Hypersensitivity: Immune Response

• Hypersensitivity is an exaggerated or inappropriate immune response
• This immune response is against antigens that leads to tissue damage, disease or even death
• The term "allergy" (allos: altered; ergon: action) means there is an altered reactivity
• The term hypersensitivity was coined in 1906 by von Pirquet
• Hypersensitivity and allergy are used interchangeably

Hypersensitivity Reactions:

• Antigen specific
• A prior exposure to specific antigens (sensitized state) is required
• Sensitized and Shocking doses are mentioned

Classification of Hypersensitivity

• Reactions occur at different times after contact with offending antigens
• Could be a few minutes (immediate)
• Or many hours (delayed)
• Immediate responses result from humoral immune responses, including antibodies and the complement system
• Delayed responses are mediated by cellular components of the immune system (T cells)
• Hypersensitivity reactions were originally divided into two categories: immediate and delayed
• In 1968, Coombs & Gell defined four types, based on mechanisms and time taken for the reaction
• A fifth category, stimulatory hypersensitivity as type V, was recently added

Types of Hypersensitivity

• Type I: Immediate
• Type II: Cytotoxic
• Type III: Immune-complex mediated
• Type IV: Delayed
• Type V: Stimulatory

Type I Hypersensitivity

• Also called anaphylactic hypersensitivity
• May involve skin (urticaria), eyes (conjunctivitis), nasopharynx (rhinorrhea, rhinitis), bronchopulmonary tissues (asthma) and gastrointestinal tract (gastroenteritis)
• Symptoms can range from minor inconvenience to death
• Reactions usually take 2-30 minutes after exposure to the antigen, but a delayed onset of 10-12 hours is possible
• Mediated by IgE
• Primary cellular component is the mast cell or basophil
• The reaction is amplified and/or modified by platelets, neutrophils, and eosinophils
• IgE binds to mast cells and basophils to undergo degranulation and release mediators
• Histamine dilates and increases permeability of blood vessels, as well as increasing mucus secretion and smooth muscle contraction
• Prostaglandins cause contraction of smooth muscle of the respiratory system and increase mucus secretion
• Leukotrienes leads to Bronchial spasms
• Anaphylactic shock signifies a massive drop in blood pressure and is fatal in minutes
• Ultimate reactions involve blood vessels and bronchiolar smooth muscle, resulting in widespread blood vessel dilation, decreased cardiac output, and bronchoconstriction (anaphylaxis)

Allergens

• Can be contacted through:
• Inhalation (plant pollens, fungal spores, house dust, grass, ragweed)
• Ingestion (foods like seafood and nuts, food additives, drugs)
• Injection (bee, wasp, and ant venoms; drugs like penicillin, vaccines)
• Contact (pollens, foods, environmental proteins)
• Typical responses to chemicals:
• Increased capillary permeability (urticaria)
• Excessive mucus production (allergic rhinitis/hay fever)
• Diarrhea or vomiting
• Asthma

Type II Hypersensitivity

• Antibody alone or with complement can cause hypersensitivity reactions
• Reactions target foreign (often erythrocytes) or autoantigens, resulting in lysis or removal of cells
• Also termed cytotoxic; is antibody and complement mediated
• Cell death or lysis is mediated through normal mechanisms by which IgG and IgM antibodies and complements perform functions including phagocytosis, lysis, and antibody dependent cellular cytotoxicity

Type II Reactions

• Blood transfusion reactions
• Hemolytic disease of the newborn (Rh disease)
• Autoimmune hemolytic anemias
• Drug reactions
• Hyperacute graft rejection

Type II (Cytotoxic) Reactions Involve:

• Activation of complement by IgG or IgM binding to an antigenic cell
• Lysis of the antigenic cell
• ABO Blood group system: Type O is a universal donor, and incompatible donor cells are lysed
• Rh Blood Group System: About 85% of the population is Rh positive, Rh negative individuals can be sensitized to destroy Rh positive blood cells
• Hemolytic disease of the newborn: Fetal cells are destroyed by maternal anti-Rh antibodies that cross the placenta

Type III Hypersensitivity

• Immune Complex Mediated Reactions involve soluble antigens circulating in serum
• Typically involves IgA antibodies
• Antibody-Antigen immune complexes are deposited in organs to activate complement and cause inflammatory damage
• Glomerulonephritis can result - causing inflammatory kidney damage
• Occurs when there is a slightly high antigen-antibody ratio
• Excess antigens cause immune complexes to form in the blood, lodging in small blood vessels
• Usual sites affected include the kidneys, skin, joints, and small blood vessels
• Deposited complexes trigger inflammation, causing tissue or vessel damage
• Rheumatoid arthritis, systemic lupus erythematosus, and serum sickness can occur
• Immune complexes produced by antigen and antibody reactions are normally removed by phagocytic cells, preventing tissue damage
• Damage can occur if there are large amounts of immune complexes that persist in tissues (arthus reaction) or systemically (vasculitis, arthritis, edema, glomerulonephritis)
• Antigens leading to this type can be microbial, autoantigens, and foreign serum components

Type III Diseases

• Localized (inhaled): Antigenic bacterial and fungal spores causing farmer’s lung
• Systemic: Microbes (Streptococcus causing streptococcal nephritis); autoantigens (DNA causing systemic lupus erythematosus) and drugs like penicillins and sulphonamides

Type IV Hypersensitivity

• Also known as cell-mediated or delayed type hypersensitivity
• Tuberculin (Mantoux) reaction is the classical example
• The reaction peaks 48 hours post-injection of antigen (PPD or old tuberculin) with a lesion characterized by induration and erythema
• Involves a T-lymphocyte (T-cell) and not antibodies or complement
• Local collection of lymphocytes and macrophages

Type IV (Cell-Mediated) Reactions

• Involve reactions by way of memory T cells
• Subsequent contacts elicit/produce a reaction
• Reactions are delayed by at least a day and is caused by the migration of macrophages and T cells to the site of foreign antigens
• Frequently displayed on the skin as itching, redness, swelling, and pain
• Examples include tuberculosis skin test, poison ivy, metals and latex gloves (3% of health care workers)

Type V Hypersensitivity

• Inappropriate stimulation of a normal cell surface receptor by an autoantibody, leading to a continuous “turned-on” state for the cell as seen in Grave's disease (hyperthyroidism)
• This is a relatively new type that is antibody mediated, and can be considered a variant of type II
• Autoantibodies target hormone receptor molecules and function in a stimulatory fashion

Type V Reactions:

• Involve antibody reactions to cell surface molecules, without cytotoxic destruction of cells
• Grave’s Disease: Antibodies attach to receptors on the thyroid gland, which stimulates the production of thyroid hormone, with symptoms of Goiter (enlarged thyroid) and bulging eyes
• Myasthenia gravis: Causes progressive muscle weakness because antibodies block acetylcholine receptors at neuromuscular synapse
• Most patients survive when treated with drugs or immunosuppressants