© 2012 Pearson Education Inc. Lecture prepared by Mindy Miller-Kittrell North Carolina State University Chapter 18 AIDS and Other Immune Disorders

Hypersensitivities Hypersensitivity –Any immune response against a foreign antigen exaggerated beyond the norm Four types –Type I (immediate) –Type II (cytotoxic) –Type III (immune complex–mediated) –Type IV (delayed or cell-mediated) © 2012 Pearson Education Inc.

Hypersensitivities Type I (Immediate) Hypersensitivity –Results from the release of inflammatory molecules in response to an antigen –Localized or systemic reaction –Develops soon after exposure to an antigen –Commonly called allergy –The antigens that stimulate it are called allergens © 2012 Pearson Education Inc.

Figure 18.1a The mechanisms of a type I hypersensitivity reaction: sensitization Allergen (antigen) Antigen-presenting cell (APC) phagocytizes and processes antigen. APC presents epitope to Th2 cell. Th2 cell B cell Plasma cell IL-4 IL-4 from Th2 cell stimulates selected B cell clone. B cells become plasma cells that secrete IgE. IgE against allergen IgE stem binds to mast cells, basophils, and eosinophils. Eosinophil Basophil IgE Mast cell Sensitization

Figure 18.1b The mechanisms of a type I hypersensitivity reaction: degranulation Subsequent exposure to allergen Degranulation Sensitized mast cell, basophil, or eosinophil Histamines, kinins, proteases, leukotrienes, prostaglandins, and other inflammatory molecules

Hypersensitivities Type I (Immediate) Hypersensitivity –Roles of degranulating cells in an allergic reaction –Degranulation occurs after cells are sensitized –Mast cells –Basophils –Eosinophils –Degranulation releases histamine, kinins, proteases, leukotrienes, and prostaglandins © 2012 Pearson Education Inc.

Hypersensitivities Type I (Immediate) Hypersensitivity –Clinical signs of localized allergic reactions –Usually mild –Site of reaction depends on portal of entry –Small inhaled allergens may reach lungs and cause asthma –Some foods contain allergens –May cause diarrhea and other gastrointestinal signs and symptoms –Local skin inflammation may produce hives or urticaria © 2012 Pearson Education Inc.

Figure 18.2 Some common allergens-overview

Figure 18.3 Urticaria

Hypersensitivities Type I (Immediate) Hypersensitivity –Clinical signs of systemic allergic reactions –Many mast cells may degranulate at once, releasing large amounts of histamine and inflammatory mediators –Acute anaphylaxis or anaphylactic shock can result –Clinical signs are those of suffocation –Must be treated promptly with epinephrine © 2012 Pearson Education Inc.

Hypersensitivities Type I (Immediate) Hypersensitivity –Diagnosis of type I hypersensitivity –Diagnosis based on detection of high levels of IgE against specific allergen –ImmunoCAP specific IgG blood test, CAP RAST, pharmacia CAP –Alternatively, can diagnose using skin tests © 2012 Pearson Education Inc.

Figure 18.4 Skin tests for diagnosing type I hypersensitivity

Hypersensitivities Type I (Immediate) Hypersensitivity –Prevention of type I hypersensitivity –Identify and avoid allergens –Identify food allergens by eliminating suspected foods from diet –Immunotherapy can help prevent allergic reactions –Administer a series of injections of dilute allergen –Must be repeated every two to three years © 2012 Pearson Education Inc.

Hypersensitivities Type I (Immediate) Hypersensitivity –Treatment of type I hypersensitivity –Administer drugs that counteract inflammatory mediators –Antihistamines neutralize histamine –Treat asthma with a corticosteroid and a bronchodilator –Epinephrine neutralizes many mechanisms of anaphylaxis –Relaxes smooth muscle –Reduces vascular permeability –Severe asthma and anaphylactic shock require emergency treatment © 2012 Pearson Education Inc.

Hypersensitivities Type II (Cytotoxic) Hypersensitivity –Results when cells are destroyed by an immune response –Often the combined activities of complement and antibodies –A component of many autoimmune diseases –Two significant examples –Destruction of blood cells following an incompatible blood transfusion –Destruction of fetal red blood cells in hemolytic disease of the newborn © 2012 Pearson Education Inc.

Hypersensitivities Type II (Cytotoxic) Hypersensitivity –The ABO system and transfusion reactions –Blood group antigens are surface molecules of red blood cells –Each person’s red blood cells have A antigen, B antigen, both antigens, or neither antigen –Transfusion reaction can result if individual receives different blood type –Donor’s blood group antigens may stimulate the production of antibodies in the recipient –Causes destruction of the transfused cells © 2012 Pearson Education Inc.

Hypersensitivities Type II (Cytotoxic) Hypersensitivity –The ABO system and transfusion reactions –Recipient has preexisting antibodies to foreign blood group antigens –Immediate destruction of donated blood cells can occur –Recipient has no preexisting antibodies to foreign blood group antigens –Transfused cells initially circulate and function normally –Eventually recipient’s immune system destroys foreign antigens © 2012 Pearson Education Inc.

Figure 18.5 Events leading to hemolysis Type A antigens on red blood cells of patient Anti-B antibody Donated red blood cells with B antigen Complement Hemoglobin Transfusion Hemolysis Agglutination and complement binding

Hypersensitivities Type II (Cytotoxic) Hypersensitivity –The Rh system and hemolytic disease of the newborn –Rh antigen –Common to red blood cells of humans and rhesus monkeys –About 85% of humans are Rh positive (Rh+) –Rh– woman carrying an Rh+ fetus may be at risk for hemolytic disease –RhoGAM administered to prevent hemolytic disease of the newborn © 2012 Pearson Education Inc.

Figure 18.6 Events in the development of hemolytic disease of the newborn-overview

Hypersensitivities Type II (Cytotoxic) Hypersensitivity –Drug-induced cytotoxic reactions –Some drug molecules bind larger molecules –Stimulate the production of antibodies –Can produce various diseases –Immune thrombocytopenic purpura –Agranulocytosis –Hemolytic anemia © 2012 Pearson Education Inc.

Figure 18.7 Events in the development of immune thrombocytopenic purpura Platelet Drug Drug-platelet complex Drug molecules bind to platelets, forming drug-platelet complex. Complexes are antigenic, triggering a humoral immune response. Antibodies bind to drug molecules; complement binds to antibodies. Complement Membrane attack complexes of complement lyse platelet, which leaks cytoplasm.

Hypersensitivities Type III (Immune Complex–Mediated) Hypersensitivity –Caused by formation of immune complexes –Can cause localized reactions –Hypersensitivity pneumonitis –Glomerulonephritis –Can cause systemic reactions –Systemic lupus erythematosus –Rheumatoid arthritis © 2012 Pearson Education Inc.

Figure 18.8 The mechanism of type III (immune-complex mediated) hypersensitivity-overview Antigens combine with antibodies to form antigen-antibody complexes. Antigen Antibody (IgG) Antigen-antibody complex Phagocytes remove most of the complexes, but some lodge in the walls of blood vessels. There the complexes activate complement. Inactive complement Active complement Antigen-antibody complexes and activated complement attract and activate neutrophils, which release inflammatory chemicals. Neutrophil Inflammatory chemicals Inflammatory chemicals damage underlying blood vessel wall.

Hypersensitivities Type III (Immune Complex–Mediated) Hypersensitivity –Hypersensitivity pneumonitis –Inhalation of antigens into lungs stimulates antibody production –Subsequent inhalation of the same antigen results in formation of immune complexes –Activates complement © 2012 Pearson Education Inc.

Hypersensitivities Type III (Immune Complex–Mediated) Hypersensitivity –Glomerulonephritis –Immune complexes in the blood are deposited in glomeruli –Damage to the glomerular cells impedes blood filtration –Kidney failure and, ultimately, death result © 2012 Pearson Education Inc.

Hypersensitivities Type III (Immune Complex–Mediated) Hypersensitivity –Rheumatoid arthritis –Immune complexes deposited in the joint –Results in release of inflammatory chemicals –The joints begin to break down and become distorted –Trigger not well understood –Treated with anti-inflammatory drugs © 2012 Pearson Education Inc.

Figure 18.9 The crippling distortion of joints characteristic of rheumatoid arthritis

Autoimmune Diseases Type III (Immune Complex–Mediated) Hypersensitivity –Systemic lupus erythematosus –Autoantibodies against DNA result in immune complex formation –Many other autoantibodies can also occur –Against red blood cells, platelets, lymphocytes, muscle cells –Trigger unknown –Immunosuppressive drugs reduce autoantibody formation –Glucocorticoids reduce inflammation © 2012 Pearson Education Inc.

Figure The characteristic facial rash of systemic lupus erythematosus

Hypersensitivities Type IV (Delayed or Cell-Mediated) Hypersensitivity –Inflammation 12 to 24 hr after contact with certain antigens –Is due to actions of antigen, antigen-presenting cells, and T cells –Delay reflects the time it takes for macrophages and T cells to migrate to and proliferate at the site of the antigen © 2012 Pearson Education Inc.

Hypersensitivities Type IV (Delayed or Cell-Mediated) Hypersensitivity –The tuberculin response –An injection of tuberculin beneath the skin causes reaction in individual exposed to tuberculosis or tuberculosis vaccine –Used to diagnose contact with antigens of M. tuberculosis –No response when individual not infected or vaccinated –Red, hard swelling develops in individuals previously infected or immunized © 2012 Pearson Education Inc.

Figure A positive tuberculin test

Hypersensitivities Type IV (Delayed or Cell-Mediated) Hypersensitivity –Allergic contact dermatitis –Cell-mediated immune response –Results in an intensely irritating skin rash –Triggered by chemically modified skin proteins that the body regards as foreign –Acellular, fluid-filled blisters develop in severe cases –Can be treated with glucocorticoids © 2012 Pearson Education Inc.

Figure Allergic contact dermatitis

Hypersensitivities Type IV (Delayed or Cell-Mediated) Hypersensitivity –Graft rejection –Rejection of tissues or organs that have been transplanted –Grafts perceived as foreign by a recipient undergo rejection –Immune response against foreign MHC on graft cells –Rejection depends on degree to which the graft is foreign to the recipient –Based on the type of graft © 2012 Pearson Education Inc.

Figure Types of grafts Autograft Isograft AllograftXenograft Genetically identical sibling or clone Genetically different member of same species

Hypersensitivities Type IV (Delayed or Cell-Mediated) Hypersensitivity –Graft-versus-host disease –Donated bone marrow cells regard patient’s cells as foreign –Donor and recipient differ in MHC class I molecules –Grafted T cells attack the recipient’s tissues –Donor and recipient differ in MHC class II molecules –Grafted T cells attack the host’s antigen-presenting cells –Immunosuppressive drugs can stop graft-versus- host disease © 2012 Pearson Education Inc.

Hypersensitivities Type IV (Delayed or Cell-Mediated) Hypersensitivity –Donor-recipient matching and tissue typing –MHC compatibility between donor and recipient difficult because of a high degree of variability –The more closely the donor and recipient are related, the smaller the difference in their MHC –Preferable that grafts are donated by a parent or sibling –Tissue typing used to match donor and recipient © 2012 Pearson Education Inc.

Hypersensitivities Type IV (Delayed or Cell-Mediated) Hypersensitivity –The actions of immunosuppressive drugs –Immunosuppressive drugs important to transplantation success –Classes of immunosuppressive drugs –Glucocorticoids –Cytotoxic drugs –Cyclosporine –Lymphocyte-depleting therapies © 2012 Pearson Education Inc.

Autoimmune Diseases Occur more often in the elderly Are more common in women than in men May result when an individual begins to make autoantibodies or cytotoxic T cells against normal body components © 2012 Pearson Education Inc.

Autoimmune Diseases Causes of Autoimmune Diseases –Estrogen may stimulate destruction of tissue by cytotoxic T cells –Some maternal cells may cross the placenta and trigger autoimmune disease later in life –Environmental factors include viral infections –Genetic factors include certain MHC genes –T cells may encounter self-antigens that are normally “hidden” –Microorganisms may trigger autoimmunity because of molecular mimicry –Failure of the normal control mechanisms of the immune system © 2012 Pearson Education Inc.

Autoimmune Diseases Examples of Autoimmune Diseases –Two major categories –Systemic autoimmune diseases –Single-organ autoimmune diseases © 2012 Pearson Education Inc.

Autoimmune Diseases Examples of Autoimmune Diseases –Single-organ autoimmune diseases –Autoimmunity affecting blood cells –Autoimmune hemolytic anemia –Autoimmunity affecting endocrine organs –Type I diabetes mellitus –Graves’ disease © 2012 Pearson Education Inc.

Autoimmune Diseases Examples of Autoimmune Diseases –Single-organ autoimmune diseases –Autoimmunity affecting nervous tissue –Multiple sclerosis –Autoimmunity affecting connective tissue –Rheumatoid arthritis © 2012 Pearson Education Inc.

Immunodeficiency Diseases Conditions resulting from defective immune mechanisms Two general types –Primary –Result from some genetic or developmental defect –Develop in infants and young children –Acquired –Develop as direct consequence of some other recognized cause –Develop in later life © 2012 Pearson Education Inc.

Immunodeficiency Diseases 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 © 2012 Pearson Education Inc.

Immunodeficiency Diseases 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 © 2012 Pearson Education Inc.

Figure Diseases associated with AIDS-overview

Table 18.6 Opportunistic Infections Associated with AIDS

Immunodeficiency Diseases Acquired Immunodeficiency Diseases –AIDS pathogenesis and its virulence factors –Human immunodeficiency virus (HIV) –Retrovirus –Two major types –HIV-1 is prevalent in the United States and Europe –HIV-2 is prevalent in West Africa © 2012 Pearson Education Inc.

Figure Artist ’ s conception of HIV Reverse transcriptase Capsid Integrase Envelope Protease tRNA gp41 gp120 ssRNA genome

Immunodeficiency Diseases Acquired Immunodeficiency Diseases –AIDS pathogenesis and its virulence factors –Origin of HIV –Likely arose from mutation of the simian immunodeficiency virus (SIV) –Estimated to have emerged in the human population around 1930 © 2012 Pearson Education Inc.

Immunodeficiency Diseases Acquired Immunodeficiency Diseases –Replication of HIV –Attachment –Entry and uncoating –Synthesis of DNA –Integration –Synthesis of RNA and polypeptides –Release –Assembly and maturation © 2012 Pearson Education Inc.

Figure The replication cycle of HIV-overview

Figure The process by which HIV attaches to and enters a host cell-overview

Figure Action of reverse transcriptase-overview

Figure The course of AIDS HIV in blood CD4 (helper) T cell count Antibody against HIV Weeks Years HIV RNA copies/ml plasma CD4 T cells/mm 3 blood Primary infection Clinical latency Opportunistic diseases Death

Immunodeficiency Diseases Acquired Immunodeficiency Diseases –Epidemiology of AIDS –First recognized in young male homosexuals in the U.S. –Now found worldwide –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 © 2012 Pearson Education Inc.

Figure The global distribution of HIV/AIDS North America 1.4 million Caribbean 240,000 Latin America 2 million Western and Central Europe 850,000 North Africa & Middle East 310,000 Sub-Saharan Africa 24.4 milion Eastern Europe & Central Asia 1.5 million East Asia & Pacific 850,000 South & Southeast Asia 3.8 million Australia & New Zealand 59,000

Immunodeficiency Diseases Acquired Immunodeficiency Diseases –Epidemiology of AIDS –HIV is transmitted primarily via sexual contact and intravenous drug use –HIV is also transmitted across the placenta and in breast milk –Certain behaviors increase the risk of infection –Anal intercourse –Sexual promiscuity –Intravenous drug use –Sexual intercourse with anyone engaging in the previous three behaviors © 2012 Pearson Education Inc.

Figure Modes of HIV transmission in males over 12 years of age in the U.S. during 2007 Male homosexual contact plus use of injected drugs Heterosexual contact Use of injected drugs Male homosexual contact Other  0.5% 32% 3% 12% 53% Adult Males

Immunodeficiency Diseases Acquired Immunodeficiency Diseases –Diagnosis, treatment, and prevention –Diagnosis involves detecting antibodies against HIV –Can indicate infection with HIV but not presence of AIDS –Small percentage of infected individuals are long-term nonprogressors –Appear not to develop AIDS –Possibly because of defective virions, mutated coreceptors for the virus, or well-developed immune systems © 2012 Pearson Education Inc.

Immunodeficiency Diseases Acquired Immunodeficiency Diseases –Diagnosis, treatment, and prevention –Antiretroviral therapy (ART) –A “cocktail” of several antiviral drugs –Reduces viral replication, but infection remains –Vaccine development has been problematic –Diseases associated with AIDS are treated individually –Individuals can slow the AIDS epidemic with numerous personal decisions © 2012 Pearson Education Inc.