oO oO Cc oO Chapter 1: Overview ofthe immune System [—¢ | ie The Clonal Selection Theory * As mentioned above, T and B lymphocytes recognize antigen by very specific c receptors present on their surface. Every naive lymphocyte has a single type of receptor of certain specificity. ( ‘* Only those lymphocytes which meet the antigen vihich their receptors recognize will undergo activation, proliferation and differentiation * The result is @ clone (family) of identical daughter cells, all having identical receptors, which can bind the same antigen wherever they find it. Thus, antigen specificity is maintained in the daughter cells. P The clonal selection theory is so-called because a certain clone of cells is selected from the pool of naive lymphocytes. ‘* Lymphocytes having receptors specific for self molecules (a person's own molecules) are normally deleted at an early stage in lymphoid cell development and are, therefore, absent from the pool of mature lymphocytes. Effector Mechanisms of Acquired Immunity These are the mechanisms by which pathogens are detected and destroyed in a Successful acquired immune response. It is very important to remember that different ( pathogens have different lifestyles and, therefore, need different mechanisms for detection, recognition and destruction: * Bells recognize antigen outside cells, where most bacteria are found. a * T-cells can detect antigens generated inside the cell, as those belonging to viruses oO or intracellular bacteria. |. Effector Mechanisms of Antibodies Antibodies work mainly to eliminate extracellular pathogens and their toxins. Antibodies are found in plasma and extracellular fluids. Immunity mediated by antibodies is called humoral immunity. It is so-called because body fluids were ‘once known as humors. Oo In general, when antibodies bind to pathogens, they help in combating infection in : many ways. They may block access of the pathogen to body cells. They may also oO start a process which eventually leads to lysis of the pathogen. All pathogens bound by antibody are eventually delivered to phagocytes for ingestion, degradation and C removal from the body. Il. Effector Mechanisms of T Cells ) Pathogens are accessible to antibodies only in the blood and extracellular spaces. 7 However, all viruses and some bacteria and parasites replicate inside cells, where they cannot be detected by antibodies. The destruction of these invaders is the function of the T lymphocytes. This is called cell-mediated immunity. In addition, T cells offer important help to B cells. The functions of T cells may be summarized as follows:Chapter 1: Overview of the Immune System 1, Cytotoxic T (Tc) cells ‘These recognize body cells infected with virus. Antigens from replicating viruses are displayed on the surface of infected cells, where they are recognized by the cytotoxic T cells. These cells directly kill the infected cells before viral replication is complete and new viruses are released to infect other cells. Tumour cells also carry abnormal antigens on their surface and are also killed by Tc cells. 2. Helper T (Th) cells The function of these cells is mainly production of cytokines. There are two main kinds of helper T cells, grouped according to the type of cytokines they produce and the main cells they help’ a-T helper 4 (Tht) cells These cells mainly secrete cytokines which help in activation of macrophages. This means making macrophages more capable of killing any bacteria inside them. This is very important because some bacteria, such as M. tuberculosis, after being ingested by macrophages, resist digestion and can survive for a long time inside. b- T helper 2 (Th2) cells These cells play a very important role in destruction of extracellular pathogens. They secrete certain cytokines which help in activation of B cells, so that they can become plasma cells and produce antibodies to deal with those pathogens. It is important to remember that the decision whether Te cells or Th cells are activated is not something which occurs by chance, but is decided by the type of pathogen and its lifestyle. The result is that the type of immune response which occurs is exactly suitable for combating that particular infection (see chapter 4). Harmful Immune Responses The work of the immune system is usually of benefit to the body, as in elimination of infections or in dealing with tumour cells. On the other hand, some immune responses may be harmful. Many medically important diseases are associated with such immune responses: © Allergy: inappropriate immune response against harmless antigens. © Autoimmune diseases: immune response against the person's own antigens. © Graft rejection: immune response against foreign tissues or organs transplanted ina person. In all the above conditions, the immune response causes harm, not benefit. Thus, whether we consider an immune response harmful or beneficial depends not only on the response itself, but also on the nature of the antigen Even during a beneficial immune response against a pathogen, some tissue damage may occur due to the immune response.Chapter 1: Overview of the Immune System aa Failure of Host Defence Mechanisms. C In some cases, a certain aspect or aspects of the immune system are deficient and the immune system is unable to free our body of infections, This is known as ¢ immunodeficiency. In very severe immunodeficiency diseases, adaptive immunity is r completely eliminated and death occurs early in life. In less severe failures, there are specific recurrent infections. AIDS is a disease in which a virus infects T helper cells , and destroys them. The person suffers from infections in which T helper cells normally play an important role in defence. Manipulation of the Immune System - At present, the usual way to treat unwanted immune responses (allergy, autoimmune diseases and graft rejection) is by immunosuppressant drugs, which inhibit all immune responses, both destructive and beneficial. If, instead, it were possible to suppress only those lymphocytes responsible for unwanted (bad) responses, the disease would be cured without affecting protective (good) immune responses. This dream of antigen-specific immunosuppression is the subject of much research but has not been very successful til now. - On the other hand, antigen-specific immunostimulation (stimulating the immune system against a particular antigen or group of antigens) has been more successful. This is done through vaccination, which involves introduction of pathogens or parts of them, in a harmless form, into the body, in order to stimulate the immune system to produce an immune response to that particular pathogen. The result is that when the person is later exposed to the same pathogen in its harmful form, he/she is ready to combat that infection because of immunological memory. McQ: 1- Regarding innate immunity, all of the following is true EXCEPT: - a: Its present in all individuals since birth and at all times. ‘ b- Itis important at the beginning of infection, c It cannot tell the difference between pathogens. ) d- It always eliminates infectious organisms successfully, - It involves mainly granulocytes. 2- Which of the following has an important role in parasitic infections? a- Neutrophils b- Mast cells - Eosinophils d- Monocytes : e- Lymphocytes acChapter 1: Overview of the Immune System Freer Which of the following is a primary lymphoid organ: @- Bone marrow b> Lymph nodes c- Spleen d- Tonsil & Peyer's patches Naive lymphocytes are: a+ Immature lymphocytes b- Present only in the bone marrow and thymus Responsible for immunological memory + Mature lymphocytes that have been activated by specific antigens &- Mature lymphocytes that have not yet met antigen Which statement about clonal selection theory is Correct: a- Every naive lymphocyte has many types of receptors. b+ Aclone of cells can recognize different antigens. - Only lymphocytes which meet antigens they recognize are activated. + The T cell receptor has 2 antigen recognition sites, The B cell receptor cannot recognize an antigen directly. + Comparing BCR and TCR, which statement is TRUE? a- The B and T cell receptors become released into the surroundings. b- In contrast to BCR, TCR has 2 antigen binding sites. c- Both are cell surface molecules. d- Both molecules cooperate in innate immune mechanisms. e- They bind to antigens non-specifically.Chapter 2: Innate Immunity 40. INNATE IMMUNITY ILOs: By the end of this chapter the student should be able to: Describe mechanisms of innate immunity Describe the innate cellular defence mechanisms Define phagocytosis Define opsonization Describe different steps of phagocytosis, Describe methods of killing in phagocytosis Describe inflammation Any individual is protected from potentially harmful microorganisms in the environment by a number of very effective mechanisms present since birth. They do not depend upon prior exposure to any particular microorganism. They are non- specific and can act against any microorganism or foreign invader. Mechanisms of Innate Immunity |. Mechanical barriers and surface secretions 1. Intact skin and mucous membranes constitute a barrier that cannot be penetrated by most microorganisms, 2. The sticky mucus covering mucous membranes traps any foreign material. 3. Cilia of the respiratory tract epithelium sweep foreign material out. 4. Blinking, sneezing and coughing reflexes expel foreign particles. 5. The flushing action of saliva, tears and urine helps in washing microbes from the body. 6. Sweat and sebaceous secretions contain substances (e.g. lactic acid and ammonia) that inhibit microorganisms. 7. Saliva, tears and mucous secretions of respiratory, alimentary and genitourinary tracts contain lysozyme which is bactericidal. 8. Gastric and vaginal acidity inhibit growth of microorganisms. I. Normal bacterial flora 1. Bacteria of the normal flora produce bacteriocins and acids that destroy microorganisms. 2. They compete with pathogens for essential nutrients, N.B.: Suppression of normal flora by antibiotics mey lead to infection with potential pathogens (superinfection), aon aOo (Chapter 2: Innate Immunity an 4 Ill, Soluble defence factors A number of microbicidal substances are present in tissues and body fluids and act in -) defence against microbes. They include: 4. Lysozyme: It is an enzyme that lyses bacteria by destroying the peptidoglycan of their cell wall. mi 2. Complement: It is a group of plasma proteins that act together to attack extracellular pathogens. The complement components are present in an inactive ~ form, and can be activated either spontaneously by certain pathogens (where it is considered to be part of innate immunity) or by antibody binding to the pathogen 5 (where it is considered to be part of acquired immunity) (Chapter 17). 2 3. Acute phase proteins: These are present at very low levels in normal serum, but ‘ their concentration rises dramatically, shortly after the onset of an infection. ) Microbial products, e.g. endotoxins, stimulate macrophages to release cytokines, which stimulate the liver to produce a large number of acute phase proteins, S These proteins limit the spread of the infectious agent or stimulate the host response. Examples include fibrinogen and C-reactive protein (CRP). 4. Interferons: There are 2 types of interferons. Type | interferon (a and 8) is part of innate immunity. It is secreted by virus-infected cells and prevents viral replication in uninfected neighbouring cells (i. it ‘interferes’ with viral replication). N.B.: Type Il (7) Interferon is secreted mainly by T cells, and is considered part of . the acquired immune response. IV. Cellular defence factors 4. Phagocytes Particles, e.g. bacteria, entering the tissue fluids or blood are rapidly engulfed by z phagocytic cells. This process of enguifment (internalization) of particulate matter is ) termed phagocytosis. Phagocytes contain digestive enzymes capable of degrading ingested material. q The main phagocytic cells are: 2 © Neutrophils * Monocytes/macrophages (monocytes in the blood and macrophages in the tissues * Dendritic cells 3 Table (3) shows a comparison between monocytes/macrophages and neutrophils. oS Phagocytosis (Fig. 2): The process of phagocytosis occurs in subsequent steps: o a- Migration (Chemotaxis): Microorganisms and injured tissues elaborate chemotactic factors that attract phagocytic cells to the site of infection. Some of oe the complement components and some cytokines may have chemotactic properties.2 b- Attachment: Phagocytes have receptors on their surface that can recognize non- specific molecules common to many pathogens, allowing attachment to them, ‘Some microorganisms may alter these molecules or cover themselves with a thick capsule that is not recognized by any phagocyte receptor. Attachment may still occur if these microorganisms become coated with molecules which the phagocytes can recognize. These may be an antibody, a complement component or other molecules (e.g. CRP). In this case, the process is called opsonization and the substance which helped phagocytosis is called an opsonin. c- Engulfment: The cytoplasmic membrane of the phagocyte surrounds the organism and encioses it in a vacuole termed phagosome, Lysosomes, which are bags of enzymes, then fuse with the phagosome forming phagolysosomes, in which the engulfed material is Killed and digested. - Killing: This ocours by 2 mechanisms: - 2 dependent mechanism: After engulfment, there is a respiratory burst consisting of a steep rise in Oz consumption. This is accompanied by an increase in the activity of a number of enzymes and leads to the generation of various reactive oxygen intermediates, such as hydrogen peroxide and singlet ‘oxygen, which are lethal to microorganisms. ~ Op independent mechanism: These are the lysosomal enzymes (lysozyme, elastase, hydrolase ... et.). @3 a)Chemotaxis ‘phagocytic cel 0° Microorganisms Killing aN Phagolysosome phagosome, a — or )Enguitment ‘b)Attachment Fig. (2): Stages of phagocytosis NVANAD aaChapter 2: Innate Immunity 3 In addition to phagocytosis, monocytes and macrophages have the following functions: Antigen presentation: Macrophages help to ‘show’ or ‘present’ part of the foreign agents they have eaten to T cells, so that the T cells can start responding to them Thus, they are among a group of cells called antigen presenting cells (APCs). Secretion: They secrete chemical mediators called cytokines, e.g. interleukins. Direct cytotoxicity: They may kill targets without engulfing them. Helminthic parasites which are too large to be engulfed can be killed by macrophages releasing their toxic contents onto them. Tumour cells can also be killed in a similar way. Table (3) Comparison between neutrophils and monocytes/ macrophages ‘Neutrophils Monocytes/ Macrophages Importance |They are the —_most| In addition to phagocytosis they numerous and most | have cther important functions. important cells of the innate immune system Count —|- 60-80% of TLC* ~ Monocytes form 1 ~ 5% of TLC - They are absent from |- They continuously leave the blood normal tissues. to the tissues where they mature During infections certain | into macrophages. chemicals (chemotactic| Examples: factors) are released to| + The Kupffer cells of the liver attract neutrophils from| + The alveolar macrophages in the blood to the site of| the lung I infection. | Response | - Rapid increase in = Slight increase in blood levels | during production = Slowly form granuloma [inflammation | - Rapidly form pus “size ‘Small Large Life-span | Shor: Long: Die after phagocytosis, Survive after phagocytosis, | forming pus cells Functions | Phagocytosis 1. Phagocytosis 2. Antigen presentation 3.Cytokine secretion 4. Direct cytotoxicity *TLC: Total leucocytic count 2. Eosinophils * They are granulocytes present mainly in tissues. * Count: In the blood, they form 1-3% of TLC.Chapter 2: Innate Immunity 14 + Functions: 1. They are mainly of importance in defence against helminthic parasite O infections. Such parasites, which are too large to be phagocytosed, can be killed by eosinophils releasing the toxic contents of their granules onto them. a. 2, They also play an important role in allergic reactions. 3. Eosinophils also have phagocytic properties. 3. Basophils and mast cells: * Basophils are found in the blood in very low concentrations (0-2% of TLC) OQ ‘* Mast cells are their tissue resicient form. They are present either around the blood vessels or in the submucosa. © Function: Both basophils and mast cells have similar functions. ‘They possess granules containing a number of important mediators such as histamine. Release of these mediators: ~ Contributes to inflammation ~ Plays an important role in allergy 4, Natural killer cells «They are large granular lymphocytes which can be distinguished from B and T lymphocytes. © Count: They constitute 10-15% of peripheral blood lymphocytes. * Functions: 1. They are capable of non-specific kiling of tumour cells and virus-infected cells in a manner similar to cytotoxic T cells; however, they differ from cytotoxic T cells in the way they recognize their targets. 2. They secrete cytokines such as interferon y. V. Inflammation Chemical mediators released at the site of infection trigger an inflammatory response. The events that occur during inflammation are vasodilatation, increased oO vascular permeability and migration of leucocytes from the blood stream across the ‘ vascular endothelium into the inflamed tissues to combat the invading microbe. This vO migration is mediated by certain molecules, termed adhesion molecules, which are expressed on the surface of leucocytes and vascular endothelium. ‘There is a lot of cooperation between innate and acquired immunity. = Innate immunity (macrophage) helps acquired immu presentation. ~ Acquired immunity (antibody) helps innate immunity (macrophage) through So opsonization. y (T cell) through antigenChapter 2: innate Immunity mcas: 1. 2 All of the following is true regarding neutrophils EXCEPT: a- They are phagocytic cells. b- They constitute the majority of peripheral blooc leucocytes c- They act mainly as part of the innate immune mechanism. d- They are capable of killing abnormal cells by induction of apoptosis. @- They are attracted to the site of infection ty the action of chemotactic factors. Macrophages perform the following functions EXCEPT: a- Antigen presentation b+ Phagocytosis c- Secretion of cytokines d- Production of antibodies e Direct cytotoxicity Which statement is TRUE concerning acute phase proteins? a. They disappear from the circulation after onset of infection. b. Endotoxins may stimulate their production c. They deprive pathogens from their essential nutrients d. They are produced by the primary lymphoid organs, @. Type I IFN is an example of acute phase proteins, All the following statements regarding phagocytosis are true EXCEPT: a- Bacteria are engulfed in phagosomes. b- Natural killer cells are the most important phagocytic cells. c- Respiratory burst is lethal to microorganisms. d- Antibodies may aid in recognition. e- Complement components (3b) enhance phagocytosis. Enhanced phagocytosis is known as: a- Agglutination b- Opsonization c- Neutralization d- Antibody-dependent cellular cytotoxicity e- Complement activationChapter 3: Antigens 76 ANTIGENS 1LOs: By the end of this chapter the student should be able to: Define antigen and immunogen Define antigenic determinants or epitopes Define hapten Describe factors affecting immunogenicity ‘An immunogen is @ substance that can stimulate the immune system to produce a specific immune response (humoral and/or cell-mediated) and can react specifically with the product of this response. ‘An antigen, on the other hand, may or may not be able to stimulate the immune system, but it can still specifically react with the product of the immune response. Accordingly, all immunogens are antigens, but not all antigens are immunogens; however, the terms immunogen and antigen are incorrectly used interchangeably. Antigenic Determinants or Epitopes © The immune system does not recognize the antigen molecule as a whole but reacts to limited parts of the molecule called epitopes. * They are very small, composed of just four to five amino acids or monosaccharide residues. © They determine the specificity of the antigen. The same antigen may possess different epitopes. * Antigens that share one or more epitopes are known as cross-reactive (heterophil) antigens (Fig. 3). sieior OME) Fig. (3): Heterophil antigens Hapten This is @ low molecular weight substance which is incapable of inducing an immune response alone, but when coupled with a carrier molecule (protein) it can act as an immunogen. Examples of haptens are drugs e.g. penicilin. ©