Hypersensitivity (extended)

• Type I (Anaphylaxis)
• Type II (Antibody-mediated type)
• Type III (Immune-complex mediated)
• Type IV (Cell-mediated hypersensitivity)

 Type I (anaphylaxis)

• A type I hypersensitivity (allergic) reaction between an allergenic antigen and immunoglobulin E (IgE) bound to mast cells, which stimulates the sudden release of immunological mediators locally or throughout the body.
• The first symptoms occur within minutes, and a recurrence may follow hours later (late-stage response). Anaphylaxis can only occur in an individual previously sensitized to an allergen, as it is the initial exposure that causes immunoglobulin E (IgE) to bind to mast cells. It is categorized as local or systemic. Local anaphylactic reactions include hay fever, hives, and allergic gastroenteritis. Systemic anaphylaxis, which produces peripheral vasodilation, bronchospasm, and laryngeal edema, can be life- threatening.
  • 
    ETIOLOGY: IgE antibodies bound to mast cells throughout the body as the result of previous exposure to an allergenic antigen (sensitization) react when the allergen is introduced a second time. The mast cells release packets containing chemical mediators (degranulation) that attract neutrophils and eosinophils and also stimulate urticaria, vasodilation, increased vascular permeability, and smooth muscle spasm, esp. in the bronchi and gastrointestinal tract. Chemical mediators involved in anaphylaxis include histamine, proteases, chemotactic factors, leukotrienes, prostaglandin D, and cytokines (e.g., TNF-aand interleukins 1, 3, 4, 5, and 6). The most common agents triggering anaphylaxis are drugs, food, and insect stings. Local anaphylactic reactions are also commonly triggered by pollens (e.g., hay fever, allergic rhinitis, allergic asthma).
  • SYMPTOMS: Local anaphylaxis causes signs to appear at the site of allergen- antibody interaction including urticaria (hives), edema, warmth, and erythema. In systemic anaphylaxis the respiratory tract, cardiovascular system, skin, and gastrointestinal system are involved. The primary signs are urticaria, angioedema, flushing, wheezing, dyspnea, increased mucous production, nausea and vomiting, and feelings of generalized anxiety. Systemic anaphylaxis may be mild or severe enough to cause shock when massive vasodilation is present.
  • TREATMENT: Local anaphylaxis is treated with antihistamines and occasionally epinephrine, if the reaction is severe. Treatment for systemic anaphylaxis includes protection of the airway and administration of oxygen; antihistamines (e.g., diphenhydramine or cimetidine to block histamine H1 and H2 receptors); IV fluids to support blood pressure) and vasopressors (e.g., epinephrine or dopamine) to prevent or treat shock. Epinephrine also is used to treat bronchospasm. Generally, drugs are given intravenously; drugs may also be given intramuscularly (e.g., diphenhydramine) or endotracheally (e.g., epinephrine). In mild cases they may be given subcutaneously. Corticosteroids may be used to prevent recurrence of bronchospasm and increased vascular permeability.
  • PATIENT CARE: Prevention: A history of allergic reactions, particularly to drugs, blood, or contrast media, is obtained. The at- risk patient is observed for reaction during and immediately after administration of any of these agents. The patient is taught to identify and avoid common allergens and to recognize an allergic reaction.
    Patients also should be taught to wear tags identifying allergies to medications, food, or insect venom at all times to prevent inappropriate treatment during an emergency. Individuals who have had an anaphylactic reaction and are unable to avoid future exposure to allergens should carry a kit containing a syringe of epinephrine and be taught how to administer it. Patients who are allergic to the venom of Hymenoptera insects (bees, wasps, hornets) can receive desensitization.
    • active anaphylaxisAnaphylaxis resulting from injection of an antigen.
    • exercise-induced anaphylaxisanaphylactoid reaction.
    • local anaphylaxis A reaction between IgE antibodies bound to mast cells and an allergen that is limited to a small part of the body.Localized edema and urticaria (hives) result and may vary in intensity.
    • passive anaphylaxis Anaphylaxis induced by injection of serum from a sensitized animal into a normal one. After a few hours the latter becomes sensitized.
    • passive cutaneous anaphylaxis ABBR: PCA.. A laboratory test of antibody levels in which serum from a sensitized individual is injected into the skin. Intravenous injection of an antigen accompanied by Evans blue dye at a later time reacts with the antibodies produced in response to the antigen, creating a wheal and blue spot at the site, indicating local anaphylaxis.
    • systemic anaphylaxis A reaction between IgE antibodies bound to mast cells and an allergen that causes the sudden release of immunological mediators in the skin, respiratory, cardiovascular, and gastrointestinal systems. The consequences may range from mild (e.g., itching, hives) to life- threatening (airway obstruction and shock).

 Type II

Type II Hypersensitivity (Antibody Mediated Type) 

• AKA:  cytotoxic type (although not always cytotoxic)
• Antibodies directed against normal or modified cell surface or tissue components induce cell lysis
• Complement Dependent
  • Two Mechanisms:
    • Direct lysis by complement activation
    • Lysis by opsonization (C3b) - often involves RBCs
  • Examples: 
    • Transfusion reactions
    • Erythroblastosis fetalis
    • Autoimmune hemolytic anemia
    • Autoimmune thrombocytopenia
    • Certain drug reactions
• Antibody-Dependent Cell-Mediated Cytotoxicity
  • Monocytes, neutrophils, eosinophils, or NK cells recognize cells by Fc portion of IgG bound to cell and kill cell without phagocytosis
  • Example:  Goodpasture's syndrome
• Anti-Receptor Antibodies
  • Noncytotoxic
  • Examples:  myasthenia gravis from antibody to acetylcholine receptor

 Type III

• Type III Hypersensitivity (Immune Complex Mediated)
  • Antigen (Ag) + antibody (Ab) complexes produce tissue damage by activation of serum mediators (primarily complement)
• Antibodies are produced by a large dose od administered antigen (~5 days after administration)
• Ag-Ab complexes are deposited in the tissues, (often inducing localized type I hypersensitivity reactions in glomeruli, joints, skin, heart, serosal surfaces, and small blood vessels, where they can activate complement
• An inflammatory reaction ensues (~10 days) with resulting fever, urticaria, arthralgias, lymphadenopathy, and proteinuria
• Inflammation in and around vessels causes an acute necrotizing vasculitis with fibrinoid deposition and acute inflammation (innocent bystander destruction)

Type IV Type IV (Cell Mediated) Hypersensitivity

Type IV hypersensitivity is often called delayed type hypersensitivity 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.

CD8+ cytotoxic T cells and CD4+ helper T cells recognize antigen in a complex with either type 1 or 2 major histocompatibility complex. The antigen-presenting cells in this case are macrophages which secrete IL-12, which stimulates the proliferation of further CD4+ T cells. CD4+ T cells secrete IL-2 and interferon gamma, further inducing the release of other Type 1 cytokines, thus mediating the immune response. Activated CD8+ T cells destroy target cells on contact while activated macrophages produce hydrolytic enzymes and, on presentation with certain intracellular pathogens, transform into multinucleated giant cells.

 

Disease	Target antigen	Effects
Diabetes mellitus type 1	Pancreatic beta cell proteins (possibly insulin, Glutamate decarboxylase)	Insulitis Beta cell destruction
Multiple sclerosis	Oligodendrocyte proteins (myelin basic protein, proteolipid protein)	Demyelinating disease Perivascular inflammation Paralysis Ocular lesions
Rheumatoid arthritis	Antigen in synovial membrane (possibly type II collagen)	Chronic arthritis Destruction of articular cartilage and bone
Some Peripheral neuropathies	Schwann cell antigen	Neuritis Paralysis
Crohn's disease	Unknown	Chronic inflammation of ileum and colon
Contact dermatitis	Environmental chemicals, e.g. poison ivy, nickel	Dermatitis with usually short-lived itching
Mantoux test* (diagnostic)	Tuberculin	Skin induration indicates TB exposure

 

• the cell or tissue damage done during diseases like tuberculosis, leprosy, smallpox, measles, herpes infections, candidiasis, and histoplasmosis;
• the skin test reactions seen for tuberculosis and other infections;
• contact dermatitis like poison ivy;
• type-1 insulin-dependent diabetes where CTLs destroy insulin-producing cells;
• multiple sclerosis, where T-lymphocytes and macrophages secrete cytokines that destroy the myelin sheath that insulates the nerve fibers of neurons;
• Crohn’s disease and ulcerative colitis; and
• psoriasis. 

Delayed hypersensitivity also plays a major role in chronic transplant rejection as a result of CTL destruction of donor cells (host versus graft rejection) or recipient cells (graft versus host rejection). Immunosuppressive drugs such as cyclosporin A or FK-506 (Tacrolimus) are given in an attempt to prevent rejection. Both of these drugs prevent T-lymphocyte proliferation and differentiation by inhibiting the transcription of IL-2.
  

Comparison of Different Types of hypersensitivity
characteristics	type-I (anaphylactic)	type-II (cytotoxic)	type-III (immune complex)	type-IV (delayed type)
antibody	IgE	IgG, IgM	IgG, IgM	None
antigen	exogenous	cell surface	soluble	tissues & organs
response time	15-30 minutes	minutes-hours	3-8 hours	48-72 hours
appearance	weal & flare	lysis and necrosis	erythema and edema, necrosis	erythema and induration
histology	basophils and eosinophil	antibody and complement	complement and neutrophils	monocytes and lymphocytes
transferred with	antibody	antibody	antibody	T-cells
examples	allergic asthma, hay fever	erythroblastosis fetalis, Goodpasture's nephritis	SLE, farmer's lung disease	tuberculin test, poison ivy, granuloma