-binding diversity. o V and J recombine always, D only in heavy chain genes. They recombine to create variety in Ig variable regions. To recombine they use RSS, which is a combination of short 7 and 9 bp regions that are recognized by RAG (the protein doing the folding) that are separated by either a 12 or a 23 region. There always be one 12 and one 23 region. What is “junctional diversity” in the context of V(D)J recombination, and how does non-homologous end-joining DNA repair contribute to this ? o To be able to successfully complete V(D)J recombination you need to repair the chromosome after cutting out the expelled DNA. To do so you open up the end that was cut, creating overhang. Tdt starts adding nucleotides until there is enough to match, and then gaps get filled. This creates even more random variety since the chromosomes are creating their own segments. Understand that naïve B-cells make IgM and IgD in receptor form (B-cell receptor). o Naïve B-cells make IgM and IgD since these are the first receptors to be made by.Alternative splice of either Cmu or Cdelta leads to either IgM or IgD. Understand there are 5 isotypes/classes of immunogobulins. You do NOT have to memorize or draw each one, but recognize what elements are different among them that contribute to functional differences. o IgG, IgM, IgD, IgA, IgE  ▪ variable regions stay the same ▪ C region: are different depending on whether they bind to delta or mu Understand that for each of the Ig types, the B-cell can make membrane-bound or soluble (antibody) forms. Why/when would the B-cell switch between these? o The B-cell would remain membrane bound until they bind to a pathogen and then they release them as antibodies, this is to keep track of which B-cells have actually found a match What is the activated B-cell trying to accomplish by expressing the antibody form of IgM? What are the benefits and limitations of doing so? o The activated B-cell are trying to get good enough matches to start the antibody until they can get even better matched. The benefits is that the adaptive immune system starts helping the innate immune system and the limitation is that it is only good enough, and therefore might miss the matches that don’t bind as well. What is somatic hypermutation of the immunoglobulin locus? When does it happen? Why does the B-cell do this during clonal expansion? o Somatic hypermutation of the immunoglobulin locus is when AID start converting cytosines into different bases to create different variations of the hyper variable regions. It happens only to activated B-cells that have been determined to be “good enough” fits. They do this during clonal expansion because the daughter cells can make more B-cells with the different mutations and then determine if they are more successful or not, if they are they can divide further. What parts of the Ig locus are involved in class/isotype switching? o The heavy chains are involved in the class/isotope switching. Review Fig 4.37 “Changes in immunoglobulin genes during a B-cell’s life”. It serves as a good outline for your studies. o Immunology 461 Study Guide Chapter 5 Understand the structural similarities vs. differences between immunoglobulin (Ig) and T-Cell Receptor (TCR) o The structures of immunoglobulin and T-Cell Receptor are very similar, in that they both have 2 domain chains, they both have a variable and a constant region, and they both combine to make a unique antigen-binding site. They are different because TCR doesn't do hypermutations, and there are no forms of TCR. What are the functions of CD3 and Zeta chain proteins in helping TCR signaling? o CD3 and Zeta chains are for helping the TCR pass the signal, since TCR have a small intercellular chain, they need help. What is the main antigen type that TCR bind? o The main type of antigen that TCR binds is short peptides from pathogens. Why do we say TCR will only bind to “presented” antigen? o We say TCR will only bind to “presented” antigens because they need to be attached to MHC. Distinguish between MHC I and MHC II class structure and function o MHC I: in all nucleated cells, CD*, cytotoxic, 1 long chain and 1 circular protein.  o MCH II: only professional antigen-presenting cells (macrophages, dendritic cells), CD4, it is a helper cell, 2 even size chains Why do most cells constitutively express MHC I but typically only “professional antigen presenter” cells (B-cells, dendritic cells, macrophages) also express MHC II? o Most cells constitutively express MHC I because MHC is used to indicate that the cell has been virally infected. MHC II is to present antigens to T cells. What is the purpose (the eventual desired outcome) of a cell presenting antigen on MHC I vs MHC II? o The purpose of presenting an antigen on MHC I is to eventually kill the infected cell to prevent further infection. The purpose of presenting an antigen on MHC II is to activate the immune system. Understand how the combination of short peptide antigen being carried by MHC and the MHC itself being class I or II work together to determine whether a given T-cell can “read” the information o MHC needs to be carrying an antigen to be recognized by T-cells. They also need to be a specific class (I or II), to bind to the correct T-cell, if it's not the correct T-cell, then the T-cell will not be able to read. What are the roles of CD4 and CD8 co-receptors as related to TCR? o The roles of CD4 and CD8 co-receptors is to help bind to the target cell, and determine if they can “read”. CD4 is to help bind and signal, and CD8 is for cytotoxic Both B-cells and T-cells have receptors that exhibit antigen specificities of immense diversity – be comfortable describing how the roles of these cells are different. o They both do V(D)J recombination to get variable receptors. However, T-cells do not hypermutate. o B-cells help identify pathogens for phagocytosis by macrophages or neutrophils. o T-cells help alert the immune system by sending out cytokine signals (MHC II) and T-cells can also send cytotoxic signals to infected cells to start the apoptosis process Understand the scenarios of T-cell interaction with target cells described in Fig 5.13. This is a good figure to help wrap your head around many concepts. Understand how an MHC I and an MHC II complex may present the same identical short peptide, yet a given T-cell will only “read” one type (hint: what will CD4 vs CD8 help the T cell recognize? Which T cell types have each?). o T-cells can only read one type of receptor because it depends what the different complexes are presenting. MHC I will present what is going on inside, which can only be read by T-cells with CD8, if this is pathogenic, then the T-cell will send cytotoxic signals. MHC II will present what's phagocytosed by the cell, which can only be read  by T-cell with CD4, if this is pathogenic, then the T-cell will send out cytokine signals to recruit more immune cells. Be comfortable with the concept that MHC on a healthy cell are presenting normal “self” peptides all of the time and only rarely upon encountering pathogens will “non-self” peptides be displayed. Why doesn’t our immune system attack our healthy cells normally? o Since different complexes are responsible for representing different things, either what is happening inside the cell or what was phagocytosed by the cell, the self presenting complexes present self proteins. and our immune system doesn’t attract our healthy cells normally because they are presenting healthy and recognizable protein segments. Understand the role of the proteasome in antigen presentation o Proteasomes are responsible for chopping up misfolded or damaged proteins. This helps with antigen presentation because during the preparation for the presentation in the cell, the little pieces that were made by the proteasome are used for display. Understand that MHC I is loaded in ER – why does this make sense based on the source of peptide and how our immune system wants to respond? o MHC I is loaded in the ER since this location allows peptides that are processed by the proteasome and transported into the ER by TAP, to efficiently bind MHC I molecules. By displaying these peptides, MHC I enables cytotoxic T cells to recognize and destroy infected or abnormal cells, ensuring effective immune surveillance and response to internal threats. Understand that MHC II is loaded in vesicles – why does this make sense based on the source of peptide and how our immune system wants to respond? o MHC II is loaded in vesicles because it presents peptides from extracellular pathogens, like bacteria or fungi, that are taken up and processed by antigen-presenting cells (APCs). This allows the immune system to activate helper T cells (CD4), which helps alert the immune system to coordinate an effective response, including stimulating B cells to produce antibodies and enhancing macrophage activity. Understand why a single cell expresses different variations of MHC genes at the same time. What does having a variety of peptide presenters accomplish? How does this strengthen our immune response? o A single cell expresses different variations of MHC genes at the same time to provide a variety of different peptides, since some variations will bind better to some peptides, this allows for the immune system to get a more complete list of the peptides that may be present. It allows for a quicker and more effective immune response, since the immune cells will know multiple peptides that a pathogen may have. Be comfortable with the idea that we have six MHC I and five MHC II isotypes.  Recognize that HLA is the name for the proteins that make the MHC isotypes. o HLA stands for Human Leukocyte Antigens, and they help identify the different isotopes of MHCs. Understand why the unusually high polymorphic nature of HLA genes is an evolutionary tool for strengthening both individual (your) immunity AND the health of the human species as a whole o The high polymorphic nature of HLA genes is an evolutionary tool that strengthens both individual immunity and the health of the human species since it allows for lots of different peptides to be identified which offers better immunity. This allows for a better chance of identifying pathogens quickier, which improves individual immunity but also species wide survival. What is the role of HLA (and therefore MHC) in influencing organ transplantation outcome? How does the specificity of TCR play a crucial role in this? Why would TCR that bind to a mismatched healthy donor cell (that presents normal human peptides) even be allowed to exist in your body in the first place if it can cause such problems? o HLA mismatches are what causes organ transplant failure. Since there are a variety of different HLA that exists, when our body does not recognize one, it identifies it as a pathogen. Technically, that pathogen is doing it’s job, since it would never naturally encounter the different types of HLA. However, the TCR identifies it as « nonself ».