PHSI2005 Immune System Immune System 1. Differentiate between specific and non-specific immune defence mechanismsInnate - Non-specific - Present from birth - Rapid response, within minutes to hours - Respond to a range of molecular signals, does not target a specific pathogen - Inflammation is a common reaction/responseAdaptive - Specific, directed at specific invaders - Can distinguish between pathogens - First exposure can take days - With repeated exposure it “remembers” prior exposure to the pathogen and then reacts more rapidly - Can be divided into cell-mediated immunity and humoral immunity 2. List non-specific innate cell and mediator functionsPathogen-associated Molecular Patterns (PAMPS): bind to leukocyte pattern recognition receptors(PRR) that activate the nonspecific immune response. The initial response of these immune cells toinvaders is to kill them or ingest them. 3. Discuss the mechanisms producing the cardinal signs of inflammationInflammation is a hallmark reaction of innate immunity.’Inflammation has 3 important roles in fighting infection in damage tissue: 1) Attracting immune cells and chemical mediators to the site 2) Producing a physical barrier to retard the spread of infection 3) Promoting tissue repair once the infection is under control (a non-immunological function)The inflammatory response is created when activated tissue macrophages release cytokines. Thesechemicals attract other immune cells, increase capillary permeability, and cause fever. Immune cellsattracted to the site in turn release their own cytokines. 4. Specify the main mediators of inflammationChemical substances, called mediators, released from injured or activated cells co-ordinate thedevelopment of the inflammatory response. • Plasma proteins such as complement and antibodies. • Other proteins such as sPLA and acute phase reactants. 2 • Cytokines and chemokines. • Lipids such as prostaglandins and PAF. • Amines such as histamine. - • ‘Gasses’ such as NO and O2 .
PHSI2005 Immune System • Kinins such as bradykinin. • Neuropeptides such as substance P 5. Outline the functions of complement • A complex series of about 20 proteolytic enzymes in the blood. • ‘Classical’ and ‘alternate’ pathways act in a cascade fashion. • Accelerated in the presence of IgGs • Lytic to many micro-organisms. • ‘Opsonise’ others.A complement is a group of plasma enzymes that are involves in the immune function.The complement cascade is similar to the blood coagulation cascade. Various intermediate of thecompliment cascade act as opsonins, chemical attractants for leukocytes, and agent that cause mastcell degranulation. 6. Outline the functions of neutrophils (margination, diapedesis, chemotaxis, amoeboid motion, phagocytosis)Neutrophil granulocytes are the most abundant type of white blood cells in mammals and form anessential part of the innate immune system. They are subdivided into segmented neutrophils (orsegs) and banded neutrophils (or bands). They form part of the polymorphonuclear cell family(PMNs) together with basophils and eosinophils.Neutrophils are normally found in the blood stream. During the beginning (acute) phase ofinflammation, particularly as a result of bacterial infection, environmental exposure, and somecancers., neutrophils are one of the first-responders of inflammatory cells to migrate towards thesite of inflammation. They migrate through the blood vessels, then through interstitial tissue,following chemical signals such as Interleukin-8 (IL-8), C5a, fMLP and Leukotriene B4 in a processcalled chemotaxis (the phenomenon in which somatic cells, bacteria, and other single-cell ormulticellular organisms direct their movements according to certain chemicals in their environment).They are the predominant cells in pus, accounting for its whitish/yellowish appearance.Neutrophils are recruited to the site of injury within minutes following trauma and are the hallmarkof acute inflammation.Neutrophils undergo a process called chemotaxis, which allows them to migrate toward sites ofinfection or inflammation. Cell surface receptors allow neutrophils to detect chemical gradients ofmolecules such as interleukin-8 (IL-8), interferon gamma (IFN-gamma), C5a, and Leukotriene B4,which these cells use to direct the path of their migration.Neutrophils have a variety of specific receptors including complement receptors, cytokine receptorsfor interleukins and interferon gamma (IFN-gamma), receptors for chemokines, receptors to detectand adhere to endothelium, receptors for leptins and proteins, and Fc receptors for opsonin.Neutrophils are phagocytes, capable of ingesting microorganisms or particles. For targets to berecognised, they must be coated in opsonins—a process known as antibody opsonisation. They caninternalize and kill many microbes, each phagocytic event resulting in the formation of a phagosomeinto which reactive oxygen species and hydrolytic enzymes are secreted. The consumption of oxygen
PHSI2005 Immune Systemduring the generation of reactive oxygen species has been termed the "respiratory burst", althoughunrelated to respiration or energy production.The respiratory burst involves the activation of the enzyme NADPH oxidase, which produces largequantities of superoxide, a reactive oxygen species. Superoxide dismutates, spontaneously orthrough catalysis via enzymes known as superoxide dismutases (Cu/ZnSOD and MnSOD), tohydrogen peroxide, which is then converted to hypochlorous acid HClO, by the green heme enzymemyeloperoxidase. It is thought that the bactericidal properties of HClO are enough to kill bacteriaphagocytosed by the neutrophil, but this may instead be a step necessary for the activation ofproteases.Margination: is the movement of leukocytes out of the circulatory system, towards the site oftissue damage or infection. This process forms part of the innate immune response, involvingthe recruitment of non-specific leukocytes. Monocytes also use this process in the absence ofinfection or tissue damage during their development into macrophages. 7. Describe the mechanism of opsonisationOpsonin: - Any molecule that targets an antigen for an immune response. - Antibodies that tag encapsulated bacteria, along with additional plasma proteinsThe term is usually used in reference to molecules that act as a binding enhancer for the process ofphagocytosis, especially antibodies, which coat the negatively-charged molecules on the membrane.In the body, opsonins convert unrecognisable particles into “food” for phagocytes. They also act as abridge between pathogen and phagocytes by binding to receptors on the phagocytes. Moleculesthat activate the complement system are also considered opsonins.Both the membrane of a phagocytosing cell and its target have a negative charge (zeta-potential),making it difficult for the two cells to come close together. Once the opsonins attach to the target,the negative charged is masked. Take note that the negative charge of the target doesnt disappear.The opsonin simply overrides the charge, making it easier for white blood cells (phagocytic cells), toundergo phagocytosis. During the process of opsonisation, antigens are bound by antibody orcomplement molecules. Phagocytic cells express receptors, CR1 and Fc receptors, that bind opsoninmolecules, C3b and antibody, respectively. With the antigen coated in these molecules, binding ofthe antigen to the phagocyte is greatly enhanced. In fact, most phagocytic binding cannot occurwithout opsonisation of the antigen.Furthermore, opsonisation of the antigen and subsequent binding to an activated phagocyte willcause increased expression of complement receptors on neighboring phagocytes.
PHSI2005 Immune System 8. Outline the functions of natural killer cells and interferonNatural killer cells (NK cells): - A type of cytotoxic lymphocyte that attacks certain tumour and virus-infected cells. - Critical to the innate immune system. - Function: The role NK cells play is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virally infected cells and respond to tumor formation, acting at around 3 days after infection. Typically immune cells detect MHC presented on infected cell surfaces, triggering cytokine release causing lysis or apoptosis. - NK cells are unique, however, as they have the ability to recognise stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named “natural killers” because of the initial notion that they do not require activation in order to kill cells that are missing “self” markers of major histocompatibility complex (MHC) class 1.Interferon: - Named for their ability to interfere with viral replication. - They are cytokines secreted by lymphocytes that aid in the immune response. - Function: Interferon-alpha (IFN-α) and interferon-beta (IFN-β) target host cells and promote synthesis of antiviral proteins to prevent viral replication. Inferferon-gamma (IFN-ϒ) activates macrophages and other immune cells 9. Distinguish between active and passive immunizationActive immunity occurs when the body is exposed to a pathogen and produces its own antibodies.Active immunity can occur naturally, when a pathogen invades the body, or artificially, as when weare given vaccinations containing dead or disabled pathogens.Passive immunity occurs when we acquire antibodies made by another animal. The transfer ofantibodies from mother to foetus across the placenta is one example. Injections containingantibodies are another. Travellers going abroad may be injected with gamma globulin (antibodiesextracted from donated human plasma), but this passive immunity lasts only about three months. 10. Define immunological memory and understand its mechanismMemory cells are long lived and continue reproducing themselves. Second and subsequentexposures to the antigen activate the memory cells and cause rapid clonal expansion, creating aquicker and stronger secondary response to the antigen. 11. Specify the characteristics of antigens and antibodiesAntigens: substances that trigger an immune response from the body and that can react withproducts of that response.Antibodies: molecules keyed to a particular pathogen that helps target it for destruction.Antigen is a substance that evokes the production of one or more antibodies. Each antibody binds toa specific antigen by way of an interaction similar to the fit between a lock and a key. The substance
PHSI2005 Immune Systemmay be from the external environment or formed within the body. The immune system will try todestroy or neutralize any antigen that is recognized as a foreign and potentially harmful invader.Antibodies refers to any molecule or molecular fragment that can be bound by a majorhistocompatibility complex (MHC) and presented to a T-cell receptor. "Self" antigens are usuallytolerated by the immune system; whereas "Non-self" antigens can be identified as invaders and canbe attacked by the immune system. 12. Outline the anatomy of the lymphatic systemThe immune system is probably the least anatomical identifiable system of the body because mostof it is integrated into the tissues of other organs, such as the skin and gastrointestinal tract. Theimmune system has 2 anatomical components: lymphoid tissues and the cells responsible for theimmune response.Lymphoid tissues are found all over the body. The 2 primary lymphoid tissues are the thymus glandand the bone marrow, both sites where cells involved in the immune response form and mature.Some types of mature immune cells do not specialise until their first exposure to the pathogen theywill fight. These mature but unspecialised immune cells are said to be naïve cells.In the secondary lymphoid tissues, mature immune cells interact with pathogens and initiateresponse. Secondary tissues are divided into encapsulated tissues and unencapsulated diffuselymphoid tissues.The encapsulated lymphoid tissues are the spleen and lymph nodes. Both have an outer wall formedfrom fibrous collagenous capsules. These spleen contains immune cells positioned so that theymonitor the blood for foreign invaders. Phagocytic cells in the spleen also trap and remove aging redblood cells. The lymph nodes are associated with the lymphatic circulation. Here there is a net flowof fluid out of capillaries and into the interstitial space. This filtered fluid is picked up by lymphcapillaries and passes through the encapsulated lymph nodes on its journey back to the circulation.Inside lymph nodes, clusters of immune cells intercept pathogens that have entered the interstitialfluid through breaks in the skin or though mucous membranes. Once these microbes have been
PHSI2005 Immune Systemswept into the lymph, immune cells in the nodes help prevent their spread throughout the body. Forexample, when you have a sore throat, lymph nodes in your neck become swollen which result fromthe presence of active immune cells that have collected in the nodes to fight infection.The unencapsulated diffuse lymphoid tissues are aggregations of immune cells that appear in otherorgans of the body. They include the tonsils at the posterior nasopharynx; the gut-associatedlymphoid tissue (GALT), which lies just under the epithelium of the oesophagus and intestines; andclusters of lymphoid tissue associated with the skin and the respiratory, urinary, and reproductivetracts. In each case, these tissues contain immune cells positioned to intercept invading pathogensbefore they get into general circulation. Because of the large surface area of the digestive tractepithelium, some authorities consider the GALT to be the largest immune organ in the body.Anatomically, the cells of the immune system can be found in highest concentrations wherever theyare most likely to encounter antigens that penetrate the epithelium. Primary Secondary (Responsible for maturation of Ag- (Sites for Ag contact and response) reactive cells) Thymus Bone Lymph Spleen (T-cell marrow nodes maturation) (Expansion of lymphatic system, separate from blood (Similar to lymph circulation. Deep nodes but part of (T-cell maturation) (B-cell maturation) cortex harbors blood circulation. mostly T-cells, Collects blood-borne superficial cortex Ags) harbors mostly B- cells) 13. List specific acquired cell and mediator functionsNaïve Cells: a lymphocyte that has not yet been exposed to a specific antigen.Clonal Expansion: reproduction of one type of lymphocyte following expansion to an antigenEffector Cells: the cell or tissue that carries out the homeostatic response
PHSI2005 Immune SystemMemory Cells: lymphocyte responsible for creating stronger and more rapid immune responsefollowing second exposure to an antigen 14. Describe the development of immunocompetence and MHC restrictionImmunocompetence: the ability of the body to produce a normal immune response followingexposure to an antigen. Immunocompetence is the opposite of immunodeficiency or immuno-incompetent or immuno-compromised.MHC restriction: refers to the fact that a given T cell will recognize a peptide antigen only when it isbound to a host bodys own MHC molecule. Normally, as T cells are stimulated only in the presenceof self-MHC molecules, antigen is recognized only as peptides bound to self-MHC molecules.MHC restriction is particularly important when primary lymphocytes are developing anddifferentiating in the thymus or bone marrow. It is at this stage that T cells die by apoptosis if theyexpress high affinity for self-antigens presented by an MHC molecule or express too low affinity forself MHC. This is ensured through two distinct developmental stages: positive selection and negativeselection.Developing T cells in the primary lymphoid organs (thymus) first express neither CD4, CD8 nor TcR (Tcell receptor). This is referred to as double negative selection. After differentiation, the T cellexpresses both CD4, CD8 and TcR. This is referred to as double positive selection. It is at this stagethat select T cells undergo apoptosis if they are found to select for self-antigen. This is a necessarystep as it prevents T cells from cascading an autoimmune response against its host tissues.Ultimately, the T cells differentiate and mature to express either CD4 and TcR or CD8 and TcR. At thispoint the T cells leave the primary lymphoid organ and enter the blood stream.Conversely, it is thought that MHC Restriction plays a pivotal role in the antiretroviral therapy usedto treat HIV/AIDS as it can increase the CD4 cell count thus increasing the likelihood for an immuneresponse to be prompted
PHSI2005 Immune System 15. Distinguish between humoral and cellular immunity (antibodies and lymphokines) Adaptive/acquired immunity can be divided into cell-mediated immunity and humoral immunity Cell-mediated: uses contact-dependent signaling in which an immune cell receptor binds to a receptor on its target cell. Humoral: uses the secreted proteins known as antibodies to carry out the immune responses. The cellular response is mediated by T-cells and the humoral response is mediated by B-cells (that produce plasma cells that produce antibodies). 16. Discuss the clonal selection hypothesisThe clonal selection hypothesis has become a widely accepted model for how the immune systemresponds to infection and how certain types of B and T lymphocytes are selected for destruction ofspecific antigens invading the body.The clonal selection hypothesis states that the germline encodes many different antigen receptors -one for each antigenic determinant to which an individual will be capable of mounting an immuneresponse. Antigen selects those clones of cells that have the appropriate receptor. The four basicprinciples of the clonal selection hypothesis are: - Each lymphocyte bears a single type of receptor with a unique specificity. - Interaction between a foreign molecule and a lymphocyte receptor capable of binding that molecule with a high affinity leads to lymphocyte activation. - The differentiated effector cells derived from an activated lymphocyte will bear receptors of an identical specificity to those of the parental cell from which that lymphocyte was derived. - Lymphocytes bearing receptors for self molecules are deleted at an early stage in lymphoid cell development and are therefore absent from the repertoire of mature lymphocytes.The clonal selection hypothesis is now generally accepted as the correct hypothesis to explain howthe adaptive immune system operates. It explains many of the features of the immune response: 1. The specificity of the response 2. The signal required for activation of the response (i.e. antigen) 3. The lag in the adaptive immune response (time is required to activate cells and to expand the clones of cells) 4. Self/non-self discrimination 17. Outline the functions of B- and T-lymphocytesB lymphocytes develop in the bone marrowThe precursors of T lymphocytes are also produced in the bone marrow but leave the bone marrowand mature in the thymus (which accounts for their designation).
PHSI2005 Immune SystemB cells (bursa-derived cells) and T cells (thymus cells) are the major cellular components of theadaptive immune response. B cells are primarily responsible for humoral immunity (relating toantibodies) whereas T cells are involved in cell-mediated immunity. The function of B cells and T cellsis to recognize specific “non-self” antigens, during a process known as antigen presentation. Oncethey have identified an invader, the cells generate specific responses that are tailored to maximallyeliminate specific pathogens or pathogen infected cells. B cells respond to pathogens by producinglarge quantities of antibodies which then neutralize foreign objects like bacteria and viruses. Inresponse to pathogens some T cells, called T helper cells, produce cytokines that direct the immuneresponse while other T cells, called cytotoxic T cells, produce toxic granules that contain powerfulenzymes which induce the death of pathogen infected cells. Following activation, B cells and T cellsleave a lasting legacy of the antigens they have encountered, in the form of memory cells.Throughout the lifetime of an animal these memory cells will “remember” each specific pathogenencountered, and are able to mount a strong and rapid response if the pathogen is detected againEach B cell and T cell is specific for a particular antigen. What this means is that each is able to bindto a particular molecular structure.Both BCRs (B cell receptors) and TCRs (T cell receptors) share these properties: They are integral membrane proteins. They are present in thousands of identical copies exposed at the cell surface They are made before the cell ever encounters an antigen. They are encoded by genes assembled by the recombination of segments of DNA They have a unique binding site. This site binds to a portion of the antigen called an antigenic determinant or epitope. The binding, like that between an enzyme and its substrate depends on complementarity of the surface of the receptor and the surface of the epitope. The binding occurs by non-covalent forces (again, like an enzyme binding to its substrate). Successful binding of the antigen receptor to the epitope, if accompanied by additional signals, results in: o stimulation of the cell to leave G0 and enter the cell cycle. o Repeated mitosis leads to the development of a clone of cells bearing the same antigen receptor; that is, a clone of cells of the identical specificity.BCRs and TCRs differ in: their structure; the genes that encode them; the type of epitope to which they bind. 18. Distinguish the roles of helper, suppressor/regulator and cytotoxic T-cellsHelper: immune cells that secrete cytokines to help other immune cells
PHSI2005 Immune SystemRegulator (formally suppressor): are crucial for the maintenance of immunological tolerance. Theirmajor role is to shut down T cell-mediated immunity toward the end of an immune reaction and tosuppress auto-reactive T cells that escaped the process of negative selection in the thymus.Cytotoxic: a lymphocyte that kills its target cells 19. Describe the mechanisms of antibody- and cell-mediated immune responses, including antigen processing and presentation, cell collaboration, cytokinesAntibody: a molecule keyed to a particular pathogen that helps target it for destruction.Antibodies are also called immunoglobulins, and this alternative name describes what the moleculesare: globular proteins that participate in the humoral immune response.Cell-mediated immunity: an immune response that does not involve antibodies but rather involvesthe activation of macrophages, natural killer cells (NK), antigen-specific cytotoxic T-lymphocytes, andthe release of various cytokines in response to an antigen. Cell-mediated immunity is directedprimarily at microbes that survive in phagocytes and microbes that infect non-phagocytic cells. It ismost effective in removing virus-infected cells, but also participates in defending against fungi,protozoans, cancers, and intracellular bacteria. It also plays a major role in transplant rejection.Antibodies are effective only against extracellular pathogens. Once a pathogen gets inside a hostcell, it can no longer be “seen” by the humoral immune system. Defending the body againstintracellular pathogens is the role of T lymphocytes, which carry out cell-mediated immunity. In thisprocess, T cells bind to cells that display foreign antigen fragments as part of a majorhistocompatibility complex (MHC) on their surface.Antigen processing is a biological process that prepares antigens for presentation the special cells, Tlymphocytes. This process involves two distinct pathways for processing of antigens from anorganisms own (self) proteins or intracellular pathogens (e.g. viruses), or from phagocytosedpathogens (e.g. bacteria); subsequent presentation of these antigens on class I or class II MHCmolecules is dependent on which pathway is used. Both MHC class I and II are required to bindantigen before they are stably expressed on a cell surface.Cytokines are small cell-signaling protein molecules that are secreted by numerous cells and are acategory of signaling molecules used extensively in intercellular communication 20. Compare and contrast defence mechanisms against bacteria and virusesWhen microorganisms— such as bacteria or viruses— invade the body, nonspecific defensemechanisms provide the first line of defense.These are the primary deterrents which ensure protection from numerous germs. There are physicaldeterrents (including the skin and nasal hairs), chemical deterrents (enzymes found in perspirationand saliva), and inflammatory reactions. These particular mechanisms are named appropriatelybecause their responses are not specific to any particular pathogen. Think of these as a perimeteralarm system on a house. No matter who trips the motion detectors, the alarm will sound.In cases where microorganisms get through the primary deterrents, there is a back-up system— thespecific defense mechanisms— which consists of two components: the humoral immune system andthe cell mediated immune system.
PHSI2005 Immune SystemThe humoral immune system protects against bacteria and viruses present in the fluids of the body.This system uses white blood cells, called B cells, which have the ability to recognize organisms thatdont belong to the body. In other words, if this isnt your house, get out! Intruders are referred to asantigens. B cells produce antibodies that recognize and bind to a specific antigen to identify it as aninvader that needs to be terminated.The cell mediated immune system protects against foreign organisms that have managed to infectbody cells. It also protects the body from itself by controlling cancerous cells. White blood cellsinvolved in cell mediated immunity are called T cells. Unlike B cells, T cells are actively involved withthe disposal of antigens. They make proteins called T cell receptors that help them recognize aspecific antigen. There are three classes of T cells that play specific roles in the destruction ofantigens: Cytotoxic T cells (which directly terminate antigens), Helper T cells (which precipitate theproduction of antibodies by B cells), and Suppressor T cells (which suppress the response of B cellsand other T cells). Differences b/w Bacteria and Viruses Bacteria VirusesStructure Cells. Usually surrounded by Not cells. Nucleic acid core with cell wall protein coatLiving Conditions Most can survive and Parasitic. Must have a host cell reproduce outside a host to reproduceSusceptibility to Drugs Most can be killed or inhibited Cannot be killed with by antibiotics antibiotics. Some can be inhibited with antiviral drugsThese differences require the body to have a variety of immune responses. 21. Describe immunological surveillance against tumours and transplantsThis theory proposes that cancerous cells develop on a regular basis, but they are detected anddestroyed before they can spread. Immune surveillance appears to recognise and control somevirus-associated tumours. In addition, some types of endogenous tumours lack surface antigens,which allows NK cells to recognise these cells as abnormal and destroy them. 22. Describe the breakdown of immunological tolerance in auto-immune diseaseSelf-tolerance: the lack of immune response by lymphocytes to cells of the body.This appears to be caused due to the elimination of self-reactive lymphocytes in a process known asclonal deletion. During development, some lymphocyte clones develop with antibodies that cancombine with MHC-self antigen complexes. The primary lymphoid tissues contain self antigens thatcan combine with these self-reactive lymphocytes and eliminate them by producing apoptosis.When self-tolerance fails, the body makes antibodies against its own components through T cell-activated B lymphocytes. The bodies attack on its own cells leads to autoimmune diseases. Theantibodies produced in autoimmune diseases are specific against a particular antigen and are usuallyrestricted to a particular organ or tissue type.
PHSI2005 Immune SystemIt is not known why self-tolerance suddenly fails but we have, however, learned that autoimmunediseases often begin in association with an infection. One particular trigger for autoimmune diseasesis foreign antigens that are similar to human antigens. When the body makes antibodies to theforeign antigen, those antibodies have enough cross-reactivity with human tissues to do somedamage.