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INNATE IMMUNITY BARRIERS CELLS: LYMPHOCYTES, MACROPHAGES, PLASMA CELLS, NK CELLS CYTOKINES/CHEMOKINES PLASMA PROTEINS: Complement, Coagulation Factors Toll-Like Receptors, TLR’s Innate immunity A hallmark of the innate immune system is that it has no memory of a previous encounter with a foreign organism. The system is good at dealing with extracellular bacteria, fungi and intracellular viruses. ADAPTIVE IMMUNITY CELLULAR, i.e., direct cellular reactions to antigens HUMORAL, i.e., antibodies Adaptive (acquired) immunity Refers to antigen-specific defense mechanisms that take several days to become protective and are designed to remove a specific antigen. This is the immunity one develops throughout life. There are two major branches of the adaptive immune responses: 1. Humoral immunity : involves the production of antibody molecules in response to an antigen and is mediated by B-lymphocytes. 2. cell-mediated immunity : involves the production of cytotoxic T-lymphocytes, activated macrophages, activated NK cells, and cytokines in response to an antigen and is mediated by T-lymphocytes. CELLS of the IMMUNE SYSTEM LYMPHOCYTES, T LYMPHOCYTES, B PLASMA CELLS (MODIFIED B CELLS) MACROPHAGES, aka “HISTIOCYTES”, (APCs, i.e., Antigen Presenting Cells) “DENDRITIC” CELLS (APCs, i.e., Antigen Presenting Cells) NK (NATURAL KILLER) CELLS NK CELLS MHC Major Histocompatibility Complex A genetic “LOCUS” on Chromosome 6, which codes for cell surface compatibility Also called HLA (Human Leukocyte Antigens) in humans and H-2 in mice It’s major job is to make sure all self cell antigens are recognized and “tolerated”, because the general rule of the immune system is that all UN-recognized antigens will NOT be tolerated GENERAL SCHEME of CELLULAR EVENTS APCs (Macrophages, Dendritic Cells) T-Cells (Control Everything) CD4 “REGULATORS” (Helper) CD8 “EFFECTORS” B-Cells Plasma Cells AB’s NK Cells CYTOKINES Cytokines are produced by a broad range of cells, including immune cells like macrophages, B lymphocytes, T lymphocytes and mast cells, as well as endothelial cells, fibroblasts, and various stromal cells; MEDIATE INNATE (NATURAL) IMMUNITY, IL-1, TNF, INTERFERONS REGULATE LYMPHOCYTE GROWTH (many interleukins, ILs) ACTIVATE INFLAMMATORY CELLS STIMULATE HEMATOPOESIS, (CSFs, or Colony Stimulating Factors) CYTOKINES/CHEMOKINES CYTOKINES are PROTEINS produced by MANY cells, but usually LYMPHOCYTES and MACROPHAGES, numerous roles in acute and chronic inflammation, AND immunity TNF, IL-1, by macrophages CHEMOKINES are small proteins which are attractants for PMNs They are important in health and disease, specifically in host responses to infection, immune responses, inflammation, trauma, sepsis, cancer, and reproduction. MHC MOLECULES (Gene Products) I (All nucleated cells and platelets), cell surface glycoproteins, ANTIGENS II (APC’s, i.e., macs and dendritics, lymphs), cell surface glycoproteins, ANTIGENS III Complement System Proteins IMMUNE SYSTEM DISORDERS WHAT CAN GO WRONG? HYPERSENSITIVITY REACTIONS, I-IV “AUTO”-IMMUNE DISEASES, aka “COLLAGEN” DISEASES (BAD TERM) Inflammation NOT due to external pathogens, MHC failure. IMMUNE DEFICIENCY SYNDROMES, IDS: PRIMARY (GENETIC) ACQUIRED) SECONDARY ( HYPERSENSITIVITY When the immune systems cause harm to the body, it is referred to as a hypersensitivity Four Types of Hypersensitivity Reactions: Type I (Anaphylactic) Reactions Type II (Cytotoxic) Reactions Type III (Immune Complex) Reactions Type IV (Cell-Mediated) Reactions 1.Anaphylactic hypersensitivity • systemic anaphylaxis - the allergin is usually picked up by the blood and the reactions occur throughout the body. Examples include severe allergy to insect stings, drugs, and antisera. • localized anaphylaxis - the allergin is usually found localized in the mucous membranes or the skin. Examples include allergy to hair, pollen, dust, dander, feathers, and food. • Disorders - Atopy ( Atopic syndrome ) - Asthma - Anaphylaxis The process of anaphylaxis consists of the following sequential events: First exposure: to an antigen (allergen),such as bee venom, results in production of IgE class of antibodies by plasma cells. The surface of mast cells contains specific receptors for IgE. IgE molecules are bound to their receptors on the surface of mast cells and basophils. Second exposure: results in binding of the antigen to IgE on the mast cells . This then triggers the release of mast cell granules, which are : • Histamine -causes constriction of smooth muscles ( ex bronchioles ), vasodilatation, Increased capillary permeability, increase bronchial mucus secretion. • Chemotactic factors for eosinophils, proteases. • Leukotrienes -causes bronchial spasms. • Prostaglandins Histamine: Dilates and increases permeability of blood vessels (swelling and redness), increases mucus secretion (runny nose), smooth muscle contraction (bronchi). Prostaglandins: Contraction of smooth muscle of respiratory system and increased mucus secretion. Leukotrienes: Bronchial spasms. Anaphylactic shock: Massive drop in blood pressure. Can be fatal in minutes. Mast Cells and the Allergic Response 2. Antibody-dependent cytotoxicity Mechanism: Either IgG or IgM is made against normal self antigens as a result of a failure in immune tolerance, or a foreign antigen resembling some molecule on the surface of host cells enters the body and IgG or IgM made against that antigen then cross reacts with the host cell surface. The binding of these antibodies to the surface of host cells then leads to: Opsonization of the host cell. Activation of the classical complement pathway causing MAC lysis ( membrane attack complex ) of the cells. ADCC (Antibody-Dependent CellMediated Cytotoxicity ) destruction of the host cells. Complement system It consists of series of proteins synthesised by liver as acute phase reactants. 1. Augments host immune defenses 2.Lysis bacteria directly with MAC 3. Participates in cytotoxic immunity and immune complex hypersensitivity reactions. The multiple activities of the complement system: Lysis Opsonization Activation of inflammatory response Clearance of immune complexes C3a……….Anaphylotoxin C3b………..opsonin C5a………..Anaphylotoxin, Adhesion, Chemotactic C5b67…………..Chemotactic complex C5b6789…………………MAC MAC; Membrane attack complex OPSONIZATION MAC LYSIS ADCC • Disorders: -Mismatched blood group -Autoimmune hemolytic anemia -Thrombocytopenia -Erythroblastosis fetalis -Goodpasture's syndrome -Membranous nephropathy 3. Immune complex-mediated Mechanism: This is caused when soluble antigen-antibody (IgG or IgM) complexes, which are normally removed by macrophages in the spleen and liver, form in large amounts and overwhelm the body . These small complexes lodge in the capillaries, pass between the endothelial cells of blood vessels - especially those in the skin, joints, and kidneys - and become trapped on the surrounding basement membrane beneath these cells. • The antigen/antibody complexes then activate the classical complement pathway. This may cause: Massive inflammation, due to complement protein C5a triggering mast cells to release inflammatory mediators; Influx of neutrophils , due to complement protein C5a , resulting in neutrophils discharging their lysosomes and causing tissue destruction and further inflammation MAC lysis of surrounding tissue cells, due to the membrane attack complex, C5b6789n; Aggregation of platelets, resulting in more inflammation and the formation of microthrombi that block capillaries; Activation of macrophages , resulting in production of inflammatory cytokines and extracellular killing causing tissue destruction. • Associated disorders: serum sickness, a combination type I and type III hypersensitivity. autoimmune acute glomerulonephritis. rheumatoid arthritis. systemic lupus erythematosus. the skin lesions of syphilis and leprosy. Arthus reaction. Post streptococcal glomerulonephritis. Lupus Nephritis. Extrinsic allergic alveolitis (Hypersensitivity pneumonitis) Delayed hypersensitivity • cell-mediated rather than antibodymediated. • T8-lymphocytes become sensitized to an antigen and differentiate into cytotoxic Tlymphocytes while effector T4lymphocytes become sensitized to an antigen and produce cytokines . CTLs, cytokines, eosinophils, and/or macrophages then cause harm rather than benefit. Summary of Hypersensitivity reactions Production of antibodies to substances most tolerate, ie allergies. Type I (acute) - Most common, starts within seconds and most often ends within 30 minutes. Anaphylaxis – causes edema, mucus, and congestion Asthma – reaction to inhaled allergen. Causes massive release of histamine and spasmatic contraction of the bronchioles. Anaphylactic shock – systemic response to an injected allergen. Can cause bronchiolar constriction, circulatory shock, and possible death. Type II (antibody-dependant cytotoxic)- as in transfusion reaction. Type III (immune complex)- large antibody-antigen complexes that get trapped under the tunic interna of blood vessels and cause inflammation. Type IV (delayed)- occur 12 to 72 hours after exposure. Delay commonly associated with travel time to lymph nodes. Cosmetics and poison ivy hapten commonly do this. Hypersensitivity Production of antibodies to substances most tolerate, ie allergies. Type I (acute) - Most common, starts within seconds and most often ends within 30 minutes. Anaphylaxis – causes edema, mucus, and congestion Asthma – reaction to inhaled allergen. Causes massive release of histamine and spasmatic contraction of the bronchioles. Anaphylactic shock – systemic response to an injected allergen. Can cause bronchiolar constriction, circulatory shock, and possible death. Type II (antibody-dependant cytotoxic)- as in transfusion reaction. Type III (immune complex)- large antibody-antigen complexes that get trapped under the tunic interna of blood vessels and cause inflammation. Type IV (delayed)- occur 12 to 72 hours after exposure. Delay commonly associated with travel time to lymph nodes. Cosmetics and poison ivy hapten commonly do this. T helper cell function They help the activity of other immune cells by releasing T cell cytokines. These cells help, suppress or regulate immune responses. • Examples: - The cell or tissue damage done during diseases like tuberculosis, leprosy, smallpox, measles, herpes infections, candidiasis, and histoplasmosis - the skin test reactions seen for tuberculosis and other infections. - contact dermatitis like poison ivy. - type-1 insulin-dependent diabetes where CTLs destroy insulin-producing cells. - multiple sclerosis, where T-lymphocytes and macrophages secrete cytokines that destroy the myelin sheath that insulates the nerve fibers of neurons. - Crohn’s disease and ulcerative colitis. - psoriasis. Table 5 - Comparison of Different Types of hypersensitivity characteristics type-I (anaphylactic) type-II (cytotoxic) type-III (immune complex) type-IV (delayed type) antibody IgE IgG, IgM IgG, IgM None antigen exogenous cell surface soluble tissues & organs response time 15-30 minutes minutes-hours 3-8 hours 48-72 hours appearance weal & flare lysis and necrosis erythema and erythema and edema, necrosis induration histology basophils and eosinophil antibody and complement complement monocytes and and neutrophils lymphocytes Allergic Contact Dermatitis Response to Poison Ivy Hapten Autoimmune Diseases A. Type II (Cytotoxic) Autoimmune Reactions Involve antibody reactions to cell surface molecules, without cytotoxic destruction of cells. Grave’s Disease: Antibodies attach to receptors on thyroid gland and stimulate production of thyroid hormone. Symptoms: Goiter (enlarged thyroid) and bulging eyes. Myasthenia gravis: Progressive muscle weakness. Antibodies block acetylcholine receptors at neuromuscular synapse. Affects 25,000 Americans (mainly women). Today most patients survive when treated with drugs or immunosuppressants. SLE Systemic lupus erythematosus, often abbreviated as SLE or lupus, is a systemic autoimmune disease (or autoimmune connective tissue disease) that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage. It is a type III hypersensitivity reaction in which bound antibody-antigen pairs (immune complexes) precipitate and cause a further immune response. SLE The disease occurs nine times more often in women than in men, especially in women in child-bearing years ages 15 to 35. LUPUS (SLE) Etiology: Antibodies (ABs) directed against the patient’s own DNA, HISTONES, NONhistone RNA, and NUCLEOLUS Pathogenesis: Progressive DEPOSITION and INFLAMMATION to immune deposits, in skin, joints, kidneys, vessels, heart, CNS, LIVER. Morphology: “Butterfly” rash (NOT discoid) , skin deposits, glomerolunephritis Clinical expression: Progressive renal and vascular disease, POSITIVE A.N.A. INSULIN-DEPENDENT DIABETES MELLITUS (IDDM) Synonym • Type I diabetes, DM-type I Accounts for 5% to 10% of diabetes in US Female to male ratio of 1:1 Effector mechanisms • CD8 T cells and autoantibodies against beta cells • Glutamic acid decarboxylase (GAD) • Insulin PATHOPHYSIOLOGY OF IDDM Pancreatic beta cells are damaged by • Infectious agents • Mumps virus, rubella virus, coxsackie B virus • Toxic chemicals Damaged beta cells present antigens which trigger immune attack in genetically susceptible INSULIN-DEPENDENT DIABETES MELLITUS (IDDM) Symptoms • • • • • Increased thirst Frequent urination Increased hunger Weight loss Fatigue RHEUMATOID ARTHRITIS (RA) Characterized by inflammation of synovial membrane of joints and articular surfaces of cartilage and bone Involved joints are swollen, warm, painful, and stiff on arising or following inactivity. Vasculitis is a systemic complication Affects 3% to 5% of U.S. population Female to male ratio of 3:1 HLA DR4 is genetic risk factor ↑ Destructive Rheumatoid Synovitis NORMAL Bi-Layered Synovium MULTIPLE SCLEROSIS (MS) Chronic unpredictable disease of CNS with four possible clinical courses Characterized by patches of demyelination and inflammation of myelin sheath Prevalence higher in Northern Hemisphere • North of 37th parallel (125 cases /100,000) • South of 37th parallel (70 cases /100,000) Female to male ratio of 2:1 MULTIPLE SCLEROSIS (MS) Effector mechanisms • Myelin basic protein is primary autoantigen for CD4 TH1 cells Radiology diagnosis • MRI for detecting demyelinating lesions (plaques) Immunodefeciency disorders Defect in B- cell, T- cell, complement or phagocytic cells. Risk factors A. prematurity B. autoimmune diseases C. lymphoproliferative disorders D. infections E. immunosuppressive drugs ImmunoDefiency Syndromes (-IDS) PRIMARY (GENETIC) (P- IDS) SECONDARY (ACQUIRED) (A-IDS) PRIMARY CHILDREN with repeated, often severe infections, cellular AND/OR humoral immunity problems, autoimmune defects B-cell disorders BRUTON (X-linked agammaglobulinemia) COMMON VARIABLE IgA deficiency T cell disorders DI GEORGE (THYMIC HYPOPLASIA) 22q11.2 Combined B and T cell disorders SCID (Severe Combined Immuno Deficiency) Wiskott Aldrich syndrome Ataxia telangiectasia (A)IDS (SECONDARY IDS) Etiology: HIV Pathogenesis: Infection, Latency, Progressive T-Cell loss Morphology: MANY Clinical Expressions: Infections, Neoplasms, Progressive Immune Failure, Death, HIV+, HIV-RNA (Viral Load) • AIDS – Acquired Immunodeficiency diseases – Acquired after birth, like HIV. – HIV targets helper T cells – Most patients with AIDS die of opportunisitic infections. – Opportunistic infection: An infection that occurs because of a weakened immune system. Opportunistic infections are a particular danger for people with AIDS. The HIV virus itself does not cause death, but the opportunistic infections that occur because of its effect on the immune system can.