HBI 014 Week 4 lecture immunology Final.pptx

HBI 014 FOUNDATION HUMAN BIOLOGY WEEK 4 LECTURES 1-3 IMMUNOLOGY  Non Specific Defences Against Infection Does not distinguish between infectious microbes Skin – major barrier made up of dead cells hat bacteria and viruses cannot penetrate Acids secreted by skin c...

HBI 014 FOUNDATION HUMAN BIOLOGY WEEK 4 LECTURES 1-3 IMMUNOLOGY  Non Specific Defences Against Infection Does not distinguish between infectious microbes Skin – major barrier made up of dead cells hat bacteria and viruses cannot penetrate Acids secreted by skin cells inhibit microbial growth Sweat, saliva and tears contain lysozyme that lyse bacterial cell walls  Two organ systems that open up to the external environment are The digestive and respiratory systems which are guarded by mucous membranes that line them Stomach acid kills most bacteria swallowed with food In the respiratory tract hairs in the nostrils filter incoming air and the mucus in the respiratory tubes traps microbes and dirt that get past the nasal filter Cilia on cells lining the tubes sweep mucus upward and out of the system Microbes that penetrate the skin or enter the tissues of the digestive or respiratory tract are confronted by non specific defensive cells  The white blood cells Found in the blood vessels as well as interstitial fluid Neutrophils and monocytes are phagocytic whites blood cells which engulf bacteria and viruses in infected tissues Macrophages (big eaters) develop from monocytes which wander actively in the interstitial fluid eating any bacteria or virus they meet Natural killer cells attack cancer cells and infected body cells especially those infected by viruses Other non specific defences include proteins that either attack microbes directly or impede their reproduction e.g interferon and complement proteins Interferons are produced by virus infected cells that help other cells resist viruses  Interferon Activity 1. Virus infects a cell 2. Turns on interferon genes in the cells nucleus 3. Cell makes interferon 4. Infected cell dies 5. Interferon diffuses to neighboring healthy cells 6. This stimulates the to produce proteins that inhibit virus reproduction This interferon activity is non virus specific – interferon made in response to one virus confers resistance to other viruses but this resistance is short term The body makes interferons in small amounts but through genetic engineering we can produce large amounts to treat viral infection including certain cancers  The Interferon Activity Mechanism Against Viruses Fig. 24.1B  Complement Proteins Complement Proteins are anti microbial proteins which circulate in inactive form in the blood plasma Named for their cooperative role with other defence mechanisms, they are activated by the immune system or microbes Some of these proteins (complement) coat the surfaces of microbes making them easier for macrophages to engulf Other complement cut lethal holes in microbial membranes They can also amplify another non specific defence – the inflammatory response  The Inflammatory Response mobilizes non specific defence forces It is a major component of our non specific defence system – any damage to tissue whether caused by microbes or physical injury or even just an insect bite, triggers this response The bite area becomes red, swollen and warmer than the surrounding area This reaction is inflammation which literally means “setting on fire”  Chain of events which make up the Inflammatory response In the figure below where a pin broken the skin and infected it with bacteria 1. damaged cells release chemical alarm signals called histamines 2. The chemicals mobilize various defences – histamines induces various blood vessels to dilate and become leakier. Blood flows into the damaged area increases and blood plasma passes out of the leaky vessels into the interstitial fluid of the affected tissues. Other chemicals attract phagocytes and other wbc’s to the area. Squeezing between cells of the blood vessel wall these wbc’s out of the blood and into tissue spaces. The local increase in blood flow, cells and fluid produces redness, heat and swelling the characteristics of inflammation. The major effect of the Inflammatory response are to disinfect and clean tissues  Chain of events which make up the Inflammatory response cont’d 3. The wbc’s present in the area engulf bacteria and remains of any body cells killed by them or physical injury Many wbc’s die in the process and their remains are also engulfed and digested The pus that often accumulates at the injury site mainly consists of dead wbc’s and fluid that has leaked from the capillaries during the Inflamm. Response which also helps prevents the spread of the infection to surrounding tissues  Role of Clotting Proteins Clotting proteins present in the blood plasma pass into the interstitial fluid during inflammation. Platelets together with clotting proteins form local clots that seal off the infected area and allow the repair of damaged tissues Healing now begins  Inflammatory Response Fig. 24.2  Other characteristics of the Inflammatory Response The IR can be localized (previous example) or widespread (systemic) Bacteria/Protozoans can get into the blood and release toxins that is carried through out the body by the blood stream and the body may react with one or several IR E.g. number of wbc’s in the blood may increase Fever – abnormally high body temp. Toxins may trigger the fever or wbc’s release chemicals that set the body’s thermostat at a higher temperature A very high fever may be dangerous but a moderate fever stimulate phagocytosis and inhibit microbial growth Effect of an overwhelming systemic IF response Sometimes an overwhelming systemic inflammatory response leads to a condition known as septic shock – high fever, low blood pressure and is the most common cause of death in Intensive Care Units Therefore localized IF response is an essential step to healing, systemic IF response can be deadly  The Lymphatic system Has 2 main functions : 1. Return tissue fluid to the circulatory system 2. Fight infection Involved in both non specific and specific defence system Consists of a branching net work of vessels, b. numerous lymph nodes (sac like organs packed with wbc’s called lymphocytes) c. tonsils d. adenoids e. appendix f. spleen It also includes the bone marrow and thymus where white blood cells develop  The Lymphatic system cont’d The lymphatic vessels carry a fluid called lymph which is similar to interstitial fluid but contains less oxygen and fewer nutrients A small amount of fluid that enters the tissues from the blood does not re-enter the blood capillaries, instead it is returned to the circulatory system via the lymphatic vessels  The Human Lymphatic System figure The enlargement of fig.24.3A shows a branched lymphatic vessel taking up fluid from tissue spaces in the skin. As shown here, fluid enters the lymphatic system by diffusing into tiny dead end lymphatic capillaries that inter mingle with blood capillaries Lymph drains from the lymphatic capillaries into larger lymphatic vessels. It re-enters the circulatory system via two large lymphatic vessels (thoracic duct, right lymphatic duct) which fuse with veins in the shoulders Lymphatic vessels resemble veins in that they have valves and depend mainly on movement of skeletal muscles to squeeze fluid along  The Human Lymphatic System Fig. 24.3A  Infection Fighting Activities of the Lymphatic System Occurs in the lymph nodes and other lymphatic organs Lymph nodes are packed with lymphocytes (smaller cells) and macrophages (larger cells) Lymph circulates through the lymphatic organs carrying microbes from infection sites in the body and sometimes cancer cells In the lymphatic organs macrophages engulf microbes in a non specific way whereas lymphocytes are activated to mount a specific response to microbes  SPECIFIC IMMUNITY When our non specific defence fail to remove an infectious agent, the immune system provides another line of defence The immune system recognizes and defends against invading microbes and cancer cells (the body indentifies them as foreign) Acts more effectively than non specific resistance and can amplify certain non specific responses such as inflammation and complement reaction Difference between non specific and Specific immune response Non specific responses are always ready to fight a variety of infections but the immune system must be primed by the presence of a foreign substance called antigens When the immune system detects an antigen it responds with an increase in the number of cells that either attack the invader directly or produce defensive proteins called antibodies Antibodies produced against that antigen are usually ineffective against any other foreign substance What are Antigens and Antibodies ? Any molecule that elicits an immune response They include certain molecules on surfaces of viruses, bacteria, mold spores, cancer cells, pollen and house dust as well as antigens on cell surfaces of transplanted organs. An antibody is a protein found in blood plasma that attaches to a particular type of antigen and helps counter its effects The immune system is extremely specific and has a remarkable memory It can remember antigens it has encountered before and react against them quickly on second an subsequent exposures E.g – if someone gets rubella (German measles) the immune system remembers certain molecules on the virus that causes rubella Thus the person is immune to re-infection because the immune system will recognize and destroy the rubella virus before it can produce symptoms of the disease The immune response unlike non specific defences is adaptive : exposure to a particular foreign agent will enhance future responses to that same agent  IMMUNITY Refers to responses to specific invaders Usually acquired through natural infection but can also be by vaccination During vaccination the immune system is exposed to a vaccine composed of a harmless variant (form) of the pathogenic microbe which stimulates the immune system to mount defences against this variant. These defences will also be affective against the actual pathogen because it has similar antigens Vaccines are effective against viral disease such as small pox, polio, mumps and measles  ACTIVE vs PASSIVE IMMUNITY Whether antigens enter your body naturally (you catch the flu) or artificially (flu shot vaccine) the resulting immunity is called active immunity because the body is stimulated to produce antibodies Passive immunity – e.g a foetus obtains antibodies from the mother’s blood stream or travellers get a shot containing antibodies to pathogens they are likely to encounter (comp. to vaccine). Both foetus and traveller have acquired antibodies passively. Passive immunity is temporary because the immune system was not stimulated by antigens. Antibodies remain effective for only a few weeks or months  LYMPHOCYTES MOUNT A DUAL DEFENCE – HUMORAL AND CELL MEDIATED IMMUNITY Lymphocytes, wbc’s that spend most of their time in tissues and organs of the lymphatic system, produce the immune response Like all blood cells they originate in the stem cells in the bone marrow. Some immature lymphocytes continue developing in the bone marrow and become specialized as B lymphocytes or B cells Other immature lymphocytes are carried by the blood to the thymus where they specialize as T lymphocytes or T cells Both T cells and B cells eventually end up in the lymph nodes and other lymphatic organs via the blood. Dual defence – B cells secrete antibodies and dissolve in the blood and immunity by B cells is called humoral immunity which defends primarily against bacteria and viruses in body fluids B cells are carried to sites of infection by blood and lymph Humoral immunity can be transferred by injection of blood plasma (containing antibodies) from an immune person to a non immune person  CELL MEDIATED IMMUNTY Second type of immunity – Cell Mediated Immunity produced by T cells Cannot by passively transferred with plasma but only by giving actual T cells from an immune individual to a non immune individual T cells circulate in the blood and lymph and attack body cells that have been infected by bacteria or viruses. T cells work against infections by fungi and protozoa and important in protecting the body from its own cells if they become cancerous T cells also function indirectly by promoting phagocytosis by other wbc’s and by stimulating B cells to produce antibodies, thus T cells are involved in both Humoral and Cell mediated immunity  Development of B cells and T cells Fig. 24.5  B cell and T cell Development When a T cell develops in the thymus or a B cell develops in the bone marrow , certain genes in the cell are activated The cells synthesizes a specific protein and build them into its plasma membrane which stick out from the cell surface These molecules are antigen receptors capable of binding on to one specific type of antigen For B cells, the receptors are actually molecules of a particular antibody that the B cell will secrete Once a B cell or T cell has its surface proteins in place it can recognize a specific antigen and mount a response to it One cell may recognize an antigen on the mumps virus while another detects a particular antigen on the tetanus causing bacterium  B cell and T cell Development We see in the figure 24.5 that after the B cells and T cells have developed their antigen receptors they leave the bone marrow and thymus and move via the blood stream to the lymph nodes, spleen and other parts of the lymphatic system In these organs many B cells and T cells remain and meet infectious agents which have penetrated the bodies outer defence Lymphatic capillaries extend into all tissues of the body (fig.24.3A) bacteria or viruses eventually enter the lymph and are carried to the lymphatic organs When a mature B cell or T cell within a lymphatic organ first encounters the specific antigen it is programmed to recognize it differentiates further and becomes a fully mature component of the immune system  Diversity of B cells and T cells There is an enormous diversity of B cells and T cells in each individual There are between 100 million to 100 billion different kinds – enough to recognize and bind virtually any kind of antigen we will meet A small population of each kind of lymphocyte lies in wait in our body genetically programmed to recognize and respond to a specific antigen A key feature of our immune system is t is prepared for almost unlimited variety of potentially harmful antigens  Antigens specific regions for antibody binding Because they elicit an immune response they do not belong to the host animal Most antigens are proteins or polysaccharrides on the surface of viruses or foreign cells e.g capsids of viruses, parts of the cell wall or capsule of bacteria macromolecules on the cell surface of other organisms such as protozoa and parasitic worms Blood cells or tissue cells from other individuals can also provide antigenic molecules In figure 24.6 antibodies usually identify localized regions called antigenic determinants on the surface of the antigen molecule Antigen-binding site a specific region on the antibody molecule recognizes the antigenic determinant by the fact that the binding site and antigenic determinant have complementary shapes Antigens may have several different determinants so different antibodies may bind to the same antigen – therefore a single antigen may stimulate the immune system to make several distinct antibodies against it  The binding of antibodies to antigenic determinants Fig 24.6  B cell Clonal Selection against specific antigens The immune system’s ability to defend against almost infinite variety of antigens depends on a process called Clonal Selection When an antigen is first introduced into the body it activates only a tiny number of lymphocytes. These selected cells then proliferate forming a clone of cells (a population of genetically identical B cells or T cells) that are specific for the stimulating antigen In fig. 24.7 the row of cells at the top represents a diverse population ob b cells in the lymph node Each B cell has a specific type of antigen receptor embedded in its surface which they have in place before they ever encounter an antigen The surface of the cell has about 100,000 copies of its particular receptor Because the cells in the figure are B cells , the receptors are antibody molecules Once the antigen enters the body, it is swept into the lymph node and binds with receptors that fit it Binding of the antigen activates the lymphocyte Primed by the interaction with the antigen, the selected cell grows and divides and differentiate further resulting in a clone of effector cells specialized in defending against the very antigen that triggered the response The effector cells secrete antibodies all of the same type with large ER a characteristic of cells actively synthesizing and secreting proteins  Clonal Selection of B cells Fig. 24.7  Clonal Selection of T cells The same kind of clonal selection mechanism operates on T cells to produce ones that carry out Cell Mediated immunity and help Humoral immunity The versatility of the immune system -its ability to defend against a virtually unlimited variety of antigens depends on the diversity of pre-existing lymphocytes with different antigen receptors The Initial Immune Response (Primary Immune Response) Results in a Type of Memory The immune system can mount an effective response the first time it encounters a antigen but it takes 2 exposures to elicit the strongest response. As indicated by the blue curve in fig 24.8A, the 2 exposures trigger 2 distinct phases of immune response. The initial phase is called the Primary Immune Response, occurs when the lymphocytes are first exposed to an antigen and form a clone of effector cells. On the far left of the graph you see the primary response does not start right away; it usually takes several days for the lymphocytes to become activated by an antigen (X) and form a clone of effector cells. When the effector cell clone forms, antibodies start showing up in the blood as shown in the graph. The antibody level is highest about 2 weeks after initial exposure Immunological Memory  Secondary Immune Response After the primary immune response, a second exposure to the same antigen elicits a faster and stronger response called the Secondary Immune Response. In the case of humoral immunity ( the antibody response) the secondary response produces very high levels of antibodies that are often more effective against the antigen than those produced during the primary response. The secondary response also lasts much longer than the primary response The red curve in fig. 24.8A illustrates the specificity of the immune response. If the body is exposed to a different antigen (Y), even after it has responded to antigen X , it responds with another primary response, this one directed against antigen Y. The response to Y is not enhanced by response to X  CELLULAR BASIS OF IMMUNOLOGICAL MEMORY Fig.24.8B Each exposure to the antigen triggers a clonal selection , resulting in a clone of lymphocytes. The cell of each clone, while all identical fall into 2 sets Effector cells and memory cells which differ from effector cells in both appearance and function. During Primary response the effector cells of the clone combat the antigen by producing antibodies if they are B cells. These effector cells usually survive only a few days. In contrast the memory cells of the clone may last for decades. They remain in the in the lymph nodes ready to be activated by a second exposure to the antigen When this happens the memory cells initiate a secondary immune response. They multiply quickly producing a large new clone of lymphocytes that make the secondary response. Like the first clone, the second clone includes effector cells that produce antibodies that actually produce the antibodies of the secondary response and the memory cells capable of responding to future exposures to the antigen. In some cases, the memory cells seem to confer lifetime immunity as in mumps or measles  Cellular Basis of Immunological Memory Fig. 24.8B  Overview : B cells are the main warriors of Humoral Immunity By connecting the concepts of clonal selection and immunological memory we can obtain an over view of our “defensive machine” we call Humoral immunity and B cells are the main warriors of this machine. Starting with the first encounter between an antigen and a collection of B cells fig.24.9 summarizes the primary and secondary responses in humoral immunity – the B cell is first selected by the antigen. In the first step surface receptors (specific antibodies) on the B cell surface bind with antigen molecules (antigenic determinants on the antigen surface) This binding triggers the growth, division and further differentiation of the selected B cell. The resulting clone contains many effector B cells called plasma cells, and a smaller number of memory B cells The plasma cells secrete antibody molecules completing the primary response. Plasma molecules may secrete up to 2,000 antibody molecules per second for their brief lifetime of 4-5 days These antibodies circulate in the blood and lymphatic fluid binding to antigens and contributing to their destruction or blocking their harmful effects. This primary response subsides as plasma cells die out An over view of Humoral Immunity Overview : B cells are the main warriors of Humoral Immunity cont’d In a sense the B cells are “reservists of Humoral Immunity”rather than actively combating antigens, they await future exposure to antigens. The Secondary response in humoral immunity can only occur if these cells contact the same antigen that triggered their production perhaps years later. If this contact does occur, the events at the bottom of the fig. is set in motion. The memory cells bind antigens and stimulated quickly to produce large new clones of cells. The cloning process is the same as in the primary response, but it occurs more rapidly and produces more plasma cells. The antibody level in the blood and lymph are much higher than during a Primary Immune Response  Antibodies are the weapon of Humoral Immunity Antibodies are proteins that serve as weapons and shaped like a Y  Antibodies are the weapon of Humoral Immunity Each Antibody is made up of 4 polypeptide chains 2 “heavy chains” and 2 “light “ chains The heavy chains of amino acids give the molecule its Y shape Bonds at the fork of the Y hold these chains together The shorter chains are the light chains of amino acids An antibody has 2 related functions in humoral immunity - to recognize and bind to a certain antigen and in doing so it assists in neutralizing it The structure allows it to do these functions. In fig 24.10B each of the 4 chains has a “C” (constant) region and a “V” (variable) region At the tip of each arm of the Y, a pair of V regions form the antigen binding site, a region of the molecule responsible for the molecule’s recognition and binding function A huge variety of shapes of the binding sites of different antibody molecules arises from a similarly variety of amino acid sequences in the in the V regions hence the term variable This structural variety gives the humoral immune system the ability to react to virtually any kind of antigen The tail of the antibody (C regions of the heavy chains) help mediate the disposal of the bound antigen. Antibodies with different kinds of C regions are grouped into different classes Humans and other mammals have 5 major classes of antibodies and each has a role in humoral immunity - one may function in the primary response and another comes into play in the secondary response. Question : How is the specificity of an antibody for an antigen analogous to enzyme specificity for its substrate ?  How Antibodies Mark Antigens for Elimination The man role of ab’s in eliminating invading microbes or molecules is to mark invaders. An antibody combines with the antigen to form an ab/ag complex, with weak chemical bonds between the antigen molecule and the ag binding site on the ab holds the complex together In fig. 24.11 - it is the binding of the abs to ags that that triggers the mechanisms to neutralize or destroy the invader – effector mechanism. Several Effector mechanisms are shown in the figure below How Antibodies Mark Antigens for Elimination cont’d 1. Neutralization : the binding of the abs physically blocks harmful ags making them harmless – abs may bind the surface molecule a virus uses to attach to a host cell. Abs may also bind toxin molecules on bacterial cells. Phagocytes such as Macrophages then dispose of the complexes. 2. Agglutination (clumping together): of viruses, bacteria or foreign eukaryotic cells. Because each ab has 2 binding sites, abs can hols a clump of invading cells together. Agglutination makes the invading cells easy to capture by pahgocytes 3. Precipitation : similar to agglutination except ab molecules link dissolved antigen molecules together and precipitate out of the solution as solids. The precipitated ags like clumps of agglutinated cells are easily engulfed by phagocytes 4. Complement Activation - One of the most important effector mechanisms in humoral immunity is the activation complement proteins by ab/ag complexes. Activated complement proteins can attach to a foreign cell and open holes in its plasma membrane, causing cell lysis and death As a whole the effector mechanisms involve specific recognition and attack phase, followed by a non specific destruction phase. Thus the abs of the humoral immune system which identify and bind foreign invaders work with the non specific defence such as 1. ? 2. ?  Monoclonal Antibodies Because of their ability to tag specific molecules or cells antibodies are widely used in research and clinical testing In the original procedure in preparing antibodies a small sample of antigen was injected into a rabbit or mouse. In response the animal response to the antigen, the animal produced antibodies which was collected from the blood. However, because the antigen usually had many antigenic determinants, the result is a mixture of many different antibodies instead of a pure preparation of one type. To make a large amount of antibody this way , many animals had to be used In the 1970’s a technique for making monoclonal antibodies was developed Monoclonal means that all the cells producing the antibodies are descendants of a single cell – they all produce identical antibody molecules monoclonal antibodies are harvested from cell cultures rather than from animals Fig. 24.12A Procedure for making monoclonal antibodies  Monoclonal Antibodies The trick in making monoclonal antibodies is the fusion of 2 cells to form a hybrid with a combination of desirable properties 1. The animal is injected with antigen that will stimulate B cells that will make the desired antibody at the same time cancerous cells are grown in a culture 2. Tumor cells then fuse with normal antibody B cell producing cell from the animal 3. The hybrid cell makes antibody molecules specific for a single antigenic determinant and is able to multiply indefinitely in a laboratory dish Large amounts of identical antibody molecules can be produced this way Applications : because of its specificity monoclonal antibodies may bind with bacteria that cause STI’s or with hormones that indicate pregnancy How ? The antibodies have been labelled by a dye and will revel the presence of the bacteria or hormone  More Applications of Monoclonal Antibodies Can be used in treatment of certain cancers – Herceptin, a genetically engineered monoclonal antibody is used for treating aggressive breast cancer Herceptin antibody molecules bind to growth-factor receptors that that are present in excess on cancer cells Thus they prevent the receptors from transmitting “grow” signals to the cells. In the future, some cancers may be treated by cancer- specific monoonal antibody attached to a cell –killing drug An effective antibody-drug combination would act like a molecular guided missile, killing only the targeted cancer cells  T cells mount the Cell Mediated Defence and aid Humoral Immunity The humoral defence system identifies and helps destroy invaders that are in the blood, lymph or interstitial fluid - outside our body cells. But many invaders including viruses enter cells and replicate in there It is the Cell Mediated Immunity produced by T cells that battles pathogens that have already entered the body cells Whereas B cells battle antigens present in the fluids, T cells only respond to antigens on he surfaces of the body’s own cells There are two types of T cells Cytotoxic T cells – attack body cells infected by pathogens Helper T cells – help to activate Cytotoxic T cells and macrophages and even help stimulate B cells to produce antibodies Helper T cells interact with other wbc’s – macrophages and B cells that function as Antigen Presenting Cells (APC’s) All of the CMI and much of the HI depend on the precise interaction of T helper cells and APC’s. This interaction activates T helper cells which then go to activate other cells of the immune system Fig. 24.13A Development of an APC and it’s interaction with a T helper cell  Antigen Presenting Cells (APC’s) APC’s presents a foreign antigen to Helper T cells Fig. 24.13A 1. Macrophage ingests a microbe (or other foreign object) and breaks it into pieces – foreign antigens Molecules of a special protein belonging to the macrophage (called self protein) 2. bind the foreign antigens (non self molecules) and 3. Display them on the cell’s surface. Each of us has a unique set of self proteins which serve as identity markers for our body cells 4. Helper T cells recognize and bind to the combination of self protein-foreign antigen displayed on the APC The ability of helper T cells to recognize a unique self-non self complex depends on the APC depend on the T cell receptors embedded in the T cells plasma membrane T cells receptors actually has 2 binding sites one for the antigen and one for the self protein The 2 binding sites enable a T cell receptor to recognize the overall shape of the self-non self complex on an APC The binding of of a T cell receptor to a self-non self complex triggers a signal – transduction pathway that activates the helper T cell. Several other kinds of signals can enhance this activation. For example certain proteins secreted by the APC such as Interlukin – 1 diffuse to the helper T cells and stimulate it  What do Helper T cells do ? T helper cells promote the immune response in several ways, with a major mechanism secretion of additional stimulatory proteins, one such protein Interlukin – 2 has 3 major effects 1. It makes the T helper cell itself grow ad divide – producing both memory cells and additional active T helper cells. This positive feedback loop amplifies the CMI defences against the antigen at hand 2. IL-2 stimulates the activity of Cytotoxic T cells 3. It helps activate B cells, thus stimulating HI as well Cytotoxic T cells are the only T cells that actually kill other cells. Infected body cells are important targets. Once activated Cytotoxic T cells can identify the infected cells the same way that T helper cells identify APC’s An infected cell has foreign antigens attached to self proteins on its surface. Like helper T cells a Cytotoxic T cell carries receptors that can bind with self-nonself complex on the infected cell The self-non self complex on an infected body cell is like a red flag to Cytotoxic T cells that have matching receptors. As shown in fig. 24.13C  Fig. 24.13C 1. Cytotoxic T cell binds to the infected cell. The binding initiates signal transduction pathway that activate the T cell, which then synthesizes several new proteins including Perforin 2. Perforin is discharged and attaches to the infected cell’s membrane making holes in it. Another T cell protein enters the infected cell and triggers a process called “Programmed Cell Death” 3. The infected cell dies and it is destroyed  Cytotoxic T cells may help Prevent Cancer People with immune deficiencies are often prone to cancer, a fact suggesting that the immune system plays a watchdog role against at least some forms of cancer During genetic changes that lead to cancer, changes occur in the normal body cells and some of these changes take place on the outer membrane surfaces of cells. Changes to the surface molecules occur in such a way that the cell mediated immune system identifies the cancer cells as foreign intruders and attract Cytotoxic T cells to destroy them  Cytotoxic T cells may help prevent Cancer cont’d Fig.24.14 shows Cytotoxic T Cells attacking a tumor cell in lab culture but this may also occur in the body Cytotoxic T cells may attack and kill cancer cells where ever they may appear It is still unknown why this built in surveillance sometimes fails allowing tumors to develop Some Scientists suggest that tumors develop when cancer cells shed the surface molecules that mark them as foreign or when cacer cells evade the immune system  The immune system depends on our molecular fingerprints Our immune system has the ability to recognize the body’s own molecules –that is to distinguish self from non self, allowing it to battle foreign molecules and cells without harming healthy body cells. Self proteins on surfaces are the keys to this ability Each person’s cells have a particular collection of self proteins that provide the molecular “fingerprints” recognized by the immune system Each of us has 2 sets of self proteins on the surfaces of our cells Class I proteins occur on all nucleated cells in the body Class II proteins are found on only a few types of cells, including B cells , Activated T cells and Macrophages The particular collections of proteins in the 2 sets of cells are specific to the individual in whom they are found, marking the body cells as “off limits” to the immune system. Our lymphocytes do not attack these molecules  The immune system depends on our molecular fingerprints cont’d The immune system not only distinguishes body cells from microbes but also can tell your cells from those of other people Genes at 6 chromosomal loci determine the structure of the main self proteins – thus in diploid cells there are 12 genes in all. Because there are hundreds of alleles in the human population for each of the gene loci, it is virtually impossible for any 2 people (except for identical twins) to have completely matching set of self proteins The immune system’s ability to recognize foreign antigens does not always work out in our favour E.g. When a person receives an organ transplant, the person’s immune system recognizes the donor’s cells as foreign and attack them. For this reason the group of self proteins genes is called “Major Histocompatability Complex” or MHC To minimize rejection the doctors look for donors with self proteins matching the recipient as closely as possible and they use drugs to suppress the immune response to the transplant  The immune system depends on our molecular fingerprints cont’d Unfortunately these drugs may also reduce the ability to fight infections However a few like Cyclosporine can suppress Cell Mediated Responses without crippling the Humoral Immunty There are 2 promising approaches to prevent transplant rejection 1. using monclonal antibodies as guided missiles to target and destroy the T cells that attack the transplant Use of stem cells to establish a new immune system that recognizes the transplant as self  Malfunction or Failure of the Immune System cause Disease Autoimmune Disease Results when the immune system turns against the body’s own molecules In systemic lupus erythematosus (lupus) for example B cells make antibodies against many sorts of molecules including DNA released by the normal breakdown of body cells Rheumatoid arthritis is another antibody mediated auto immune disease leading to damage and painful inflammation of the cartilage and bone of joints Insulin dependent diabetes – the insulin producing cells of the pancreas are targets of the autoimmune cell mediated responses In multiple sclerosis (MS) the most common neurological disease in developed countries T cells react against myelin, a protein that insulates the axons of neurons and destroy the function of neurons in the spinal cord  Malfunction or Failure of the Immune System cause Disease Most medicines currently available for treating auto immune diseases either suppress immunity in general or are limited to alleviation of specific symptoms Immunodeficiency Disease in contrast are a variety of defects in which immuno-deficient people lack one or more components of the immune system and as a result are susceptible to infections that would ordinarily not cause a problem. In the rare congenital disease called severe combined immuno deficiency (SCID), both B cells and T cells are inactive and people with SCID are extremely sensitive to even minor infections. Their only hope for survival was to live behind protective barriers or receive successful bone marrow transplant that would supply functional lymphocytes Immunodeficiency is not always an inborn condition – Hodgkin’s Disease, a type of cancer affects lymphocytes and depress the immnue system. Radiation therapy and drug treatments used against many cancers may have the same effect  Effects of Physical and Emotional Stress Physical and emotional stress can also weaken both the immune system and non specific defences In a study students were studied just after vacation and then again during and exams – their Natural Killer cells were less effective and interferon levels were low How does stress affect our immune system ? Nerve fibres penetrate the organs that produce lymphocytes and lymphocytes have receptors for chemicals secreted by nerve cells.  Allergies are over reactions to certain environmental triggers Allergies are abnormal sensitivities to antigens in our surroundings. Antigens that cause allergies are called allergens. Protein molecules on Pollen Proteins on the surface of tiny mites that live in house dust Animal dander are common allergens People who are allergic to cats and dogs are allergic to proteins in their saliva They become sensitized to salivary proteins deposited on the fur when the animal licks itself. Allergic reactions occur very rapidly and to tiny amounts of allergens Allergic reaction can occur in different parts of the body including nasal passage, bronchi, digestive tract and skin. Symptoms include sneezing, coughing, upset stomach and itching The symptoms of an allergy result from a 2 stage reaction sequence in fig.24.17  Two stages of the Allergic reaction The first stage is called sensitization occurs when the person is first exposed an allergen – e.g pollen The B cells makes a special class of antibodies in response. Some of these antibodies attach to receptor proteins on the surfaces of mast cells , normal body cells that produce histamine and other chemicals that trigger the inflammatory response. In this example mast cells are in the nose Second stage : begins when the person is exposed to the same antigen later Allergen binds to the antibodies attached to the mast cells causing the cells to release histamine, which triggers the allergic symptoms As in the Inflammatory response it causes blood vessels to dilate and leak fluid. Histamine also elicits other symptoms such as nasal irritation, itchy skin and tears Antihistamines – are drugs that interfere with histamines reaction giving temporary relief Fig. 24.17  SEVERE ALLERGIC REACTION Allergies range from seasonal nuisances to severe, life threatening responses. Anaphylactic Shock : an especially dangerous type of allergic reaction Some people are extremely sensitive to certain allergens such as the venom from a bee sting. Any contact with these allergens makes their mast cells release inflammatory chemicals very suddenly As a result, their blood vessels dilate abruptly, causing a precipitous drop in blood pressure (shock) which is potentially fatal. Fortunately, anaphylactic shock can be counteracted with injections of the hormone epinephrine Exercise The binding of ___________ to _________ on the surface of a ________ cell causes that cell to release a molecule called __________, which stimulate fluid los from blood vessels  AIDS leaves the body defenceless HIV is deadly because it destroys the immune system leaving the body defenceless against most invaders HIV can infect a variety of cells but it prefers T helper cells (cells that activate other T cells and B cells) When HIV depletes the body of T helper cells, the body cannot carry out CMI or HI responses. Death usually results not from AIDS but from another infectious agent or cancer Treatment – usually a combination of drugs which combat the virus in many different ways making it hard for drug resistant strains to arise – a problem with single drug treatment Multi drug combinations are usually complicated and expensive affordable only to richer countries. Some patients cannot tolerate the side effects of the drugs Research options include injecting patients with HIV resistant stem cells that could give rise to HIV resistant T cells. Challenge – HIV continually mutates to new forms, a single infected person may have different strains of the virus