Immediate (type 1) hypersensitivity: Th2-mediated diseases These disorders are characterized by abnormally strong Th2 responses against environmental antigens that are essentially ignored by the ~75-80% of the population that does not suffer from allergies All the clinical and pathologic manifestations of allergy are the result of cytokines produced by Th2 cells (Fig. 2) IL-4 stimulates B cells specific for the antigens to produce IgE antibody, which then binds to mast cells When the antigen binds to this antibody, it activates mast cells to release many mediators (histamine, proteases, cytokines) that cause the acute vascular and smooth muscle reactions and inflammation that are typical of allergies IL-5 made by Th2 cells activates eosinophils, which can exacerbate tissue damage Th2 cells also secrete IL-13, which acts on mucosal epithelial cells to stimulate secretion of mucus Bronchial asthma is a Th2-mediated disease about which you will hear more in the �Organs� block The propensity to develop allergies is genetic, but the actual genes that may be causative have not been definitively identified How antibodies damage tissues: types 2 and 3 hypersensitivity Antibodies other than IgE can cause severe tissue injury In some cases, antibodies may be produced against cell or tissue antigens and may deposit on cells or in the tissues (antibody-mediated, or type II, hypersensitivity) Usually, these are autoantibodies, and their production reflects a failure of self-tolerance In other cases, antibodies against self-antigens or microbial antigens may form immune complexes if the antigens are present in the circulation, and these complexes may deposit in vascular walls (immune complex-mediated, or type III, hypersensitivity) The �tail� of the antibody activates a series of plasma proteins that make up the are activated by microbes or by antibodies bound to microbes and tissue antigens, and are deposited on these surfaces Various products of complement bring in leukocytes (inflammation); are recognized by phagocytes, resulting in phagocytosis of coated cells; and promote death of cells on which complement proteins are deposited The tail of the antibody (called the Fc piece because this fragment has a propensity to and neutrophils) Once these pathways are activated, they cause disease in several ways (see Fig. 4) A. If the antibody is deposited on a cell (e.g. erythrocyte or platelet), the combined action of complement and Fc receptors results in that cell being eaten and destroyed by phagocytes (This is the basis of red blood cell and platelet depletion in autoimmune hemolytic anemia and thrombocytopenia, respectively.) B If the antibody is deposited on a solid surface the phagocytes may be activated and release toxic substances that induce inflammation and damage the tissue (as in

some forms of glomerulonephritis) C. Less commonly, antibodies can cause disease by interfering with normal molecules (such as hormones and hormone receptors), without any actual tissue injury; examples include myasthenia gravis (BMB) and Graves� disease (M&N) F. How T lymphocytes damage tissues: type 4 hypersensitivity T lymphocytes injure tissues by two principal mechanisms (Fig. 4) 1 CD4+ T lymphocytes of the Th1 subset produce cytokines that activate macrophages (mainly IFN-?) and recruit inflammatory cells (TNF) Th17 cells secrete cytokines that also recruit leukocytes, such as neutrophils, and may thus be major contributors to inflammation in T cell-mediated hypersensitivity disorders These reactions are called Delayed type hypersensitivity, because they take 24-48 hours t develop after antigen challenge (the classical example is a PPD skin test) Th1 and/or Th17 reactions against self-antigens or against persistent microbes are responsible

for many chronic disorders that you will hear about (Crohn�s disease, type-1 diabetes, multiple sclerosis, rheumatoid arthritis) 2 CD8+ CTLs directly kill host cells, as in viral hepatitis (mentioned above) CTL-mediated cell injury may also contribute to some Th1-mediated disease such as

type-1 diabetes