Immunopathology PDF

CONTENTS : Overview of normal immune response Cells and tissues of the immune system Overview of lymphocytes activation and adaptative immune response Overview of disorders of the immune system (Hypersensitivity Reactions , Autoimmune Diseases Immunodeficiency, amyloidosis). INTRODUCTION...

CONTENTS : Overview of normal immune response Cells and tissues of the immune system Overview of lymphocytes activation and adaptative immune response Overview of disorders of the immune system (Hypersensitivity Reactions , Autoimmune Diseases Immunodeficiency, amyloidosis). INTRODUCTION: Immunity : is the protection against pathogens Immune system: is the collection of cells and molecules that are responsible for defending the body against pathogens NORMAL IMMUNE RESPONSE : Reactions to foreign pathogens carried out through 2 mechanisms : 1. Innate ( natural/native) immune response. 2. Adaptive(acquired/ specific) immune response. INNATE IMMUNE RESPONSE: General features : Components: mediated by cells and proteins that are 1.Proteins : always present in the body (present from the start) Complements Immediate. Other plasma proteins First line of defense 2. Cells : Reacts against foreign pathogens and Epithelial cells (barriers e.g skin and dead/damaged cells mucous membranes) Non specific Phagocytic cells (neutrophils, macrophages) Dendritic cells Natural Killer (NK) cells INNATE IMMUNE RESPONSE: 3. Receptors: called Pattern recognition receptors Expressed by cells of the innate immunity to sense microbial structures (pathogen-associated molecular patterns) or substances released from dead cells (damage-associated molecular patterns) Several classes of these receptors have been identified.  Toll-Like Receptors TLR ( recognize microbes)  NOD-Like Receptors ( NLR ) and the Inflammasome (mainly necrotic cells, lipids, ions , some microbes)  C-type lectin receptors CLR and mannose receptors (microbes) INNATE IMMUNE RESPONSE: Recognition of damaged cells or microbes will activate innate immune cells in order to eliminate the offending pathogen. ( How?) INNATE IMMUNE RESPONSE: Functions:- The innate immune cells provide defense against pathogens by the following reactions: 1. inflammatory response :several products responsible for vascular and cellular changes seen in inflammatory response (e.g inflammatory cytokines and complement components) are synthesized during innate immune reactions. 2. anti-viral defense through production of type I interferons that degrade viral nucleic acid and inhibit viral replication 3. innate immune system generates signals that stimulate the subsequent, more powerful adaptive immune response ADAPTIVE IMMUNE RESPONSE: General features Components Specialized(specificity) and powerful Cells and their protein products Normally silent ( respond only to specific pathogen) Lymphocytes (T cells and B cells/antibodies) Receptors : TCR and BCR Types: Humoral ( mediated by B cells) against extracellular pathogen. Cellular (mediated by T cells) against intracellular pathogens. ADAPTIVE IMMUNE RESPONSE: ¡ Functions are :  Direct elimination of microbes by antibodies or cytotoxic T cells  Secretion of cytokines that recruit and activate other inflammatory cells to eliminate the microbes. CONTENTS : Cells and tissues of the immune system CELLS AND TISSUES OF THE IMMUNE SYSTEM: The cells of the immune system consist of:  Lymphocytes : the principal effector cells of the immune system. Have specific receptors for antigens and mount both adaptive response (T and B lymphocytes) and innate response (NK cells)  Antigen presenting cells (APCs) , which capture and display microbial and other antigens to the effector cells (lymphocytes and other cells)  Others (neutrophils, mast cells, eosinophils …etc) 1. Lymphocytes: 2 groups : 1. Adaptive lymphoid cells 2. innate lymphoid cells Lymphocytes: Adaptive lymphoid cells : Include T cells and B cells Both cells are generated in the primary lymphoid organs with different sites of maturation T lymphocytes mature in the thymus, whereas B lymphocytes mature in the bone marrow. Mature lymphocytes reside in 2ry lymphoid organs ( LN, spleen, Mucosal surfaces-MALTs) Both cells express surface structures act as a binding site for foreign antigens and it is called antigen receptors and accordingly we have 2 types of antigen receptors on lymphocytes: in B cells are called B-cell receptors (BCR) , while in T-cell are called T-cell receptors(TCR)  All lymphocytes go through 3 phases of maturation : 1. Naïve : express receptors but not responded yet to Lymphocytes: any antigen. A. Adaptive 2. Effector: recognized an antigen and become activated, responsible for elimination of the microbes. Lymphoid Cells : 3. Memory: recognized an antigen, survive in functionally silent state after elimination of the antigen, responsible for rapid response upon re-infection.  T-lymphocytes: T for Thymus derived. Mediate cellular immunity Constitute 60-70% of circulating lymphocytes. Recognize only Ag presented in association with MHC molecules. (MHC restrictions) Express the following molecules on their surface : 1) TCR : heterodimer molecule (α +β ) + 5 polypeptide chains (CD3 complex + 2ζ chain ) 2) Co- receptors : e.g CD4, CD8, CD28 ( co-stimulatory receptor ) 3) Others  Types : T helper/ CD4 + : has multiple subclasses (TH 1-2-17). Secrete cytokines that mediate activation and differentiation of both B and cytotoxic T cells, helps to activate macrophages, support innate inflammatory response ( neutrophil stimulation) Cytotoxic T cells/CTL/CD8+ : direct killing of intracellular microbes T-lymphocytes: Regulatory T cells : suppress immune response ( control tolerance to self antigens and hence are impaired in autoimmune diseases) B-Lymphocytes: Bone marrow derived. Mediate humoral immunity Constitute 10-20% of circulating lymphocytes. Recognize soluble and cell associated proteins , lipids, polysaccharides and nuclei acids without the need for MHC molecule. Express surface molecules: 1) BCR ( IgM + signaling molecule Igα and Igβ) 2) Co-receptor CD 21 BCR  B-Lymphocytes: BCR & CO receptors B-Lymphocytes: Activated B-lymphocytes mature in to plasma cells which synthesize and secrete different classes of Antibodies (immunoglobulins). Antibodies are divided into five major classes, IgM, IgG, IgA, IgD, and IgE. Structure of antibodies:  The basic structures of all antibodies are same.  Each antibody consists of four polypeptides– two identical heavy chains (H) and two identical light chains (L). Those chains are connected by disulfide bonds to form a "Y" shaped molecule.  There are five types of Ig heavy chain (in mammal) denoted by the Greek letters: α, δ, ε, γ, and µ , and two types of Ig light chain (in mammal), which are called lambda (λ) and kappa (κ).  Each chain, wither L or H is composed of : variable (V) region and the constant (C) region. Amino acids sequences in the C region determine the action and the class of the antibody.  Each antibody is made up of 2 fragments : Fab ( fragment of antigen binding). Fc ( fragment crystallizable ) contains binding sites for phagocytic cells and complement components B-LYMPHOCYTES B. Innate Lymphoid Cells are populations of lymphocytes that lack TCRs but produce cytokines similar to those made by T cells. They are classified into three groups, which produce IFN-γ, IL-5, or IL-17 cytokines, respectively. Natural Killer (NK ) cells are related to group 1 ILCs based on their production of IFN-γ. NK cells:  NK cells are innate immune cells, as they are functional without prior activation and do not express highly variable receptors for antigens.  Express two types of receptors: 1) Inhibitory receptors recognize self class I MHC molecules, which are expressed on all healthy cells. 2) activating receptors recognize molecules that are expressed or upregulated on stressed or infected cells.  Normally, the effects of inhibitory receptors dominate over those of activating receptors, preventing spontaneous activation of the NK cells. Innate Lymphoid Cells NK cells:  Functions: 1) Direct microbial killing. 2) secrete cytokines such as interferon-γ (IFN- γ), which activates macrophages and defense against intracellular microbes. 2. Antigen-presenting Cells (APC) Cells that are specialized to capture antigens and display them to lymphocytes. Includes: 1) B cells ( present antigens to TH cells ) 2) Macrophages ( present antigens to T cells) 3) Dendritic cells (DC) :  DC are the most important antigen presenting cells for initiating T-cell responses against protein antigens.  have numerous fine cytoplasmic processes that resemble dendrites Antigen-presenting Cells (APC) Dendritic cells (DC) ……….. Several features of DCs account for their key role in antigen capture and presentation :- 1. These cells are located at the right place to capture antigens where microbes and foreign antigens commonly enter the body ( under the epithelia, in the interstitial spaces) 2. upon activation, they ideally positioned themselves in T cell zone in lymphoid organs in order to present the antigen to T cells 3. express many receptors for capturing and responding to microbes ( TLR) 4. express high levels of MHC and other molecules ( co-stimulators e.g B7 proteins) needed for antigen presentation and activation of T cells. Antigen-presenting Cells (APC) ¡ Dendritic cells (DC) ……….. ¡ 2 subclasses of DC: Feature Plasmacytoid DC Follicular DC Location blood and lymphoid spleen and lymph nodes organs(spleen and LNs) (GC of Lymphoid follicles) Function major sources display antigens only to of the anti-viral cytokine B type I interferon, Lymphocytes and promote antibody responses 3. Lymphoid Tissues: Lymphoid tissues are tissue involved in immune response. Generally are classified in to : 1. generative (also called primary, or central) lymphoid organs, in which T lymphocytes and B lymphocytes are synthesized, mature and become competent to respond to antigens. Includes: Thymus and Bone Marrow 2. peripheral (or secondary) lymphoid organs, in which adaptive immune responses to microbes are initiated. Include : Lymph nodes, spleen, cutaneous and mucosal lymphoid systems 2ry lymphoid organs are organized to concentrate antigens, APCs, and lymphocytes in a way that optimizes interactions between these cells and the development of adaptive immune responses. Most of body`s lymphocytes are present in them. CYTOKINES  Messenger Molecules of the Immune System  are proteins that secreted to mediate immune and inflammatory reactions  The most well recognized cytokines are called interleukins, a name implying a role in communication between leukocytes.  Different cytokines contribute to specific types of immune responses. For example : in innate immune response the secreted cytokines are IL-1 and IL-12 while in adaptive response IL-2 and IL-17.  The knowledge gained about cytokines has numerous practical therapeutic applications. Inhibiting cytokine production or actions can control the harmful effects of inflammation and tissue-damaging immune reactions. MHC Molecule (Major Histocompatibility Complex): The peptide display system of adaptive immune response Also called HLA (Human Leukocytes Antigen) Is an important molecule that function to display peptides for recognition by CD4+ and CD8+ T lymphocytes. Genetic variations in MHC molecules are associated with many immunologic diseases. Encoded on cluster of genes located on chromosome 6. 2 classes (MHC I and MHC II ) MHC Molecule (Major Histocompatibility Complex): The peptide display system of adaptive immune response 1. MHC class I :  In all nucleated cells  Encoded in 3 regions on MHC gene - HLA A,B,C on  Has 2 binding sites : 1. Ag binding site to be presented for TCR on T cells 2. CD8 binding site ( to ensure that only CD8 T cells will react with Antigen presented by MHC I)  Binds and displays intracellular antigens (viruses ) MHC Molecule (Major Histocompatibility Complex): The peptide display system of adaptive immune response MHC class II :  In specific types of cell ( macrophages, B cells and APC specially dendritic cells)  Encoded in single region on MHC gene - HLA D which contains three subregions: DP, DQ, and DR.  Has 2 binding sites : 1. Antigen binding site 2. CD4 binding site  Binds and displays extracellular antigens MHC Molecule (Major Histocompatibility Complex): HLA genes are highly polymorphic. The HLA genes are closely linked on chromosome 6, so they are passed from parent to offspring en bloc Each set of maternal and paternal HLA genes is referred to as an HLA haplotype. In most populations the probability that an unrelated donor will share the same two HLA haplotypes is very low. The implications of HLA polymorphism for transplantation are obvious Grafts from unrelated donors will elicit immune responses in the recipient and be rejected. Only identical twins can accept grafts from one another, without fear of rejection This ability of MHC molecules to trigger immune responses is the reason these molecules are often called antigens MHC Molecule (Major Histocompatibility Complex): MHC molecule influences both protective and harmful immune responses:-  It will determine whether a specific person’s T cells can recognize and mount a protective response to a specific pathogen  inheritance of some HLA genes may make individuals susceptible to hay fever.  many autoimmune diseases are associated with particular HLA alleles CONTENTS : Overview of lymphocytes activation and adaptative immune response Overview of disorders of the immune system (Hypersensitivity Reactions , Autoimmune Diseases Immunodeficiency, amyloidosis). Overview Of Lymphocyte Activation And Adaptive Immune Response: Adaptive immune response occurs over sequential steps which are : 1) antigen recognition 2) activation, proliferation and differentiation of lymphocytes into effector , memory and regulatory cells. 3) elimination of the antigen 4) decline of the immune response with memory cells being the long-lived survivors. these general principles apply to protective responses against microbes as well as pathologic responses that injure the host. Overview Of Lymphocyte Activation And Adaptive Immune Response: 1. antigen recognition:  Pathogens are captured, processed by tissue dendritic cells and then displayed to the surface in association with MHC molecules.  Pathogen recognition by T and B lymphocytes via their antigen receptors. Overview Of Lymphocyte Activation And Adaptive Immune Response: 2. Activation and differentiation of lymphocytes : A. Cell-Mediated Immunity: Activation of T Lymphocytes:  Involves both helper and cytotoxic T lymphocytes.  Naïve T cells are activated by the antigens and then differentiate in to effector and memory cells  Activated T-Helper cells (CD4+ lymphocytes) differentiate in to multiple classes of effector H T-cells (TH 1,TH 2,TH 17) that secrete different types of cytokines to mediate different functions.  Activated CD8+ lymphocytes differentiate in to effector cytotoxic T cells (CTLs) that directly kill cells harboring cytoplasmic microbes. Overview Of Lymphocyte Activation And Adaptive Immune Responses: B. Humoral Immunity: Activation of B Lymphocytes : Involves 2 pathways: T-cell independent : where antigens (lipid and polysaccharide type) directly engage to BCR on the surface of Naïve B cells. T-cell dependent : where TH response is required to activate B cells. (antigens are proteins) Activated B cells differentiate into memory B cells and antibody producing Plasma cells (effector cells). Features of the produced antibodies:  Antibody specificity : antibodies are produced with the same specificity of the antibody on BCR that first recognized the antigen.  (isotype) switching : Production of functionally different classes of antibodies, all with the same specificity. (why?)  Affinity maturation: production of antibodies with higher affinity for the antigen. This will greatly improve the quality of humoral response. Overview Of Lymphocyte Activation And Adaptive Immune Responses: 3. elimination of microbes by CTL or Antibodies.  Cell-Mediated Immunity :The principal mechanism of killing by CTLs depends on the perforin–granzyme system.  Humoral Immunity :Produced antibodies combats microbes in numerous ways : Neutralization of microbe and toxins: Antibodies bind to microbes and prevent them from infecting cells. Opsonization and phagocytosis : mainly by IgG. Antibody dependent cytotoxicity : through interaction with NK cells Lysis of the microbes by activation of complement system (classical pathway) mainly by IgG and IgM. IgG antibodies pass through the placenta and provide passive immunity for neonates. IgA antibodies are secreted into mucosal tissues to neutralize pathogens there. IgE coats parasites and acts with eosinophils and mast cells to kill them.  T-cell Independent Pathway T-cell dependent Pathway ACTIVATION OF B-LYMPHOCYTES: Overview Of Lymphocyte Activation And Adaptive Immune Responses: 4. Decline Of Immune Responses And Immunologic Memory: The majority of effector lymphocytes die by apoptosis ( extrinsic pathway ) after the pathogen is eliminated. memory cells, which may survive for years after the infection. They represent an expanded pool of antigen-specific lymphocytes and they respond faster and more effectively when re- exposed to the antigen than do naïve cells. DISEASES OF THE IMMUNE SYSTEMS : Immune responses are normal defense mechanisms designed to protect our body against harmful environmental factors. But sometimes these responses can be defective and result in various diseases : for example:  Inadequate immune response will cause Immunodeficiency diseases  Excessive immune response will cause Hypersensitivity disorders  Inappropriate immune response will cause autoimmune diseases  abnormal products of immune response will cause amyloidosis Contents Causes of hypersensitivity reactions Classification of hypersensitivity reactions Introduction: Immune responses are normally protective and strictly controlled so as to efficiently eradicate pathogens without causing injuries to host tissues. Under certain conditions these protective responses can cause tissue injuries Hyper sensitivity reactions : A person who mount an immune response to certain antigen is said to have (sensitivity or being sensitive) to that antigen, so typically if that immune response is excessive then it is termed ( hypersensitivity ) Injurious immune reactions that seen in such cases are grouped under the term hypersensitivity reactions , and the resulting diseases are called hypersensitivity diseases Inappropriate or un controlled immune response/hypersensitivity can take many forms: Sometimes immune response might be directed against normally harmless antigens or inappropriately targets host tissues, and in such situations, the normally beneficial response is the cause of disease. Causes of hypersensitivity reactions: Hypersensitivity reaction (HSR) is a pathologic immune response that results from various abnormalities: 1. Autoimmunity : If the immune response was directed against self antigen.(autoimmune diseases) 2. if the immune response was directed against foreign antigen but: o the antigen is persistent ( aggressive response as severe inflammation seen in destructive granuloma of TB and syphilis or excessive production of antibodies that eventually will precipitate on host tissues and cause injuries as seen in post streptococcal gloemerulonephritis) o the antigen is similar to a normal host antigen ( cross reactivity) e.g. ( rheumatic heart disease) o sometimes in the process of eradicating the infection, host tissues are injured e.g ( viral hepatitis where cytotoxic T cells will eliminate virally infected cells) Introduction: 3. allergic condition: in which individuals are genetically predispose to have un usual immune response to certain non-infections and otherwise harmless antigens to which all persons are exposed but against which only some react. Hyperactive immune response: General features : 1. tissue injury is mediated by the same mechanisms that normally function to eliminate infectious pathogens—namely, antibodies, effector T lymphocytes, and various other effector cells. 2. The fundamental problem in these diseases is that the immune response is triggered and maintained inappropriately. 3. stimuli for these abnormal immune responses are difficult or impossible to eliminate (e.g., self antigens, persistent microbes, or environmental antigens) 4. these diseases tend to be chronic and debilitating, and are therapeutic challenges 5. Since inflammation is a major component of the pathology of these disorders, they are sometimes grouped under the term immune mediated inflammatory diseases Classification of Hypersensitivity Reactions According to the underlying mechanism responsible for tissue injury: 1. Antibody mediated tissue injury : Type I,II and III 2. T -Cell mediated tissue injury : Type IV Contents Type I hypersensitivity reactions HSR type I (immediate) Often called allergy (allergic reaction) occurs rapidly (typically within minutes following exposure to the offending antigen). The severity ranges from mild localized reaction ( hey fever) to extremely fatal ( anaphylaxis) Components: 1. Ag: allergen ( environmental, non infectious) e.g. Dust 2. Ab: IgE 3. cells :  TH2. TH2 cells produce IL-4, which stimulates B cells to differentiate into IgE- secreting plasma cells; IL-5, which activates eosinophils and mast cells ; and IL- 13, which activates mucosal epithelial cells to secrete mucus.  mast cells (release mediators that act on blood vessels and smooth muscle as well as cytokines that recruit and activate inflammatory cells). HSR type I (immediate) Steps : 1. Activation of TH2 cells and production of IgE antibody  Exposure to specific allergen (Allergens may be introduced by inhalation, ingestion, or injection)  Activation of TH2 cells to secrete cytokines (IL4 IL5,IL13.).  production of the specific IgE antibody by B cells (IgE class switching) 2. Sensitization of mast cells by IgE antibody.  Binding of IgE specific antibody to the surface of mast cells.  These antibody-bearing mast cells are sensitized to react if the specific antigen (the allergen) binds to the antibody molecules at anytime. HSR type I (immediate) 3. Activation of mast cells and release of mediators  Itoccurs upon re-exposure to the specific allergen which will bind to IgE on the surface of mast cells. This will activate mast cells and triggers a series of biochemical signals that culminate in the secretion of various mediators from the mast cells. release of mediators. As : Vasoactive amines ,lipid mediators , and cytokines. HSR type I (immediate) Mediators in Type 1 HSR: Vasoactive amines Lipid mediators Cytokines Rapidly released as they Newly synthesized from important for the late-phase are pre-synthesized and lipids on plasma membrane. reaction. ( released late already stored in mast cells Control early phase because their synthesis granules. response involves transcription and Control early phase Cause: translation processes). response Intense bronchospasm, Cause: inflammatory Cause: vasodilation, increased mucus secretion reaction and tissue damage increased vascular PGD2 and Leukotrienes TNF, chemokines, IL-4,5 permeability in addition to bronchial spasm and increase secretion of mucus. histamine HSR type I (immediate) Development of Allergies : An increased propensity to develop immediate hypersensitivity reactions is called atopy. Factors implicated in development of allergies : 1st : genetic factors:  Susceptibility to immediate hypersensitivity reactions is genetically determined( certain HLA serotypes and positive family history).  Genetically susceptible individuals tend to have higher serum IgE levels and more IL-4–producing TH2 cells than does the population. HSR type I (immediate) Development of Allergies : 2nd Environmental factors  Exposure to environmental pollutants, is an important predisposing factor for allergy.  Viral infections of the airways are important triggers for bronchial asthma, an allergic disease affecting the lungs  The incidence of many allergic diseases is increasing in developed industrial countries. HSR type I (immediate) clinical and pathological manifestations : The clinical manifestations may be local or systemic, and range from mildly annoying rhinitis to fatal anaphylaxis. e.g. localized: mild (hay fever) severe (asthmatic attack ) generalized fatal ( anaphylaxis) Clinical Phases of the reaction: two well defined phases: 1. Immediate phase: occurs within 5 to 30 minutes after exposure to an allergen and subsiding by 60 minutes. Characterized by Vascular and bronchial response. Mediated by vasoactive amines and lipid mediators. 2. Late phase : sets in 2 to 8 hours later, may last for several days. Characterized by Tissue destruction ( mucosal epithelial cells) and inflammation. Mediated by cytokines.  Clinical Clinical and Pathologic Manifestations HSR type I Anaphylaxis (may be Syndrome Respiratory airway obstruction due (immediate)caused by drugs, bee sting, food) to laryngeal edema, bronchospasm and increase mucus secretion in the airways Circulatory Fall in blood pressure (shock) Clinical examples : caused by vascular dilation Gastrointestinal vomiting, abdominal cramps, and diarrhea. Bronchial asthma Airway obstruction caused by bronchial smooth muscle hyperactivity; inflammation and tissue injury caused by late-phase reaction Allergic rhinitis, Increased mucus secretion; inflammation of sinusitis (hay fever) upper airways and sinuses Food allergies Increased peristalsis due to contraction of intestinal muscles, resulting in vomiting Sequence of Events in Immediate (Type I) Hypersensitivity Reaction Contents Type II hypersensitivity reaction Type II HSR Antibody-Mediated Disorder Components : 1. Ag : antigen attached / fixed to the cells or tissues Endogenous : extracellular, intracellular Exogenous : adsorbed to cell surface as drug metabolites 2. Ab :Ig M, Ig G Type II HSR Antibody-Mediated Disorder Mechanisms for antibody mediated diseases in HSR II :- 1. opsonization and phagocytosis. In this type of reaction after coating/ opsonizing the target cells, Abs interact with Fc receptors on the surface of phagocytes and neutrophils through Fc fragment. in addition to that, Abs involved in this reaction are high affinity Abs i.e. they are capable of fixing and activating complement components These reaction will activate phagocytosis and killing of target cells E.g. In hemolytic disease of the newborn in which IgG anti–red blood cell antibodies from the mother cross the placenta and cause destruction of fetal red blood cells  TYPE II HSR ANTIBODY - MEDIATED DISORDER Type II HSR Antibody-Mediated Disorder 2. complement activation and inflammation : Direct via Membrane attack complex or indirectly via formation of complement products some of which will act as chemotaxins and recruit leukocytes (neutrophils and monocytes). The recruited inflammatory cells are responsible for tissue damage by releasing lysosomal enzymes e.g proteases and reactive oxygen species. E.g Acute rheumatic fever , valvular disease caused by streptococcus infection in which antibodies for streptococcal cell wall antigen cross-reacts with myocardial antigen resulting in macrophage activation and inflammatory mediated injury to heart valves.  TYPE II HSR ANTIBODY - MEDIATED DISORDER Type II HSR Antibody-Mediated Diseases 3. Antibody-mediated cellular dysfunction without directly causing cell injury or inflammation. Inhibitory effect as seen in myasthenia gravis where antibodies against acetylcholine receptors in neuromuscular junction block acetylcholine receptors on the motor plate of skeletal muscle thus inhibiting the transmission of signals resulting in muscular weakness. Stimulatory effect as seen in Graves disease (hyperthyroidism) where antibodies against TSH receptors stimulate thyroid epithelial cells to secrete thyroid hormones resulting in hyperthyroidism.  TYPE II HSR ANTIBODY - MEDIATED DISEASES Contents Type III hypersensitivity reaction  Type III HSR Immune Complex–Mediated Diseases Components: 1. Ag: circulating antigens (endogenous/exogenous) 2. Ab: Ig G (commonly ) Reaction can be localized, or generalized. Steps of the reaction: 1. Formation of Immune Complexes. After antigen introduction, antibodies are formed. Antibodies interact with antigens that are circulating in the body with subsequent formation of circulating/soluble Ag/Ab immune complexes. 2. Deposition of Immune Complexes. Kidneys, joints and small blood vessels are the preferred sites for deposition of immune complexes ( organs where blood is filtered at high pressure to form other fluids). Medium to large size immune complex that formed in excess are usually the pathogenic ones. Type III HSR Immune Complex–Mediated Diseases 3. Inflammation and Tissue Injury : immune complexes may deposit in tissues or blood vessels, and elicit an acute inflammatory reaction by activating complement, with release of breakdown products, or by engaging Fc receptors of leukocytes. The inflammatory reaction causes tissue injury. Type III HSR Immune Complex–Mediated Diseases Type III HSR can be localized or generalized. Clinical features varies according to the site of IC depositions. Generally symptoms as fever, urticaria, joint pain (arthralgia), lymph node enlargement, and proteinuria appear. The resultant inflammatory lesion is termed vasculitis if it occurs in blood vessels, glomerulonephritis if it occurs in renal glomeruli, arthritis if it occurs in the joints. Diseases are diagnosed based on the clinical presentation, and detection of deposited immunocomplexes. This maybe done using immunofluorescence microscopy where complexes can be seen as granular deposits. Consumption of complement during the active phase of the disease decreases serum levels of C3, which can be used as a marker for disease activity. Type III HSR Immune Complex–Mediated Diseases Clinical examples:. Serum sickness a diffuse immune complex disease. Associated with presence of large amount of Ag and large amount of sensitized Abs leading to formation of massive amount IC that deposit in various organs. It can be acute reaction or chronic reaction where the antibody responses are repeated due to persistent antigens e.g SLE. Type III HSR Immune Complex–Mediated Diseases Arthus reaction an example for localised Immune Complex mediated Disease:  Acute immune complex mediated vasculitis.  Occurs by injecting an antigen into the skin of a previously sensitized body (contains Abs specific for that antigen).  Immune complex will form and deposit in the wall of blood vessels at the injection site triggering inflammatory response and tissue injury.  Type III HSR Immune Complex–Mediated Diseases Arthus reaction Contents Type IV hypersensitivity reaction (Type IV HSR) T Cell–Mediated Diseases Two types of T cell mediated reactions are capable of causing tissue injury and disease: (1) cytokine-mediated inflammation, in which the cytokines are produced mainly by CD4+ T cells, and (2) direct cell cytotoxicity, mediated by CD8+ T cells. (Type IV HSR) T Cell–Mediated Diseases CD4+T Cell–Mediated Inflammation:  Also called Delayed Type Hypersensitivity (DTH) reaction.  Tissue destruction is mediated by cytokines produced by CD4+ T cells (TH).  The effector cells are of TH1 subclass, but TH17 might also be involved.  Pathogenesis: 1. Naïve T helper cells are activated in secondary lymphoid organs by recognition of peptide antigens displayed by dendritic cells and differentiate in to TH1 and TH 17. 2. TH1 secretes IFN- γ which activates macrophages ( classical pathway). Macrophages will produce substances that will: destroy microbes and damage tissues, and promote inflammation. TH17 secretes IL17 and recruits neutrophils which will cause tissue destruction by release of lysosomal enzymes and reactive oxygen species.  (Type IV HSR) T Cell–Mediated Diseases CD4+T Cell–Mediated Inflammation: (Type IV HSR) T Cell–Mediated Diseases CD4+T Cell–Mediated Inflammation: Microscopic morphology : Initially : accumulation of mononuclear cells, mainly CD4+ T cells and macrophages, around venules, producing perivascular “cuffing. (Type IV HSR) T Cell–Mediated Diseases CD4+T Cell–Mediated Inflammation: 3. With persistent antigens and prolonged DTH reaction: The initial perivascular CD4+ T cell infiltrate is progressively replaced by macrophages over a period of 2 to 3 weeks. These accumulated macrophages typically exhibit morphologic evidence of activation; that is, they become large, flat, and eosinophilic- called The epithelioid cells. Which occasionally fuse under the influence of cytokines (e.g., IFN-γ.) to form multinucleated giant cells. The collection of these cells that typically surrounded by a collar of lymphocytes and fibroblasts ,is called granuloma. (Type IV HSR) T Cell–Mediated Diseases CD4+T Cell–Mediated Inflammation (Type IV HSR) T Cell–Mediated Diseases CD4+T Cell–Mediated Inflammation:  Clinical examples: 1. Tuberculin skin test (mantoux test )*is a type of delayed tissue hypersensitivity reaction against antigens ( mycobacterium Tb/ PPD ) administered to the skin of previously immunized individuals. This will result in a detectable cutaneous reaction ( redness and swelling) within 24 to 48 hours ( hence the name delayed ). leishmanin skin test (Type IV HSR) T Cell–Mediated Diseases CD4+T Cell–Mediated Inflammation: 2. Contact dermatitis: a common example of tissue injury resulting from DTH reactions. Usually follows contact with environmental antigens ( drugs, poisons..etc) Presents clinically as vesicular dermatitis ( skin rash) Pathogenesis: the environmental chemical binds to and structurally modifies self proteins forming neoantigens. These neoantigens are recognized as foreign by T cells, leading to cytokine production and inflammation. 3. CD4+ T cell–mediated inflammation is the basis of tissue injury in many organ- specific and systemic autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis in addition to diseases probably caused by uncontrolled reactions to bacterial commensals, such as inflammatory bowel diseases. (Type IV HSR) T Cell–Mediated Diseases CD8+ T Cell–Mediated Cytotoxicity: CD8+ CTLs kill antigen-expressing target cells. Clinical examples: 1. type 1 diabetes 2. graft rejection (CTLs are directed against graft MHC molecules) 3. Reaction against viral Infections: in viral hepatitis, killing of infected cells leads to elimination of the infection, but in some cases, it is responsible for cell damage that accompanies the infection (Type IV HSR) T Cell–Mediated Diseases CD8+ T Cell–Mediated Cytotoxicity: CD8+ lymphocytes also produce cytokines, notably IFN-γ, which are involved in macrophages activation and mediation of DTH like reactions  (Type IV HSR) T Cell–Mediated Diseases CD8+ T Cell–Mediated Cytotoxicity: CONTENTS  Autoimmune Diseases  Rejection of Transplants  Autoimmune Diseases: Introduction: Refers to immune reaction against self (auto) antigens. Mediated by both high affinity autoantibodies and self reactive T cells. It may be : Organ specific or multisystem diseases. Normal persons are unresponsive (tolerant) to their own (self) antigens, and autoimmunity results from a failure of self-tolerance. Therefore, understanding the pathogenesis of autoimmunity requires familiarity with the mechanisms of normal immunologic tolerance. Immunologic Tolerance: Definition and Mechanisms: Immunologic tolerance is a state of unresponsiveness to an antigen Self-tolerance is Un responsiveness to one`s own tissue/ self antigens. During development of T and B cells , few cells will express TCRs and BCRs that will recognize self antigens (autologous antigens). Surely, self antigens can not be removed. Mechanisms to control self reactive lymphocytes were developed by the body (mechanisms for tolerance) in order to overcome this problem. There are two broad mechanisms recognized for tolerance : 1. central tolerance 2. peripheral tolerance Immunologic Tolerance: Mechanisms: Central tolerance : -Takes place in primary lymphoid organs ( thymus and bone marrow) -In which immature lymphocytes are introduced to self antigens for the first time and those who react to autologous antigens are eliminated by apoptosis in a process called deletion or negative selection. Some autoreactive CD4+ T cells survive and develop into regulatory T cells. Some self reactive B cells might also undergo BCR rearrangement with production of new non reactive receptors (receptor editing) Immunologic Tolerance: Mechanisms: Central tolerance, however, is imperfect. How ? Not all self antigens are present in the thymus or bone marrow. And hence lymphocytes bearing receptors for such autoantigens escape into the periphery causing tissue damage. This problem was solved by peripheral tolerance. Immunologic Tolerance: Mechanisms: Peripheral tolerance : Takes place in the peripheral tissues To silence potentially autoreactive lymphocytes that skipped the central tolerance Mechanisms: 1. Anergy. 2. Suppression by regulatory T cells. 3. Deletion by apoptosis. 4. immune-privileged sites. Immunologic Tolerance: Mechanisms: 1. Anergy : This term refers to functional inactivation (rather than death) of lymphocytes. And it can be mediated through : Stimulation of Co-inhibitory receptors expressed on self reactive T and B cells Inhibition or blockage of Co-stimulatory receptors or signals on self reactive T and B cells Immunologic Tolerance: Mechanisms: 2. Suppression by regulatory T cells. Is a population of CD4+T cells that suppress immune response and characterized by expression of high level of CD25 co-receptors. Develop both in the thymus and peripheral lymphoid organs. the inhibitory effect of these cells is mediated by: 1. secretion of immunosuppressive cytokines (IL-10, TGF-β ) 2. competitive blocking co-stimulatory molecules. ( Reg T cells express CTLA-4, which may bind to B7 molecules on APCs and reduce their ability to activate T cells via CD28 ) Immunologic Tolerance: Mechanisms: 3. Deletion by apoptosis: through activation of both intrinsic / extrinsic pathways 4. Some self antigens are hidden (shielded/sequestered) from the immune system because the tissues in which these antigens are located do not communicate with the blood and lymph ( e.g. eye, brain and testis).These tissues are called immune-privileged sites. Unless released into the circulation -due to trauma or infection- , these antigens fail to elicit immune responses and are essentially ignored by the immune system. CONTENTS  Autoimmune Diseases (mechanisms of autoimmunity; general principles, genetic and environmental factors) Mechanisms of Autoimmunity: General Principles -So how self tolerance might break to give rise to pathologic autoimmunity? This results from combined effects of susceptibility genes, which influence lymphocyte tolerance, and environmental factors, such as infections or tissue injury, that alter the display of self antigens. Role of genetic Factors in Autoimmunity: There is abundant evidence that inherited genes play a role in the development of autoimmune diseases: 1. Autoimmune diseases have a tendency to run in families, and there is a greater incidence of the same disease in monozygotic than in dizygotic twins. Mechanisms of Autoimmunity: General Principles 2. Several autoimmune diseases are linked to the HLA locus, especially class II alleles (HLA-DR, HLA-DQ). 3. Several cytogenetic and linkage studies in families are revealing many genetic polymorphisms that are associated with different autoimmune diseases. Role of Infections, Tissue Injury, and Other Environmental Factors in autoimmunity: Microbes may induce autoimmune reactions by several mechanisms: 1. Infections are associated with increased expression of co-stimulatory molecules on APCs which will favor a breakdown of T cell tolerance and subsequent T cell activation. Mechanisms of Autoimmunity: General Principles 2. microbes may share cross-reacting epitopes with self antigens, so the resultant immune response will extend to self tissues ( molecular mimicry) e.g. rheumatic fever. the display of tissue antigens also may be altered by a variety of environmental insults. E.g. ultraviolet (UV) radiation and local trauma will cause cell injury and may lead to the exposure of hidden intracellular antigens Hormonal influence also was proposed especially with the strong gender bias of autoimmunity, with many of these diseases being more common in women than in men. Mechanisms of Autoimmunity: General Principles An autoimmune response may itself promote further autoimmune attack. Tissue injury caused by an autoimmune response may lead to exposure of self antigen epitopes that were previously concealed but are now presented to T cells in an immunogenic form. The activation of such autoreactive T cells is called epitope spreading, because the immune response spreads to epitopes that were not recognized initially. This is one of the mechanisms that may contribute to the chronicity of autoimmune diseases. Clinical examples of autoimmune diseases Important diseases: - SLE (systemic lupus erythematosus) RA (Rheumatoid Arthritis) SS (Sjögren Syndrome) CONTENTS  Rejection of Transplants Rejection Of Transplants A condition in which the recipient’s immune system recognizes the donor graft as foreign and attacks it. Mediated by T cells and antibodies of the recipient. Due to HLA gene polymorphism :The major antigenic differences between a donor and recipient that result in rejection of transplants are differences in HLA alleles Rejection Of Transplants  Recognition of Graft Allo-antigens: Grafts exchanged between individuals of the same species are called allografts. Following transplantation, the recipient’s T cells recognize donor antigens from the graft (the allogeneic antigens, or alloantigens) by two pathways: Direct : graft antigens are presented directly to recipient T cells by graft APCs Indirect : graft antigens are processed by recipient APC (like any foreign antigen) and then presented to recipient T cells. Both pathways will lead to T-cell mediated tissue damage via activation of cytotoxic T cells and T helper cells (TH1 subclass). Rejection Of Transplants Direct pathway is responsible for acute graft rejection and the indirect one for chronic rejection type. Rejection Of Transplants  Mechanisms of Graft Rejection: Rejection is a process in which T lymphocytes and antibodies produced against graft antigens react against and destroy the grafts. Rejection is classified into three types on the basis of clinical and pathological features. Each type of rejection is mediated by a particular kind of immune response. 1. hyperacute rejection : immediate, mediated by preformed antibodies usually to vascular endothelial cells of the graft. Prevented by pre- operative cross matching. Under the microscope : extensive inflammatory infiltrate into vascular lumen ( neutrophils) and fibrinoid necrosis of the vascular wall along with thrombi are seen. Hyperacute Graft Rejection Rejection Of Transplants 2. Acute rejection: days to weeks after transplantation. It may also appear suddenly months or even years later, after immunosuppression is tapered or terminated. It is mediated by T cells and antibodies that are activated by allo-antigens in the graft. Subdivided in to : a) Acute cellular rejection: mediated by CD8 T cells via direct destruction of graft cells OR by CD4 T cells that secrete cytokines and induce inflammation and cell damage. Under the microscope: Extensive tissue infiltrate ( CD8+and CD4+ cells) associated with tissue necrosis. b) Acute humoral or antibody rejection : also called vascular. In which antibodies will bind graft vascular endothelial cells with activation of complements (via classical pathway). The result is tissue destruction and inflammation of graft tissues in addition to occlusion of blood vessels. Under the microscope: inflammation and necrosis of vascular wall, deposits of complements byproducts and thrombosis. Rejection Of Transplants The recognition of cellular rejection is important because, in the absence of accompanying humoral rejection, most patients respond well to immunosuppressive therapy Acute cellular rejection Acute Humoral Rejection Rejection Of Transplants 3. Chronic rejection: occurs over months to years (indolent), mediated mainly by T cells (both CD4&CD8) and to lesser extent by antibodies. Microscopically: fibrosis and thickening of vascular wall is the predominant feature (interstitial fibrosis and vascular arteriolosclerosis) These microscopic changes results from increased activities of interstitial fibroblasts and vascular smooth muscles due to secreted cytokines by T cells. Interstitial mononuclear cell infiltrates are typically sparse. Methods of Increasing Graft Survival: 1. better matching of the donor and the recipient improves graft survival. (HLA gene polymorphism) 2. Immunosuppression of the recipient is a necessity in all organs transplantation (rejection is mediated by immune response) e.g. Cyclosporine suppresses T cell–mediated immunity by inhibiting transcription of cytokines genes principally genes for IL-2. 3. Induce donor-specific tolerance in recipient T cells. This is done to circumvent the untoward effects of immunosuppression ( increased susceptibility infections and neoplasms). This can be done through inhibition of co-stimulatory signals required for T cells activation. CONTENTS  Transplantation of Hematopoietic Stem Cells (HSCs), general principles and complications Transplantation of Hematopoietic Stem Cells (HSCs): A special form of transplant that is used to treat some hematologic diseases ( malignancies, bone marrow failure conditions as aplastic anemia, immunodeficiencies ). Transplanted HSCs are harvested from the umbilical cord blood of newborn infants or from the peripheral circulation after they are mobilized from the bone marrow by administration of hematopoietic growth factors. The problem with this form of transplant is that ,the recipient marrow should be irradiated or treated with chemotherapy to destroy the immune system (and some times, cancer cells) and to “open up” niches in the microenvironment of the marrow that nurture HSCs, thus allowing the transplanted HSCs to engraft. Transplantation of Hematopoietic Stem Cells (HSCs): Destruction of recipient immune system will result in two major problems that complicate this form of transplantation and differentiate it from other solid oragn transplants: 1. graft-versus-host disease 2. immune deficiency. Transplantation of Hematopoietic Stem Cells (HSCs): Graft-Versus-Host Disease Occurs when immunologically competent cells or their precursors are transplanted into immunologically crippled recipients, and the transferred cells recognize allo-antigens in the host and attack host tissues. seen most commonly in the setting of HSC transplantation and some forms of solid organ transplants. On receiving allogeneic HSCs, an immunologically compromised host cannot reject the graft, but T cells present in the donor graft perceive the host’s tissue as foreign and react against it. Ultimately causing inflammation and killing recipient cells Mediated by donor T cells (CD4+ & CD8+) Transplantation of Hematopoietic Stem Cells (HSCs): Graft-Versus-Host Disease There are two forms of GVHD: a) Acute : days to weeks after transplantation. Characterized by epithelial necrosis principally in three target organs ( liver manifested as jaundice, GIT – bloody diarrhea, and skin as rash ) b) Chronic : develops gradually or following the acute form. Patients develop skin lesions. To eliminate this disease, deletion of graft T cells was done. But, this approach proven to be a mixed blessing because an increased incidence of tumor recurrence, infections and even graft failure were reported. Transplantation of Hematopoietic Stem Cells (HSCs): Immune Deficiencies This is due to the slow reconstitution of the adaptive immune system (derived from donor HSC), after the recipient’s immune system is destroyed or suppressed to allow the graft to take. During this period recipients are susceptible to a variety of infections, mostly with viruses, such as CMV and EBV. Contents Primary immunodeficiency Secondary immunodeficiency Introduction: Immune deficiencies can be divided into 1. primary (or congenital) immunodeficiency disorders, which are genetically determined. 2. secondary (or acquired) immunodeficiencies, which may arise as a result of underling condition such as cancer, immunosuppression, malnutrition. Immunodeficiencies are manifested clinically by increased infections, which may be newly acquired or reactivation of latent infections Primary immunodeficiency diseases A group of conditions in which the underlying cause of impaired immune response is genetically inherited. usually detected in infancy, between 6 months and 2 years of age. telltale sign being susceptibility to recurrent infections. Clinical examples: Primary immunodeficiency (impaired adaptive immune response) 1. Severe Combined Immunodeficiency: (SCID) ! Pathology: impaired development of mature T lymphocytes and/or B lymphocytes. ! C/P: fetus with severe recurrent / persistent infections by a wide range of pathogens, including Candida albicans, Pneumocystis jiroveci, Pseudomonas, cytomegalovirus, varicella ! Forms : 1. X-linked SCID : mutation in gene coding for receptors for cytokines IL-2,4,7,9,15. all these cytokines are important for expansion of immature B and T cell precursors in generative lymphoid organs. 2. Autosomal recessive SCID mutations in adenosine deaminase (ADA) which results in accumulation of metabolites that are toxic to T cells and inhibit DNA synthesis. ! Histopathology: Thymus as well as other lymphoid tissues are hypoplastic. marked depletion of both T and B cells. Treatment : HSC transplantation. Primary immunodeficiency (impaired adaptive immune response) 2. X-Linked Agammaglobulinemia: (XLA) / Bruton disease ! Pathology : failure of pre–B cells to differentiate into mature B cells resulting in absence of gamma globulins in the blood. Mutation in Bruton tyrosine kinase (BTK) a signal transduction molecule. ! C/P: almost always in males ( X linked) Discovered by age of 6 months recurrent respiratory bacterial infections ( almost always, Haemophilus influenzae, Streptococcus pneumoniae, or Staphylococcus aureus) persistent Giardia lamblia infections ( no Ig A) and Enteroviruses. ! Histopathology: Profound reduction in the number of B cells in the blood and secondary lymphoid organs and an absence of germinal centers and plasma cells in these organs. T-cell numbers and responses may be normal. Treatment: Iv Immunoglobulins Primary immunodeficiency (impaired adaptive immune response) 3. DiGeorge Syndrome (Thymic Hypoplasia due to 3rd & 4th pharyngeal pouches defects) ! Pathology: deficient T-cell maturation due to congenital defect in the thymus ! C/P : recurrent infections by intracellular infections bacteria, viruses, fungi and protozoa. parathyroid gland hypoplasia, midline developmental abnormalities Histopathology: T cell depletion from lymphoid organs Normal serum levels of B cells and immunoglobulins Treatment : thymic transplantation. Contents Primary immunodeficiency (impaired innate immune response)  Primary immunodeficiency (impaired innate immune response) Inherited defects that typically affect leukocyte functions or the complement system and lead to increased vulnerability to infections Types 1. Defects in Leukocytes Function 2. Defects in the Complement System 1. Defects in Leukocytes Function:  Leukocyte adhesion deficiencies (LADs) : defects in adhesion molecules with impaired leukocyte recruitment to the site of infection. E.g. LAD1 (inherited defects in integrins )and LAD2 (defect in synthesis of functional sialyl-Lewis X, the ligand for E- and P-selectins).  Chronic granulomatous diseases : defects in phagocyte oxidase an enzyme required for synthesis of ROS. This will result in defective intracellular bacterial killing. Primary immunodeficiency (impaired innate immune response) Defects in Leukocytes Function  Chédiak-Higashi syndrome: defective fusion of phagosomes and lysosomes due to defect in gene encodes for LYST protein ( protein that regulates lysosomal trafficking) C/P: recurrent infections due to impaired phagocytosis. abnormalities in : melanocytes (leading to albinism), cells of the nervous system (associated with nerve defects), and platelets (causing bleeding disorders)  TLR defects : are rare. E.g. TLR3, a receptor for viral RNA, result in recurrent herpes simplex encephalitis Primary immunodeficiency (impaired innate immune response) 2. Defects in the Complement System:  Deficiencies of complement components: e. g o deficiencies in early complement components (C2,C4,C3) associated with increased viral and bacterial infection. o Deficiencies in late complement components (C5-C9 ) susceptibility to recurrent neisserial (gonococcal and meningococcal) infections, as Neisseria bacteria have thin cell walls and are especially susceptible to the lytic actions of complement.  Defects in complement regulatory proteins : result in excessive complements activation with subsequent inflammation or cell injury. E.g. o deficiency of C1 inhibitor (C1 INH) in hereditary angioedema (condition characterized by over-production of bradykinin, which is a potent vasodilator, patients clinically present with edema of skin and mucosal surfaces such as larynx and GIT) Contents Secondary immunodeficiency Secondary immunodeficiency ! a group of conditions where Impaired immune response is due to acquired underlying cause such as : Cancer, Diabetes ,Malnutrition ,chemotherapy or radiation therapy, immunosuppressive drugs , chronic infection (AIDS) ! secondary immune deficiencies are more common than the disorders of primary genetic origin Exercise: ! Considering the basic principles for development of normal immune response, discuss the underlying pathogenesis of impaired immune response and the possible clinical consequences for immune deficiency among the following patients categories:  cancer patients  diabetic patients  malnourished patients,  patients under chemo-radiotherapy  patients on immuno-suppressive drugs