Basic Immunology PDF

Basic immunology Professor Abdel Nasser El Moghazy  IMMUNOLOGY AND THE IMMUNE SYSTEM  Immunity: The term immunity usually means resistance of the body to pathogenic microbes, their toxins or to other kinds of foreign substances  Immunology  Study of the components and functi...

Basic immunology Professor Abdel Nasser El Moghazy  IMMUNOLOGY AND THE IMMUNE SYSTEM  Immunity: The term immunity usually means resistance of the body to pathogenic microbes, their toxins or to other kinds of foreign substances  Immunology  Study of the components and function of the immune system  Immune System  Molecules, cells, tissues and organs which provide non- fi specific and specific protection against  Microorganisms Microbial toxins  Tumor cells  There are two main types of immunity :  1. Innate or Inborn immunity. Natio  It is present from the birth and is inherited from the mother to offspring - through the placenta. It is not acquired from the previous attack of -  2. Acquired or Adaptive immunity.  It is not present from the birth but is acquired during one’s own life. It is - developed in response to a disease caused by the infection of microbes or vaccine.  Innate immunity Innate immunity refers to nonspecific defense mechanisms that come into play immediately or within hours of an antigen's appearance in the body.  Characteristics of Innate Immunity &   It acts immediately as the first line of defense against infectious agents.   Non-specific defense mechanism.   Such mechanisms are present from birth   Did not depend upon having previous contact with any particular microorganism.   Effective against a wide range of microorganism Elements of Innate Immunity  The elements of the innate (non-specific) immune system include:  Anatomical barriers:(skin and mucosal membranes)  Cells: (phagocytes, NK cells...)  Humoral components: (complement, cytokines)  First line Defense 1-SKIN Anatomical barriers  It offers a physical and chemical barrier to bacteria. The physical barrier comprises the dead outer keratinous layer, living epithelial cells and also the thickness of the skin through which no bacteria can penetrate  The skin is providing a protective cover to the body.  It secretes some acids like Pyruvic acid and Lactic acid by sweat glands, which creates acidic environment on the skin. -- Acid pH inhibits growth of disease producing bacteria  Bactericidal long chain fatty acids in sebaceous gland secretions  1-SKIN First line Defense Anatomical barriers  One of the main functions of the skin is to protect the host from invasion, and it does so by employing physical barriers, biomolecules, and an intricate network of resident immune and non-immune cells and skin structures  It offers a physical and chemical barrier to bacteria. The physical barrier comprises the dead outer keratinous layer, living epithelial cells and also the thickness of the skin through which no bacteria can penetrate  The skin is providing a protective cover to the body.  It secretes some acids like Pyruvic acid and Lactic acid by sweat glands, which creates acidic environment on the skin. Acid pH inhibits growth of disease producing bacteria  Bactericidal long chain fatty acids in sebaceous gland secretions Biomolecules of the Skin  Antimicrobial peptides (AMPs) and lipids are the main  classes of biomolecules that participate in skin defense by disrupting bacterial membrane The most thoroughly studied AMP families in human  skin are the defensins and the cathelicidins, which are produced by a variety of cells in the skin such as keratinocytes, fibroblasts, dendritic cells, monocytes, and macrophages, and sweat and sebaceous glands pH of the Skin  The pH of human skin is 5.4‒5.9, which makes the  skin an inhospitable environment for potential pathogens. Myeloid Cells  Skin-resident myeloid cells include Langerhans  cells, dermal dendritic cells, macrophages, mast cells, and eosinophils.. 2-Respiratory tract  a. The hairs of the nose act as filter to foreign particles inhaled with air  b. The cough and sneezing reflexes help to expel foreign particles.  c. The sticky mucous layer fixes inhaled microbes, in addition it contains antimicrobial substances  Cilia, tiny muscular, hair-like projections on the cells that line the airway, are one of the respiratory system's defense mechanisms. Cilia propel a liquid layer of mucus that covers the airways. The mucus layer traps pathogens (potentially infectious  microorganisms) and other particles, preventing them from reaching the lungs. Cilia beat more than 1,000 times a minute, moving the  mucus that lines the trachea. Pathogens and particles that are trapped on the mucus layer are coughed out or moved to the mouth and swallowed 3.The gastrointestinal tract  a. Human saliva has some antibacterial activity.  b. The buccal cavity and the large intestine contain normal bacterial flora which oppose establishment of pathogenic species.  c. The hydrochloric acid and the digestive enzymes have antimicrobial action  35 / 4.The genito-urinary system a. The frequent flushing during micturition is probably the most important factor in maintaining sterility of the urethra.  b. The acidic pH (5-6) of urine in healthy individuals is also a protection against bacterial infection.  c. The stratified epithelium of the adult vagina is resistant to penetration by bacteria.  d. The commensal lactobacilli produces a highly acidic vaginal secretion by fermenting the glycogen, inhibiting the growth of other bacteria 5.The conjunctiva  a. Eyelids acts as a very efficient mechanical barrier.  b. Tears are rich in lysozyme, the enzyme with antibacterial action  Second line of defense Cellular Factors:  Cellular factors. There are two major cellular components involved in non-specific immunity, phagocytic cells (Phagocytosis ) and natural killer cells ↳ Thiemer cell  (A) Phagocytic cells:  If an organism or foreign body penetrates an epithelial surface it encounters phagocytic cells  The phagocytic cells include macrophages and Neutrophils, Basophils, Eosinophils.  Their function is to engulf particles, including infectious agents, internalize them and destroy them by process called phagocytosis  Phagocytosis: It is a process by which phagocytic cells engulf organisms and other foreign particles. The process of phagocytosis involves the following steps :  The stepes of Phagasskesis : Phagocytosis  1. Chemotaxis is the process by which phagocytes are - attracted to microorganisms. -  2. Attachment: The phagocyte then adheres to the or microbial cell. This adherence may be facilitated by opsonization – Enguitment coating the microbe with plasma proteins. ~  3. Ingestion: Pseudopods of phagocytes engulf the microorganism and enclose it in a phagosome to complete ingestion. 692  4. Digestion: Lysosomes fuse with the phagosome to form a digestive vacuole. The microbeSis killed and - - digested. rick mysosomes 6) Excretion enzymes Phagocytosis Figure 16.8a  (B) Natural Killer Cells  Natural killer (NK) cells attack virus-infected body cells and cancer cells  Killing of cells infected by intracellular pathogens eg. viruses and tumor cells - Release chemicals that enhance the inflammatory response  Biochemical Factors: or Humoral factors  The major biochemical factors are Interferon and Complement system.  1-Interferon:  These are group of soluble non-toxic glycoproteins produced in small amount by all cells of the body.  A special defense works specially against viral infection.  They offer resistance by blocking viral m-RNA transcription there by disrupting the viral life-cycle..  The interferon reaches the uninfected cells; it makes them resistant to the viral infection. Biochemical Factors:  2-Lactoferrin and transferrin:  By binding iron, an essential nutrient for bacteria, these proteins limit - bacterial growth.  3-Interleukin-1:  a protein with numerous immune system functions,  Including activation of T cells, endothelial cells, and macrophages;  mediation of inflammation; and stimulation of the synthesis of lymphokines, and collagenases. Biochemical Factors  4-Beta lysine: Bactericidal protein present in the blood and secreted by the blood platelets. 5-C-reactive protein (CRP): serum proteins increased rapidly following infection. CRP recognizes and binds, Ca++ found on a wide variety of bacteria and fungi Biochemical Factors 6- Complement The complement system consists of a number of small proteins found in the blood, in general synthesized by the liver, and normally circulating as inactive precursors (pro-proteins).  Consists of ~30 proteins that complement the action of the immune system  Functions:  Stimulate leukocytes  Lyse bacteria  Increase phagocytosis  Pathogens (such as bacteria, & fungi, and viruses) INNATE IMMUNITY Barrier defenses: (all animals) Skin Recognition of traits shared Mucous membranes by broad ranges of Secretions pathogens, using a small Internal defenses: set of receptors Phagocytic cells Rapid response Natural killer cells Antimicrobial proteins Inflammatory response ADAPTIVE IMMUNITY Humoral response: (vertebrates only) Antibodies defend against Recognition of traits infection in body fluids. specific to particular pathogens, using a vast Cell-mediated response: array of receptors Cytotoxic cells defend against infection in body cells. Slower response  Specific (acquired immunity)   This is a specific reaction of the body against (Non- self), foreign agents (called antigens), in which its immune products react specifically with the stimulating agent, it is conventionally divided into passive and active immunity, both of which may be either natural or artificial (discussed in later).  Specific immunity may be humoral (due to production of antibodies) or  cell – mediated (due to sensitization of T- lymphocyts)  Acquired (Specific) Immunity Humoral Immunity Involves antibodies (secreted from B cells) dissolved in the blood plasma. Demonstrated as a immune response using only the blood serum. Defense against bacteria, bacterial toxins, & viruses. Acquired (Specific) Immunity Cell-Mediated Immunity Involves the activities of specific white blood cells (T cells). Defense against cancer cells, virus- infected cells, fungi, animal parasites, & foreign cells from transplants.  =>-  1-Natural active acquired immunity:  It follows infections whether clinical (i.e. diseases) or sub clinical  infections it leaves the individual with long- lasting immunity (e.g.  measles, mumps, small pox and poliomyelitis) or with immunity of short  duration (e.g. influenza virus).  2- Artificial active acquired immunity:  It follows immunization of the individual with one of the following  immunizing agents: -Live attenuated vaccines: (e.g.) BCG for (T.B) and Sabin vaccine for (Poliomyelitis) -Killed vaccines: (e.g.) Salk vaccine for (Poliomyelitis) and TAB for (Typhoid and paratyphoid fever). -Recombinant DNA vaccines: The genes responsible for the production of certain immunizing bacterial or viral antigens are used in the development of new, improved, or safe vaccines, (e.g.) hepatitis B. : g5 lis  (B) Passive acquired immunity:  Passive immunity involves either the transfer of antibodies or in some diseases, of sensitized T-lymphocytes. The duration is short – lived, depending on the life span of the transferred antibody or cells and there be  memory developed. Once the passive immunity disappears, the host is again susceptible to the disease.  Passive immunity may occur naturally or artificially:  1- Natural passive acquired immunity:-  It is transferred from mother to fetus (IgG) across the placenta and via  colostrums during lactation (IgA).  The protective effect of this immunity  remains for about six months after birth.  2- Artificial passive acquired immunity:  Involves administration of various antitoxins or gammaglobulines, as in the treatment of tetanus, diphtheria, gas gangrene and snake bite.  Administration of transfer factor, may be clinical importance in the management of certain viral infections, fungal diseases, parasitic infestation,  bacterial, bacterial infections and tumor disorders.  In certain diseases, for example tuberculosis and leprosy, immunity can only be transferred by white blood cells from immune person, not by antibodies.  Basic immunology Professor Abdel Nasser El Moghazy  Cells of Immune Systems Innate Immunity: Granulocytes (neutrophils, eosinophils, and basophils), monocyte/macrophages, and natural killers (NK) cells. Specific Immunity: T-cells (thymus-drived), B-cells (bursa derived), Antigen Presenting Cells (APC). T-cells mediate cellular immunity and B- cells mediate humoral immunity.  Cells of TRANSPORT ERYTHROCYTES, immune systems OF 02 AND CO2 LEUKOCYTES DEFENSE OF THE BODY 1. NEUTROPHILS PHAGOCYTOSIS 2. BASOPHILS PRODUCTION Loading…OF HISTAMINE 3. EOSINIPHILS AGAINST CERTAIN PARASITES AND SPECIAL PHAGOCYTOSIS 4. MONOCYTES PHAGOCYTOSIS 5. LYMPHOCYTES B CELLS—ANTIBODY PRODUCTION T CELLS—CELL-MEDIATED IMMUNITY PLATELETS BLOOD CLOTTING Cells of immune systems 1- Neutrophils (microphages): Migrate to the site of infection (chemotaxis). Posses phagocytic activity. Produce inflammatory and immune mediators such as prostaglandin and Interleukins respectively.  2- Eosinophils (acidophils): Produce histaminase, inflammatory and immune mediators suchLoading… as prostaglandin and interleukins respectively. Participate in anaphylactic hypersensitivity reaction  3- Basophils (in connective tissue called mast cells): Produce inflammatory mediators (histamine and other vaso-active amines). Participate in anaphylactic hypersensitivity reaction  4- Monocytes (macrophages): Monocytes circulate in blood for 3 days, then migrate to tissues and change to macrophages. Macrophages make up the cells of the reticuloendothelial system (RES). Usually macrophages of the blood are referred as monocytes and those found in connective tissue are called histocytes e.g. in liver (Van Kupffer cells), in lymph node (dendritic) and in skin (Langerhans).  Migrate to the site of infection (chemotaxis). Posses high phagocytic activity. Produce inflammatory and immune mediators such as prostaglandin and interleukins respectively. Posses receptors for Fc fragment of the antibody and C3b fragment of the complement. Digest M.O. and present them as antigens to lymphocytes to induce specific immune response and so are called antigen-presenting cells (APC). Destroy cells having viral antigens on their surface and antibody coated cells  5- Natural killer cells (NK): kill tumor cells and virus infected cells. 6- Killer cells (K): kill antibody coated cells. 7- Lymphocytes : there are two main subsets, B So. and T, the main characteristics of them are listed below ce ↳o 1- x sIr Cells Involved in Innate Immunity Macrophase is respons to anti acterial Phagocytosis Macrophag Presentation to I e lymphocytes Monocyte Phagocytic Anti-bacterial Neutrophil PMN Anti-parasite Immunity - Allergy Eosinophil ?Protection of mucosal surfaces? - Basophil Allergy Protection of Mast cell mucosal surfaces - Allergy  B-lymphocytes: B-lymphocytes antibody secreting cells. Fully differentiated B-cells that secrete high level of antibody are called plasma cells. Mature B-cells that come into contact but not develop into plasma cells are often referred to as memory B-cells B lymphocyte precursors arise from lymphoid stem cells and migrate, in birds to the bursa of Fabricius, a lymphoid organ in the hindgut. Loading… In mammals, which do not possess such a bursa, the bursal analogue in the embryo is the liver or spleen, while in adults B lymphocyte maturation into plasma cells (large lymphocytes) takes place in the bone marrow The mature B cells are then released into the circulation and secondary lymphoid tissues and are involved in the synthesis of specific immunoglobulin (antibodies).These B lymphocytes constitute 15-30% of the total peripheral lymphocytes and their life span is short (5-7 days).  T -lymphocytes classification According to their function. T cells are classified into four subclasses: 1) T helper (Th) cells: which enhance T or B cell response T-helper (TH): Produce interleukins (lymphokines or cytokines) which stimulate T-cells, allow B-cells to proliferate and differentiate and stimulate phagocytic activity by phagocytes 2) T suppressor (Ts): which suppress T or B cell response. T- suppressor (TS): modulate immune response by inhibiting over immune reaction 3) T cytotoxic (Tcs) cells: which lyses virally infected cells, tumor cells or grafts? T-cytotoxic (TC): able to kill virus- infected cells, tumor cells and foreign rejected grafts 4) T delayed hypersensitivity (Tdh) which is the effectors cells that produce lymphokins in response to antigenic  stimulation. T-delayed hypersensitivity (TD): produce Platomic B-lymphocytes T-lymphocytes cas , Named after fabricus found in chicken and Named after thymus gland on which their responsible for antibody formation. In maturation depends humans, bursa equivalent includes bone marrow, Peyers patches and appendix. Constitute 30% of total lymphocytes Constitute 70% of total lymphocytes Of short life span (days or weeks) Of long life span (months or years) Upon stimulation, they proliferate and Upon stimulation, they proliferate and fo differentiate into plasma cells producing differentiate into effector T-cells. Some of specific antibody or immunoglobulin “Ig” T-cells subsets produces lymphokines Have receptors for antigens (usually IgM, or Have receptors for antigens called T-cell IgD) called B-cell receptor (BCR) receptor (TCR) Produce memory cells Produce memory cells Have receptors for Epestein-Barr virus Form rosettes with sheep RBCS Have glycoprotein markers on their surface  Tissues of the Immune System Primary Lymphoid Organs 1-Bone marrow: The bone marrow is the site of blood cell formation after birth. All blood cells are derived from stem cells. These stem cells have the capacity for self- renewal and differentiation into every type of cell found in the blood In mammals, mature B-lymphocytes develop from stem cells in the bone marrow  2-thymus: the thymus is derived into two anatomically distinct regions. These regions are the cortex and medalla. I Pre-T-cells migrate from the bone marrow to the thymus and enter the cortex. About 90% of the cells die in the thymic cortex the remaining 10% undergo a process of differentiation. The 10% surviving cells represent T-cells that can recognize antigens on APC it's derived into both of corfex and medulla  Secondary Lymphoid organs Spleen: The spleen is a major secondary lymphoid organ. Foreign antigens in the circulation are filtered through the spleen and come in contact with lymphocytes and APCs that initiate a specific immune response. Fetal Liver: In the fetus, the liver is the primary site of hematopoiesis. Lymph nodes Lymphocytes and APC in lymph nodes  II-Adapive immunity (acquired immunity) Specific defense mechanism, effective against a specific MO. Depend upon having previous contact with a particular microorganism. Microorganisms that overcome the innate non-specific immunity come up against the host's second line of Dar formt defense. Godig  In this type of immunity, antigens of the invading M.O. come in contact with cells of the immune system (macrophages and lymphocytes) to initiate the acquired specific immunity which may be humoral (appearance of antibodies) or cellular (cytotoxic effects  Antigens (immunogens) Antigens "Ags" are substances capable of acting as 10 specific stimulants for the specific immune response. Characterizes of antigens 1) Foreignness: only molecules that are foreign to the circulation ofLoading… an animal are immunogenic. The more foreignness the more powerful the antigen 2) Molecular size: small molecules such as monosaccharides and amino acids are not immunogenic, while proteins and polysaccharides are immunogenic.  the specificatie What is of entigens 3) Specificity, only restricted portions of them are involved in the actual binding with the antibody combining sites. antigenic determinants (epitopes). Epitope or Antigenic Determinant: That portion of an antigen that combines with the products of a specific immune response 4) Chemical complexity: a molecule must possess certain degree of chemical complexity in order to be immunogenic. 5) Physical form: In general, particulate /  Hapten: Is a low molecular weight substance which can not stimulate an immune response by itself; however, if it is carried on a larger molecules (e.g.Loading… if it is bound to a protein carrier), it becomes antigenic and can induces a specific immune response and react specifically with it, (e.g. polysaccharide capsule of pneumococci).  Common types of I antigens: a. Bacterial antigens: e.g. cell wall (O), flagellar (H), capsular and fimbrial antigens. Also extracellular antigens (e.g. exotoxins) and intracellular antigens (e.g.  Antibodies Immunoglobulins Antibody (Ab): A specific “Igs” protein which is produced in response to an immunogen and which reacts with an antigen Antibodies are glycoproteins synthesized and S i secreted by plasma cells in response to antigenic stimulation of B cells. They are present in the serum and tissue fluids of all mammals and responsible for immune reactions called (Humural immunity or antibody mediated immunity).  Structure of immunoglobulin molecule (Ig) Basic structure: The basic unit of Ig molecule is formed of four polypeptide chains; two light and two heavy chains hold together by inter chain disulphide bonds. Light chains: These are two identical short chains, each consists of about 200 amino acids. According to the amino acid sequence, there are two types of light chains; kappa and lambda. The Ig molecule contains either kappa  According to the amino acid sequence, there are five types of heavy chains; gamma, alpha, Mu, delta and epsilon. According these types of heavy chains, there are five types of immunoglobulins (IgG, IgA, IgM, IgD and IgE ) Disulphide bonds: There are two types of disulphide bonds: Inter chain disulphide bonds: These are three bonds. The first bond is present between the two heavy chains. The other two bonds; each joins a light chain with the adjacent heavy chain.  Each light and heavy chain consists of two regions: The variable (V) region: It is a segment formed of one domain called the variable domain since it shows marked variations of its amino acid sequence. The variable region is present in the amino (N) terminal portion of the chain. The constant (C) region: The rest of the Ig molecule shows little variation and relatively constant in its amino acid sequence. The constant region is present towards the carboxy (C) terminal portion of Ig molecule. Loading…  ThereTypes are fiveoftypes immunoglobulins of immunoglobulins (IgG, IgA, IgM, IgD and IgE ). They differ from each other in size, charge, amino acid composition, and carbohydrate content. 1. IgG: Is the major immunoglobulin, and comprises about 70- 75% of the total immunoglobulins in normal human sera. IgG is monomeric protein. It predominates in secondary antibody response against bacterial, viral and fungal infections and it is the only type that can pass through the placenta.  2. IgM: Is the largest of the immunoglobulin molecules; it has pentameric structure. It comprises about 10% of immunoglobulins in normal serum. The greater size of IgM molecule is due to five units (each similar to one IgG unit), linked through disulphide bonds 3.IgA: It is found to small extent in serum (serum IgA), but predominantly in the external seromucous secretions of the respiratory, gastrointestinal, and genitourinary tracts, including tears, sweat, saliva, and milk (secretory IgA).  4. IgE:. It has a special attraction to mast cells and basophils. IgE play an important role in hypersensitivity reactions and in defense against parasitic infections. 5. IgD:. Its function is unknown; but it has been suggested that IgD on B cells prevents the development of immunological tolerance when the cell encounters an antigen.  Mechanism of antibody When an antigenproduction enters the body, it is trapped by phagocytic cells and transported to the local lymph nodes. Antigens which are disseminated by the blood stream are trapped by the endothelial cells in the spleen. The second step is digestion of the particulate antigen into the macrophages then presenting the antigen to the B lymphocytes. The third step is that of antigen recognition by B lymphocytes by two parameters; being foreign and its antigenic determinants Theories for antibody formation: 1) Instructive (Template) theory: This suggested that antigen acts as a template around which a standard unfolded gamma globulin chain could be molded to provide a complementary shape of the antigen. The produced immunoglobulin molecule will stimulate the B lymphocytes to produce other immunoglobulin molecules with the same shape.  2) Colonal selection theory: This theory is widely accepted. It assume that each individual has a very large number of different classes of lymphocytes, each class is called clone (class of lymphocytes and its progeny), and each clone is capable of responding to only one antigen When the antigen is introduced into the body it selects the best "fit" clone by means of surface receptors (antibody molecule) and stimulate it to differentiate into plasma cell that multiply and produce antibodies  Monoclonal antibodies A monoclonal antibody is an antibody that is specific to a single antigen. In vitro hybridoma technology was used to synthesize monoclonal antibodies. Hybridoma technology involves fusion of myeloma cells with plasma cell derived from the bone marrow or spleen of a host immunized with the appropriate antigen. The resultant hybrid cells are called hybridoma; separated out as single clones and continue to proliferate unchecked as a malignant cell and secretes the products of the two parent cells.  Clinical application of the monoclonal antibodies: 1. Diagnosis of infectious diseases ( Known monoclonal antibody + unknown organism). 2. Assay of hormones. 3. Identification of cell-surface markers. 4. Isolation and purification of human products prepared in bacteria(by genetic engineering), e.g. vaccines and interferons. 5. Passive immunization (to transfer a specific artificial passive acquired immunity). 6. A possible therapeutic role in tumors.  Antigen dose response relationship: The time interval between the introduction of an antigen and the appearance of full immune response could be divided into two stages a) inductive stage: the introduced antigen is first phagocyted by a macrophage, which do not produce antibodies, but it process the antigen in some way and present it to "B" cells in the form of activated antigen. In most cases the induction may require the collaboration of "T" helper cells together with the macrophages.  b) productive stage: in this stage the activated Primary and secondary antibody Primary response response Following the first dose of antigen administration there is a lag phase where no antibodies can be detected (inductive stage). This is followed by a phase in which the antibody titer rises logarithmically reaching a small plateau and finally decline again. IgM appears first then IgG, but IgM concentration declines more rapidly than IgG  No las Phas Secondary response When an animal is reinjected with the same antigen weeks, months or even years after the primary antibody have subsided, there is a more rapid antibody response and to a higher level and for a longer period. This may be explained to be due to the presence of antigen sensitive memory cells. During the secondary response, the level of IgM is more or less the same as the primary response, whereas IgG production is far greater  Items Primary Secondary Definition. Introduction of an Secondary or antigen for the first time. subsequent exposure to the same antigen. Slow (a latent period of Rapid (within few several days before hours to few days). Onset. response). Low; (gradual increase). High (rapid increase). Antibody level. For short duration (the For long duration antibody decreases (months or years). Persistence. rapidly). ·Predominately Absent before primary Present during exposure secondary or subsequent Immune memory. immune response.  Immunization Artificial passive immunization Live vaccines: Before a live organism can be administered as a vaccine, it must be attenuated, i.e. rendered harmless. This is most frequently achieved by growing the organism and then frequently sub culturing it in the laboratory. Such propagation under unnatural conditions tends favor the emergence of mutant strains that are not harmful to the human host. Live vaccines produce an ongoing stimulus to the immune system due to the multiplication of the M.O. in the host  Killed Vaccines: These vaccines are completely safe but the immunity conferred by them, even when given with adjuvant, is often inferior to that resulting from live vaccine or natural infection. Because self-replication of the microorganism does not occur, booster doses of vaccine are necessary Moreover, injected killed vaccine (e.g. cholera) may stimulate systemic antibody synthesis without initiating an adequate response in the intestine, i. e. the site of natural infection  Toxoids: In diseases such as tetanus and diphtheria, the organisms multiplying locally producing potent exotoxin responsible for life- threatening effects on heart and nervous system. These exotoxins, when purified and inactivated with formalin are known as toxoids which are non-toxigenic but are still antigenic. When toxoids are combined with an adjuvant, their administration leads to the production of antitoxin by the recipient  Genetically engineered products: In diseases when the causative agent cold not be cultivated e.g. hepatitis B.  Bacterial products: (e.g.) toxoids of diphtheria and tetanus. Recombinant DNA vaccines: The genes responsible for the production of certain immunizing bacterial or viral antigens are used in the development of new, improved, or safe vaccines, (e.g.) hepatitis B, Vibrio cholerae and meningococcus X  Immune tolerance Immune tolerance: A state of unresponsiveness to a specific antigen or group of antigens to which a person is normally responsive. Loading… Immune tolerance is achieved under conditions that suppress the immune reaction and is not just the absence of a immune response. Immune tolerance can be defined as a state in which a T cell can no longer respond to antigen. The T cellX"tolerates" the antigen.  Immune tolerance can result from a number of causes including: Prior contact with the same antigen in fetal life or in the newborn period when the immune system is not yet mature; Prior contact with the antigen in extremely high or low doses; Exposure to radiation, chemotherapy drugs, or other agents that impair the immune system; Heritable diseases of the immune system; Acquired diseases of the immune system such as HIV/AIDS. X The Complement system  The complement system A defensive system consisting of over 30 proteins produced by the liver and found in circulating blood serum. Complement kills microbes in three different ways – 1. opsonization – 2. inflammation – 3. Cytolysis  ⑤ General Properties of Complement Synthesized mainly by liver hepatocytes. Most circulate in the serum in functionally inactive forms Designated by numbers, by letter symbols. Primary role is cell lysis. Activity of complement destroyed by heating sera to 56 C for 30 minutes. IgM and IgG are the only immunoglobulin capable of activating complement (classical pathway). Complement activation can be initiated by complex polysaccharides or enzymes (alternative or properdin pathway). The complement system contribute to chemotaxis, opsonization, immune adherence, anaphylatoxin formation, virus neutralization, and other physiologic functions  Pathma A Cascade system The complement works as a cascade system. – Cascade is when one reaction triggers another reaction which trigger others and so on. These types of systems can grow exponentially very fast. 30 profine in the snrum sette From liver  The Classical Pathway The classical pathway is considered to be part of the specific immune response because it relies on antibodies to initiate it. C1 becomes activated when it binds to the ends of antibodies  The building of a C3 activation complex Once C1 is activated, it activates 2 other complement proteins, C2 and C4 by cutting them in half C2 is cleaved into C2a and C2b C4 is cleaved into C4a and C4b Both C2b and C4b bind together on the surface of the bacteria C2a and C4a diffuse away  C3 Activation complex I C2b and C4b bind together > - on the surface to form a C3 activation complex The function of the C3 activation complex is to activate C3 proteins. – This is done by cleaving C3 into C3a and C3b  C3b Many C3b molecules are produced by the C3 activation complex. The C3b bind to and coat the surface of the bacteria. C3b is an opsonin – Opsonins are molecules that bind both to bacteria and phagocytes – Opsonization increases phagocytosis by 1,000 fold. Opsonins  C3a C3a increases the inflammatory response by binding to mast cells and causing them to release histamine Building the C5 activation complex Eventially enough C3b is cleaved that the surface of the bacteria begins to become saturated with it. C2b and C4b which make up the C3 activation complex has a slight affinity for C3b and C3b binds to them When C3b binds to C2b and C4b it forms a new complex referred to as the C5 activation complex  The C5 activation complex The C5 activation complex (C2b, C4b, C3b) activates C5 proteins by cleaving them into C5a and C5b Many C5b proteins are produced by the C5 activation complex. These C5b begin to coat the surface of the bacteria. Hypersensitivity reactions The immune system is concerned with protection of the host against foreign antigens, particularly infectious agents. Inappropriate immune response may be: 1.Allergy: exaggerated immune response against environmental antigens. 2.Autoimmunity: misdirected immune response against the host’s own cells. 3. Alloimmunity: immune response directed against beneficial foreign tissues e.g. blood transfusion or organ Loading… transplantation. 4. Immune deficiency: inability of the immune system to protect the host.  Hypersensitivity Is an altered immunologic response to an antigen tha results in tissue damage. Hypersensitivity reactions: inflammatory immune responses induced by repeated antigen exposure resulting in host tissue damage. Allergen: is an antigen capable of stimulating hypersensitivity reactions Types of Allergen: Exogenous: 1- Animal products. 2- Drugs ( penicillin) 3- Food : Egg albumen, Corn, peanuts, soybeans, milk, and seafood. 4-. Mold spores. Loading… 5-Plant pollens. Endogenous: -Self antigen. Types of Hypersensitivity: Hypersensitivity reactions are divided according to mechanism of action into four groups: 1-Type I (Immediate hypersensitivity). 2-Type II (Cytotoxic hypersensitivity). 3-Type III (Immune complex hypersensitivity). 4-Type IV (Cell-mediated hypersensitivity).  Type I Hypersensitivity It is also known as immediate or anaphylactic hypersensitivity. The reaction may involve skin (urticaria and eczema), eyes (conjunctivitis), nasopharynx (rhinitis), bronchopulmonary tissues (asthma) and gastrointestinal tract (gastroenteritis). The reaction may cause from minor inconvenience to death. The reaction takes 15-30 minutes from the time of exposure to the antigen. Sometimes the reaction may have a delayed onset (10-12 hours).  Mechanism: * First exposure to allergen I Allergen stimulates B lymphocytes to form antibody (IgE type). IgE fixes, by its Fc portion to mast cells and basophils. * Second exposure to the same allergen The antigen fixes directly to IgE (which is already fixed to mast cell) leading to activation and degranulation of mast cells and release of mediators These mediators cause vasodilatation, increased capillary permeability, mucus hypersecretion, smooth muscle spasm, and tissue infiltration with eosinophils, helper T cells, and other inflammatory cells.  Mediators of Type I Hypersensitivity Immediate effects 1. Histamine: Vasodilatation and increased vascular 2. Leukotrienes: permeability. Bronchial smooth muscles contraction 3. Prostaglandin : Causes bronchospasm. 4. Platelet activating factor (PAF) : platelet aggregation, release of histamine, bronchospasm, increased vascular permeability, and vasodilation 5. Eosinophil chemotactic factor（ECF-A: 6. Bradykinin: Vasodilation Clinical examples of type I hypersensitivity 1. Systemic anaphylaxis: a very dangerous condition Allergic reactions after injection of drugs (penicllin) or serum 2. Respiratory allergic diseases : 1) Allergic asthma：acute response, chronic response 2) Allergic rhinitis, Allergic rhinoconjunctivitis 3. Gastrointestinal allergic disease 4. Skin allergy: Eczema (atopic dermatitis), Acute urticaria 9 Clinical examples on Type I Hypersensitivity: 1-Localized reaction in Skin: Urticaria Eczema Loading… 2-Systemic Anaphylaxis: In bloodstream. Lethal effect.  -Systemic Anaphylaxis * Systemic form of Type I hypersensitivity * Allergens: Drugs: penicillin * Clinical picture: Shock due to sudden decrease of blood pressure, respiratory distress due to bronchospasm, cyanosis, edema, urticaria * Treatment: corticosteroids injection, epinephrine, antihistamines set  Methods of diagnosis Type I hypersensitivity 1) History taking for determining the allergen involved 2) Skin tests: 15 30 mi - Intradermal injection of different allergens A wheal and (erythema) develop at the site of allergen to which the person is allergic 3) Determination of total serum IgE level- Radioimmunosorbent test (RIST)  Management of Type I hypersensitivity 1) Avoidance of specific allergen. 2) Hyposensitization: Minute quantities of the responsible allergen is injected in increasing doses over a long period. 3) Drug Therapy: corticosteroids injection, epinephrine, antihistamines  Type II Hypersensitivity: -Known as Cytotoxic Hypersensitivity. involve immunoglobulin G or immunoglobulin M antibodies bound to cell surface antigens, with subsequent complement fixation. -Allergen could be: 1-Endogenous: Cell surface protein. 2-Exogenous: Drug metabolite adsorbed onto cell membrane. -Sites of occurrence of Type II reactions: On cell surface (Example: RBCs). * Mechanisms of type II hypersensitivity reactions: Complement-mediated cell lysis. Complement fixation to antigen antibody complex on cell surface. The activated complement will lead to cell lysis. Phagocytosis mediated cell lysis. Phagocytosis is enhanced by the antibody (opsinin) bound to cell antigen leading to opsonization of the target cell Both processes result in lysis of the Ab-coated cell  Clinical examples of Type II responses include: – Certain autoimmune diseases where Ab’s produced vs membrane Ag’s Grave’s Disease – Ab’s produced vs thyroid hormone receptor Myasthenia Gravis – Ab’s produced vs acetylcholine recpetors Autoimmune hemolytic anemia – Ab’s produced vs RBC membrane Ag’s – Hemolytic Disease of the Newborn – Hyperacute graft rejection Blood Transfusion Graft rejection Type III (Immune Complex) Reactions Involve reactions against soluble antigens circulating in serum. Usually involve IgA antibodies. Antibody-Antigen immune complexes are deposited in organs, activate complement, and cause inflammatory damage. Glomerulonephritis: Inflammatory kidney damage. Occurs when slightly high antigen-antibody ratio is present. Immune Complex Mediated Hypersensitivity Kher 0 Type III Hypersensitivity: - Clinical Examples on Type III Hypersensitivity. --Two types: 1-Localized in skin: Example: Arthus reaction. Intradermal injection of antigen in skin; necrotizing. 2-Systemic: Example: Serum sickness disease..  Clinical Examples on Type III Hypersensitivity Local form (Arthus reaction): Developed in persons injected with an antigen intradermal or subcutaneous, to which antibodies are found circulating in the blood and so microprecipitate is formed at the site of injection i.e. within the walls of the local blood vessels e.g. during frequent administration of insulin. 0  Clinical Examples on Type III Hypersensitivity Systemic form (Serum sickness): Developed in persons receiving large doses (10-12 ml) of foreign serum such as horse diphtheria antitoxin or tetanus antitoxin. Antibodies will be formed against the foreign protein present in the horse serum. The antibodies formed will react with the large quantity of the foreign protein "Ag" remaining the blood. The resulting "Ag"-"Ab" complex cause serum sickness. Serum sickness consists of inflammatory changes in various organs e.g. glomerulonephritis in kidney, myocarditis and valvitis in heart, swelling in joints and urticaria in skin. 0  Delayed hypersensitivity (Type IV) - It is cell mediated and not antibody mediated. Mechanism of delayed hypersensitivity - Cells responsible for this type of hypersensitivity are the sensitized T-lymphocytes i.e. it is associated with cellular immunity. - The T cell necessary for production of the delayed hypersensitivity are the T- delayed hypersensitivity or TD cells, which become sensitized to certain antigen  Type IV (Cell-Mediated) Reactions –. – Reactions are delayed by one or more days (delayed type hypersensitivity). Delay is due to migration of macrophages and T cells to site of foreign antigens. – Reactions are frequently displayed on the skin: itching, redness, swelling, pain. – Anaphylactic shock may occur. Accompanied by the release of lymphokines, and consists of inflammatory changes. - Has slow onset of action taking 24-48 hours to reach maximum and persists for long time. - Unlike other forms of hypersensitivity, it can not be passively transferred from one animal to the other by serum, but can be transferred by T-lymphocytes. - Delayed hypersensitivity is classified into two types; Tuberculin (Infection) type Contact dermatitis type  Tuberculin type – – ID inoculation of PPD in sensitized individual leads to indurations & inflammation in 48-72 hrs. This is not same as skin test done for Type I hypersensitivity. – Used for diagnosis / exclusion of diagnosis of many bacterial / fungal / parasitic / viral and autoimmune diseases. 0 Clinical example: Tuberculin test: Contact allergy (contact dermatitis) Occur after sensitization with a variety of metals e.g. nickel, chromium; chemicals e.g. potassium dichromate and acrylates found in cloth; drugs e.g. sulfa and penicillin in local cream or ointment; also plant materials e.g. chlorogenic acids found in some vegetables. - Such substances are only antigenic after combination with serum proteins i.e. they are only haptens. - The reaction consists of redness, swelling, itching, vesicles, scaling and exudation Summary Loading…  classification of hypersensitivity reaction Type Description Time Mechanism, Typical manifestation ⑮Type I IgE-mediated 2-3min Ag induce cross-linkage Systemic anaphylaxis hypersensitivity of IgE bound to mast cells Localized anaphylaxis: or basophils with release -Hay fever, Asthma, of vasoactive mediators Hives, Food Allergy Eczema. Type II Ab-mediated 5-8h Ab directed against cell- Blood-transfusion cytotoxic surface Ags mediates cell reactions. hypersensitivity destruction via C activation Erythroblastosis fetalis Autoimmune hemolytic anemia.  classification of hypersensitivity reaction Type Description Time Mechanism Typical Manifestations TypeIII Immune complex 2-8h Ag-Ab complexes Localized Arthus -mediated deposited in various reaction hypersensitivity tissues induce C acti- Generalized reactions: vation and an ensuing Serum sickness, inflammatory response Glomerulonephritis Rheumatoid arthritis SLE Delayed reactions Type IV cell-mediated 24-72h Sensitized TDTH cells Contact dermatitis, hypersensitivity release cytokines that Tuberculous lesions, activate Macrophages, Graft rejection. which mediate direct  The function of C5a C5a disperses away from the bacteria. – Binds to mast cells and increases inflammation. – Most powerful chemotactic factor known for leukocytes  Building the Membrane Attack complex C5b on the surface of bacteria binds to C6 The binding of C6 to C5b activates C6 so that it can bind to C7 C7 binds to C8 which in turn binds to many C9’s Together these proteins form a circular complex called the Membrane attack complex (MAC) & -  Membrane Attack complex The MAC causes Cytolysis. – The circular membrane attack complex acts as a channel in which cytoplasm can rush out of and water rushes in. The cells inner integrity is compromised and it dies