Genpath 2.pdf

General Pathology Chapter 6: Diseases of the Immune System Humoral Immunity: Activation of B Lymphocytes and Elimination of...

General Pathology Chapter 6: Diseases of the Immune System Humoral Immunity: Activation of B Lymphocytes and Elimination of Local reactions Extracellular Microbes - Diverse & vary depending on the portal of entry of the allergen Upon activation, B lymphocytes proliferate and then differentiate into Cutaneous rash/ blisters (skin allergy, hives) plasma cells that secrete different classes of antibodies with distinct Nasal & conjunctival discharge (allergic rhinitis & conjunctivitis) functions Immediate reaction: Antibody responses to most protein antigens require T cell help and are - (+) vasodilation, vascular leakage said to be T-dependent - Changes evident within minutes after exposure & subside in a few hours B cells that recognize protein Ags by their Ig receptors endocytose these Late-phase reaction: Ags into vesicles, degrade them, and display peptides bound to MHC II - 2-24 hours later without exposure to Antigen & may last for several days - (+) infiltration of tissues with eosinophils, neutrophils, basophils, for recognition by Th cells monocytes & CD4+ T cells Th1 Th2 Th17 Most immediate hypersensitivity disorders are caused by excessive Th2 Cytokines IFN-γ IL-4, IL-5, IL-13 IL-4, IL-5, IL-13 responses – stimulate IgE production & promote inflammation produced Cytokines that Activation of Th2 Cells & Production of IgE Antibody TG F-β, IL-6, IL-1, induce this IFN-γ, IL-12 IL-4 IL-23 Generation of Th2 cells = presentation of the Ag to naïve CD4+ Th Cells subset Stim. of IgE IL-4 Acts on B cells to stimulate class switiching to IgE & promotes the Immunological production, Recruitment of development of additional Th2 cells Macrophage reactions activation of neutrophils, IL-5 Involved in the development & activation of eosinophils activation triggered mast cells and monocytes IL-13 Enhances IgE production and acts onC epithelial cells to stimulate eosinophils mucus secretion Host defense Intracellular Helminthic Extracellular Th2 cells against microbes parasites bacteria, fungi - Produce chemokines that attract more Th2cells, as well as other WBCs, to Immune- the reaction site Immune-mediated - (+) Chronic atopic diseases sometimes classified as Th2-high & Th2-low mediated chronic Asthma Role in chronic Allergies inflammatory Atopic dermatitis disease inflammatory diseases (often - Antagonists of Th2 cytokines (IL-4, IL-5) = most effective in the Th2-high diseases (often autoimmune) group autoimmune) Sensitization & Activation of Mast Cells Mast Cells Its - Bone-marrow derived cells - Location explains why local immediate hypersensitivity reactions often occur in these sites Small blood vessels Nerves Subepithelial tissues - (+) cytoplasmic membrane-bound granules: “metachromatic granules” (+) biologically active mediators (+) acidic proteoglycans that bind basic dyes (Toluidine Blue) - Activated by the cross-linking of high-affinity IgE Fc Receptors - Be triggered by complement components = anaphylatoxins C5a C3a - Mast cell secretagogues: Protein antigens, by virtue of CD40L- and cytokine-mediated helper T-cell Chemokines: IL-8 actions, induce the production of antibodies of different classes, or isotypes Codeine & Morphine (IgG, IgA, IgE) = isotype switching Bee venom: (+) Adenosine melittin Helper T cells also stimulate the production of antibodies with high affinities Physical stimuli: heat, cold, sunlight for the antigen = affinity maturation - Basophils - Improves the quality of humoral immune response Similar to mast cells but not normally present in tissues Both express a high-affinity receptor FcERI HYPERSENSITIVITY: IMMUNOLOGICALLY MEDIATED TISSUE INJURY ▪ specific for the Fc portion of IgE & avidly binds IgE antibodies HYPERSENSITIVITY Mediators of Immediate Hypersensitivity Injurious immune reactions that are responsible for the pathology Mast cell activation = degranulation associated with immunologic diseases Granule Contents This term arose from the idea that individuals who have been previously Vasoactive amines Histamine exposed to an antigen manifest detectable reaction to that antigen & are - Intense smooth muscle contraction therefore said to be sensitized - Increases vascular permeability Excessive or harmful reaction to an antigen - Stimulates mucus secretion (nasal, General Features: bronchial & gastric glands) Enzymes Chymase, Tryptase, Acid Hydrolases Can be elicited by exogenous environmental antigens (microbial or - Cause tissue damage nonmicrobial) or endogenous self antigens - Generation of kinins & activated - (+) itching of the skin, anaphylaxis (fatal) components of complement (C3a) Imbalance between the effector mechanisms of immune responses and the Proteoglycans - Not directly involved control mechanism that serve to limit such responses Heparin, Chondroitin Sulfate Development is usually associated with the inheritance of particular - Package & store the amines in the susceptibility genes (HLA and non-HLA genes) granules The problem is that these reactions are poorly controlled, excessive or Lipid Mediators misdirected - Arachidonic acid-derived products - Associated with activation of phospholipase A2 Classification: Hypersensitivity Reactions – based on the underlying immunologic mechanism Leukotrienes Leukotrienes C4 & D4 - Most potent vasoactive & spasmogenic agents - Increasing vascular permeability - (+) bronchial smooth muscle contraction Leukotriene B4 - Highly chemotactic for neutrophils, eosinophils & monocytes Prostaglandin D2 - Most abundant mediator produced in mast cells by the cyclooxygenase pathway - Intense bronchospasm - Increase mucus secretion Platelet-Activating Factor - Lipid mediator produced by some Type 1 Hypersensitivity: Immediate Hypersensitivity (PAF) mast cell populations that is not derived from arachidonic acid Rapid immunologic reaction occurring in a previously sensitized individual - (+) platelet aggregation that is triggered by the binding of an Ag to IgE antibody on the surface - (+) histamine release of mast cells - (+) bronchospasm Systemic disorder - Increased vascular permeability - Injection/ Ingestion of an antigen into a sensitized individual - vasodilation Bee sting Peanut allergens Page 4 of 15 | NEXILIS  General Pathology Chapter 6: Diseases of the Immune System Cytokines - play an important role at several stages of immediate hypersensitivity Local Immediate Hypersensitivity Reactions reactions TNF Promote leukocyte recruitment 10-20% of the population suffers DTH morphology IL-1 - typical: late-phase reaction from allergies involving localized Accumulation of Chemokines reactions to common environmental mononuclear cells IL-4 Amplifies Th2 response allergens (CD4+ T cells & (+) Urticaria, Allergic Rhinitis (Hay macrophages) Fever), Bronchial Asthma, Atopic Perivascular “cuffing” Dermatitis, Food allergies Venules – endothelial hypertrophy Type 2 Hypersensitivity: Antibody-Mediated Hypersensitivity Antibodies that react with antigens present on cell surfaces or in the ECM Histamine & leukotrienes cause disease by destroying these cells, triggering inflammation, or - Released rapidly from sensitized mast cells interfering with normal functions - Trigger intense immediate reactions: Antibodies may be specific for normal cell/ tissue antigens Edema (autoantibodies) or for exogenous antigens (chemical/ microbial proteins) Mucus secretion Opsonization & Phagocytosis Smooth muscle spasm Chemokines Phagocytosis - Set the stage for the late-phase response by recruiting additional WBCs - Largely responsible for depletion of cells coated with antibodies - Also cause epithelial cell damage - Opsonized by IgG - IgG/IgM Epithelial cells Deposited on cell surfaces - Also produce soluble mediators (chemokines) May activate complement pathway (classical pathway) ▪ Activation: formation of Membrane Attack Complex (MAC) ▪ Disrupts membrane attack complex → disrupts the membrane by “drilling holes” → osmotic lysis ▪ Effective: cells & microbes with thin cell walls Antibody-Dependent Cellular Cytotoxicity (ADCC) Cells that are coated with IgG antibody are killed by NK cells & macrophages - Bind to the target by their receptor for the Fc Fragment of IgG - (+) cell lysis (-) phagocytosis ADCC & Phagocytosis occur in the following situations: 1. Transfusion reactions – incompatibility 2. Hemolytic Disease of the Fetus & Newborn (Erythroblastosis Fetalis) Late-Phase Reaction Rh (-) Mother = maternal IgG against Rh (+) Fetus Leukocytes are recruited that amplify and sustain the inflammatory 3. Autoimmune Hemolytic Anemia (AIHA), Agranulocytosis, Thrombocytopenia response without additional exposure to the triggering antigen Produce antibodies against their own blood cells Eosinophils 4. Certain drug reactions - Abundant WBC population in these reactions Inflammation - Recruited to sites of immediate hypersensitivity by chemokines, eotaxin - IL-5: most potent eosinophil-activating cytokine Antibodies deposit: - (+) Charcot-Leyden Crystals - Basement membrane & ECM (+) protein galecin-10 - Result: injury d/t inflammation Sometimes released into the extracellular space C5a (+) sputum of asthmatic patients - Direct the migration of granulocytes (BEN) and monocytes, & Promote inflammation & enhance Th2 response = allergic reactions anaphylatoxins (C5a & C3a) = ↑ vascular permeability Major cause of symptoms in some Type 1 Hypersensitivity disorders Release of substances from WBCs that damage tissues: (allergic asthma) - Lysosomal Enzymes (Proteases) Tx: broad-spectrum anti-inflammatory drugs (steroids) > antihistamine Basement membrane, collagen, elastin & cartilage - Generation of ROS Development of Allergies Antibody-Mediated Inflammation Susceptibility to immediate hypersensitivity reactions is genetically - Glomerulonephritis determined - Vascular rejection (Organ grafts) Atopy Cellular Dysfunction - Propensity to develop immediate hypersensitivity reactions - Atopic individuals Antibodies directed against cell surface receptors impair function without causing cell injury or inflammation Higher serum IgE levels More IL-4-producing Th2 cells - Myasthenia Gravis → muscle weakness (+) 50% have a family history of allergy - Graves Disease → Hyperthyroidism Environmental Factors - Pollen, cat hair, dust mites Nonatopic Allergy - 20-30% of immediate hypersensitivity reactions are triggered by non- antigenic stimuli Temperature extremes Exercise - Do not involve Th2 cells or IgE - Mast cells are abnormally sensitive to activation by various nonimmune stimuli Systemic Anaphylaxis Characteristics: - Vascular shock - Widespread edema - - Difficulty in breathing Extremely small doses of antigen may trigger Type 3 Hypersensitivity: Complex-Mediated Hypersensitivity anaphylaxis Antigen-antibody complexes produce tissue damage mainly by eliciting - Within minutes after inflammation at the sites of deposition exposure to allergens - Initiated when Ag combines with Ab in the circulation = Immune complexes (+) itching, hives & that typically deposit in vessel walls skin erythema - Less frequently, formed at site where Ag has been “planted” previously (in (+) contraction of bronchioles & respiratory distress situ immune complexes) Laryngeal Edema Antigen that form immune complexes: ▪ Hoarseness - Exogenous ▪ Compromises breathing Foreign protein that is injected/ produced by infectious microbe (+) vomiting, abdominal cramps, diarrhea, & laryngeal obstruction - Endogenous ▪ Patient may go on shock & die within the hour Individual produces antibody against self-antigens (autoimmunity) Tend to be systemic - Kidney = glomerulonephritis - Joints = arthritis - Small blood vessels = vasculitis Page 5 of 15 | NEXILIS  General Pathology Chapter 6: Diseases of the Immune System Systemic Immune Complex Disease Responses of Differentiated Effector T Cells Serum Sickness On repeat exposure to an antigen, Th1 cells secrete cytokines (IFN-y) - Prototype of a systemic immune complex disease responsible for many of the manifestations of DTH - Administration of large amounts of foreign serum or antibodies from other Classically Activated Macrophages individuals/ species - IFN-y-activated Pathogenesis: 3 Phases Ability to phagocytose & kill microorganism is markedly augmented Formation of - Introduction of protein Ag = formation of Abs (1 Express more class II MHC molecules = enhance Ag presentation Immune week after Ag exposure) Secrete TNF, IL-1 and chemokines = promote inflammation Complexes - Abs secreted into the blood, react with the Ag = Produce more IL-12 = ↑ Th1 response (+) immune complexes - Serve to eliminate the offending antigen Deposition of - Circulating immune complexes are deposited in - Activation sustained + continued inflammation = (+) tissue injury Immune vessels = (+) tissue deposition Activated Th17 cells > - neutrophils & monocyty Complexes - Complexes (medium-sized) = under conditions of - Secrete IL-17, IL-22, chemokines & other cytokines slight Ag excess are the most pathogenic - Recruit neutrophils & monocytes to the reaction = promote inflammation - Organs where blood is filtered at high pressure to Clinical Examples: CD4+ T Cell-Mediated Inflammatory Reactions (DTH) form fluids (urine & synovial fluid) are sites where immune complexes become concentrated & tend to Tuberculin Reaction deposit (Glomeruli & Joints) - Intracutaneous injection of purified protein (tuberculin) Inflammation & - Once complexes are deposited in tissues = (+) - In a previously sensitized individual Tissue Injury acute inflammatory reaction (+) reddening & induration of the site: 8-12 hours - Clinical features: 10 days after Ag administration Peak: 24-72 hours → slowly subside ✓ Fever - Persistent/ Nondegradable Antigens (MTB) ✓ Urticaria Macrophage infiltration in the lungs over a period of 2-3 weeks ✓ Joint pain Sustained activation: ✓ Lymph node enlargement ▪ Macrophage → epitheloid cells → (+) granulomas = chronic ✓ Proteinuria inflammation (granulomatous inflammation) - Complement proteins can be detected at the site Helminthic Infections of injury, during the active phase of the disease: - Schistosomiasis Consumption of complement = ↓C3 (serum Worms lay eggs that elicit granulomatous reactions levels) – used to monitor disease activity Rich in eosinophils – elicited by strong Th2 responses Calternative pathways MORPHOLOGY Contact Dermatitis Acute Vasculitis - Contact with urushiol (poison ivy/ oak) - Principal morphologic manifestation if Immune complex injury - Itchy, vesicular dermatitis - (+) Fibrinoid Necrosis – seen in IF microscopy; deposits along the - Same mechanism for drug reactions – (+) skin rashes glomerular basement membrane Rheumatoid arthritis Acute Serum Sickness Chronic Serum Sickness Multiple Sclerosis - Single exposure to a large - Repeated/ prolonged Inflammatory Bowel Disease amount of antigen exposure to an antigen - Lesion tends to resolve as a - SLE – persistent antibody CD8+ T Cell-Mediated Cytotoxicity result of catabolism of the response to autoantigens Kill antigen-expressing target cells immune complexes Play an important role in graft rejection In a virus-infected cell, viral peptides are displayed by class I MHC Local Immune Complex Disease molecules, and the complex is recognized by the TCR of the CD8+ T lymphocytes Arthus reaction - Localized area of tissue necrosis resulting from acute immune complex Killing of infected cells lead to elimination of the infection = responsible vasculitis (skin) for cell damage that accompanies the infection - Reaction can be produced experimentally by intracutaneous injection of Involves perforins & granzymes, preformed mediators contained in the Ag in a previously immunized animal that contains circulating antibodies lysosome-like granules of CTLs against the antigen - Perforin – facilitates the release of the granzymes from the complex - As the antigen diffuses into the vascular wall, it binds the preformed - Granzymes – proteases that cleave & activate caspases = (+) apoptosis antibody, and large immune complexes are formed locally - Complexes precipitate in the vessel walls & cause fibrinoid necrosis Imposed thrombosis worsens the ischemic injury * in 17 only Type 4 Hypersensitivity: T-Cell Mediated Hypersensitivity Cell-mediated hypersensitivity is caused by inflammation resulting from cytokines produced by CD4+ T cells AUTOIMMUNE DISEASES CD4+ T cell-mediated - Environmental & self-antigens Autoimmunity – immune reactions against self antigens Hypersensitivity - Autoimmune & chronic inflammatory It should be noted that the mere presence of autoantibodies does not diseases indicate that an autoimmune disease exists – older age groups CD8+ T cells (Cell - Dominant mechanism of tissue injury – Ideally, at least 3 requirements should be met before a disorder is Killing) follow viral infections categorized as truly caused by autoimmunity: 1. Presence of an immune reaction specific for some self antigen or self CD4+ T Cell-Mediated Inflammation tissue 2. Evidence that such a reaction is not secondary to tissue damage but Produced by T cells induce inflammation that may be chronic & destructive is of primary pathogenic significance The prototype of T cell-mediated inflammation is delayed-type 3. The absence of another well-defined cause of the disease hypersensitivity (DTH) Organ-Specific Disease Systemic Disease An antigen administered into the skin of a previously immunized individual Immune responses directed against a Diseases in which the autoimmune - Detectable: 24-48 hrs single organ or tissue reactions are against widespread - (+) Inflammatory reaction contribute to organ-specific diseases antigens Th1 – activated macrophages - Type 1 DM - SLE Th17 – greater neutrophil component - Multiple sclerosis - Goodpasture syndrome Activation of CD4+ T cells Naïve CD4+ T cells recognize peptides displayed by DCs & secrete IL-2 - Stimulate proliferation of the antigen-responsive T cells APCs produce: - IL-12 Induce differentiation of CD4+ T cells to the Th1 Subset - IFN-y Promotes further Th1 development = amplify reaction - IL-1, IL-6, IL-23 (close relative of IL-12) Induce differentiation to the Th17 subset Some of the differentiated effector cells enter the circulation & join the pool of memory T cells – persist for long periods (years) Page 6 of 15 | NEXILIS