MPAB 022 Section A Lecture Presentation (Systemic) PDF

SECTION A MPAB 022 (MED SCI) SYSTEMIC MEDICAL SCIENCE By Dr Maepa  Systemic Pathology Pathology is the scientfc study of the structural and functonal changes which occur in cells, tssues and organs as a result of injuries, abnormal stmuli or genetc abnormalites, and t...

SECTION A MPAB 022 (MED SCI) SYSTEMIC MEDICAL SCIENCE By Dr Maepa  Systemic Pathology Pathology is the scientfc study of the structural and functonal changes which occur in cells, tssues and organs as a result of injuries, abnormal stmuli or genetc abnormalites, and the consequences for the organism. What is immunology? Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with: - The physiological functoning of the immune system in states of both health and disease; - Malfunctons of the immune system in immunological disorders (viz. autoimmune diseases, hypersensitvites, immune defciency, transplant rejecton); - The physical, chemical and physiological characteristcs of the components of the immune system in vitro, in situ, and in vivo. htps://www.pathology.health.nsw.gov.au/clinical-services/about-pat hology/immunopathology htps://www.youtube.com/watch?v=k9cQAyP3bYmmc OVERVIEW OF THE IMMUNE SYmSTEM Learning objectives: You should be able to: Describe the structure and function of primary and secondary lymphoid organs. Distinguish innate from adaptive immunity. Describe both humoral and cellular constituents of the immune system Discuss the principles of specificity, memory, diversity and self- recognition  The Immune System concept Map. Is able to generate an enormous variety of cells and soluble molecules (e.g. antbodies or immunoglobulins) capable of specifcally recognizing and eliminatng an apparently limitless variety of foreign invaders. These cells and molecules act together in a dynamic and ofen dependent network9 whose complexity rivals that of the nervous system. The cells of the immune system are distributed throughout every anatomical part or site of the body (possibly with the excepton of the cornea), and indeed, many of them actvely travel or ‘migrate’ around or patrol the body just lik9e well-trained and well-armed soldiers (immunosurveillance).  TYPES OF IMMUNE SYSTEM Natural/Innate (Naïve) immunity It is natural and acts in a non-specifc fashion, i.e. it does not discriminate between diferent types of invaders (i.e. No antgenic specifcity required. It is considered the frst line of defence. It has two major components, viz. Humoral branch: Comprised by components of the complement system, enzymes such as lysozyme, interferons, etc. Cellular branch: Made of neutrophils (AKA Polymorphonuclear leuk9ocytes), macrophages, and Natural k9iller (NK) cells.  TYPES OF IMMUNE SYSTEM Adaptve/ Acquired/Secondary immunity A highly evolved immune system of specifc responses, i.e. it can easily distnguish between diferent invaders, pathogens or antgens. Characterized by antgenic specifcity, i.e. it acts in a highly specifc manner. Also has 2 main branches or components, viz. Humoral branch: Comprised by antgen-specifc antbodies, and cytok9ines. (Mediated by B cells which diferentates into antbody- producing plasma cells). Cellular branch: Made of antgen-specifc B- and T- lymphocytes, cytotoxic T- cells, antgen-presentng cells (APCs), MHC antgens. Note: - The innate immune system is ofen sufcient to destroy invading microbes. However, if it fails to clear the infecton rapidly then it actvates the adaptve or acquired immune response, which then tak9es over. - The connecton between the two systems is mediated by messenger molecules k9nown as cytok9ines (which are any of the numerous secreted low-molecular weight proteins that regulate the intensity and duraton of the immune response by exertng a variety of efects on lymphocytes and other immune cells). Characteristc Immunologic Features of Adaptve Immunity Adaptve immunity displays four (4) characteristc immunologic atributes, viz. Antgenic specifcity, Diversity, Immunologic memory (~ memory), and Self/ non-self-recogniton. Antgenic specifcity The concept of vaccinaton or immunizaton, which produces a state of acquired immunity illustrates exactly what is meant by the term specifc. For example, vaccinaton with poliomyelits virus vaccine induces resistance to a later infecton by poliomyelits virus but not to infecton by infuenza virus. Again, the annual fue vaccinaton indicates that the immune system developed against a partcular year’s strain of the infuenza virus does not necessarily protect against the new strain of the following year. Diversity The immune system is capable of generatng tremendous diversity in its antgen-recogniton molecules (i.e. B- and T-cell receptors and immunoglobulins). This, therefore, allows it to recognize billions of unique structures (epitopes or antgenic determinants) on foreign antgens. Immunologic memory (~ memory) Once the immune system has recognized and responded to a specifc antgen, it exhibits immunologic memory, i.e. a second encounter with the same antgen induces a heightened state of immune reactvity. Self/ non-self-recogniton The ability of the immune system to distnguish self from non-self and respond only to non-self-molecules is essental since the outcome of an inappropriate response to self can lead to development of autoimmune diseases, some of which may proof to be fatal.  REVIEW QUESTIONS Can you now: Defne immunity? List the components of the innate & adaptve immune system? List the main characteristcs of the innate and adaptve immune systems? Compare and contrast the humoral and cellular adaptve immunity? Compare & contrast the innate & acquired immune systems? Compare and contrast the primary and secondary adaptve immune responses to an antgen? List at least three reasons why the study of the immune system is important to you personally as a ‘budding’ scientst?  THE ORGANS, CELLS AND MOLECULES OF THE IMMUNE SYSTEM The specifc immune cells originate in the bone marrow and mature into fully- fedged immune cells in the primary lymphoid organs, capable of recognising and destroying foreign invaders. A. Primary or central lymphoid organs: i. Thymus, and ii. Bone marrow. NB. These two primary organs provide appropriate microenvironments for the development and maturaton of T- and B-lymphocytes, respectvely. B. Secondary or peripheral lymphoid organs: i. Lymph nodes, ii. Spleen, and iii. Mucosa-associated lymphoid tssues (MALT) – located in the respiratory tract and GIT, such as gut- associated lymphoid tssue or GALT, which trap antgen from defned tssues or vascular spaces, and are sites where mature lymphocytes can interact efectvely with the antgen. Note: Blood vessels and lymphatc systems connect these organs, unitng them into a functonal integrated whole.  Thymus (Primary) Development and maturaton of T lymphocytes in the Thymus: Precursor T cells enter the thymus from the bone marrow via the blood circulaton (note there are no aferent lymphatc vessels), They frst enter the cortex, and then begin to mature into functonal T lymphocytes. (Check9 page 2c for the structure of the thymus) o They go through complete and rigorous two-step thymic educaton process, viz. positve and negatve selecton processes, under the guidance of thymic cortcal epithelial cells. Positve selecton: T cells which bear a TCR (receptors) which can bind self-major histocompatbility complex molecule (MHC) molecules are selected to survive and proliferate. Cells which are not positvely selected, i.e. T cells which lack9 a functonal TCR, or T cells which possess a TCR which lack9s afnity for self-MHC molecules, are triggered to undergo apoptosis. Negatve selecton: Positvely selected thymocytes must then go through a second phase of selecton called negatve selecton. Functonally, during negatve selecton any T cell that is presented with and recognizes a self-peptde/antgen in the context of self-MHC molecule within the thymus is triggered to undergo apoptosis. The purpose of this process is to eliminate all potentally self-reactve T cells as early as possible during thymic development in  Spleen (Secondary) From the primary lymphoid organs, the T and B lymphocytes enter the blood circulaton and colonize the various secondary lymphoid organs. Among these the most prominent are the lymph nodes and spleen, in which lymphocytes consttute a signiicant percentage of the total cell populaton. The largest secondary lymphoid organ positoned high in the lef abdominal cavity. Normally weighs 150g. Adapted to flter the blood. It responds, therefore, to systemic infectons. The spleen is not supplied by aferent lymphatcs. Blood-borne cells and antgens are carried into the spleen through the splenic artery, which emptes into the marginal zone. Antgen enters the marginal zone; interdigitatng dendritc cells, which carry the antgen to the (Periarteriolar lymphoid sheaths) PALS, trap it. More of the re-circulatng lymphocytes pass daily through the spleen than all of the lymph nodes combined. Pg 25-37 Self Study: Other Organs and Structure of Primary and Secondary Immune System htps://www.youtube.com/watch?v=r8r1yNeQcp0 Cells of the Immune System (Innate vs Adaptive)  MOLECULES OF THE IMMUNE SYSTEM Antgens (AKA Immunogens): Antgens are foreign substances that can be recognized by the immunoglobulin receptor of B cells (i.e. BCR) and/or by the T cell receptor (i.e. TCR) when complexed with MHC molecules on APCs. The exact part of the antgen that is recognized by the immune system antgen receptors is called an epitope. A single antgen can have more than one epitope, each of which is recognized by a diferent antbody or TCR. Proteins are the most potent immunogens, with polysaccharides rank9ing second. In contrast, lipids and nucleic acids generally do not serve as immunogens unless they are complexed with proteins or polysaccharides. Antgens that can elicit an immune response are called complete antgens, in contrast to incomplete antgens, or haptens, which are low-molecular-weight substances that are not immunogenic by themselves. However, if atached to a larger carrier molecule, they become immunogenic. Note: Once the antbodies have been induced against a hapten, they will react with it even if the hapten is not link9ed to the carrier protein.  Factors that Determine the Immunogenicity of a Substance: i. Degree of foreignness: Generally, the greater the phylogenetc distance between two species, the greater the structural (and therefore, the antgenic) disparity between them. For example, the common experimental antgen, bovine serum albumin (BSA) is not immunogenic when injected into cow but is strongly immunogenic when injected into rabbit. ii. Molecular size: The most actve immunogens tend to have a molecular mass of at least 100 000 Daltons (Da). iii. Chemical compositon and heterogeneity: Copolymers or heteropolymers (i.e. monomers of more than one type) composed of diferent amino acids or sugars are usually more immunogenic than homopolymers (composed of single amino acid or sugar). iv. Susceptbility to antgen processing and presentaton: Large, insoluble macromolecules generally are more immunogenic than small, soluble ones because the larger molecules are more readily phagocytosed and processed. Macromolecules that cannot be degraded and presented with MHC molecules are poor immunogens. v. Genotype of the recipient host or animal: The genetc consttuton (genotype) of an immunized animal infuences the type of immune response the animal manifests, as well as the degree of the response. vi. Immunogen dosage and Route of administraton: Each experimental immunogen exhibits a partcular dose-response curve, which is determined by measuring the immune response to diferent doses and diferent administraton routes. An insufcient dose will not stmulate an immune response either because it fails to actvate enough lymphocytes or because, in some cases, certain ranges of low doses can induce a state of immunologic unresponsiveness, or tolerance.  MOLECULES OF THE IMMUNE SYSTEM Antbodies (AKA Immunoglobulins): Antbodies are serum proteins of the immunoglobulin class that are secreted by plasma cells. They can be defned operatonally as proteins reactng with antgens. Chemically they can be classifed into fve classes: IgA, IgD, IgE, IgG and IgM, based on structural and antgenic propertes. These immunoglobulins share some common features: All immunoglobulins are composed of Light (L) and Heavy (H) chains (See Figure).  Other molecules of immune system Cytokines (AKA Interleukins): A large group of soluble molecules that mediate interactons between cells, i.e. they are involved in signalling between cells during immune responses. All cytok9ines are proteins or glycoproteins. They fall into a number of categories: Interferons (IFNs): - Limit the spread of certain viral infectons (i.e. are antviral in functon – induce a state of antviral resistance in uninfected cells). - For example, IFN-α and IFN-β produced by virally infected cells. - IFN-γ is released by actvated TH1 cells. Interleukins (IL): Secreted mainly by T cells, though some are also produced by mononuclear phagocytes or by tssue cells. Have a variety of functons and many cause other cells to divide and diferentate, for example, IL-4 produced by actvated T cells induce B cell proliferaton and diferentaton. Tumour necrosis Factors α and β (TNF- α & TNF- β) and Transforming growth factor- β (TGF- β): Have a variety of functons, but are partcularly important in mediatng infammaton and cytotoxic reactons. ANTIGEN-ANTIBODY REACTION:  Assignment # 1 Pg 64 of lecture notes Black9board Groups Feedback9-Next Class afer Recap Immune Disfunction and Its consequences. The innate and adaptve immunites depict a multcomponent interactve system the primary functon of which is to protect the host from either infectous diseases and/or cancer. However, sometmes the immune system fails to protect the host adequately or misdirects its actvites to cause discomfort, debilitatng disease or even death. Thus, there are several common manifestatons of immune dysfuncton: a. Hypersensitvity reactons (e.g. systemic anaphylaxis, food allergy, penicillin allergy, and asthma, etc.). b. Graf rejecton and graf-versus-host disease (e.g. rejecton of donor heart or k9idney, etc.). c. Blood transfusion reactons. d. Autoimmune diseases (e.g. systemic lupus erythematosus, rheumatoid arthrits, etc.). e. Immunodeiciency (e.g. HIV and AIDS, SCID, etc.). https://www.youtube.com/watch?v=WUtw8_8zp2o  Types of Hypersensitivity Reactions: Depending upon the rapidity, duraton and type of the immune response involved, these 4 types are broadly grouped into: 1. IMMEDIATE TYPE: - On administraton of antgen, reacton occurs immediately (within seconds to minutes) - Mediated largely by humoral antbodies (B cell-mediated) - Includes Type I, II and III. 2. DELAYED TYPE: - Reacton is slower in onset and develops within 24-48 hours, - Efect is prolonged. - Mediated by cellular response (T cell mediated) - Includes Type IV.  TYPE 1: ANAPHYLACTIC (ATOPIC) REACTION: Aetology of type I: Mediated by humoral antbodies of IgE type or reagin antbodies in response to an allergen. Defnite cause of reacton to allergen not k9nown, but the following are possible hypotheses a) Genetc basis: E.g. there is a 50% chance that a child born to both parents allergic to an antgen may have similar allergy. High levels of IgE in hypersensitve individuals and low level of suppressor T cells are observed in persons with certain HLA types, partcularly HLA-B8. b) Environmental pollutants: Increases mucosal permeability leading to increased entry of allergens, c) Concomitant factors: Allergic responses link9ed to simultaneous occurrence of certain viral infectons of upper respiratory tract in a susceptble individual.  Pathogenesis of type I Reaction Includes partcipaton by B lymphocytes and plasma cells, mast cells and basophils, neutrophils and eosinophils. Mechanism: i. First contact with an allergen, sensitzaton occurs. - Circulatng B cells get actvated and diferentate to form IgE-secretng plasma cells. - The formed IgE antbodies bind to Fc receptors on surface of mast cells and basophils, which are then fully sensitzed for the next event. ii. During the second contact with same allergen: - IgE antbodies on the surface of mast cells and basophils are cross-link9ed by allergen, leading to cell membrane damage and lysis, infux of sodium and water and then degranulaton of mast cells and basophils. iii. The released granules contain important chemicals and enzymes with proinfammatory propertes eg- Histamine, serotonin, vasoactve intestnal peptde (VIP), etc.. iv. Efects of the released chemicals: Increased vascular permeability. Smooth muscle contracton. Early vasoconstricton followed by vasodilataton; Shock9; Increased gastric secreton; Increased nasal and lacrimal secretons; and Increased migraton of eosinophils and neutrophils at the site of local injury as well as their rise in blood (eosinophilia and  TYPE II HYPERSENSITIVITY: CYTOTOXIC (CYTOLYTIC) REACTION Defniton: Reactons by humoral antbodies that atack9 cell surface antgens on the specifc cells and tssues and cause lysis of target cells. Appears generally within 15-30 minutes afer exposure to antgen. Aetology: Generally, have partcipaton by: Complement system, Tissue macrophages, Platelets, NK cells, Neutrophils, & Eosinophils, The main antbodies are IgG and IgM. Reactons are tssue specifc and occur afer antbodies bind to tssue- specifc antgens, most ofen on blood cells.  PATHOGENESIS a. The antgen on surface of target cell (foreign cell) atracts and binds to Fab porton of the antbody (IgG or IgM) forming antgen-antbody complex. b. The unatached Fc fragment of antbodies (IgG or IgM) forms a link9 between the antgen and complement. c. This causes the actvaton of the classical pathway of serum complement which generates actvated complement component, C3b, following the splitng of C4 and C2 by C1, Into C4a & C4b and C2 into C2a & C2b, respectvely. d. Actvated C3a bound to the target cell acts as an opsonin (allow interacton with receptors) and atracts phagocytes to the site of cell injury and initates phagocytosis. e. Ag-Ab complexes also actvate complement system and exposes membrane atack9 complex (MAC) that atack9s and destroys the target cell Note: Serum Complement: a series of dissolved proteins that protect against a variety of pathogens. The actvity of complement in serum can be determined by its ability to lyse red blood cells in vitro.  Examples of type II Hypersensitivity Are typically on Blood Cells and some other body cells and tssues. i. Due to cytotoxic antbodies to blood cells: E.g.s a. Autoimmune haemolytc anaemia: - Red blood cell injury brought about by autoantbodies reactng with antgens present on red cell membrane. b. Transfusion reactons due to incompatble or mismatched blood transfusion. ii. Due to cytotoxic antbodies to tssue components: a. Graves’ disease (Primary hyperthyroidism): - Thyroid autoantbodies are formed which reacts with the TSH-receptor to cause hyperfuncton and proliferaton (i.e. stmulatng autoantbodies). b. Male sterility: - Ant-sperm antbodies are formed which react with spermatozoa and cause impaired motlity as well as cellular injury. c. Type 1 diabetes mellitus: - Islet cell autoantbodies are formed which react against islet cells leading to their destructon and hence defciency of insulin.  TYPE III: IMMUNE COMPLEX MEDIATED (ARTHUS) REACTION: Basically result from, depositon of antgen-antbody (Ag-Ab) complexes formed between antgens and appropriate antbodies on tssues, Followed by actvaton of complement system & infammatory reacton → Tissue Injury. Onset tak9es place about six (6) hours afer exposure to antgen. Not tssue specifc & occurs when Ag-Ab complexes fail to get removed by the immune system. Aetology of type III Hypersensitvity: There are three (3) possible aetologic factors precipitatng type III reacton: viz. Persistence of low grade microbial infecton, Extrinsic environmental antgen, & Autoimmune process.  TYPE IV: DELAYED-TYPE HYPERSENSITIVITY (DTH) REACTION: Tissue injury by Cell-mediated immune response. No antbodies are involved (contrary to types I, II & III). A slow, prolonged response of specifcally-sensitzed T lymphocytes. Reacton occurs about 24 hours afer exposure to antgen. Efect prolonged, may be up to 14 days. Aetology of type IV hypersensitvity reactons: Involves mast cells and basophils, macrophages, CD4+ and CD8+ T cells, which typically aggregate at the site of injury to form granulomas. Antgen-specifc efector T cells are stmulated leading to macrophage actvaton and localized infammaton and oedema.  TRANSPLANTATION IMMUNOLOGY Solid tssues can be transplanted successfully from one individual to another, but the graf will be viable only if the donor and the recipient are immunologically similar enough to avoid immunologic rejecton. The immune system can be partally inactvated with various immunosuppressive drugs, which are used in clinical medicine to facilitate the acceptance of transplants. In the clinical setng, there are several forms of transplantaton: Autografs- The patent is serving as both the donor and recipient Isografs-Tissue transplantaton between genetcally identcal individuals of the same species, as in genetcally syngeneic mouse strains or identcal twins. Homografs (Allografs)- Transplants between individuals of the same species who are not genetcally identcal (same blood type, relatves etc.) Xenografs- Tissue transplants between animals of diferent species (as in liver transplants between monk9eys and humans, or pigs and humans).  Transplant rejection All homografs/ allografs invariably evoke some transplant rejecton, which is mediated by antbodies and a delayed cellular immune reacton. There are three (3) major types of rejecton; viz. hyperacute, acute, and chronic. Hyperacute-Typically occurs due to the presence of preformed antbodies against the donor’s antgens. Typically occurs during the operaton. Acute-Occurs most ofen within the frst few week9s of transplantaton but may evolve later when the immunosuppressive treatment becomes inefectual. Chronic-Evolves slowly over a period of several months or years. It also involves both antbody- and cell-mediated responses htps://www.youtube.com/watch?v=Xfs3rI2NZssw Examples of Some Commonly Used Immunosuppressive therapies: o Drugs: - e.g. cyclosporine – which inhibits IL-2 producton, and thus impairs T cell responses; or - Cyclophosphamide, which inhibits proliferaton of lymphocytes. o Antbodies to T-cell antgens, to reduce the number of these cells. Disadvantages of use of Immunosuppressive therapy: It predisposes the patent to infectons. Some drugs such as cyclosporine may have signifcant side efects and are nephrotoxic. Risk9 of cancers is also increased.  Blood transfusion: Transfusion of blood from one person to another is a form of transplantaton. In contrast to solid organs (such as k9idney, heart, liver, cornea, etc.), however, blood is a tssue that is composed of dissociated cells circulatng inside the vessels. Because RBCs outnumber white blood cells (WBCs) by an order of magnitude, the success or failure of blood transfusions depends primarily on the compatbility of the donor and the recipient with regard to their RBC blood group antgens. Every RBC carries a set of surface antgens, which can be divided into three groups: Major blood group antgens (ABO), Minor blood group antgens (e.g. M and N positve (MNS system), K positve (Kell system), and Lea or Leb positve (Lewis system) [there are more than two hundred minor Blood groups that can complicate Blood transfusion] And Rh (D+,D-) blood group antgens. htps://www.youtube.com/watch?v=cKnEdvrmHK4  The ABO Blood Group System: These are the major blood group antgens. Encoded by three (3) genes that can give the following six (6) genotypes: AA, AB, AO, BO, BB, and OO. The A and B genes are dominant over the O gene, so there are only four (4) blood groups: A (AA, AO), B (BB, BO), AB, and O. The ABO antgens have corresponding natural antbodies: Group A blood (A oligosaccharide is present) & contains ant-B antbodies, Group B blood (B oligosaccharide is present) & contains ant-A antbodies, and the Group AB (A and B oligosaccharides are present) & blood does not contain natural antbodies to A or B antgen. Group O group (neither A nor B, only their precursor H oligosaccharide present) & contains both ant-A and ant-B antbodies.  The ABO Blood Group and Complications Thus, A blood can be given to group A and to AB recipients, because the blood of these recipients does not contain antbodies to group A antgen. Group AB blood can be given only to AB group recipients, because all other groups’ persons contain antbodies to A or B or both. O group blood can be given to recipients of all blood groups. Accordingly, individuals with AB blood group are called universal recipients and those with O blood group are considered universal donors. If the blood of an A group donor is infused into a B group recipient, the natural antbodies to A in the recipient will react with the donor’s RBCs and cause their haemolysis. This transfusion reacton presents clinically with chills, shivering, and even mild fever. If the transfusion reacton is not diagnosed and terminated immediately, massive haemolysis may cause: - Shock9, - With microthrombi, ads - Disseminated intravascular coagulaton (DIC) - Some patents may even die (i.e. reacton may be fatal). - Jaundice, from bilirubin released from haemolysed RBCs, develops in those who survive. - Acute renal failure is a common complicaton.  How to avoid Blood Transfusion Reactions: Note: Ymou cross-match the donor’s blood with the blood of the recipient before the transfusion by mixing the serum of the recipient with the RBCs of the donor, and vice versa. Briefy, The RBCs are incubated at room temperature in vitro. The RBCs that are compatble with the serum will remain suspended in the fuid. However, if there are antbodies in the serum, these will atach to the RBCs and agglutnate them. Blood that agglutnates in the cross-match is not suitable for transfusion ….Agglutnaton Test.. This process can also detect signifcant incompatbilites of minor blood group antgens.  Rh Factor Incompatibility: Only three antgens, k9nown as cde/CDE are strong antgens in the Rh blood group system, and Of these only the d/D antgen is of practcal signifcance. Persons who have the dominant allele D, are Rh positve (Rh+), and those who have two recessive d/d alleles are Rh negatve (Rh-) (there is no "d" antgen; lowercase "d" indicates the absence of D). For example, an individual can be AB RhD positve, and at the same tme M and N positve (MNS system), K positve (Kell system), and Lea or Leb positve (Lewis system). Many of the blood group systems were named afer the patents in whom the corresponding antbodies were initally encountered. In contrast to the ABO antgens, which are complemented with natural antbodies, Rh antgens do not have natural antbodies.  AUTOIMMUNE DISEASES: Defniton: A state in which the body’s immune system fails to distnguish between “self” and “non-self” and reacts by formaton of autoantbodies against one’s own tssue antgens. It loses its sense of self and non-self, which permits an immune atack9 upon the host. I.e. there is loss of tolerance to one’s own tssues: autoimmunity is the opposite of immune tolerance. Thus, there is a break9down of auto- tolerance. Immune tolerance= is a normal phenomenon present since foetal life and is defned as the ability of an individual to recognise self-tssue antgens. Immune Tolerance may either through Natural or Induced or Acquired mechanisms:  Natural Immune Tolerance mechanisms Clonal deleton or eliminaton: During embryonic development, T cells maturing in thymus acquire ability to distnguish self from non-self, Those T cells that fail this are then eliminated by apoptosis for the tolerant individual. Because some T cells act as helper cells for B cells, it is more efcacious to induce tolerance in T cell populatons. Remember the Positve and Negatve selecton in slide 12: T cells which bear a TCR (receptors) which can bind self-major histocompatbility complex molecule (MHC) molecules are selected to survive and proliferate. Cells which are not positvely selected, i.e. T cells which lack9 a functonal TCR, or T cells which possess a TCR which lack9s afnity for self-MHC molecules, are triggered to undergo apoptosis. Positvely selected thymocytes must then go through a second phase of selecton called negatve selecton. Functonally, during negatve selecton any T cell that is presented with and recognizes a self-peptde/antgen in the context of self-MHC molecule within the thymus is triggered to undergo apoptosis. The purpose of this process is to eliminate all potentally self-reactve T cells as early as possible during thymic development in order to prevent the development of autoimmunity.  Induced or Acquired Tolerance mechanisms: Results from medical manipulatons carried out to atenuate or suppress the immune or allergic response. For example: Hyposensitzaton, or “ allergy shots” Use of immunosuppressant mechanisms to prevent graf rejecton. Ant-infammatory medicaton to reduce damage by autoimmune disorders.  Diagnosis of Autoimmune disorder: It is made when: i. The existence of autoantbodies can be documented. ii. There is evidence that the immune mechanisms are pathogenetcally important and have caused the pathologic lesions, and iii. There is direct or indirect evidence of the immune nature of the disorder. For example, a disease is presumably autoimmune if it shows a favorable response to treatment with immunosuppressive drugs or if it can be diagnosed by immunologic techniques. htps://www.hopk9insmedicine.org/health/conditons-and-diseases/disorders -of-the-immune-system  Three common autoimmune diseases are: 1. Type 1 diabetes: The immune system atack9s the cells in the pancreas that mak9e insulin. Insulin removes sugar from the blood to use as energy. 2. Rheumatoid arthrits: This type of arthrits causes swelling and deformites of the joints. An auto-antbody called rheumatoid factor is in the blood of some people with rheumatoid arthrits. 3. Lupus: This disease that atack9s body tssues, including the lungs, k9idneys, and sk9in. Many types of auto-antbodies are found in the blood of people with lupus. Types of autoimmune diseases  IMMUNODEFICIENCY DISEASES https://www.stlukes-stl.com/health-content /health-ency-multimedia/1/000818.htm Failure or defciency of immune system Manifests by occurrence of repeated or recurrent infectons. Traditonally are classifed into two (2) types: Primary and Secondary immunodefciencies. PRIMARY immunodeiciencies: Usually results from genetc or developmental abnormalites of immune system. Defect is normally congenital, i.e. present at birth although it may NOT manifest itself untl later in life. May afect either adaptve or innate immunity or both. Adaptve IR defciencies involve: - B & T lymphocytes, - Cytok9ine receptors, - Immunoglobulins, etc. Innate IR defciencies involve: - Non-specifc mediators, for example, phagocytes, complement, etc. Some examples of (PI) are: Severe combined immunodefciency (SCID) in which both T and B cell defcient. Note: B cell defect is not evident in the frst few months of the afected infant’s life. Why? Because antbodies are passively obtained either from Transplacental circulaton or from mother’s milk9 (colostrum). DiGeorge syndrome: Thymic hypoplasia. Autosomal recessive agammaglobulinaemia (Ab defciencies). SECONDARY immunodeiciencies: Usually arise from acquired suppression of the immune system. Infectons (e.g. AIDS (HI virus), bacteria, etc.). Cancer (Chemotherapy; irradiaton), Lymphoid neoplasms (lymphomas, leuk9aemias), Malnutriton (Protein defciency), Transplant cases (Immunosuppressive therapy).  Examples of Primary Immunodefciency. Severe Combined Immunodefciency (SCID) Stems from defects in lymphoid development that afect either T cells or both T and B cells. There are very low numbers of circulatng lymphocytes. There is failure to mount IR mediated by T cells. The thymus does not develop (→ Thymic Aplasia). The few circulatng T cells in SCID patents do not respond to stmulaton by mitogens (e.g. Phytohaemagglutnin or PHA ~ a lectn or sugar-binding protein), indicatng their failure to respond to foreign antgens. Myeloid and Erythroid cells appear NORMAL in both NUMBER and FUNCTION. Indicatng that only LYmMPHOID cells are depleted. SCID results in Severe Recurrent Infectons and usually fatal in early years of life. SCID is initally manifested by infectons, such as fungal and viral, normally dealt with by T cell immunity. DiGeorge Syndrome (Congenital Thymic Aplasia): The most severe form of the immune disorders involving failure of the thymus to undergo normal development. Characterized by congenital complete absence of a thymus. A developmental defect (Intrauterine developmental anomaly). Associated with deleton in the embryo of q11 region on chromosome 22. Treatment of DiGeorge Syndrome: Currently, there are already encouraging experimental data that indicate that some of these children may be saved by genetc engineering. “Bubble children” (so called because they must be placed in strict isolaton from all environmental pathogens) have already received transplants of genetcally modifed lymphoid cells. Transplanted cells have successfully repopulated the bone marrow of these immunodefcient children and colonized the secondary lymphoid organs, thus completely correctng the immunodefciency in a dozen children.  Examples of Secondary Immunodefciency. Nutritonal immunodeiciency: Malnutriton increases the risk9 of infant mortality from infecton through reducton in cell- mediated immunity, reduced CD4+T helper cells, reduced T cell help, and a reducton of secretory IgA. Trace elements, iron, selenium, copper, and zinc are important in immunity. Lack9 of these elements can lead to; diminished neutrophil k9illing of bacteria and fungi, susceptbility to viral infectons, and diminished antbody responses. Vitamins A, B6, C, E, and folic acid are important in overall resistance to infecton. Lack9 of Antoxidant actvity is associated with reduced NK cell actvity, lack9 of cytok9ine producton, and reduced actvity of the phagocytc cells.  Agent or Drug-Induced Immunodefciency Exposure to any of a number of chemical and biological agents that induce immunodefciency state. Drugs used to combat autoimmune diseases such as Rheumatoid arthrits or SLE (e.g. ant-infammatory agents); or drugs used for immunosuppressive therapy (e.g. cyclosporine A) to blunt the atack9 of the immune system on transplanted organs. htps://www.mometrix.com/academy/immunomodulators-and-immunos  ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS): Aetology: Caused by an RNA retrovirus, Human immunodefciency virus (HIV), a type of human T cell leuk9aemia- lymphoma virus (HTLV) Have tropism for molecules present on CD4+ T cells (the HI virus uses the gp120 protein to dock9 on CD4+T cells). Is cytolytc for T cells causing immunodefciency (cytopathic virus). Two forms are described: 1. HIV-1 – an aetologic agent for AIDS in US & Central and SADEC countries; 2. HIV-2 – causes AIDS in West Africa and parts of India. Both are zoonotc infectons, and a species of chimpanzees are the natural reservoir. Routes of Transmission P 111/2 A. Sexual transmission B. Transmission via blood and blood products C. Perinatal transmission D. Occupatonal transmission E. Transmission by other body fuids  Pathogenesis of HIV and AIDS: Largely related to the depleton of CD4+ T cells (helper T cells) resultng in profound Immunosuppression. HIV shows tropism for CD4 molecule receptor. CD4+ T cell destructon: Viral partcles replicated in the CD4+ T cells start forming buds on the cell membrane of the host cell, and these buds damage part of the cell membrane and hence cause death of CD4+ T cells by apoptosis. htps://www.atrainceu.com/content/1-part-i-etology-and-epidemiology -hivaids-0 Three faces of HIV  AIDS is characterized by the following: Unusual infectons, such as the opportunistc fungal pathogen Pneumocysts carinii, which causes pneumonia called PCP (P. Carinii Pneumonia). Other bacterial infectons such as M. tuberculosis are also common. Protozoa (cryptosporidia and microsporidia) are the commonest pathogens isolated in patents with diarrhoea and weight loss, but enteric bacteria such as Salmonella and Campylobacter spp. May also be found. Discomfort on swallowing is usually caused by Candidiasis (thrush), but cytomegalovirus can cause oesophageal ulceraton. Neurological complicatons in AIDS are due to: - Direct efects of HIV infecton; - Opportunistc infectons; or - Lymphoma. Spinal cord and peripheral nerve disease also occur. Toxoplasmosis, a protozoal infecton, causes cysts in the brain and neurological defcit.  The Diagnosis of AIDS includes: Evidence of infecton with HIV-1 (presence of antbodies or virus in blood). Greatly diminished numbers of CD4+ T cells (< 200cells/mm3). Impaired or absent Delayed type hypersensitvity (DTH) is a cell-mediated immune response, and Occurrence of opportunistc infectons, such TB, pneumonia, severe wastng diarrhoea; and Various malignancies such as Kaposi sarcoma. Self study: 122-131 (IMMUNITYm TO SOME INFECTIOUS DISEASES) Review Questons: 7.1. What is the mechanism of type I hypersensitvity? 7.2. Which common diseases are caused by type I hypersensitvity reactons? 7.3. What is the pathogenesis of anaphylactc shock9? 7.4. What are the two basic mechanisms of type II hypersensitvity? 7.5. Compare the role of type II hypersensitvity in haemolytc anaemia, Graves’ disease, and myasthenia gravis. 7.6. Give examples of diseases caused by type III hypersensitvity reactons? 7.7. Compare Arthus phenomenon with systemic lupus erythematosus. 7.8. What is the mechanism of type IV hypersensitvity? 7.c. What common diseases are caused by type IV hypersensitvity reactons? 7.10. What is the diference among autografs, isografs, homografs, allografs, and xenografs? 7.11. What is the diference among hyperacute, acute, and chronic transplant rejecton? 7.12. What is the pathogenesis and what are the clinical features of graf-versus-host reacton? 7.13. Hoe could one determine whether a unit of donated blood could safely be transfused into a person in need of blood transfusion? 7.14. Describe the pathogenesis of erythroblastosis foetalis resultng from maternofoetal Rh incompatbility. 7.15. What is k9ernicterus? 7.16. What are pathogenesis and clinical and pathologic fndings in systemic lupus erythematosus? 7.17. If the viral load begins to increase in the blood of an HIV-infected individual and the level of CD4+T cells decrease, what would this indicate about the infecton?