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IMMUNOLOGY 7105306 HYPERSENSITIVITY (UPDATED) Part-11 References: Immunology , David Male et al 8th ed 2013 Basic Immunology , Abul K. Abbas and Andrew H. Lichtman, 3ed, 2011 Instructor: Dr Alaeddin Abuzant, PhD Microbiology and Immunology Email: [email protected] The immune system is required for defending the host against infections ( and tumor cells) However, excessive ( uncontrolled ) or aberrant immune responses are capable of causing tissue injury and disease. Such immune responses are called hypersensitivity reactions. In general, hypersensitivity reactions may occur in two situations: 1- Uncontrolled excessive responses to foreign antigens that may result in tissue injury. 2- An aberrant immune responses that may be directed against self (autologous) antigens, as a result of the failure of self-tolerance that result in autoimmune diseases. What are the mechanisms of different types of hypersensitivity reactions? What are the major clinical and pathologic features of diseases caused by these reactions what principles underlie treatment of such diseases? Types of Hypersensitivity Reactions On the basis of the principal immunologic mechanism that mediates hypersensitivity reactions, these reactions can be classified: 1- Immediate hypersensitivity, or type I hypersensitivity: It is a type of pathologic reaction that is mediated by the release of mediators from mast cells. It is mostly triggered by the production of excessive amount of IgE antibody directed against environmental antigens ( foreign antigens/allergen ) and the binding of IgE to mast cells in various tissues. 2- Type II hypersensitivity: It is mediated by antibodies directed against self cellular or tissue antigens that either cause A- Damage these cells or tissues B- Impair their functions. 3- Type III hypersensitivity: it is mediated by antigen-antibody complex (immune complexes) that may deposit in blood vessels in various tissues, causing inflammation and tissue injury. Note: type II and III are mediated by antibodies other than IgE 4- Type IV hypersensitivity: It is mediated by T lymphocytes that attack self antigens in tissues to cause tissue injury 1- Immediate Hypersensitivity Reactions ( Type I hypersensitivity) Immediate hypersensitivity is a rapid immunologic reaction that is mediated certain mediators released from activated mast cells Immediate hypersensitivity reactions are also called allergy, or atopy Individuals with a strong propensity to develop these reactions are said to be “atopic.” …..allergic individuals Such reactions may affect various tissues and may be of varying severity in different individuals. The reactions caused by mast cell mediators can be classified as 1- Immediate phase reactions : some of the mast cells cause mediators ( such as histamine) cause a rapid increase vascular permeability and smooth muscle contractions that may occur within minutes of reintroduction of antigen into a previously sensitized atopic individual (hence the name immediate hypersensitivity) 2- late phase reaction inflammatory reaction: is mediated by other mast cell mediators which are cytokines ( Chemokines) that recruit Neutophils and Eosinophils over several hours resulting in inflammation that is mainly responsible for the tissue injury Common types of immediate hypersensitivity reactions include: Hay fever Food allergies Bronchial asthma Anaphylaxis Allergies ( type I hypersensitivity) are the most frequent disorders of the immune system, estimated to affect about 20% of the population. The sequence of events in the development of immediate hypersensitivity reactions consists of: I- Sensitization: Occurs in atopic person upon exposure (first exposure) to an environmental antigen ( foreign antigens). Such antigen are called allergens In response to an allergen, atopic people tend to produce large amount of IgE antibodies that bind to IgE to Fc receptors of mast cells. This process is called sensitization 2- Activation of mast cells and the release of mast cell mediators: Upon re-exposure to the same allergen, this allergen causes cross-linking of the bound IgE antibodies on mast cells. This cross-linking of the bound IgE antibodies on mast cells causes aggregation of the IgE to Fc receptors) triggers the release of mast cell mediators The immune response triggered in atopic individuals upon exposure to a particular allergen results in the activation of TH2 cells and the production of IgE antibody Normal individuals do not mount strong TH2 responses to most foreign antigens. In atopic individuals (so far unknown reasons), cellular adaptive immune responses, to certain foreign antigens, tend to skewed toward the development of a dominant TH2 cells. Recall that cytokines produced by TH2 cells causes the production of IgE antibodies by ( class switching) Foreign antigen that trigger allergic reactions are know as (allergens) Example of common allergens: proteins in pollen, certain foods, insect venoms, or animal dander, certain drugs such as penicillin. Any atopic individual may be allergic to one or more of these antigens IgE antibody class switching: Two of the cytokines secreted by TH2 cells, interleukin (IL)-4 and IL-13, stimulate B lymphocytes ( that have receptors for the same allergen that trigger the development of TH2 cells) These cytokines that cause IgE antibody class switching in these B cells Therefore, in atopic persons, immune responses to certain antigens ( allergens) produce large amounts of IgE antibody (this does not happen in most people that usually do not mount a strong TH2 response upon exposure to the same antigens) It is believed that the propensity toward TH2 development, and consequently IgE production that may result in immediate hypersensitivity reactions has a strong genetic basis, with many different genes playing contributory roles. ACTIVATION OF MAST CELLS AND SECRETION OF MEDIATORS In an atopic individual, an immune response triggered by an allergen causes the production of large amount of IgE antibodies that bind to high-affinity Fc receptor on mast cells that is specific for the ε heavy chain of IgE antibodies (known as FcεRI )(Fc epsilon RI) (Fig. 11-3). This process of coating mast cells with a large amount IgE is called “sensitization,” This is because coating of mast cells with a large number of IgE antibody molecules specific for a particular allergen makes the mast cells very sensitive to activation by subsequent ( next time) exposure to the same allergen. Note: Suppose we have an antigen called X In normal individuals, exposure to X antigen may elicit (induce) small amount of anti-X IgE antibodies ( recall that in response to most antigens , normal individuals do not develop an immune response that is largely skewed toward TH2) In contrast, in atopic people , the immune response to X antigen is largely skewed toward TH2 …..TH2 cytokines…IgE class switching…production of large amount of anti X IgE antibody So, in an X antigen atopic person (allergic to X antigen), mast cells become coated with a large number of anti- X IgE antibody molecules ( the presence of a large number of one type of IgE directed against X antigen makes mast cells very sensitive to activation upon reexposure to the same allergen). Upon re-exposure to X antigen, X antigen bind to several IgE antibodies ( cross- link several IgE antibodies ) found on the surface of mast cells ( assuming that X antigen is a muti-valent antigen). This causes aggregation of several FcεRI that is necessary to trigger an activation signal that is strong enough for activation of mast cells. Activation of mast cells results in the release of mast cell mediators that are enough to cause immediate hypersensitivity reactions upon re-exposure to x antigen…that causes large number of eggergations of the Fc receptor on mast cells…enough to trigger a string signal needed for mast cells activation In contrast, in normal individuals, mast cells may have a small number of anti X IgE antibody bound to it….. Normally ..these mast cells in normal individuals may also be coated with different types of IgE antibodies. However, each type of these IgE antibodies is also found in small number on the surface of mast cells. Upon re-exposure to X antigen, the X antigen may bind to anti-X IgE antibodies on the surface of mast cells. Since there is only a small number of anti-X IgE on the surface of mast cells, X antigen will not be able to cross link these antibodies..and thus no aggregation FcεRI happens …..accordingly, there will be no strong activation signal would be generated that will be enough to activate mast cells ( since IgE antibody on mast cell are found in small number, these antibodies will be distributed on the surface of mast cell so that they will not be close enough to each other in such a way that the X antigen ( upon re-exposure) will not be able to cross-link bound IgE antibodies on the surface of mast cells since they locate far a way from each other) . Small number of Anti X IgE antibodies High number of Anti X IgE antibodies Upon Re-Exposure to X antigen In normal individual In atopic individual No cross-linking of anti X IgE on the surface of mast cell Cross-linking of anti X IgE on the surface of sensitized mast cell No aggregation FcεRI happens, thus no activation signal Mast cell mediators are NOT released Aggregation FcεRI happens that lead to the induction of the activation signal X antigen do NOT cross link anti X IgE on the surface of mast cell because they are far from each other on the surface of mast cell (low number) Mast cell mediators are released X antigen cross link anti X IgE on the surface of sensitized mast cell (anti X IgE are close to each other so that they can be easily cross-inked)(found in high number) No aggregation of Fc receptor Aggregation of Fc receptor No Activation signal Activation signal is triggered No mast cell mediators are released Mast cell mediators are released The sequence of events in immediate hypersensitivity. Immediate hypersensitivity diseases are initiated by the introduction of an allergen, which stimulates TH2 reactions and immunoglobulin E (IgE) production. IgE binds to Fc receptors (FcεRI) on mast cells, and subsequent exposure to the allergen activates the mast cells to secrete the mediators that are responsible for the pathologic reactions of immediate hypersensitivity. Mast cells are present in all connective tissues, and which of the body’s mast cells are activated by cross-linking of allergen-specific IgE often depends on the route of entry of the allergen. Example: Inhaled allergens activate mast cells in the sub mucosal tissues of the bronchus, Ingested allergens activate mast cells in the wall of the intestine. The high-affinity Fcε receptor, called FcεRI, consists of three chains, one of which binds the Fc portion of the ε heavy chain very strongly, the other two chains of the receptor are signaling proteins. The same FcεRI also is present on basophils, the circulating counterpart of mast cells, but the role of basophils in immediate hypersensitivity is not as well established as the role of mast cells. The activation signal lead to three types of responses in the mast cell: 1. Rapid release of granule contents (degranulation/exocytosis) 2. Synthesis and secretion of lipid mediators (products of arachidonic acid metabolism) 3. Synthesis and secretion of cytokines The most important mediators produced by mast cells are: 1. Vasoactive amines (histamine) and proteases that are released fronm the granules of mast cells, 2. Products of arachidonic acid metabolism 3. Cytokines . Mast cell mediators have different actions 1- Mast cell mediators released from mast cell degranulation, these include A- Histamine: it causes: Dilation of small blood vessels, Increases vascular permeability Stimulates transient contraction of smooth muscles. B- Proteases: that may cause damage to local tissues. 2- Arachidonic acid metabolites . These include: A- prostaglandins, which cause vascular dilation B- leukotrienes, which stimulate prolonged smooth muscle contraction 3- Cytokines and chemokines:these induce local inflammation (the late phase reaction). Thus, mast cell mediators are responsible for 1- Acute vascular and Smooth muscle reactions 2- inflammation These two effects of mast cell mediators are the hallmarks of immediate hypersensitivity. Cytokines produced by mast cells stimulate the recruitment of leukocytes, which mediate the late phase inflammatory reaction The principal leukocytes involved in this reaction are: 1. Eosinophils 2. Neutrophils 3. TH2 cells Mast cell-derived tumor necrosis factor (TNF) and IL-4 promote Neutrophil and Eosinophil rich inflammation. The inflammation is mediated by proteases released from these cells that cause tissue damage Eosinophils are prominent components of many allergic reactions and are an important cause of tissue injury in these reactions. These cells are activated by the cytokine IL-5, which is produced by TH2 cells and mast cells. The TH2 cytokine, IL-13 acts on airway epithelial cells to stimulate the secretion of mucus Note: Chemokines produced by mast cells and by epithelial cells in the tissues also contribute to Neutrophil and Eosinophil to the site of the allergic reaction Biochemical events in mast cell activation. Cross-linking of immunoglobulin E (IgE) on a mast cell by an allergen stimulates phosphorylation of immunoreceptor tyrosine–based activation motifs (ITAMs) in the signaling chains of the IgE Fc receptor (FcεRI), which then initiates multiple signaling pathways. These signaling pathways stimulate the release of mast cell granule contents (amines, proteases), the synthesis of arachidonic acid metabolites (prostaglandins, leukotrienes), and the synthesis of various cytokines. These mast cell mediators stimulate the various reactions of immediate hypersensitivity. TNF, tumor necrosis factor CLINICAL SYNDROMES OF TYPE I HYPERSENSITIVITY Immediate hypersensitivity reactions have diverse clinical and pathologic features, all of which are attributable to mediators produced by mast cells in different amounts and in different tissues (Fig. 11-5). Examples of Type I Hypersensitivity Reactions: Hey fever ( A mild Type I hypersensitivity reaction): It is characterized by allergic rhinitis and sinusitis, which are reactions to inhaled allergens, such as the ragweed protein of pollen. Increased production of mucus in the nasal mucosa seen in Hey fever is mediated by histamine released from mast cells and by IL-13 produced by TH2 cells. Late phase reactions seen in Type I hypersensitivity reactions may lead to more prolonged inflammation. Food allergies: ingested allergens trigger mast cell degranulation found in intestinal tissue . The released histamine causes increased peristalsis that may result in diarrhea Bronchial asthma: Is a form of respiratory allergy in which inhaled allergens (often undefined) stimulate bronchial mast cells of the lungs to release mediators , which include leukotrienes Leukotrienes cause repeated bouts of bronchial constriction and excessive secretion of mucus that may lead to airway obstruction. Chronic asthma is characterized by: 1- the presence of a large numbers of eosinophils in the bronchial mucosa 2- the bronchial smooth muscle becomes hyper-reactive to various stimuli NOTE: Some cases of asthma are NOT associated with IgE production, although all are caused by mast cell activation. In some affected persons, asthma may be triggered by cold or exercise that cause mast cell activation by unknown mechanism. Anaphylaxis (Anaphylactic Shock) It is the most severe form of immediate type I hypersensitivity reaction that is caused by widespread mast cell degranulation (systemic…in all body tissue) in response to a systemic antigen ( an allergen that reaches the blood stream) Anaphylaxis is defined as a systemic Type I hypersensitivity reaction that is characterized by edema in most body tissues, including the larynx ( causes airway obstruction) and is associated by a sudden fall in blood pressure. Accordingly, anaphylaxis is a life-threatening reaction because of the sudden fall in blood pressure and airway obstruction THERAPY OF TYPE I HYPERSENSITIVITY REACTIONS: The therapy for immediate hypersensitivity reactions (Type I) is aimed at 1- Inhibiting mast cell de-granulation 2- Antagonizing ( stop) the effects of mast cell mediators 3- Reducing inflammation You need to know and memorize the ENTIRE table Please, pay attention to the information framed in RED II- Desensitization Desensitization involves repeated administration of small doses of an allergen, that may stop the allergic response to this allergen ( so that the patient stop being allergic to this allergen and will not have an allergic response to it in the future) This treatment may work by changing the T cell response away from TH2 dominance or by inducing tolerance (anergy) in allergen specific T cells. Evolution and Type I Hypersensitivities: What is known about IgE antibodies and mast cells is : IgE antibody and eosinophils are important mechanisms of defense against helminthic infections Mast cells play a role in innate immunity against some bacteria. Anyhow, it is still important to address the following question: Why evolution has preserved (IgE antibody/mast cell) -mediated allergic immune response whose major effects are pathologic.?????? There is no good answer to this puzzle!!!!!!!!???????? Moreover, it is NOT understood why common environmental antigens (allergens) induce immune reactions (that involves TH2 cells….IgE antibodies …. and mast cells) that are capable of causing considerable damage ( maybe because of genetic factors) . TYPE II Hypersensitivity These are caused by antibodies (other than IgE antibodies). 1- Auto-antibodies and 2- Cross-reacting antibodies: Definitions: 1- Auto-antibodies (self-reacting) antibodies directed against self antigens. Such antibodies are generated because of the of that are generated because of the failure of self-tolerance 2- Cross-reacting antibodies are kind of auto-antibodies that are generated in certain microbial infections. In these cases the antibodies induced against a particular microbial antigen is also able to recognize and bind to a self antigen that is very similar to the microbial antigen to which the antibody was directed against….hence the name cross-reacting reacting antibodies …..(In this case, microbial infection causes failure of self tolerance) An example of microbial Infection that causes the production of cross-reacting antibodies that are produced against microbial antigens. . Type II Hypersensitivity Diseases Caused by Self-Reacting Auto-antibodies Type II hypersensitivity is a type of an autoimmune disease that is caused by autoantibodies (self-reacting) that are directed against self antigens found on extracellular matrix components or cell surface molecules. A- Autoantibodies bind to self-antigens on extracellular matrix: In this case, the Fc regions of the auto-antibodies bind to Fc receptors on Macrophages and Neutrophils causing their activation. Upon activation, these cells, start to release lysosomal enzymes and Reactive Oxygen intermediates , resulting in inflammation and damage the adjacent tissues. In addition, the Fc regions of certain autoantibodies resulting in complement activation causing damage to adjacent tissue. The generated complement fragments function as chemokines to recruit more leukocyte. Tissue inflammation mediated by autoantibodies bind to selfantigens on extracellular matrix B- Auto-antibodies bind to self cell surface antigens (molecules )( Example: on the surface of erythrocytes and platelets): In this case, these cells become opsonized by the Fc region of the bound antibodies and by complement fragments such as C3b. Opsonized cells may be ingested and destroyed by host phagocytes. In addition, activation of complement on the surface of these cells may result in their destruction C- Auto-antibodies bind to certain self antigens (molecules) that function as cell surface receptors such as hormone receptors or neurotransmitter receptors In this case, these self-reacting auto-antibodies may interfere with normal cellular functions ((without causing tissue injury)). In this case, the target of the auto-antibodies are cell surface receptors..such as hormone receptors or neurotransmitter receptors) …see examples on next slide 1- Graves’ disease is an autoimmune disease that is caused by self-reacting autoantibodies directed against hormone receptor (TSH receptor). Binding of self-reacting auto-antibodies to the hormone receptor may directly activate receptors ( mimicking their physiologic effect of hormone binding to this receptor) A form of hyperthyroidism called Graves’ disease: In this case, self reacting autoantibodies antibodies against the receptor for thyroid-stimulating hormone (TSH) stimulate thyroid cells to produce large amounts of T2 and T4 hormone ……… 2- Myasthenia gravis is an antoimuune disease that is caused by self-reacting auto antibodies directed against neurotransmitter receptor ( Acetylcholine receptor) : Myasthenia gravis is a autoimmune disease that is mediated by self-reacting autoantibodies directed against the acetylcholine receptor on muscles. This will inhibit neuromuscular transmission, causing paralysis. Self-reacting auto-antibodies interfering with normal cellular functions, such as hormone or a neurotransmitter receptor You need to know and memorize this table DO NOT MEMORISE THIS TABLE Type II Hypersensitivity Diseases Caused Cross-Reacting Antibodies: Remember that cross-reacting antibodies are kind of auto-antibodies that are generated during certain microbial infections. In these cases the antibodies induced against a particular microbial antigen is also able to recognize and bind to a self antigen that is very similar to the microbial antigen to which the antibody was directed against….hence the name cross-reacting antibodies ….. During infection with certain microbes, the infecting microbe may cause failure of self tolerance to trigger the generation of cross-reacting antibodies that recognize both microbial and host self antigens at the same time The indicate that the infecting microbial pathogen has an antigen that is very similar to host antigen….in this case the induction of an immune response to the microbial antigen could be behind the failure of self tolerance to that antigen Examples of clinical situations caused by microbial induced cross-reaction antibodies (Type II hypersensitivity caused by cross-reacting antibodies ): 1- Gummas seen during the late stages of case of Syphilis (Caused by the bacterial pathogen Treponama pallidum) 2- Arthritis as well as Cardiac and Neuronal complications that are seen during the late stages of Lyme disease, (caused by the bacterial pathogen Borrelia burgdorferi) 3- Rheumatic fever: cross-reacting antibodies that could be generated in response to certain strains of the bacterial pathogen Streptococcus pyogenes that bind to heart valves heart and results in inflammation of heart valves ( one of the clinical situations described as poststreptococcal complications) Type III Hypersensitivity Type III Hypersensitivities are autoimmune diseases that are mediated by immune complexes generated by: 1- Self-reacting auto-antibodies directed against soluble self antigens 2- Cross-reacting antibodies directed against soluble self antigens These immune complexes tend to deposit in blood vessels specially: 1- At turbulence sites where blood vessels make branches or 2- In blood capillaries with high pressure (such as these found in Glomeruli of the kidneys and synovium of joints). Immune complexes deposited (precipitate) in blood vessels induce inflammation by attracting and activating leukocytes as well as activating complements by the Fc region of antibodies in immune complexes. Activation of phagocytes and complement resulting in the destruction to adjacent cell and tissue such as endothelial cells of blood vessels . In addition, the complement by-products that recruit leukocytes and induce inflammation. Accordingly, Immune complex diseases tend to be systemic complications and often manifested as vasculitis, arthritis, and nephritis. Examples of a type III hypersensitivity disease: 1- Glomerulonephritis: which is one the clinical conditions of post-streptococcal complications. This clinical situation is induced by the formation of immune complexes by cross-reacting antibodies seen in response to infections caused by certain strains of Streptococcus pyogenes. Glomerulonephritis may lead to renal failure ( Type III hypersensitivity caused by cross-reacting antibodies) 2- Serum sickness: is induced by systemic administration of a protein antigen, which induces an antibody response and leads to the formation of circulating immune complexes. Example: human serum sickness can occur after a person receives injections of serum from other individuals or animals, which sometimes is used for the treatment of snakebite or exposure to rabies virus. 3- The Arthus reaction : an an autoimuune reaction that is mediated by immune comlexes in experimental animals Initially, an experimental animal is injected by a foreign protein that induces an immune response that generates antibodies . After certain period of time, the same animal that was previously immunized is injected again by the same foreign protein. This results in the formation of immune complexes in blood vessels at the site of the second injection resulting in a local cutaneous vasculitis Some More examples of human diseases that are caused by the deposition of immune complexes THERAPY OF TYPE II and TYPE III HYPERSESNISTIVITIES Therapy for these diseases aims to reduce inflammation and its injurious consequences with drugs such as 1- Corticosteroids 2- Plasmapheresis is used to reduce levels of circulating antibodies or immune complexes. 3- Treatment of patients with an antibody specific for CD20, a surface protein of mature B cells, results in depletion of the B cells (it is useful for treating antibody and immune complex–mediated diseases) Novel approaches for inhibiting the production of auto-antibodies 1- Antagonists that block CD40L and thus inhibit helper T cell–dependent B cell activation. 2- Attempts to induce of tolerance in cases auto-antigens are known. These newer therapies are at the stage of preclinical testing and early clinical trials. (Delayed Type Hypersensitivity Reactions) Type IV Hypersensitivity Reactions Delayed Type Hypersensitivity Reactions are caused by 1- Autoimmunity due to activation of self-reacting T cells ( failure of self tolerance) and 2- By responses to environmental antigens. Note: T cell-mediated autoimmune diseases tend to be limited to a particular organs or tissue and are not usually systemic. 1- Autoimmunity Caused By Self Reacting T cells : These autoimmune reactions mediated by self reacting T cells are usually directed against particular cellular antigens with restricted tissue distribution. ( most likely because of the failure of self tolerance) 2- By responses to environmental antigens. A- Contact sensitivity to chemicals is a T cell-mediated reaction. B- Tissue injury also may accompany T cell responses to microbes. 1- In tuberculosis, a T cell–mediated immune response is raised against Mycobacterium tuberculosis. However, the response becomes chronic because the infection is difficult to eradicate the bacterium ( Mycobacterium tuberculosis) The resultant granulomatous inflammation causes injury to normal tissues at the site of infection. 2- In hepatitis virus infection, the virus itself may not be highly cytopathic, but the cytotoxic T lymphocyte (CTL) response to infected hepatocytes may cause liver injury 3- Superantigens cause massive-nonspecific polyclonal T cell activation by certain microbial toxins produced by some bacteria and viruses . These toxins are called super antigens that bind to invariant parts of T cell receptors on many different clones of T cells, regardless of antigen specificity of the TCR This causes massive non-specific activation of these T cells that can lead to production of large amounts of inflammatory cytokines, that may lead to life-threatening clinical condition know that is called septic shock (or similar to Bacterial toxic shock) . . Mechanisms of Tissue Injury In Type IV Hypersensitivity Reactions T cell-mediated tissue injury seen in a delayed-type hypersensitivity reaction is mediated by CD4+ T cells or CD8+ CTLs ( or BOTH) (Fig. 11-11). The mechanisms of tissue injury are the same as the mechanisms used by T cells to eliminate cell-associated microbes. 1- The Role of CD4+ T cells: CD4+ T cells may react against cell or tissue antigens and secrete cytokines that induce local inflammation and activate macrophages. Different diseases may be associated with activation of TH1 and TH17 cells. TH1 cells are the source of IFN-γ, the principal macrophage activating cytokine TH17 cells are thought to be responsible for recruitment of leukocytes, including Neutrophils. Tissue damage mediated by self reacting CD4+ T cells seen in autoimmune diseases is caused due to excessive activation the Macrophages and Neutrophils ( this may lead to release of lysosomal enzymes and free radicals from activated cells, which cause tissue injury) 2- The Role of CD8+ T cells CD8+ T specific for antigens on host cells may directly kill these cells. NOTE: In many T cell-mediated autoimmune diseases, both CD4+ T cells and CD8+ T cells specific for self antigens are present, and both contribute to tissue injury. Mechanisms of T cell–mediated tissue injury. T cells may cause tissue injury and disease by two mechanisms: (1) delayed type hypersensitivity reactions (A), which may be triggered by CD4+ and CD8+ T cells and in which tissue injury is caused by activated macrophages and inflammatory cells, and (2) direct killing of target cells (B), which is mediated by CD8+ CTLs. Note: APC, antigen-presenting cell; CTLs, cytotoxic T lymphocytes. T cell Mediated Autoimmune Diseases are Typically Chronic and Progressive. This is because of the following reasons: 1- Continuous T cell-macrophage interactions tend to amplify the autoimmune reaction. (self reacting T cells ) 2- In T cell mediated autoimmune diseases, persistent tissue injury result in the release of hidden self protein antigens OR alteration of self proteins. ( release of self proteins that are not usually exposed to T cells) This may result in exacerbating the autoimmune disease ( as well as tissue injury) due to activation of T cells that are specific for the above mentioned proteins This phenomenon of exacerbation of T cell mediated autoimmune diseases is called “epitope spreading” to indicate that the initial immune response against one or a few self antigen epitopes may expand to include responses against many more self ntigens. Chronic inflammatory diseases that are initiated by self reacting T cells immune reactions are called T Cell mediated -mediated inflammatory diseases. The therapy for T cell–mediated hypersensitivity disorders is designed to reduce inflammation. This could be achieved by: 1- Using corticosteroids 2- Antagonists against cytokines (such as TNF). Antagonists of TNF have proved to be beneficial in patients with rheumatoid arthritis and inflammatory bowel disease. 3- Inhibition of T cell responses with immunosuppressive drugs such as cyclosporine. Many newer agents are being developed to inhibit T cell autoimmune responses such as . 1- These include agents that block co-stimulators such as B7 2- Antagonists against cytokines receptors such as IL-2 receptor 3- Induction of tolerance in self reacting T cells (so far, no successful clinical trials have been reported yet) Note: In the previous table, please, pay attention to the genetic association. Some of these genes (mutation in these genes) were discussed in the chapter of TOLEANCE. Mutations in the genes (PTPN22 and NOD-2) may be the reason behind the failure of self tolerance