Lecture 22: Hypersensitivity Disorders - 11/04/2024 PDF

The Coombs and Gell classification of the four types of hypersensitivity reaction Hypersensitivity refers to harmful immune responses against foreign antigens:  Environmental antigens,  Drugs,  Microbes....

The Coombs and Gell classification of the four types of hypersensitivity reaction Hypersensitivity refers to harmful immune responses against foreign antigens:  Environmental antigens,  Drugs,  Microbes. 3 Hypersensitivity reactions may be specific for different types of antigens: Reactions against Reactions against self Reactions against nonmicrobial antigens: autoimmunity. microbes. environmental antigens. Immune responses Most healthy individuals do Failure of the normal not react against common, against microbial antigens mechanisms of self- tolerance results in T cell may cause disease if the generally harmless reactions are excessive or environmental substances, and B cell reactions the microbes are but 20% or more of the against one’s own cells unusually resistant to population is abnormally and tissues that are called eradication and thus the autoimmunity responsive to one or more infections are persistent. of these substances. These individuals produce IgE (immunoglobulin E) antibodies that cause allergic diseases 4  Classification of Hypersensitivity Diseases  Hypersensitivity diseases are commonly classified according to the type of immune response and the effector mechanism responsible for cell and tissue.  These mechanisms include some that are predominantly dependent on antibodies and others predominantly dependent on T cells, although humoral and cell-mediated immunities often coexist, and both contribute to tissue injury in many hypersensitivity diseases. 5 Comparison of allergy, transplantation, and Autoimmunity  Allergic diseases, the diseases arising from transplantation, and autoimmune diseases all involve effector mechanisms that correspond to the type II, III, and IV hypersensitivity reactions.  Unique to allergic disease is the type I hypersensitivity reaction mediated by IgE. 6  Abs against streptococcal cell-wall Ags cross-react with Ags on heart tissue (rheumatic fever) The immune response to the bacteria produces antibodies against various epitopes of the bacterial cell surface. Some of these antibodies (yellow) cross-react with the heart, whereas others (blue) do not. An epitope in the heart (orange) is structurally similar, but not identical, to a bacterial epitope (red). 7 Infections associated with the start of autoimmunity. 8 Types of antibodies that cause disease 9  Effector mechanisms of antibody-mediated disease  Auto Abs that are receptor agonists mimic the natural ligand of the receptor and cause the receptor to transduce activating signals in the absence of its ligand.  In contrast, autoAbs that are receptor antagonists do not activate signaling on binding to the receptor and they block the natural ligand from binding to the receptor and activating its signaling function. 10 AutoAbs (agonist) against the TSH receptor cause overproduction of thyroid hormones and Graves’ disease. Thyroid epithelial cells make thyroglobulin. Iodide (green) is taken up and used to iodinate and cross-link tyrosine residues of thyroglobulin (left half of the figure). TSH from the pituitary gland binds to the TSH receptor on thyroid cells, inducing the endocytosis and breakdown of iodinated thyroglobulin, with release of the thyroid hormones T3 and T4. T3 and T4 signal the pituitary to stop releasing TSH (upper right panel). In Graves’ disease, autoAbs bind to the TSH receptor of thyroid cells, mimicking TSH and inducing the continuous synthesis and release of thyroid hormones. In patients with Graves’ disease, the production of thyroid hormones becomes independent of the presence of TSH and of the body’s requirements for thyroid hormones (lower right panel). 11 AutoAbs (antagonist) against the acetylcholine receptor cause myasthenia gravis. In a healthy neuromuscular junction, signals generated in nerves cause the release of acetylcholine, which binds to the acetylcholine receptors of the muscle cells, causing an inflow of sodium ions that indirectly causes muscle contraction (upper panel). In patients with myasthenia gravis, autoAbs specific for the acetylcholine receptor reduce the number of receptors on the muscle-cell surface by binding to the receptors and causing their endocytosis and degradation (lower panel). Consequently, the efficiency of the neuromuscular junction is reduced, which is manifested as muscle weakening. 12 Diseases mediated by Abs against cell-surface receptors.  Antibodies act as agonists when they stimulate a receptor on binding it, and as antagonists when they block a receptor’s function on binding it. 13 Diseases Caused by Cell- or Tissue-Specific Antibodies Antibodies that cause cell- or tissue-specific diseases are usually autoantibodies produced as part of an autoimmune reaction, but sometimes the antibodies are specific for microbes. 14 Three mechanisms destroy RBCs in autoimmune hemolytic anemia. RBCs opsonized with IgG can be bound and engulfed by phagocytes in the spleen that bear an Fcγ receptor (lower left panel) a complement receptor (lower middle panel) or both types of receptor (not shown). Complement fixation on the RBC surface can also lead to complement-mediated lysis of the opsonized erythrocyte. 15 Pathologic features of antibody-mediated glomerulonephritis  A, Glomerulonephritis induced by an antibody against the glomerular basement membrane (Goodpasture’s syndrome).  The light micrograph shows glomerular inflammation and severe damage, and immunofluorescence shows smooth (linear) deposits of antibody along the basement membrane. B, Glomerulonephritis induced by the deposition of immune complexes (systemic lupus erythematosus).  The light micrograph shows neutrophilic inflammation, and the immunofluorescence and electron micrograph show coarse (granular) deposits of antigen-antibody complexes along the basement membrane. 16  Sequence of immunologic responses in experimental acute serum sickness Immune Complex- Mediated Disease The major mechanism of tissue injury in ICMD is inflammation within the walls of blood vessels, resulting from complement activation and binding of leukocyte Fc receptors to antibodies in the deposited complexes. 17 Human Immune Complex–Mediated Diseases  Glomerulus of a patient with SLE.  Deposition of immune complexes causes thickening of the basement membrane.  Neutrophils (N) are also present, attracted by the deposited immune complexes. 18  Human Immune Complex–Mediated Diseases  Immune complex-mediated diseases are usually caused by antigen-antibody complexes that form in the circulation and are deposited in multiple tissues, producing systemic disorders.  The immune complexes that cause disease may be composed of antibodies bound to either self antigens or foreign antigens.  Almost all of these diseases are systemic, but a few are restricted to kidneys, perhaps because, in those cases, complexes are formed only in the glomerular basement membrane. 19 Mechanisms of T cell–mediated diseases  T lymphocytes injure tissues by either producing cytokines that induce inflammation or directly killing target cells.  Inflammatory reactions are elicited mainly by CD4+ T cells of the Th1 and Th17 subsets. In some T cell–mediated disorders, the principal mechanism of tissue injury is killing of cells by CD8+ CTLs.  The T cells that cause tissue injury may be autoreactive, or they may be specific for foreign protein antigens that are present in or bound to cells or tissues.  T lymphocyte–mediated tissue injury may also accompany strong protective immune responses against persistent microbes, especially intracellular microbes that resist eradication by phagocytes and antibodies. 20 T Cell–Mediated Diseases  Many organ-specific autoimmune diseases are caused by activation of autoreactive T cells by self antigens, leading to cytokine release and inflammation.  This is thought to be the major mechanism underlying rheumatoid arthritis, multiple sclerosis (MS), type 1 diabetes, psoriasis, and other autoimmune diseases  Type 1 diabetes, also called insulin-dependent diabetes mellitus (IDDM) or juvenile-onset diabetes, is caused by the selective autoimmune destruction of the insulin-producing cells of the pancreas. 21  Comparison of histological sections of a pancreas from a healthy person and a patient with type 1 diabetes. Panel a is a micrograph of healthy human pancreas, showing a single islet. The islet is the discrete light-staining area in the center of the photograph. It is composed of hormone-producing cells, including the β cells that produce insulin. Panel b shows a micrograph of an islet from a patient with acute onset of type 1 diabetes. The islet shows insulitis, an infiltration of lymphocytes from the islet periphery toward the center. The lymphocytes are the clusters of cells with darkly staining nuclei. 22  Granulomatous inflammation  A, Lymph node from a patient with tuberculosis containing granulomas with activated macrophages, multinucleate giant cells, and lymphocytes. In some granulomas, there may be a central area of necrosis (not shown). Immunohistochemical studies would identify the lymphocytes as T cells. B, Mechanisms of granuloma formation.  Cytokines are involved in the generation of Th1 cells, activation of macrophages, and recruitment of leukocytes. Prolonged reactions of this type lead to the formation of granulomas. APC, Antigen-presenting cell; IFN-γ, interferon-γ; TNF, tumor necrosis factor. 23  Delayed-type hypersensitivity (DTH) reaction  In the classic animal model of DTH, a guinea pig was first immunized by the administration of a protein antigen in adjuvant; this step is called sensitization. About 2 weeks later, the animal was challenged subcutaneously with the same antigen, and the subsequent reaction was analyzed; this step is called the elicitation phase.  Humans may be sensitized for DTH reactions by microbial infection, by contact sensitization with chemicals and environmental antigens, or by intradermal or subcutaneous injection of protein antigens.  Subsequent exposure to the same antigen (called challenge) elicits the reaction. For example, purified protein derivative (PPD), a protein antigen of Mycobacterium tuberculosis, elicits a DTH reaction, called the tuberculin reaction, when it is injected into individuals who have been exposed to M. tuberculosis. A positive tuberculin skin test response is a widely used clinical indicator of previous or active tuberculosis infection. 24 Type 4 Hypersensitivity Reaction Mantoux Test = Purified Protein Derivative (PPD) = Tuberculin Skin Test (TST) (Tb) 0.1 mL intradermal Skin (dermis) Subcutan eous fat Prior TB Exposure? Type 4 NO YES Indurated Hypersensitivity Reaction flat chemokines T- T-Cell Cell Macrophage Sangnya A Upadhyaya PY4 25 Cytokine Antagonists in Clinical Use or Trials 26 Therapeutic Approaches for Immunologic Diseases 27 A model for the pathogenesis of systemic lupus erythematosus 28 A model for the pathogenesis of rheumatoid arthritis  Some 80% of patients with rheumatoid arthritis make IgM, IgG, and IgA Abs specific for the Fc region of human IgG. Rheumatoid factor is the name given to these anti-Ig autoAbs. 29  The effects of treatment of RA with anti-TNF-α  The current treatment of autoimmune diseases is targeted at reducing immune activation and the injurious consequences of the autoimmune reaction.  Agents include those that block inflammation, such as antibodies against cytokines and integrins, and those that block lymphocyte activation or destroy lymphocytes.  A future goal of therapy is to inhibit the responses of lymphocytes specific for self antigens and to induce tolerance in these cells. 30