Type I-IV Hypersensitivity Reactions

Type I Hypersensitivity

  • First exposure to pollen:
    • Pollen binds to mast cells.
    • No immediate symptoms.
    • The state persists for a while.
  • Re-exposure to pollen:
    • Pollen interacts with immunoglobulin E (IgE) antibodies embedded in mast cells.
    • Triggers degranulation of mast cells, releasing chemical mediators.
    • This response essentially represents an acute inflammatory response.
  • Chemical mediators released:
    • Vasoactive amines (e.g., histamine).
    • Lipid mediators (e.g., prostaglandins).
    • Cytokines.
  • Rapid effects of these mediators:
    • Vasodilation.
    • Increased vessel wall permeability (leading to swelling).
    • Smooth muscle contraction in airways and lungs (in severe cases).
  • Late phase reaction:
    • Mast cells trigger later cytokine production.
    • A delayed response that occurs some time after the initial reaction.
  • Immediate reaction:
    • Pollen binds to IgE receptors on mast cells.
    • Triggers degranulation and release of histamine and other chemical mediators.
    • Release of membrane phospholipids (arachidonic acid), leading to prostaglandins and leukotrienes.
  • Effects of released substances:
    • Prostaglandins and histamine: immediate vasodilation, increased vascular permeability, smooth muscle contraction.
    • Leukotrienes and cytokines: recruit leukocytes, causing ongoing tissue damage via the inflammatory response.
  • Histamine is rapidly inactivated by histaminase, limiting its acute effects.
  • Severe reactions can be fatal.
  • Late phase reaction: occurs several hours after exposure, less severe than the initial phase.
  • Localized reactions:
    • Urticaria (hives): welts on the body.
    • Atopic dermatitis: a common form of dermatitis, often starting in childhood.
    • Angioedema: swelling of the lips, tongue, etc.
  • Systemic reactions (anaphylactic shock):
    • Involve respiratory distress due to constricted bronchioles.
    • System-wide vasodilation and increased vascular permeability can lead to cardiovascular failure and collapse.
    • Symptoms include loss of consciousness, hives, tongue swelling, inability to swallow, rapid throat swelling.
  • Urticaria (Hives):
    • Characterized by a "wheel and flare" reaction.
    • Wheel: central raised area with white oedema (swelling).
    • Flare: surrounding redness due to vasodilation and inflammation.
    • May be accompanied by sweating and a feeling of being hot and flushed.
  • Angioedema:
    • Extreme swelling due to increased vascular permeability in localized areas of the body.
  • Urticaria triggers:
    • Varied and can be unknown.
    • Examples:
      • Exposure to air.
      • Heat or cold.
      • Contact with a chemical allergen.
  • Clinical settings:
    • Treatments or products can trigger reactions.
    • First aid training is essential.
    • Monitor localized reactions for systemic symptoms.
    • Do not let someone go home until symptoms improve. Escalate to ambulance if symptoms worsen.
  • Anaphylactic shock:
    • Adults with known allergies often carry an EpiPen for self-injection of adrenaline.
    • Adrenaline counteracts histamine effects quickly, alleviating immediate symptoms.
    • Buys time to get medical help.

Type II Hypersensitivity: Antibody-Dependent Cell-Mediated Cytotoxicity

  • Involves the body responding to its own components, mediated by antibodies.
  • Antigen is located on the cell surface or in connective tissue.
  • Antibodies initiate an immune response against the body's own cells, leading to cell lysis, phagocytosis, or apoptosis.
  • Also called antibody-dependent cell-mediated cytotoxic response.
  • Mechanisms involved:
    • Antibody binding activates the complement system.
      • Complement proteins trigger a cascade, activating immune cells and intensifying the response.
      • Complement cascade is initiated by a complement protein binding to the antigen-antibody complex on the cell.
      • This leads to activation of further complement proteins.
    • Complement fragments attract immune cells like neutrophils.
      • Neutrophils bind to the antibody via Fc receptors on their surface.
      • After binding, neutrophils release aggressive substances (e.g., radical oxygen species) that cause cellular damage, inflammation, and cell death.
    • Activated complement proteins bind to the target cell surface, marking it for opsonization.
      • Marked cells are recognized by phagocytes (e.g., macrophages).
      • Macrophages use Fc receptors to bind to the antibody and engulf the target cell.
    • The complement system leads to the formation of a membrane attack complex (MAC).
      • MAC inserts into the plasma membrane, causing an influx of extracellular fluid.
      • The cell swells and eventually lyses.
    • Bound IgG antibodies are recognized by natural killer (NK) cells.
      • NK cells possess Fc receptors that bind to the antibody, leading to NK cell activation.
      • NK cells release perforin, which inserts into the plasma membrane, causing target cell lysis.
      • NK cells also release granzymes, which initiate apoptosis.
  • In some diseases, antibodies may be directed towards cell surface receptors, disrupting normal cell function.
    • Antibody blocks the receptor, preventing signal transmission.
    • Antibody binds to and activates the receptor.
  • Type II hypersensitivity reactions usually cause cell death: complement-mediated or complement-independent.
    • Cell death via lysis enhances inflammation.
  • IgG and IgM antibodies are directed at cells of the body, causing damage through:
    • Complement actions (opsonization, phagocytosis).
    • Recruiting phagocytes.
    • Complement-mediated inflammation (membrane attack complex).
    • Changes to receptors.
  • Cell dysfunction in thyroid cells: antibodies against thyroid cell receptors turn on thyroid hormone production.
  • Antibodies binding to receptors can also block receptor action.
  • Pemphigus vulgaris:
    • Activation of a protease that cleaves desmosome connections between keratinocytes.
    • Leads to a blistering condition.
    • Keratinocytes split apart, causing exudate and inflammation.

Type III Hypersensitivity: Immune Complex Reactions

  • Certain ratios of antigens and antibodies form complexes that are too small to be phagocytosed.
  • These complexes get trapped in tissues, triggering complement-mediated inflammation.
  • Recruits inflammatory cells, causing tissue damage.
  • Often occurs in blood vessels or connective tissue.
  • Diseases have a range of symptoms.
  • Systemic lupus erythematosus:
    • Can present as a mask-like rash on the face.
    • Also has constitutional symptoms (e.g., joint issues).
  • Immune complexes consist of antibodies bound to antigens.
  • Antigens and immune complexes float freely in the blood (soluble immune complexes).
  • Antigens can be external (foreign) or internal (self).
  • IgM or IgG antibodies bind to antigens, forming complexes of various sizes.
  • Smaller immune complexes are more likely to remain in blood circulation.
  • Circulating immune complexes deposit on the blood vessel wall, especially in small vessels.
  • Immune complexes rapidly initiate the complement system.
  • Neutrophils are attracted by activated complement proteins and bind to the antibody, releasing destructive substances.
  • Damage to endothelial cells increases vessel permeability, resulting in leakage into surrounding tissue, causing inflammation and damage.
  • Discriminating features from Type II hypersensitivity:
    • Type III initiating components are soluble before depositing on the vessel wall.
    • Tissues with small blood vessels are most affected.
  • Complement system activation is more rapid and stronger in Type III.
  • Immune complex lodges within vessels, recruiting neutrophils, triggering inflammation.
  • Acute inflammatory response can become a chronic inflammatory response.
  • Lupus:
    • Kidneys and joints are affected.
    • Fine vasculature of vessels in the face is affected.
    • Leads to a butterfly-type rash.

Type IV Hypersensitivity: Delayed-Type Hypersensitivity

  • Harmful effects produced by cell-mediated immunity.
  • Mediated by Th1 cells (TD cells).
  • Responsible for contact dermatitis, tissue damage in infectious diseases, and tissue graft rejection.
  • Contact hypersensitivity (e.g., poison oak dermatitis):
    • Initiated by contact with the antigen (allergen).
    • A hapten binds to a carrier protein in the host.
    • The complex is ingested by a macrophage and presented on a class II MHC.
    • Th1 cells recognize the antigen, become activated, and increase in numbers.
  • Second exposure:
    • Th1 cells react with the antigen. Release cytokines. This results in attraction of more macrophages followed by inflammation and skin lesions.
    • Characteristic skin lesions appear after 24 hours, peaking at 48-72 hours.
  • Timeline: delayed hypersensitivity due to the timeline for reaction. This means it could appear 12-72 hours after exposure.
  • Antigen presenting cells, like Langerhans cells in the skin, uptake allergens.
  • They process and present it with its major histocompatibility type two molecule, and they migrate to lymph nodes, where they can then interact with helper T cells and CD8 positive T cells to trigger those reactions within tissues.
  • Inflammatory and cell lysis responses.
  • CD4 T cells produce pro-inflammatory cytokines, leading to tissue injury.
  • CD8 positive or cytotoxic T cells respond, producing porphyrins or branulycin or granzymes that damage local tissue.
  • Direct action of the CD8 positive T cells causing that damage directly without necessarily the inflammatory component of that.
  • Diseases include contact dermatitis, type one diabetes, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and coeliac disease.
  • Contact dermatitis:
    • Rash develops on areas of contact.
    • Appears as a dry, irritated dermatitis.
    • Common allergen is the adhesive on dressings.
    • Localized around the lips: suspects could be food, drink, makeup, or skincare products.
    • Around the eyes: could be from products that have come into contact.
    • Nickel allergies: rashes on areas of contact with cheap metal jewellery.

Photo Reactions

  • Aberrant reaction where the allergen (photoallergic) or toxin (phototoxic) alone cannot cause the reaction.
  • Certain wavelengths of light (usually UVA and visible light) trigger the reaction.
  • Photo reactions come in two types: photo irritancy and photo allergic.

Phototoxic Reaction (Photoirritancy)

  • Chemical substance, when exposed to light, causes direct damage or direct inflammatory damage to tissues.
    • No allergic response.
    • Appears like a bad sunburn, often with blistering.
    • Post-inflammatory hyperpigmentation is common.
  • Known photosensitizing chemicals will cause a reaction in pretty much anyone exposed to those.
    • Due to a direct tissue response not specific to individual.
  • Phototoxic molecules in a low excitability state change to a high excitability state when exposed to light.
    • Highly excitable molecules convert neighboring molecules to free radicals, causing tissue damage and triggering inflammation.
  • Over time, can develop into a photoallergy as well.
  • Common photo toxic compounds include:
    • Medications: antibiotics (tetracycline, sulfonides, and quinolones), antifungals (Resifulvan), other pharmaceuticals (Sorrelin's five fluorouracil, naproxen).
    • Topical agents: coal tar preparations, essential oils (citrus oils).
    • Plants: parsley.
    • Naturally occurring molecules: porphyrins.
  • Dermal clinicians:
    • Use light-based devices and can trigger these reactions.
    • Thorough client consultation is needed to check for exposure to known phototoxic agents (medications).
    • MEMS database (drug database) explains the properties of different medications, including their phototoxic potential.
    • Photosensitizing medications are often a red flag contraindication for treatments.

Photoallergic Response

  • Requires light and a chemical compound in someone who is allergic.
  • A type IV reaction
  • It looks a lot more like the allergic contact dermatitis.
    Comparing Photo Reactions:
  • Phototoxic vs. Photoallergic:
    • Often difficult to differentiate.
    • Phototoxic: quicker, requires larger exposure, develops only on sun-exposed skin, looks like an exaggerated sunburn with blistering.
    • Photoallergic: has a rough drier looking erythematous rash like the type one reactions the type three reactions rather. Longer time. 24-72 hours to develop. Type IV immune response reaction.
  • Hyperpigmentation
    * Generally speaking it's what we call post inflammatory hyperpigmentation. So it is in most instances fairly superficial. And in most cases that would clear up in six months or so.
    * It's a shorter term issue.