Immunopathology

• Hypersensitivity


  A normal but exaggerated or uncontrolled immune response to an antigen that can produce inflammation, cell destruction, or tissue injury
• Immunization/Sensitization


  An immunologic reaction dependent on the host's response to a subsequent exposure of antigen
• Allergy


  An altered reaction to external substances
• Atopy


  An inherited tendency to respond to naturally occurring inhaled and ingested allergens with continued production of IgE
• Allergens


  Antigens that trigger allergic reactions, these low molecular weight substances can enter the body by being inhaled, eaten, or administered as drugs
• Environmental substances that can trigger hypersensitivity reactions

  • Dust
  • Metals (particularly nickel)
  • Chemicals
• Cytokine storm


  An exaggerated immune response, e.g. influenza virus can trigger high levels of cytokine secretion
• Self antigens


  Very small immune responses to self antigens is normal and occur in most people. When these become an exaggerated response, or when tolerance to other antigens breaks down, hypersensitivity reactions can occur.
• Food allergies


  Can cause severe allergic reactions and even death from food-induced anaphylaxis. There is no current treatment, the disease can only be managed by allergen avoidance or treatment of symptoms.
• Types of hypersensitivity reactions

  • Type I - Immediate
  • Type II - Cytotoxic
  • Type III - Immune Complex
  • Type IV - Cell Mediated
• Type I hypersensitivity reactions

  • Can range from life-threatening anaphylactic reactions to milder manifestations associated with food allergies
  • The distinguishing feature is the short time lag, usually seconds to minutes, between exposure to antigen and the onset of clinical symptoms
  • The key reactant present is IgE
• Etiology of type I hypersensitivity

  • Atopic allergies are mostly naturally occurring, and the source of antigenic exposure is not always known
  • Atopic illnesses have a strong familial or genetic tendency
  • Common agents that cause anaphylactic reactions are drugs (e.g. systemic penicillin) and insect stings
• Immunologic activity in type I hypersensitivity

  1. Mast cells (tissue basophils) are the cellular receptors for IgE, which attaches to their outer surface

  2. IgE is primarily synthesized in the lymphoid tissue of the respiratory and gastrointestinal tracts

  3. Normal immune response is a function of Th1 cells which produce IFN-gamma, but in people with allergies, Th2 cells respond instead and produce IL-3, IL-4, IL-5, IL-9, and IL-13

  4. IL-4 and IL-13 are responsible for the final differentiation that occurs in B cells, initiating the transcription of the gene that codes for the epsilon-heavy chain of IgE

  5. IL-5 and IL-9 are involved in the development of eosinophils, while IL-4 and IL-9 promote development of mast cells

  6. IL-4, IL-9, and IL-13 all act to stimulate overproduction of mucus, a characteristic of most allergic reactions
• Sequence of events in immediate (type I) hypersensitivity

  1. Introduction of an allergen stimulates Th2 responses and IgE production in genetically susceptible individuals

  2. IgE binds to Fc receptors (FcεRI) on mast cells

  3. Subsequent exposure to the allergen activates the mast cells to secrete the mediators that are responsible for the pathologic manifestations of immediate hypersensitivity
• Mediators of allergy and asthma

  • Histamine, leukotriene C4, interleukin-4 (IL-4), and interleukin-13 (IL-13) are major mediators
  • All are formed by basophils and released in large quantities after stimulation with interleukin-3
• Acute allergic reaction


  Antigen-induced release of histamine and lipid mediators from mast cells
• Chronic allergic reaction


  1. Recruitment of eosinophils

  2. Liberation of mast cell products by histamine-releasing factors

  3. Neurogenic inflammation involving neurotrophins and neuropeptides
• Atopic individuals


  • Produce allergen-specific IgE antibodies
  • Positive reactions to extracts of common airborne allergens when tested with a skin prick test
  • T cells respond to allergens by inducing cytokines produced by Th2 cells (e.g. IL-4, IL-5, IL-13) rather than Th1 cells (e.g. IFN-γ, IL-2)
• Individuals without atopy


  Produce an asymptomatic, low-grade immunologic response to airborne allergens
• Exposure of skin, nose or airway to allergen in person with atopy


  Produces symptoms (skin redness, sneezing, wheezing) within minutes
• Localized reaction


  Occurs as an immediate response to mediators produced by mast cell degranulation, can consist of urticaria and angioedema, severe but rarely fatal
• Generalized/Anaphylactic reaction


  Dramatic and rapid in onset, physiologic effects of primary and secondary mediators on target organs (cardiovascular, respiratory, GI, skin)
• Type II hypersensitivity


  • Reactants are IgG and IgM, triggered by antigens on cell surfaces (altered self or heteroantigens)
  • Antibody coats cells and promotes phagocytosis by opsonization and complement activation
  • Complement can trigger cellular destruction by coating cells with C3b or complement-mediated lysis
• Transfusion reaction


  Occurs when patient is given blood for which antibodies are already present, can range from acute hemolysis to undetected decrease in RBC survival
• Factors affecting extent of transfusion reaction

  • Temperature at which antibody is most active
  • Plasma concentration of antibody
  • Immunoglobulin class
  • Extent of complement activation
  • Density of antigen on RBC
  • Number of RBCs transfused
• Acute hemolytic transfusion reaction

  Occurs within minutes/hours, due to pre-formed antibodies, often associated with ABO incompatibility and IgM antibodies
• Delayed hemolytic transfusion reaction

  Occurs within 2 weeks, due to secondary response and IgG antibodies, often involves Rh, Kell, Duffy, Kidd antigens
• Hemolytic disease of the newborn (HDN)


  Occurs when mother has been exposed to fetal blood group antigens that differ from her own, leading to IgG antibodies that cross placenta and destroy fetal RBCs
• Autoimmune hemolytic anemia


  Antibodies directed against self-antigens on RBCs, can be warm reactive (IgG) or cold reactive
• Warm autoimmune hemolytic anemia is characterized by IgG antibodies and may be primary or secondary to other diseases/infections/drugs
• Warm reactive antibodies


  Antibodies that react at 37°C
• Cold reactive antibodies


  Antibodies that react only below 30°C
• Warm autoimmune hemolytic anemia

  • Accounts for more than 70 percent of autoimmune anemias
  • Characterized by formation of IgG antibody, which reacts most strongly at 37°C
  • May be primary with no other disease association, or secondary to another disease process
• Associated diseases with warm autoimmune hemolytic anemia

  • Viral or respiratory infections (e.g. infectious mononucleosis, cytomegalovirus, chronic active hepatitis)
  • Immunoproliferative diseases (e.g. chronic lymphocytic leukemia, lymphomas)
  • Certain drugs (e.g. acetaminophen, penicillins, cephalosporins, rifampin, sulfonamides, methyldopa)
• Cold autoagglutinins


  • Less frequent cause of immune hemolytic anemias
  • Typically found in persons in their fifties and sixties
  • Thought to be triggered by antigens on microorganisms
  • Belong to the IgM class
  • Most are specific for the Ii blood groups on red cells
  • Usually don't cause clinical symptoms, only if exposed to cold
• Diseases associated with cold autoagglutinins

  • Chronic lymphocytic leukemia
  • Non-Hodgkin's lymphoma
  • Myelodysplastic syndrome
  • Connective tissue diseases (e.g. systemic lupus erythematosus)
  • Virus and respiratory infections in children
• Type II Reactions Involving Tissue Antigens

  Antibody-mediated, tissue damage is complement-dependent
• Examples of Type II Reactions

  • Good Pasture's Syndrome (anti-glomerular basement membrane antibody)
  • Hashimoto's thyroiditis (anti-thyroid peroxidase, anti-thyroglobulin)
  • Myasthenia Gravis (anti-acetylcholine receptor)
  • IDDM (islet cell antibodies, insulin autoantibodies, anti-GAD65)
• Coombs' Test


  Direct: Detects antibody or complement on red blood cells

  Indirect: Detects antibody in patient's serum
• Type III Hypersensitivity


  Involves IgG or IgM, destruction is complement-mediated

  Antigen is soluble, forms immune complexes that deposit in tissues