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The Immune System and Disease: Hypersensitivity III and IV

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The Immune System and Disease: Hypersensitivity III and IV

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    1. The Immune System and Disease: Hypersensitivity III and IV Nicole D. Powell powell.424@osu.edu September 20, 2006

    2. Lecture Objectives Understand mechanisms mediating Type III & IV hypersensitivity reactions. Understand representative diseases involving Type III & IV hypersensitivity reactions. Understand characteristics of subtypes of Type IV hypersensitivity reactions.

    5. Immune System Dysregulation Autoimmunity a dysregulation in the immune response in which ones own immune system attacks and destroys self cells/tissues Hypersensitivity uncontrolled or excessive responses against foreign (and self) antigens leading to exaggerated inflammation and tissue damage Immunodeficiency a congenital or aquired state in which the immune system is in a compromised or absent a state

    6. Hypersensitivity: The Four Basic Categories Type I Hypersensitivity: A reaction in a sensitized person in which immediate life-threatening events may ensue. Also known as an anaphylactic reaction. Type II Hypersensitivity: Antibody reacts with antigen on the surface of a cell leading to the its destruction. Also known as an antibody-dependant or "cytotoxic reaction." Type III Hypersensitivity: Antigen-antibody complexes clump and aggregate near blood vessels attracting an acute inflammatory reaction. Also known as an "immune-complex mediated." Type IV Hypersensitivity: Mobilization of T cells and macrophages after exposure to antigen in a sensitized individual. Also known as a "cell-mediated reaction."

    8. Type III Hypersensitivity Occurs within hours (5-12h) after exposure to antigen Immune complexes (aggregations of antigens and IgG and IgM antibodies) form and deposit in blood vessels & tissues. Normally, immune complexes are removed by mononuclear phagocyte system. In Type III hypersensitivity, these complexes are persistent. Deposits generally accumulate at sites where antigen is localized or at sites of turbulence (vessel branches) or high pressure (kidney glomeruli and synovium). Thus, immune complex diseases sometimes manifest as vasculitis, arthritis, or nephritis.

    9. What is an immune complex? An immune complex is the combination of an antigen with an antibody specific for that antigen. In a normal immune response, after an antigen-antibody reaction, the immune complexes are processed by proteases or ingested by phagocytes/APCs When antigen persists in the body for long periods or high levels of antigen are encountered at one time, immune complexes reach such high levels that they are no longer soluble Immune complexes may themselves cause disease when they are deposited and aggregate in blood vessels or tissue

    14. Serum Sickness: Transient Type III Hypersensitivity Serum sickness is a classic example of a transient immune complex-mediated syndrome. Caused by an injection of a foreign protein or proteins leads to an antibody response. Antibodies form immune complexes with the circulating foreign proteins, deposited in small vessels and activate complement and phagocytes Symptoms occur 7-10 days after injection of serum Symptoms include chills, fever, rash, vasulitis, nephritis and arthritis Symptoms usually last 1-2 weeks before spontaneously subsiding. Long-lasting immune sequelae generally do not occur.

    15. Examples/Causes of Serum Sickness Antivenin (serum from horses immunized with snake venoms) is used as a source of neutralizing antibodies to treat people suffering from the bites of poisonous snakes Use of anti-lymphocyte globulin, employed as an immunosuppressive agent in transplant recipients Rarely, after the administration of streptokinase, a bacterial enzyme, used as a thrombolytic agent to treat patients with a myocardial infarction or heart attack

    17. Type IV Hypersensitivity Often called delayed type hypersensitivity (DTH) as the reaction takes two to three days to develop. Unlike the other types, it is not antibody mediated but rather is a type of cell-mediated response. Involves CD4+ Th1-driven, cell-mediated immune reactions Important cytokines involved in this response include IL-2 and IFN-gamma Macrophages, CD8 T cells, and NK cells are important effector cells in the DTH response. Activated CD8 cells destroy target cells on contact

    18. Mechanisms Mediating DTH responses The same mechanisms that mediate protective responses against pathogens mediate immunopathology

    19. Different types of DTH reactions Tuburculin type hypersensitivity - (injected into the skin) Contact hypersensitivity - (absorbed by the skin) Granulomatous inflammation (indigestible foreign material)

    20. Tuberculin Test (Mantoux PPD test) Test to determine previous exposure/infection with Mycobacterium tuberculosis Small amounts of tuberculin are injected intradermally A local T cell-mediated inflammatory reaction evolves over 24-72 hours in individuals previously exposed to the bacterium The response is mediated by TH1 cells and infitrating inflammatory mediators, causing visible swelling.

    21. Contact Hypersensitivity Typical are highly reactive small molecules that can easily penetrate intact skin especially if they cause itching that leads to scratching. (e.g. poison ivy) Can be elicited by either CD4 or CD8 T cells Inflammation occurs when the sensitizing chemical comes in contact with the skin and interacts with proteins of the body, allowing them to be recognized by the immune system Two phases of contact hypersensitivity sensitization and elicitation

    24. Poison Ivy: A classic example of contact hypersensitivity

    25. Granulomatous Inflammation Granulomas are aggregates of chronic inflamatory cells which form nodules in the millimeter size range Formed by the aggregation and proliferation of macrophages due to a persistant and uncleared antigen, and may last for weeks or longer This reaction is, in terms of its clinical consequences, by far the most serious type of DTH response

    26. Causes of Granulatomous Inflammation Specific Infections: Mycobacteria (tuberculosis, leprosy, others), syphilis, brucellosis, fungi, parasites (e.g. Schistosoma). Exogenous materials: e.g. wood, grit, silica or asbestos dust, talc, suture material, silicone Endogenous foreign bodies: e.g. keratin, necrotic bone or adipose tissue, uric acid crystals (gout). Specific chemicals: Beryllium.Drugs:Hepatic granuloma due to allopurinal, phenylbutazone, sulphonamides. Unknown: Sarcoidosis, Crohn's disease.

    27. Crohns disease Type of Inflammatory Bowel Disease (IBD) of lower ileum Abdominal pain, diarrhea, rectal bleeding, weight loss, fever. Thought to be due to unresolved DTH Initial presentation may be in oral cavity and pharynx 6% present with oral lesions at some time

    29. Critical Questions What are the important immune mechanisms leading to each type of hypersensitivity? What are some of the clinical consequences of Type III and Type IV hypersensitivity? Are there benefits to a DTH response?

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