MCAT Immune System
MCAT Immune System MCAT
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This 22 page Study Guide was uploaded by Tejaswi Sudhakar on Thursday April 21, 2016. The Study Guide belongs to MCAT at NYU School of Medicine taught by MCAT in Spring 2016. Since its upload, it has received 39 views. For similar materials see MCAT in Professional Education Services at NYU School of Medicine.
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Date Created: 04/21/16
8.1 Structure of the Immune System Two Divisions of the Immune System: Innate (non-specific) vs. Adaptive (specific) Immunity o Innate immunity: made up of defenses that are always active against infection Con: non-specific immunity – lacks ability to target specific invaders over others Location: acts near entry points into the body Innate immunity is NOT learned, adaptive immunity is LEARNED Innate immune system includes: antimicrobial molecules (1), phagocytes (cells that ingest and destroy pathogens) – ex. dendrites and macrophages and activate an inflammatory response, secreting proteins (cytokines) that trigger an influx of immune cells from the blood and recruit more phagocytes (notably monocytes) which can mature into macrophages and neutrophils o Adaptive immunity: defenses that target a specific pathogen (B- cells & T-cells) Con: slower to act (but can maintain an immunological memory of the infection to produce a faster attack in subsequent infections) Adaptive immunity is developed as immune cells (B-cells & T- cells) learn to recognize and respond to particular antigens Adaptive immunity can be divided into humoral immunity (driven by B-cells) and cell-mediated immunity (provided by T-cells) B-cells = humoral immunity b/c B-cells dissolve and act in the blood (rather than within cells) T-cells = cell-mediated immunity b/c they coordinate the immune system and directly kill virally infected cells Activated B-cells secrete antibody molecules that bind to antigens (specific components unique to invader) and destroy the invader directly or mark it for attack by others T-cells recognize antigens displayed on cells o Some T-cells help to activate B-cells and other T- cells ; other T-cells directly attack infected cells o T- and B-cells spawn memory cells that promptly eliminate invaders encountered before if innate immunity fails, adaptive immunity steps in Anatomy of the Immune System o Bone marrow = produces all leukocytes (WBCs), B-cells, T-cells B-cells: when B-cells leave the bone marrow, they are mature but naïve (b/c they haven’t been exposed to an antigen) T-cells = mature in the thymus o Spleen = location of blood storage (1), activation of B-cells, which convert into plasma cells to produce antibodies of adaptive immunity (2), filters blood and lymph (3), site where immune system responses can be mounted (4) o Lymph Nodes = site where immune response can be mounted (1), filter lymph (2) B-cells can be activated in lymph nodes (in addition to spleen) Note: Lymph nodes are NOT glands – they don’t secrete products into the blood (endocrine) or ducts (exocrine) Swelling of lymph nodes = activation of immune system o Gut-associated lymphoid tissue (GALT) = other immune tissue is found near the digestive system (site of potential invasion by pathogens) ex. tonsils & adenoids (head), Peyer’s patches (small intestine), lymphoid aggregates (appendix) 2 Types of Leukocytes: Granulocytes & Agranulocytes (presence or absence of granules in the cytoplasm) o Both granulocytes and agranulocytes come from a common precursor: hematopietic stem cells (like RBCs & platelets) Granulocytes: neutrophils, eosinophils, basophils (BEN) Agranulocytes: lymphocytes & monocytes (ALM) Lymphocytes = responsible for antibody production (1), immune system modulation (2), targeted killing of infected cells (3) Monocytes = phagocytic cells in the bloodstream o They become macrophages in tissues; o Many tissues have resident populations of macrophages with specific names Microglia = macrophages of CNS Langerhans cells = macrophages of skin Osteoclasts = macrophages of bone o These granules contain toxic enzymes which can be released by exocytosis and are effective against bacterial, fungal, and parasitic pathogens o Real World Application: Abnormal WBC populations indicate a type of infection: if 90% of WBCs = neutrophils = a bacterial infection is present, if 20% of WBCs = eosinophils = invasive parasitic infection 8.2 The Innate Immune System Non-cellular Defenses = skin, respiratory passages (cilia & mucous membranes) First line of defense = skin (integument) – provides a physical barrier between the outside world and our internal organs (preventing pathogens from entering the body) o antibacterial enzymes (defensins) = found on skin, sweat = antimicrobial properties o Cut in skin = entry point for pathogens into body (deeper wound = deeper penetration) Respiratory passages = mucous membranes lined with cilia to trap particulate matter and push it up towards the pharynx where it can be swallowed or expelled o While mucus helps to trap smoke and dirt, it also helps to prevent viruses and bacteria from gaining access to deeper lung tissue Other mucous membranes (around the eye and mouth) produce a nonspecific bacterial enzyme called lysozyme (in tears & saliva) GI Tract = Stomach acid, gut bacteria o Stomach secretes acid (kills pathogens) o Gut is colonized by bacteria (lack ability to cause infection), b/c there’s a large bacterial population in the gut, many potential invaders are not able to compete & are kept away o Antibiotics ↓ population of gut flora, providing an opportunity for growth of pathogens The newborn’s GI tract is susceptible to infection b/c newborn’s immune system is underdeveloped and the GI tract is not yet colonized Breast milk contains antibodies that are effective to defend newborns against GI infections Complement System = blood proteins o Complement can be activated through a classical pathway (requires binding of an antibody to a pathogen) or an alternative pathway (does not require antibodies) Complement proteins punch holes in the cell walls of bacteria, making them osmotically unstable Despite association with antibodies, complement is non-specific b/c it can’t be modified to target a specific organism Interferons o To protect against viruses, cells infected with viruses produce interferons Interferons = proteins that prevent viral replication and dispersion Interferons cause nearby cells to ↓ production of both viral and cellular proteins (1), ↓ permemability of cells, making it harder for a virus to infect them (2), upregulate MHC class I and II molecules, resulting in ↑ antigen presentation and better detection of the infected cells by the immune system (next section) Interferons = responsible for flu symptoms that occur during viral infection (fever, muscle soreness, tiredness) Cells of the Innate Immune System (Macrophages, Natural Killer Cells, Granulocytes) If bacteria, viruses, fungi, or parasites breach the above defenses – the cells of the innate immune system are ready to attack! o Macrophages = agranulocyte, reside within tissues Derive from blood-borne monocytes and can become a resident (permanent) population within a tissue Step 1: When bacterial invader enters a tissue, macrophages become activated Step 2: activated macrophage does 3 things (1) activated macrophage phagocytizes the invader through endocytosis (2) digests the invader using enzymes (3) presents little pieces of the invader (antigen) to other cells using a protein called MHC (major histocompatibility complex) o MHC binds to an antigen (peptide of antigen) and carries it to the cell surface, where it can be recognized by cells of the adaptive immune system (4) macrophage releases cytokines (chemicals that stimulate inflammation and recruit additional immune cells to the area) MHC molecules: class I All nucleated cells in the body display MHC Class I molecules o Any protein produced within a cell can be loaded onto MHC-I and presented on the surface of the cell- Figure 8.4 Endogenous Pathway for Antigen Presentation (MHC Class I) MHC-I exists in all nucleated cells. This allows the immune system to monitor the health of these cells and to detect if the cells have been infected with a virus or another intracellular pathogen; only those cells that are infected would be expected to present an unfamiliar (nonself) protein on their surface Therefore, the MHC-I pathway is often called the endogenous pathway because it binds antigens from inside the cell. Cells that have been invaded by intracellular pathogens can then be killed by a group of T- cells (cytotoxic T-lymphocytes) to prevent infection of other cells. MHC class II: MHC class II molecules are displayed by professional antigen- presenting cells (Professional antigen-presenting cells = macrophages, dendritic cells in the skin, some B-cells, and certain activated epithelial cells) o These phagocytic cells pick up pathogens from the environment, process them, and then present them on MHC- II o While antibody production is linked to adaptive immune system, cells of the innate immune system can also present antigens b/c these antigens originated outside of the cell, this pathway = exogenous pathway the presentation of an antigen by an immune cell may result in the activation of both the innate and adaptive immune systems Fig 8.5. Exogenous Pathway for Antigen Presentation (MHC Class II) MHC-II exists only in professional antigen-presenting cells. o TLDR: Major histocompatibility complex molecules (MHCs) are joined with antigens. The MHC–antigen complex then goes to the cell surface to display the antigen. This allows the immune system to monitor the health of cells. MHC-I is in all nucleated cells and presents endogenous antigens. MHC-II is in antigen-presenting cells and presents exogenous antigens o Macrophages and dendritic cells also have special receptors known as pattern recognition receptors (PRR) such as toll-like receptors (TLR) PRRs are able to recognize the category of the invader (bacterium, virus, fungus, or parasite). This allows for the production of appropriate cytokines to recruit the right type of immune cells; each immune cell has different weapons that can target particular groups of pathogens Natural Killer Cells: nonspecific lymphocyte, are able to detect the downregulation MHC and induce apoptosis in these virally infected cells (cancer cells do this, so NK cells offer protection from cancer) o some pathogens avoid defenses by causing downregulation of MHC molecules, making it hard for T-cells to recognize presence of an infection Granulocytes = BEN (basophils (and closely related mast cells), eosinophils, and neutrophils) o Neutrophils = most populous leukocyte, short-lived (5 days), for bacterial infections target bacteria by chemotaxis – the sensing of bacteria products and migration of neutrophils to follow these products back to the bacterium source Neutrophils can also detect bacteria once they have been opsonized (marked with an antibody from a B-cell) Dead neutrophil collections = responsible for pus formation during infection Other cells, like natural killer cells, macrophages, monocytes, and eosinophils, also contain receptors for antibodies and can attack opsonized bacteria o Eosinophils = allergic reactions and invasive parasitic infections Activated eosinophils release histamine (inflammatory mediator) – this results in vasodilation and increased leakiness of blood vessels, allowing movement of additional immune cells (macrophages and neutrophils)from the blood into tissues o Basophils = allergic responses (lowest population) Both basophils and mast cells release large amounts of histamine in response to allergens, leading to inflammatory responses 8.3 The Adaptive Immune System The adaptive immune system can be divided into two divisions: humoral immunity and cell-mediated (cytotoxic) immunity - Each involves the identification of the specific pathogen and organization of an appropriate immune response Humoral Immunity Humoral immunity = involves the production of antibodies o Antibodies are produced by B-cells (lymphocytes that originate and mature in the bone marrow and are activated in the spleen and lymph nodes) o Antibodies (also called immunoglobulins [Ig]) carry out many functions Just as antigens can be displayed on the surface of cells or can float freely in blood, chyle (lymphatic fluid), or air, antibodies can also be present on the surface of a cell or secreted into body fluids When an antibody binds to an antigen, the response will depend on the location For antibodies secreted into body fluids, there are 3 main possibilities: o (1) first, once bound to a specific antigen, antibodies may attract other leukocytes to phagocytize those antigens immediately (opsonisation, as described earlier) o (2) antibodies may cause pathogens to clump together or agglutinate, forming large insoluble complexes that can be phagocytized o (3) antibodies can block the ability of a pathogen to invade tissues, essentially neutralizing it For cell-surface antibodies, the binding of antigen to a B- cell causes activation of that cell, resulting in its proliferation and formation of plasma and memory cells, as described later in this chapter o In contrast, when antigen binds to antibodies on the surface of a mast cell, it causes degranulation (exocytosis of granule contents), allowing the release of histamine and causing an inflammatory allergic reaction o Antibodies = Y-shaped molecules (made up of two identical heavy chains and two identical light chains) Disulfide linkages & noncovalent interactions = hold heavy & light chains together Each antibody has an antigen-binding region at the tips of the Y (the variable region (domain) Within this region, there are specific polypeptide sequences that will bind one, and only one, specific antigenic sequence Part of the reason it takes so long to initiate the antibody response is that each B-cell undergoes hypermutation of its antigen-binding region, trying to find the best match for the antigen Only those B-cells that can bind the antigen with high affinity survive, providing a mechanism for generating specificity called clonal selection The remaining part of the antibody molecule is known as the constant region (domain) o It is this region that cells such as natural killer cells, macrophages, monocytes, and eosinophils have receptors for, and that can initiate the complement cascade o Each B-cell makes only one type of antibody, but we have many B- cells, so our immune system can recognize many antigens. Further, antibodies come in five different isotypes (IgM, IgD, IgG, IgE, and IgA). While the specific purposes of each antibody isotype is outside the scope of the MCAT, you should know that the different types can be used at different times during the adaptive immune response, for different types of pathogens, or in different locations in the body Cells can change which isotype of antibody they produce when stimulated by specific cytokines in a process called isotype switching Figure 8.7. Structure of an Antibody Molecule Not all B-cells constantly produce antibodies o Antibody production = energetically expensive, there is no reason to expend energy producing antibodies that are not needed o Instead, naïve B-cells (those that have not yet been exposed to an antigen) wait in the lymph nodes for their particular antigen to come along o Upon exposure to the correct antigen, a B-cell will proliferate and produce two types of daughter cells Plasma B cells produce large amounts of antibodies memory B-cells stay in the lymph node, awaiting re-exposure to the same antigen. This initial activation takes ~ 7-10 days and is known as the primary response The plasma cells will eventually die, but the memory cells may last a lifetime If the same microbe is encountered again, the memory cells jump into action and produce the antibodies specific to that pathogen This immune response, called the secondary response, will be more rapid and robusts o The development of these lasting memory cells is the basis of the efficacy of vaccinations. Cytotoxic Immunity (T-cells) T-cells mature in the thymus, where they undergo both positive and negative selection o Positive selection = refers to maturation of T-cells that can respond to the presentation of antigen on MHC (cells that can’t respond to MHC antigen undergo apoptosis) o Negative selection = refers to causing apoptosis in cells that are self- reactive (activated by proteins produced by the organism itself) o maturation of T-cells is facilitated by thymosin, a peptide hormone secreted by thymus Once the T-cell has left the thymus, it is mature but naïve. Upon exposure to antigen, T-cells will also undergo clonal selection so that only those with the highest affinity for a given antigen proliferate o There are three major types of T-cells: helper T-cells, suppressor T-cells, and killer (cytotoxic) T-cells Helper T-cells (T or CD4 T-cells) coordinate the immune h response by secreting lymphokines Lymphokines = capable of recruiting other immune cells (such as plasma cells, cytotoxic T-cells, and macrophages) and ↑↑ their activity The loss of these cells (as occurs in HIV infection) prevents the immune system from mounting an adequate response to infection CD4 T-cells respond to antigens presented on MHC-II molecules o Because MHC-II presents exogenous antigens, CD4 T-cells are most effective against bacterial, fungal, and parasitic infections Cytotoxic T-cells (T oc CT , fLr cytotoxic T-lymphocytes, + CD8 T-cells) = capable of directly killing virally infected cells by injecting toxic chemicals that promote apoptosis into the infected cell CD8 T-cells respond to antigens presented on MHC-I molecules Because MHC-I presents endogenous antigens, CD8 T- + cells are most effective against viral (and intracellular bacterial or fungal) infections TLDR: CD4 T-cells are better at fighting extracellular infections, while CD8 T-cells are better at targeting intracellular infections Suppressor or regulatory T-cells (T reg also express CD4, but can be differentiated from helper T-cells because they also express a protein called Foxp3 These cells help to tone down the immune response once infection has been adequately contained These cells also turn off self-reactive lymphocytes to prevent autoimmune diseases: this is termed self- tolerance Many suppressor T-cells were formerly self-reactive T-cells that have been turned off. When a suppressor T-cell inactivates another lymphocyte, it can either target it for destruction or promote its conversion into another suppressor T-cell Finally, memory T-cells can be generated. Similar to memory B- cells, these cells lie in wait until the next exposure to the same antigen. When activated, they result in a more robust and rapid response ACTIVATION OF THE ADAPTIVE IMMUNE SYSTEM There are five types of infectious pathogens: bacteria, viruses, fungi, parasites (including protozoa, worms, and insects), and prions (for which there are no immune defenses) o bacterial infection = extracellular pathogen, viral infection = intracellular pathogen Bacterial (Extracellular Pathogen) Infections o Macrophages = lookout for potential invaders – engulf the bacteria and release inflammatory mediators Macrophages also digest the bacteria and present antigens from the pathogen on their surfaces in conjunction with MHC-II cytokines attract inflammatory cells (including neutrophils & additional macrophages) Mast cells are activated by the inflammation and degranulate, resulting in histamine release and ↑↑ leakiness of the capillaries This allows for immune cells to leave blood to travel to affected tissue The dendritic cell (that presents the MHC-II complex) then leaves the affected tissue and travels to the nearest lymph node, where it presents the antigen to B-cells B-cells that produce the correct antibody proliferate through clonal selection to create plasma cells and memory cells Antibodies then travel through the bloodstream to the affected tissue, where they tag the bacteria for destruction At the same time, dendritic cells are also presenting the antigen to T-cells, activating a T-cell response + In particular, CD4 T-cells are activated. These cells come in two types, one activates macrophages and ↑↑ their ability to kill bacteria, the other activates B-cells After the pathogen has been eliminated, plasma cells die, but memory B- and T-cells remain. These memory cells allow for a much faster secondary response upon exposure to the pathogen at a later time Viral (Intracellular Pathogen) Infections o In a viral infection, the virally infected cell will produce interferons, which ↓↓ the permeability of nearby cells (↓↓ the ability of the virus to infect these cells), ↓↓ the rate of transcription and translation in these cells (↓ the ability of the virus to multiply), and cause systemic symptoms (malaise, muscle aching, fever) o The virally infected cells also present intracellular viral proteins (antigens) on their surface in conjunction with MHC-I o CD8 T-cells will recognize the MHCI-antigen complex as foreign and will inject toxins into the cell to promote apoptosis In this way, the infection can be blocked before it spreads to nearby cells In the event that the virus downregulates the production and presentation of MHC-I molecules, natural killer cells will recognize the absence of MHC-I and will cause apoptosis of this cell o Again, once the pathogen has been cleared, memory T-cells will be generated that can allow a much faster response to be mounted upon a second exposure RECOGNITION OF SELF AND NONSELF Self-antigens = proteins and carbohydrates present on the surface of every cell of the body Allergies and autoimmunity are part of a family of immune reactions classified as hypersensitivity reactions. o Autoimmunity: Under normal circumstances, these self-antigens signal to immune cells that the cell is not threatening and should not be attacked. However, when the immune system fails to make the distinction between self and foreign, it may attack cells expressing particular self-antigens o Hypersensitivity: when the immune system misidentifies a foreign antigen as dangerous when, it is not (ex. pollen, peanuts are not threatening, yet people’s immune systems are hypersensitive to these antigens and become overactivated when these antigens are encountered in what is called an allergic reaction) The human body strives to prevent autoimmune reactions very early in T-cell and B-cell maturation processes. T-cells are educated in the thymus. Part of this education involves the elimination of T-cells that respond to self-antigens, called negative selection. Immature B-cells that respond to self-antigens are eliminated before they leave the bone marrow. However, this process is not perfect, and occasionally a cell that responds to self-antigens is allowed to survive o Most autoimmune diseases can be treated with therapy; one example is administration of glucocorticoids (modified cortisol), which have immunosuppressive qualities Examples of Autoimmune diseases: Autoimmune diseases can result in destruction of tissues, causing various deficiencies. Type I diabetes mellitus results from autoimmune destruction of the β-cells of the pancreas IMMUNIZATION – PASSIVE VS. ACTIVE Active Immunity = immune system is stimulated to produce antibodies against a specific pathogen o The means by which we are exposed to this pathogen may either be natural or artificial. o Through natural exposure, antibodies are generated by B-cells once an individual becomes infected. Artificial exposure (through vaccines) also results in the production of antibodies; however, the individual never experiences true infection Instead, he or she receives an injection or intranasal spray containing an antigen that will activate B-cells to produce antibodies to fight the specific infection. The antigen may be a weakened or killed form of the microbe Passive immunity = results from the transfer of antibodies to an individual o The immunity is transient because only the antibodies, and not the plasma cells that produce them, are given to the individual o Examples = the transfer of antibodies across the placenta during pregnancy to protect the fetus and the transfer of antibodies from a mother to her nursing infant through breast milk o In some cases of exposure (rabies virus or tetanus), intravenous immunoglobulin may be given to prevent the pathogen from spreading 8.4 The Lymphatic System The immune system and the lymphatic system are related. B-cells proliferate and develop within the lymphatic system, especially the lymph nodes. STRUCTURE OF Lymphatic system = made up of one-way vessels that become larger as they move toward the center of the body o These vessels carry lymphatic fluid (lymph) and the vessels join to comprise a large thoracic duct, which then delivers the lymphatic fluid into the left subclavian vein (near the heart) o Lymph nodes = structures along the lymphatic vessels Lymph nodes contain a lymphatic channel, as well as an artery and a vein The lymph nodes provide a space for the cells of the immune system (B-cells & T-cells) to be exposed to possible pathogens cancers are prone to spread via lymphatic channels. To ensure all cancer has been removed, lymph nodes are removed at the same time Function of the Lymphatic System = secondary system for circulation o Function 1= Equalization of Fluid Distribution At the capillaries, fluid leaves the blood and goes into the tissues. The quantity of fluid that leaves the tissues at the arterial end of the capillary bed depends on both hydrostatic and oncotic pressures (Starling forces) Remember that the oncotic pressure of the blood draws water back into the vessel at the venule end, once hydrostatic pressure has decreased Because the net pressure drawing fluid in at the venule end is slightly less than the net pressure pushing fluid out at the arterial end, a small amount of fluid remains in the tissues Lymphatic vessels drain these tissues and subsequently return the fluid to the bloodstream o Lymphatic system offer sprotection – ex. if blood has a low [albumin] conc., the oncotic pressure of the blood is ↓↓ & less water is driven back into the blood at the venule end Thus, this fluid will collect in the tissues As long as the lymphatic channels are not blocked, much of this tissue fluid may eventually return to the bloodstream via the lymphatic system Only when the lymphatic system is overwhelmed does edema occur—swelling due to fluid collecting in tissue o Function 2 = Transportation of Biomolecules lymphatic system also transports fats from digestive system into the blood Lacteals = small lymphatic vessels, located at the center of each villi in the small intestine o Fats, packaged into chylomicrons by intestinal cells, enter the lacteal for transport o Lymphatic fluid carrying many chylomicrons = chyle (white) o Function 3 = Immunity lymph nodes = place for antigen-presenting cells and lymphocytes to interact B-cells proliferate & mature in the lymph nodes in collections called germinal centers
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