Hypersensitivity Reactions: Types and Mechanisms

• Focus is on immune disorders, specifically hypersensitivity reactions.
• Includes defining hypersensitivity, its classification, physiology, associated diseases, testing, and treatment.

Hypersensitivity Reactions

• This is a heightened state of immune response.
• It's an exaggerated response to a typically harmless antigen.
• This reaction relies on the host's response, not the antigen's nature.
• Results in host tissue injury and disease.
• Classified by the Gel and Coombs classification system.

Gell and Coombs Classification of Hypersensitivity Reactions

• Type I: IgE mediated, mast cell degranulation. (e.g. asthma, hay fever)
• Type II: Antibody-mediated cell surface reactions that cause cytotoxicity, complement activation. (e.g. Hemolytic anemia, HDFN)
• Type III: Immune complex mediated, complement activation. (e.g. Arthus reaction)
• Type IV: Cell mediated, sensitized T cells, activated macrophages. (e.g. Contact dermatitis)
• Types I-III are considered immediate hypersensitivity. Symptoms occur within minutes to hours after antigen exposure.
• Type IV is delayed hypersensitivity. Symptoms appear 24-48 hours after antigen exposure.
• Types I and IV cause allergies.
• Types II & III involve complement.
• Type I reactions typically take 2-30 minutes.
• Type II Reactions typically take 5-8 hours
• Type III Reactions typically take 2-8 hours
• Type IV Reactions typically take 24-72 hours

TYPE I HYPERSENSITIVITY

• It is IgE Mediated and Immediate
• Also known as "anaphylactic hypersensitivity" or "immediate hypersensitivity".
• Common allergens include pollen, certain foods (peanuts, shellfish, dairy products), mold spores, animal dander, dust mites, insect venom, certain drugs (penicillin), and latex.
• Key components: IgE, mast cells, basophils, and eosinophils.
• Clinical manifestations arise from the release of preformed or newly synthesized mediators from mast cells and basophils.
• These symptoms can include rhinitis ("hay fever"), allergic asthma, food allergies, urticaria ("hives"), wheal and flare, eczema, and a potentially fatal systemic anaphylaxis.
• Serum factor: IgE antibody. It is the least abundant (1%) in serum.
• Not involved in typical immune response such as complement fixation and opsonization.
• IgE binds to mast cells (in tissue) and basophils (in blood).
• IgE cell membranes binding increases half life from 2-3 days up to ~ 10 days.
• Allergic reactions cannot occur at first exposure. They require a sensitization phase.
• Subsequent exposure leads to an activation phase.
• Different molecular mechanisms activate at different times in mast cells leading to early phase reactions (primary mediator) and late phase reactions (secondary mediators).
• More severe clinical manifestations are due to early-phase response.

Sensitization Phase

• APCs process and present allergens to Th2 cells.
• People with allergies have a Th2 type of T helper cell predominates
• Th2 cells induce production of allergen-specific IgE.
• Th2 cells produce IL-4 and IL-13, which induce the transcription of IgE genes by Ig class-switching.
• IgE binds to FceRI receptors on mast cells and basophils.
• FcεRI receptors are high-affinity receptors that are abundant on mast cells and basophils; they bind the Fc portion of the IgE molecule.

Activation Phase

• Allergen cross-links adjacent cell-bound IgEs.
• This stimulates mast cells and basophils to degranulate.
• Chemical mediators are released, bind to target organs, and produce allergy symptoms.
• Histamine and heparin are primary mediators (most abundant), causing early symptoms (30-60min)
• Prostaglandin, cytokines, and leukotrienes are secondary mediators, causing late-phase inflammation reactions (6-8 hrs)

Factors Affecting Allergic Response

• Allergic reactions arise only in certain people because they have high levels of circulating IgE in response to a small amount of antigen.
• Genetics also play a role, including MHC genes inheritance, genes coding for IgE receptors on mast cells/basophils, and HLA class II associations.
• Designed to drive out or prevent further entry to potential parasitic pathogens.
• Where parasitic infections are rare, response range from bothersome to life threatening

Treatments for Type I Hypersensitivity

• Avoidance of allergens.
• Drug therapy using antihistamines, bronchodilators, mast cell stabilizers, corticosteroids, and epinephrine.
• Monoclonal anti-IgE antibody: binds to the Fc region of circulating IgE, preventing it from binding to mast cells and basophils
• Allergy immunotherapy (AIT): Gradually administer increasing doses of allergen.
• It induces immune tolerance by shifting to Th1 type, inducing Treg cells, or inducing IgG4 antibody that block binding of allergen to IgE

Testing for Type I Hypersensitivity

• In Vivo Skin Tests: Apply a panel of allergens to separate sites on the skin, waiting 15 to 20 minutes.
• A positive test results in a wheal and flare at the application site.
• Total IgE can be detected in patient serum via RIST (Radio-Immuno-Sorbent-Test).
• IgE to a specific allergen can be detected in patient serum via RAST (Radio-Allergo-Sobent-Test).

TYPE II HYPERSENSITIVITY

• Antibody-mediated cytotoxic hypersensitivity.
• Key components are IgG and IgM directed against a cell surface antigen.
• Effects of the antibodies include cell destruction, inhibition of cell function, and increase in cell function.
• Major players are antibody, complement, and phagocytes.

Cell damage in Type II Hypersensitivity

• Activation of classical pathway of complement and cell lysis happens.
• Opsonization and phagocytosis of the cell.
• Antibody-dependent cell-mediated cytotoxicity (ADCC) occurs

Clinical Examples

• Transfusion reactions
• Hemolytic disease of the newborn (HDN)
• Autoimmune hemolytic anemia (Warm reactive antibodies, Cold agglutinins, and Paroxysmal cold hemoglobinuria)
• Organic-specific autoimmune disorder (Anti-Glomerular Basement Membrane (Anti-GBM) disease and Hashimoto's disease)

Hemolytic Disease of the Newborn (HDN)

• A pregnant woman produces antibodies to Rh antigens (usually RhD) on fetal RBCs.

Testing for Type II Hypersensitivity

• Indirect Antiglobulin Test (IAT) or Coombs' test tests the patient serum for antibodies to RBC antigens.
• It is testing the woman's blood for antibody to Rh antigen and done during prenatal visits to screen for potential problems
• Direct Antiglobulin Test (DAT) is also used
• This is testing patient's red blood cells to determine if coated with antibody and/or complement in vivo
• It detects transfusion reaction, AIHA, HDFN.
• Done immediately after birth if mother has antibody.

TYPE III HYPERSENSITIVITY

• It's immune complex mediated
• Key components are IgG and IgM directed against a soluble antigen.
• Small antigen-antibody complexes precipitate out and deposit in tissues.
• This process activates C', increasing vasodilation and vasopermeability.
• Macrophages and neutrophils then migrate to the affected areas and release their lysosomal enzymes, resulting in tissue damage.
• Target tissues are vascular endothelium, kidneys (glomerular basement membrane), joint lining, and lungs (pulmonary alveolar membranes)

Clinical Examples of Type III Hypersensitivity

• Arthus Reaction: Localized inflammation characterized by redness and edema, peaks at 3 to 8 hours and is seen after booster injection of vaccines.
• Serum Sickness
• Some autoimmune diseases (e.g., systemic lupus erythematosus and rheumatoid arthritis)
• Reactions to bee stings
• Drug reactions (e.g., penicillin)
• Sequelae to infections (e.g., post-streptococcal glomerulonephritis)

Serum Sickness

• Is a Generalized type III hypersensitivity reaction.
• Caused by passive immunization of humans with animal serum (vaccine or anti-serum therapy).
• Produces antibodies against the foreign animal proteins in patients.
• Causes immune complexes to form and deposit in tissues.
• Symptoms include headache, fever, nausea, joint pain, rashes, and lymphadenopathy

Testing for Type III Hypersensitivity

• Testing for ANAs (Anti-Nuclear-Antibody) is done for systemic autoimmune disease (e.g. SLE).
• Testing for rheumatoid factor (an anti-IgG) to diagnose rheumatoid arthritis.
• Fluorescent staining of tissue sections to detect deposited immune complexes.
• Testing complement levels: which may be decreased in the serum during periods of high disease activity.

TYPE IV HYPERSENSITIVITY

• Cell-mediated, Delayed Reactions
• Th1 cells and macrophages are involved.
• APCs present antigen to naïve T helper cells, which differentiate into Th1 cells.
• Th1 cells release cytokines that attract and activate macrophages.
• Macrophages induce inflammation.
• Cytotoxic T lymphocytes are recruited and destroy target cells.
• Manifestations occur upon second or subsequent exposure to allergen.
• Initial sensitization phase occur 1 - 2 weeks after 1st contact
• Elicitation phase is not immediate as it may take some time for right Th1 cells to arrive at site and Symptoms peak at 48-72 hours
• Clinical manifestations occur upon second or subsequent exposure to allergen
• Antibody and complement are not directly involved
• Duration of reaction varies - ranges from several days to several weeks after allergen removal

Clinical Examples of Type IV Hypersensitivity

• Infections with intracellular pathogens (Mycobacterium tuberculosis, Mycobacterium leprae, Pneumocystis carinii, Leishmania species, and herpes simplex virus)
• Hypersensitivity pneumonitis: Allergic diseases of the lungs caused by inhalation of bacterial and fungal spores (Farmer's lung disease, bird breeder's lung disease, and humidifier lung disease)
• Contact Dermatitis: Low-molecular-weight compounds contact the skin and act as haptens to sensitize Th1 cells. Examples include poison ivy, poison oak, nickel salts, materials in cosmetics and hair dyes, and latex. Skin eruptions with erythema, swelling, and papules are produced.

Skin Testing for Delayed Hypersensitivity

• Mantoux method is a skin test for tuberculosis exposure or T-cell function. Antigen is injected intradermally, using PPD (purified protein derivative) Check in 48-72 hours (A positive test is >15mm induration or hardening)
• False positive can be BCG vaccinated or infected with Non-TB mycobacteria
• Interferon Gamma Release Assays (IGRA) Measure production of IFN-γ by patient T cells stimulated with MTB antigens
• Quantiferon TB Gold Plus assay Patient blood is incubated in special tubes with MTB antigens (specific to TB, not in vaccine nor Non-TB Mycobacteria) Plasma is tested for IFN-g by ELISA.
• T-SPOT-TB test Patient mononuclear cells are incubated with MTB antigens and tested for IFN-g by ELISpot.
• Patch test -Antigen applied to skin surface, Test for cause of persistent contact dermatitis, Read 48-72 hours - (+) test = redness with papules or tiny blisters
• Skin testing for immunodeficiency: Inject common antigens intradermally.

Summary - Type I Hypersensitivity

• Release of mediators from IgE-sensitized mast cells and basophils occurs after cross-linking by allergen.

Summary - Type II Hypersensitivity

• Cell destruction is caused by antibody and complement, opsonization, or ADCC,Antibody binds to cell receptor and stimulates or inhibits cell function.

Summary - Type III Hypersensitivity

• Antigen- antibody complexes activate complement, Neutrophils are recruited and release lysosomal enzymes that cause tissue damage.

Summary - Type IV Hypersensitivity

• Antigen-sensitized Th1 cells release cytokines, Recruit macrophages, Induce inflammation,Activate Tc cells to cause direct cell damage.