Unit 5-Immune disease PDF

Chapter 6 Diseases of the Immune System Unit 5 Dr. Angela LI School of MHS  2 Dr. Angela LI, School of MHS, Tung Wah College Part 1 Review of immuni...

Chapter 6 Diseases of the Immune System Unit 5 Dr. Angela LI School of MHS  2 Dr. Angela LI, School of MHS, Tung Wah College Part 1 Review of immunity  3 Dr. Angela LI, School of MHS, Tung Wah College Inflammation is the second line of defense. Is one of the nonspecific defense. Figure 3.1 Lines of defense.  4 Immunity (Revision) Dr. Angela LI, School of MHS, Tung Wah College (Refer to immunology) Innate: present before birth, “natural” ▫ First line defense ▫ Second line defense Adaptive: developed by exposure to pathogens, or in a broader sense, antigens not recognized by the MHC ▫ Major Histocompatibility Complex  Also called HLA (Human Leukocyte Antigens) in humans  Major job is to make sure all self cell antigens are recognized and tolerated  5 Dr. Angela LI, School of MHS, Components of the immune systems Tung Wah College Cells ▫ lymphocytes, T-cell or B-cell ▫ Plasma cells ▫ Macrophages (APCs, i.e., antigen presenting cells) ▫ dendritic cells (APCs, i.e., antigen presenting cells) ▫ NK (natural killer) cells Tissues ▫ Generative lymphoid organs ▫ Peripheral lymphoid organs Selected molecules ▫ MHC molecules (Class I MHC and Class II MHC) ▫ cytokines  6 Dr. Angela LI, School of MHS, Innate immunity Tung Wah College Barriers Cells: macrophages, NK cells Cytokines/chemokines Plasma proteins: complement, coagulation factors Toll-like receptors Adaptive immunity Cellular, i.e., direct cellular reactions to antigens Humoral, i.e., antibodies  7 Dr. Angela LI, School of MHS, Tung Wah College  8 Dr. Angela LI, School of MHS, Adaptive Immunity Tung Wah College Cell-mediated immunity ▫ Cytotoxic T lymphocytes: CD8  Cytotoxic cell: Kill infected cell  Memory cells ▫ Helper T lymphocytes: CD4  TH1 : important in the control of bacterial intracellular infection. Active macrophages, stimulate the phagocytosis  TH2: active B cells to produce antibodies. Humoral immunity ▫ B lymphocytes  Antibody secretion from plasma cells IgA, IgD, IgE, IgG, IgM  Memory cells  9 Dr. Angela LI, School of MHS, Tung Wah College 1. Antigen Recognition and cell activation 2. Clonal selection 3. Removal of invader (antigen)  10 Dr. Angela LI, School of MHS, Tung Wah College  11 Dr. Angela LI, School of MHS, Tung Wah College  12 Dr. Angela LI, School of MHS, Tung Wah College  13 Dr. Angela LI, School of MHS, Tung Wah College  14 Dr. Angela LI, School of MHS, Tung Wah College Part 2 Disease of the immune system  15 Dr. Angela LI, School of MHS, Tung Wah College Disease of the immune system Hypersensitivity and Autoimmune Rejection of Tissue Transplants Immunodeficiency syndromes  16 1. Hypersensitivity Dr. Angela LI, School of MHS, Tung Wah College State of reactivity to antigen that is greater than normal, denotes a deleterious rather than a protective outcome Hypersensitivity disorders result from immune responses to exogenous and endogenous antigens that produce inflammation and cause tissue damage. ▫ Abnormal immune response  inflammatory response  tissue damage Four types: ▫ Type I, immediate hypersensitivity reaction ▫ Type II, antibody-mediated reaction ▫ Type III, immune complex-mediated reaction ▫ Type IV, cell-mediated hypersensitivity reaction  17 Table 6-1 Dr. Angela LI, School of MHS, Tung Wah College  18 Dr. Angela LI, School of MHS, 1. Hypersensitivity Tung Wah College Type I, Immediate hypersensitivity reaction ▫ “Immediate” means seconds to minutes. ▫ Also called allergy ▫ IgE mediated response that leads to the release of inflammatory mediators from sensitized mast cells  E.g., food allergy, hay fever (allergic Rhinitis), anaphylaxis ▫ Two stage of response  Immediate reaction (early-phase)  Late-phase reaction  19 Dr. Angela LI, School of MHS, Tung Wah College  20 Dr. Angela LI, School of MHS, Tung Wah College 1. Hypersensitivity Type I, Immediate hypersensitivity reaction  Immediate reaction ▫ Last about 1 hour ▫ Sensitized mast cell binding of the antigen produces degranulation of the sensitized mast cell with release of performed mediators ▫ Vasodilation, nonvascular smooth muscle contraction  Late-phase reaction ▫ The following 2-24 hour ▫ Result from recruitment of eosinphils, along with the release of cytokines and membrane phospholipids from the mast cell. ▫ Similar symptom to stage one, but last longer  21 Dr. Angela LI, School of MHS, Tung Wah College  22 Dr. Angela LI, School of MHS, Tung Wah College  23 1. Hypersensitivity Dr. Angela LI, School of MHS, Tung Wah College Type I, Immediate hypersensitivity reaction Mast Cell–derived Mediators: ▫ Responsible for the initial, some times explosive, symptoms of immediate reaction. Also lead to the late-phase reactions. ▫ Preformed (primary) mediators Vasoactive amines: Most important is histamine. Cause blood vessels’ smooth muscle relaxation (vasodilation) and increased vascular permeability (edema, hives) Other smooth muscle spasm (bronchospasm) Increase mucus secretion (nasal, bronchial, and gastric glands) Enzymes: proteases, acid hydrolases Tissue damage Production of kinins and complement Proteogycans: package and store amines  24 1. Hypersensitivity Dr. Angela LI, School of MHS, Tung Wah College Type I, Immediate hypersensitivity reaction Mast Cell–derived Mediators: (cont.) ▫ Lipid mediators Leukotrients: Most potent vasoactive and spasmogenic agent known. Increase vascular permeability and bronchial smooth muscle spasm Prostaglandin D2 By cyclooxygenase pathway. Cause intense bronchospasm as well as increased mucus secretion. Platelet-activating factor (PAF) Cause platelet aggregation, release of histamine, bronchospasm, increase vascular permeability, and vasodilation. Chemotactic for neutrophils and eosinophils ▫ Cytokines TNF, IL-1, chemokines Promote leukocyte recruitment.  25 Dr. Angela LI, School of MHS, Tung Wah College Clinical features of type 1 ▫ Result from release of mast cell mediators as well as the eosinophil-rich inflammation. ▫ Immediate hypersensitivity reaction  Dependent on the coordinated actions of variety of chemotactic, vasoactive, and spasmogenic compounds.  Histamine and leukotrients released rapidly and responsible for the intense immediate reactions – edema, mucus secretion, smooth muscle spasm.  Other mediators will contribute to late-phase response by recruiting additional leukocytes (inflammatory cells) and epithelial cell damage. ▫ Late-phase reaction  Most important cells are eosinophils. They secrete enzymes and protein which damage epithelial cells. Combined with other mediator, they directly activate mast cell.  The recruited cells amplify and sustain the inflammatory response without additional exposure to the triggering antigen.  26 Dr. Angela LI, School of MHS, Tung Wah College  27 1. Hypersensitivity Dr. Angela LI, School of MHS, Tung Wah College Local Reaction (allergy) Depending on the portal of entry of the allergen. ▫ Skin allergy, hives (cutaneous swelling) ▫ Allergic rhinitis and conjunctivitis (nasal and conjunctival discharge) ▫ Food allergy (allergic gastroenteritis) ▫ Hay fever ▫ Bronchial asthma Clinical manifestation ▫ Local changes  28 1. Hypersensitivity Dr. Angela LI, School of MHS, Tung Wah College Systemic Anaphylactic Reaction Extreme general allergic reaction Characterized by vascular shock, wide-spread edema, and difficulty in breathing. Very small amount dose of allergen may trigger anaphylaxis. Clinical manifestation: ▫ Initial manifestation: immediate reaction after expose to allergen: itching, hives, skin erythema ▫ Shortly followed by: bronchospasm, respiratory distress, laryngeal edema. Vomiting, abdominal cramps, diarrhea, laryngeal obstruction, may go into shock.  29 Dr. Angela LI, School of MHS, Tung Wah College Systemic Anaphylactic Reaction  30 Dr. Angela LI, School of MHS, 1. Hypersensitivity Tung Wah College Type II, antibody-mediated reaction Binding of antibodies to normal or altered surface antigens induce target cell destruction. ▫ E.g. certain drug actions, incompatible blood transfusion, Graves disease, Rh hemolytic Cell destruction by: ▫ Opsonization and phagocytosis  E.g. transfusion reactions ▫ Inflammation  Responsible for tissue injury in some forms of glomerulonephritis ▫ Cellular dysfunction  Antibody directed against cell surface receptors impair or dysregulate function without causing cell injury or inflammation. E.g. myasthenia gravis, Graves disease. Treatment: remove the antigen causing the reaction 30  31 Dr. Angela LI, School of MHS, Tung Wah College  32 Dr. Angela LI, School of MHS, Tung Wah College Figure 4.7 Type II antibody-mediated hypersensitivity reaction. Cell-bound antigen binds to IgG or IgM antibodies leading to a cytotoxic reaction. RBC, red blood cell.  33 Dr. Angela LI, School of MHS, Tung Wah College Figure 25-2. immune mechanisms of glomerular disease. (A) Antiglomerular membrane antibodies leave the circulation and interact with antigens that are present in the basement membrane of the glomerulus. (B) Antigen-antibody complexes circulating in the blood become trapped as they are filtered in glomerulus.  34 1. Hypersensitivity Dr. Angela LI, School of MHS, Tung Wah College Type III, immune complex–mediated reaction ▫ Indirect damage caused by the complement (plasma protein system) activation stimulated by the deposition of insoluble antigen-antibody complexes. ▫ E.g., SLE and rheumatoid arthritis ▫ Morphologic changes:  Acute necrotizing vasculitis (fibrinoid necrosis)  35 Dr. Angela LI, School of MHS, Tung Wah College Type III, immune complex– mediated reaction Phase I: Formation of blood-borne immune complexes Phase II: deposition of immune complexes in tissues. Complement activation at the site of immune complex deposition Phase III: Tissue injury caused by immune complex. Leads to attraction of leukocytes that are responsible for vessel and tissue injury.  36 Dr. Angela LI, School of MHS, Tung Wah College  37 1. Hypersensitivity Dr. Angela LI, School of MHS, Tung Wah College Type IV, T cell–mediated hypersensitivity reaction ▫ Direct CD8+ T cell-mediated toxicity, attacking all infected cells with recognized antigens, whether the antigen is harmful or not. E.g., hepatitis, graft rejection ▫ Delayed hypersensitivity reactions (24-72 hr) are mediated by antigen- specific T cells (CD4+ T cell). E.g., tuberculin or Mantoux test  Sensitization phase: antigen intake and then T cells are activated  Elicitation phase: memory T cells are stimulated by a subsequent exposure to a specific antigen. Chemical mediator are released, resulting in a visible local reaction at the site of antigen entry.  Immune injury mainly caused by infiltration of mononuclear cells and lymphocytes  38 Dr. Angela LI, School of MHS, Tung Wah College  39 Dr. Angela LI, School of MHS, Tung Wah College Figure: Type IV, cell-mediated hypersensitivity reactions, which include (A) direct cell-mediated cytotoxicity in which CK8+ T cells kill the antigen- bearing target cells, and (B) delayed-type hypersensitivity reactions in which presensitized CD4+ cells release cell-damaging cytokines.  40 Dr. Angela LI, School of MHS, Tung Wah College  41 Dr. Angela LI, School of MHS, Tung Wah College Mantoux test: a diagnostic tool for tuberculosis The Mantoux skin test consists of an The size of induration is measured intradermal injection of exactly one 48–72 hours later. Erythema tenth of a milliliter of PPD tuberculin. (redness) should not be measured.  42 Dr. Angela LI, School of MHS, Tung Wah College Figure 18.11 A positive tuberculin test  43 Dr. Angela LI, School of MHS, Tung Wah College  44 Dr. Angela LI, School of MHS, 2. Autoimmunity Tung Wah College Refers to immune reactions against self antigens. Failure to distinguish “self” from “non-self”. May result from the loss of self-tolerance. An individual begins to make autoantibodies or cytotoxic T cells against normal body components Causes damage to specific organs or to the entire system ▫ Specific organs (type II): e.g. Graves (in ch11) ▫ Systemic effect (type III): e.g. SLE Mechanisms: ▫ Genetic susceptibility (family tendency)  Strong genetic predisposition  Are more common in women than in men ▫ Environmental factors – trigger  45 Dr. Angela LI, School of MHS, Tung Wah College  46 Dr. Angela LI, School of MHS, Tung Wah College  47 2. Autoimmunity Dr. Angela LI, School of MHS, Tung Wah College Systemic Lupus Erythematosus (SLE) Autoimmune response; Type III hypersensitivity reaction (antigen- antibody complex mediated). ▫ The presence of a persistent antigen resulting in a chronic disease. Antigen–antibody binding stimulates inflammation and complex deposition in involved organs Antigen: (self cells) ▫ Components of cell (cell membrane, cytoplasm, nucleus) Antibodies: ▫ Activation of B cells, producing antibodies  Autoantibodies: antinuclear antibodies (ANA), antiphospholipid, anticytoplasmic ▫ Activation of T cells, promoting inflammation and permanent organ damage  48 Dr. Angela LI, School of MHS, Tung Wah College  49 Dr. Angela LI, School of MHS, Systemic Lupus Erythematosus (SLE) Tung Wah College Pathogenesis: progressive deposition and inflammation to immune complex deposits, in skin, joints, kidneys, vessels, heart, CNS ▫ Tissue injury: refer to Type III hypersensitivity Clinical expression: progressive renal and vascular disease, positive antinuclear antibodies (ANA). ▫ Local  Skin, musculoskeletal, pulmonary, and kidney  Characteristic facial rash across nose, cheeks – butterfly rash  Arthritis, glomerulonephritis, etc. ▫ Systemic  Fatigue, pleural effusion, pericardial effusion  50 “Butterfly Rash” Dr. Angela LI, School of MHS, Tung Wah College  51 Dr. Angela LI, School of MHS, Tung Wah College 3. Rejection of Tissue Transplants Occur after allograft (transplantation of body tissue) Graft rejection ▫ Allograft: grafts from unrelated individuals  Skin; kidneys; lungs; heart; bone marrow ▫ Problem: foreign tissue; immune system reacts to foreign MHC, rejects and destroys it  Better the MHC match, the better the outcome ▫ Rejection:  Cell-mediated hypersensitivity and humoral response  Inflammation, necrosis with eventual destruction of organ  52 Dr. Angela LI, School of MHS, Tung Wah College  53 Dr. Angela LI, School of MHS, Tung Wah College 4. Immunodeficiency syndromes Conditions resulting from defective immune mechanisms Two types: ▫ Primary immunodeficiency  Result from some genetic or developmental defect  Develop in infants and young children ▫ Secondary immunodeficiency (acquired)  Develop as direct consequence of some other recognized cause/disease. E.g., leukemia, AIDS  Develop in later life  54 Dr. Angela LI, School of MHS, 4. Immunodeficiency syndromes Tung Wah College Primary Immunodeficiency Diseases ▫ Many inherited defects in all the body’s lines of defenses  Chronic granulomatous disease  Severe combined immunodeficiency disease (SCID)  DiGeorge syndrome  Bruton-type agammaglobulinemia  55 Dr. Angela LI, School of MHS, Tung Wah College  56 4. Immunodeficiency syndromes Dr. Angela LI, School of MHS, Tung Wah College Acquired Immunodeficiency Diseases ▫ Result from a number of causes  Severe stress  Excess production of corticosteroids suppresses cell-mediated immunity  Malnutrition and environmental factors  Inhibit production of B cells and T cells  Acquired immunodeficiency syndrome (AIDS)  Opportunistic infections, low CD4+ cells, presence of HIV  57 Dr. Angela LI, School of MHS, 4. Immunodeficiency syndromes Tung Wah College ▫ AIDS pathogenesis and its virulence factors  Human immunodeficiency virus (HIV)  Retrovirus ▫ The enzyme reverse transcriptase (RT) is used by retroviruses to transcribe their single-stranded RNA genome into single-stranded DNA and to subsequently construct a complementary strand of DNA, providing a DNA double helix capable of integration into host cell chromosomes.  Two major types ▫ HIV-1 is prevalent in the United States and Europe ▫ HIV-2 is prevalent in West Africa  58 Dr. Angela LI, School of MHS, Tung Wah College  59 Dr. Angela LI, School of MHS, Tung Wah College HIV Replication of HIV ▫ Attachment ▫ Entry and uncoating ▫ Synthesis of DNA ▫ Integration ▫ Synthesis of RNA and polypeptides ▫ Release ▫ Assembly and maturation  60 HIV Dr. Angela LI, School of MHS, Tung Wah College ▫ Epidemiology of AIDS  HIV in blood, semen, saliva, vaginal secretions, and breast milk concentrated enough to cause infection  Must be injected into the body or contact a tear or lesion in the skin or mucous membranes  HIV is transmitted primarily via sexual contact and intravenous drug use  HIV is also transmitted across the placenta and in breast milk  Increased risk of HIV  IV drug users  Multiple sex partners  Unprotected sex  61 Dr. Angela LI, School of MHS, AIDS Tung Wah College Progress from HIV infection to AIDS ▫ HIV infects CD4 helper T lymphocytes, dendritic cells and macrophages. ▫ Antibody produce after infection, but antibodies cannot destroy all viral cells. ▫ Hallmark of AIDS: loss of cell-mediated and humoral immunity because of loss of CD4 TH1 lymphocytes  62 Dr. Angela LI, School of MHS, Tung Wah College  63 Dr. Angela LI, School of MHS, Tung Wah College  64 Dr. Angela LI, School of MHS, Tung Wah College AIDS Clinical Features ▫ Clinical latency: no symptom ▫ Clinical manifestation  Fever, weight loss, diarrhea, generalized lymphadenopathy  Multiple opportunistic infections  Neurologic disease  Secondary neoplasma  65 Dr. Angela LI, School of MHS, Tung Wah College Figure 06-42. Clinical course of HIV infection. A, During the early period after primary infection there is dissemination of virus, development of an immune response to HIV, and often an acute viral syndrome. During the period of clinical latency, viral replication continues and the CD4+ T-cell count gradually decreases, until it reaches a critical level below which there is a substantial risk of AIDS-associated diseases. B, Immune response to HIV infection. A cytotoxic T lymphocyte (CTL) response to HIV is detectable by 2 to 3 weeks after the initial infection, and it peaks by 9 to 12 weeks. Marked expansion of virus-specific CD8+ T-cell clones occurs during this time, and up to 10% of a patient's CTLs may be HIV specific at 12 weeks. The humoral immune response to HIV peaks at about 12 weeks. (Redrawn from Fauci AS, Lane HC: Human immunodeficiency virus disease: AIDS and related conditions. In Fauci AS, et al (eds): Harrison's Principles of Internal Medicine, 14th ed. New York, McGraw-Hill, 1997, p 1791.)  66 Dr. Angela LI, School of MHS, Tung Wah College Figure 4.11 Manifestations of HIV infection and AIDS  67 Dr. Angela LI, School of MHS, Content Tung Wah College Part I: Review of immunity Part II: Disease of the immune system ▫ Hypersensitivity  Type I, immediate hypersensitivity reaction  Mechanism  Local Reaction (allergy)  Systemic reaction (Anaphylactic Reaction)  Type II, antibody-mediated reaction  Type III, immune complex-mediated reaction  Type IV, cell-mediated hypersensitivity reaction ▫ Autoimmune  Systemic Lupus Erythematosus (SLE) ▫ Rejection of Tissue Transplants ▫ Immunodeficiency syndromes  Acquired Immunodeficiency Diseases (AIDS)