Overview Of Hypersensitivity

• Hypersensitivity denotes an immune response.
• This response results in exaggerated or inappropriate reactions.
• These reactions are harmful to the host.
• They occur following contact with specific antigens.
• The process requires a sensitizing dose of antigen. This first dose primes the immune system.
• A subsequent shocking dose of the same antigen follows. This second dose results in injurious consequences.
• Reactions are classified into four categories. This classification was proposed by Gell and Coombs.
• The classification relies on the time elapsed from antigen exposure to the reaction. It also relies on the arm of the immune system involved.

Type I Hypersensitivity (Immediate Or Anaphylactic)

Pathophysiology

• This type is also known as IgE-mediated or reagin-dependent hypersensitivity.
• The reaction is always rapid. It occurs within minutes of exposure to an antigen.
• Exposure to the allergen activates Th2 cells.
• Th2 cells stimulate B-cells to undergo class switching. These B-cells produce IgE antibodies.
• The produced IgE binds to the Fc portion of mast cells and basophils. This binding occurs with high affinity.
• This process is called sensitization. The IgE-coated mast cells are ready for repeat antigen encounters.
• Upon re-exposure, the allergen cross-links the bound IgE on the mast cells.
• This cross-linking activates the mast cell. It leads to the degranulation of basophils and mast cells.
• Pharmacologically active mediators are released within minutes.

Key Mediators

• Primary mediators are pre-existing compounds. They are present inside basophils and mast cells.
• Histamine is the most important primary mediator. It causes vasodilation and increased capillary permeability.
• Histamine also induces smooth muscle contraction.
• Serotonin is found in mast cells and platelets. It causes vasoconstriction and increased capillary permeability.
• Eosinophilic chemotactic factors of anaphylaxis attract eosinophils to the site of action.
• Secondary mediators are produced upon stimulation. They are generated after mast cell degranulation.
• Prostaglandins are lipid autacoids derived from arachidonic acid. They cause bronchoconstriction and vasodilation.
• Leukotrienes are synthesized through the lipoxygenase pathway. They are potent mediators of prolonged bronchoconstriction.
• Platelet-activating factor causes platelet aggregation and inflammation.

Clinical Manifestations

• The reaction occurs in two forms. These forms are anaphylaxis and atopy.
• Anaphylaxis is an acute and systemic manifestation. It is potentially fatal.
• Symptoms include generalized pruritus, urticaria, and angioedema.
• Respiratory symptoms include laryngeal edema and bronchospasm.
• Cardiovascular collapse and shock may occur.
• Atopy is a recurrent and localized manifestation. It involves a familial predisposition to produce high levels of IgE.
• Examples include asthma, allergic rhinitis, and allergic gastroenteropathy.

Type II Hypersensitivity (Cytotoxic)

Pathophysiology

• This reaction is mediated by IgG or IgM antibodies.
• These antibodies are directed against antigens on the cell membrane or extracellular matrix.
• The antigen-antibody reaction leads to complement activation.
• This activation results in the formation of a membrane attack complex. The complex damages the cell membrane and causes osmotic lysis.

Mechanisms Of Tissue Injury

• Opsonization and phagocytosis mark cells for destruction by macrophages.
• Complement activation recruits leukocytes to the site. Neutrophils release lysosomal enzymes and reactive oxygen intermediates to cause damage.
• Antibody-dependent cell-mediated cytotoxicity is another major mechanism. Cytotoxic cells bind to the Fc receptors of antibodies coating the target cells.
• Antibodies can also cause cellular dysfunction without causing direct cell injury. They may inhibit or stimulate cell surface receptors.

Clinical Manifestations

• Blood transfusion reactions and Rh incompatibility are classic examples. Rh incompatibility causes erythroblastosis fetalis.
• Autoimmune hemolytic anemia involves autoantibodies against red blood cells. Penicillin can induce this by acting as a hapten on the cell surface.
• Goodpasture syndrome involves antibodies acting against tissue basement membranes.
• Receptor-mediated dysfunction is seen in myasthenia gravis and Graves disease. In myasthenia gravis, antibodies inhibit acetylcholine receptors.

Type III Hypersensitivity (Immune Complex-Mediated)

Pathophysiology

• This reaction is mediated by antigen-antibody immune complexes.
• The introduction of a protein antigen triggers antibody production. These IgG or IgM antibodies are secreted into the blood.
• The antibodies react with circulating soluble antigens. They form antigen-antibody complexes.
• Normally, the mononuclear-phagocyte system removes these complexes.
• In conditions of antigen excess, the clearance capacity is exceeded.

Mechanisms Of Tissue Injury

• Immune complexes are deposited in various tissues. Medium-sized complexes formed in slight antigen excess are the most pathogenic.
• Deposition occurs in small blood vessels, synovial membranes, and glomerular basement membranes.
• Deposited complexes initiate an acute inflammatory reaction. They potently activate the complement system.
• Complement activation produces inflammatory mediators like C3a and C5a.
• Polymorphonuclear cells are attracted to the site of deposition. They release lysosomal enzymes, causing severe tissue damage and fibrinoid necrosis.

Clinical Manifestations

• Arthus reaction is a localized manifestation. It causes hemorrhagic necrosis and vascular occlusion at the site of injection.
• Hypersensitivity pneumonitis is a clinical example of an Arthus reaction in the lungs. It occurs due to the inhalation of fungal or bacterial antigens like in farmer's lung.
• Serum sickness is a systemic inflammatory reaction. It is caused by the deposition of immune complexes at multiple body sites.
• Systemic lupus erythematosus and post-streptococcal glomerulonephritis are classic systemic examples.

Type IV Hypersensitivity (Delayed Or Cell-Mediated)

Pathophysiology

• This reaction does not involve antibodies. It is exclusively mediated by the cellular immune system.
• The response is delayed. It typically starts hours or days after primary contact and manifests in 48 to 72 hours.
• An antigen specifically stimulates and sensitizes T-lymphocytes.
• Upon re-exposure, these sensitized T-lymphocytes release lymphokines.
• Lymphokines induce severe inflammation and attract phagocytes to the area. Macrophages are activated to release inflammatory mediators.

Cell Types Involved

• CD4+ helper T cells recognize tissue antigens presented by antigen-presenting cells.
• These CD4+ cells release multiple cytokines. The cytokines stimulate macrophages and frequently induce granuloma formation.
• CD8+ cytotoxic T cells recognize cell surface antigens directly. They directly kill targeted cells and mediate tissue injury.

Clinical Manifestations

• The four Ts summarize this type. They are T cells, Transplant rejections, TB skin tests, and Touching (contact dermatitis).
• Contact dermatitis occurs after sensitization to substances like poison oak, heavy metals, or topical drugs.
• These substances act as haptens on the skin. They enter the epidermis and combine with body proteins to become complete antigens.
• Tuberculin skin test is a diagnostic application. Purified protein derivative is injected intradermally.
• A firm, red indurated lesion appears after 48 to 72 hours if the individual was previously infected with Mycobacterium tuberculosis.
• Erythema multiforme and Stevens-Johnson syndrome involve CD8+ T cells targeting the skin tissues.

Summary