107 Immune Disorders – Type I Hypersensitivity Reactions

Type I Hypersensitivity Reactions
Type I hypersensitivity reactions, commonly known as immediate allergic reactions, occur when the immune system inapropriately responds to harmless substances known as allergens, which are considered exogenous, non-self antigens.  Common allergens include shellfish, nuts, strawberries, pollen, dust, mold, aspirin, cat dander, bee venom, and penicillin.

Risk Factors – Type I Hypersensitivity Reactions:

Age and genetics appear to be the largest risk factors for the development of Type I Hypersensitivity Reactions.  With children being more at risk for the development of allergies.  The term atopy refers to the development of IgE hypersensitivity reactions, and the term atopic allergies is often used to highlight the genetic component which is risk factor, and tendency of allergies to run in families.  A third risk factor is the environment, and exposure to allergens such as dust, mold, pollen, foods, medications, pets, bees, soaps, etc.  Studies have found that urban children are more susceptible to developing allergies and asthma in comparison with children raised in rural settings.  It is hypothesized that exposure to pollutants and/or rural environments may influence the development of the immune system.

Mechanism of Type I Hypersensitivity Reactions:

Unfortunately, Type I Hypersenstivity can develop when the following steps occur in the body:

1. Step One: Exposure to Allergen:
   Allergens can enter the body through inhalation, ingestion, injection, or direct contact with skin.
2. Step Two:  Inapropriate Immune Response Initiated, Sensitizing Mast Cells and Basophils:
   • Antigen Presentation: Antigen-presenting cells (APCs), such as macrophages, phagocytose allergens, travel to lymphoid tissues (e.g., lymph nodes) and present them to Helper CD4+ T cells (T_H cells) using their cell surface transmembrane major histocompatibility complex class II (MHC II) molecules.
   • T_H Cell Activation: T_H cells with specific T cell receptors (TCRs) that bind to the allergen become activated by binding to the allergen-MHC II complex on the APC that then secretes activating cytokines (e.g., monokines).  The T_H cells then proliferate.  The activated daughter T_H cells express the same TCRs and are capable of activating B cells.
   • B Cell Sensitization: At the same time, B cells can phagocytose allergens, become sensitized, and display the antigen on their surface using MHC II molecules.  Activated T_H cells with TCRs that are able to bind the allergen-MHC II complexes on the surface of these sensitized B cells, secrete activating cytokines leading to the activation of B cells.  B cells then proliferate to produce daughter plasma cells.
   • IgE Production: Plasma cells produce IgE antibodies that specifically bind to the allergen.  The plasma cells produce IgE antibodies that specifically bind to the allergen through their Fab portion.  The Fc portion of these IgE antibodies bind to the Fc receptors on mast cells and basophils, leaving the IgE’s Fab portion free to bind allergen.  Once IgE antibodies are bound to the Fc receptors, the mast cells and basophils are termed “sensitized”
     Note:  IgE antibodies are typically a class/type of antibody that is produced against helminths (parasitic worms).  It is thought that the T_H cells are responsible for stimulating B cells to produce the IgE class of antibodies.  It is unclear as to why allergens can provoke the same mechanism in some individuals.
3. Re-exposure to Allergen:  Causes Allergy Signs and Symptoms
   Upon re-exposure, the allergen binds to IgE on sensitized mast cells and basophils, causing these cells to degranulate and release pro-inflammatory cytokines such as histamine, leukotrienes, prostaglandins, and bradykinin.  Initially bradykinin and histamine are released initiating inflammation and then prostaglandins and leukotrienes are released which have longer half-lifes that can prolong inflammation.  Mast cells also release chemokines and other chemical messengers which attract and activate neutrophils and eosinophils.  Both neutrophils and eosinophils can release cytokines, chemokines and chemicals that further stimulate inflammation and cause tissue damage.
4. Inflammation:  Mechanism
   The released cytokines (e.g., histamine, bradykinin, prostaglandin, and leukotriene) cause vasodilation, increased capillary permeability, and hyperemia, leading to symptoms such as redness, warmth, swelling, and the formation of exudate (leaked fluid), resulting in edema.
5. Mast Cells:  Location
   Mast cells are strategically located within mucosal surfaces, and normally play a crucial role in defending against pathogens and other harmful substances.  Signs and symptoms of allergic reactions, depend on the location of the allergen stimulated mast cells in the body.  Let’s examine effects within the following locations:  respiratory tract, gastrointestinal (GI) tract, cutaneous and vasculature tissue.
   • Respiratory Mucosae:  When triggered, in the respiratory mucosae, mast cell and basophil degranulation can cause symptoms like itching, sneezing, tearing of the eyes, and nasal inflammation, as seen in allergic rhinitis (hay fever).  Indoor allergens like dust can cause year-round symptoms.  Over the counter (OTC) antihistamines, such as Claritin, can alleviate these symptoms by blocking histamine from binding to histamine receptors on the endothelial cells of blood vessel walls, preventing vasodilation and increased capillary permeability that would have led inflammation.  Blocking histamine receptors on sensory neurons with antihistamines can reduce itching sensations.
   • Cutaneous:  Skin exposure to allergens such as bee stings, lotions, soaps, pet dander, poison ivy, or latex can trigger Type I hypersensitivity reactions, leading to a variety of symptoms.  When allergens enter through the skin (subcutaneous exposure), they can cause dermatitis, which manifests as a rash, itching, hives, redness, wheal-and-flare reactions, and in some cases, eczema. Dermatitis often presents with symptoms like itching and redness, while hives are characterized by raised, itchy welts.  Wheal-and-flare is used to describe the rounded flat-topped area of swelling (wheal) and redness (flare) in the irritated area of the skin.  Eczema, a chronic form of dermatitis, typically appears as a persistent rash on the face, trunk, and extremities. This condition is often linked to genetic factors, indicating a predisposition to developing skin-related allergic reactions.
   • Digestive Mucosae:  Ingested allergens in food, drink, or oral medications, stimulate mast cells in the mucosa of the digestive tract, and degranulation leads to inflammation and irritation of the GI tract which induces nausea, vomiting, and diarrhea.  Ingested allergens can also lead to skin reactions, due to the allergen being absorbed by intestinal cells and into intestinal capillaries to spread the allergen throughout the body’s bloodstream.  This results in immune reactions that are symptomatic in the cutaneous tissues, such as urticaria (skin rashes) and hives.  Food allergens can cause severe anaphylactic reactions, leading to swelling of the respiratory tract and difficulty breathing in addition to dangerously low blood pressure (hypotension) and anaphylactic shock.
   • Vasculature:  Intravenous exposure to allergens, such as through an injected drug, introduces the allergen directly into the bloodstream.  This can trigger sensitized mast cells and basophils (that are covered in allergen specific IgE antibodies), leading to a massive release of pro-inflammatory cytokines. The extensive release of pro-inflammatory cytokines such as histamine causes widespread vasodilation, which can result in severe hypotension (low blood pressure).  This situation poses a significant risk of anaphylactic shock, which can lead to life-threatening complications such as cardiac arrest, respiratory arrest, and organ failure if not promptly treated.

Severe Signs and Symptoms – Anaphylaxis

Anaphylaxis is a severe, life-threatening reaction characterized by symptoms such as massive vasodilation, hypotension, fainting, confusion, irritability, bronchoconstriction, respiratory distress, and hypoxia. It also includes generalized itching, hives, and swelling.  Anaphylaxis can be triggered by systemic exposure to allergens, such as nuts, shellfish, insect stings, and various drugs.  The pathophysiology involves a massive release of histamine and other mediators, causing systemic vasodilation and increased capillary permeability, which lead to a drop in blood pressure and shock.  This results in insufficient oxygenated blood flow to tissues.  Bronchoconstriction and airway obstruction contribute to respiratory acidosis, while metabolic acidosis arises from a switch to anaerobic cellular respiration, producing lactic acid. The combined respiratory and cardiovascular impairments cause severe hypoxia, which can quickly lead to loss of consciousness, cardiac arrest, or respiratory arrest. Immediate treatment is crucial.

Symptoms of anaphylaxis include itching, hives, swelling, coughing, difficulty breathing, dizziness, fainting, loss of consciousness, low blood pressure, a sense of fear or panic, anxiety, and a rapid weak pulse.  Gastrointestinal distress, such as nausea, vomiting, and diarrhea, may also occur, along with edema around the eyes, lips, tongue, hands, and feet.  The primary treatment involves the immediate administration of epinephrine (EpiPen), followed by medical attention, including calling emergency services (911).  Supportive care may include proper positioning, CPR if necessary, supplemental oxygen, and glucocorticoids.

Signs and Symptoms – Comparing Respiratory Allergies and Extrinsic Asthma

Signs and symptoms of Type I hypersensitivity reactions are largely dependent on the location of the reaction within the body.  As mentioned above, the mechanism involves the inhalation of allergens, which triggers mast cells in the respiratory tract to release pro-inflammatory cytokines such as histamine.  Inhaled allergens, such as pollen or cat hair, can lead to respiratory allergies or conditions like extrinsic asthma.

Respiratory Allergies (e.g., Hay Fever or Allergic Rhinitis):  As mentioned above, symptoms of respiratory allergies include sneezing, itchy and watery eyes, and a runny nose.  Unlike infections with the common cold virus, which usually present with a fever, allergic rhinitis does not typically include fever as a symptom.

Extrinsic Asthma: Asthma, although not an allergy itself, can be triggered by allergens invoking the same sensitizing mechanism of mast cells and basophils.  However, asthma involves more severe symptoms than hay fever and asthmatic attacks involve the lower airways, unlike hay fever which is typically confined to the upper airways.  Asthma is characterized by bronchoconstriction, bronchiole swelling, increased mucus production, coughing, and difficulty breathing.  The condition involves the immune system’s response to allergens, where mast cells and basophils in the respiratory mucosa play a key role.  Upon exposure to allergens, helper T cells recruit eosinophils and stimulate B cells, which then produce IgE antibodies. These antibodies bind to mast cells and basophils, and upon subsequent allergen exposure, they trigger a massive release of histamine, bradykinin, prostaglandin, and leukotriene.  This release leads to significant inflammation, swelling, and mucus production in the respiratory tract, and stimulation of bronchial smooth muscles causing bronchoconstriction.  Additionally, the recruitment of neutrophils and eosinophils can exacerbate and prolong the tissue damage as well as signs and symptoms.

During an asthma attack, the excessive mucus and bronchoconstriction can lead to air trapping in the alveoli, significantly reducing airflow and causing symptoms like coughing, wheezing, and dyspnea (difficulty breathing).  Poor oxygenation of the blood can further stimulate a sympathetic response, leading to feelings of anxiety, fear, and reduced neuron function, which may result in weakness, dizziness, and loss of consciousness.  In severe cases, an asthma attack can be fatal if not treated promptly.  Chronic effects of asthma involve the accumulation of damage to cells within the lungs that can lead to permanent loss of functional tissue and fibrosis (scarring) within the lungs.  The condition has a genetic component, making some individuals more susceptible to asthma and allergies, with these traits often running in families.  Asthma will be discussed in more detail in the Respiratory Unit.

Management of Allergies:

Management of allergies involves several approaches.  Medications such as antihistamines (e.g., Claritin, Reactin) are used to block the effects of histamine, while corticosteroids help reduce inflammation.  In emergency situations, epinephrine (commonly administered through an EpiPen) is essential for its bronchodilation and vasoconstriction effects, which can quickly reverse severe symptoms.  Immediate medical attention is required, including calling 911 and performing CPR if necessary.  Prevention strategies include avoiding known allergens and carrying emergency medications, such as asthma inhalers containing bronchodilators and/or corticosteroids.  Although allergy testing has limitations in terms of what can be tested for, it can be beneficial in identifying specific allergens to avoid.

Immediate and Late Phase Reactions

Immediate Phase as the name suggests is depicted by immediate signs and symptoms.  The immediate phase is due to mast cell activation releasing histamine, PGs & other preformed mediators of vascular permeability & vasodilation.  Often in allergy tests, potential allergens are injected into the subcutaneous tissue of the arm.  After 1-30minutes, the arm is examined for “Wheal and Flare” allergic reactions, which involves signs of inflammation (redness, warmth, swelling, itching).  After 8 hours, the late phase reaction of increased inflammation may take place if the injected substance is an allergen for the individual.

Late Phase is characterized by signs and symptoms that develop 8-12 hours after exposure to the allergen.  The late phase response is due to synthesis of more mast cell cytokines including leukotrienes, which have a long half life.  These cytokines recruit other leukocytes such as Eosinophils which leads to sustained edema and inflammation (and in asthma more bronchoconstriction and difficulty breathing) → sustained irritation and inflammation can cause more tissue destruction over time.

Summary:

• Type I Hypersensitivity Reactions
  • Definition: Immediate allergic reactions triggered by harmless substances (allergens= exogenous, non-self antigens).
  • Common Allergens: Shellfish, nuts, strawberries, pollen, dust, mold, aspirin, cat dander, penicillin.
• Mechanism on Type I Hypersensitivity Reactions:

1. Exposure to Allergen: Inhalation, ingestion, or skin contact.
2. Immune Response:

• 1. • Antigen Presenting Cells (APCs, such as macrophages) phagocytose allergens and use their cell surface transmembrane major histocompatibility complex class II (MHC II) molecules to present them to Helper CD4+ T cells (TH cells).
     • T_H cells with T cell receptors (TCRs) that bind to the allergen become activated by the APC cells that are presenting allergens. TH cells become activated and proliferate.
     • At the same time B cells phagocytose allergens and become sensitized, displaying the antigen on their cell surface using MHC II molecules.
     • T_H cells that are able to bind both the allergen (through their TCR), bind to the sensitized B cells and activate the B cells.  B cells proliferate to produce daughter plasma cells.
     • The plasma cells produce IgE antibodies that specifically bind to the allergen through their Fab portion.
     • The Fc portion of these IgE antibodies bind to the Fc receptors on mast cells and basophils, leaving the IgE’s Fab portion free to bind allergen.  Once IgE antibodies are bound, the mast cells and basophils are termed “sensitized”
     • IgE antibodies are typically a type of antibody that is produced against helminths (parasitic worms).  It is thought that the TH cells are responsible for stimulating B cells to produce the IgE class of antibodies.

3. Re-exposure to allergen:

• 1. • Allergen binds to IgE on mast cells and basophils, stimulating degranulation and release of pro-inflammatory cytokines (histamine, leukotrienes, prostaglandins, bradykinin). Initially bradykinin are released and then prostaglandins and leukotrienes which prolong inflammation.

4. Inflammation:

• 1. • Cytokines stimulation vasodilation, increased capillary permeability.
     • Symptoms: Redness (due to hyperemia), warmth (due to increased blood flow, blood being slightly warmer than the rest of the body), swelling (due to leaking of plasma into affected tissue beds), exudate = leaked fluid, edema.

5. Mast cells:

• 1. • Mast cells are strategically located within mucosal surfaces to provide defense, and when triggered will therefore lead to symptoms like itching, sneezing, tearing of eyes, and nasal inflammation.
     • Allergic rhinitis (hay fever) is an example.
     • Indoor allergens like dust can cause year-round symptoms.
     • Antihistamines like Claritin help alleviate symptoms by blocking histamine binding to endothelial cells of blood vessel walls, preventing vasodilation and increased capillary permeability that would have led inflammation.
     • Ingested allergens stimulate mast cells in the mucosa of the digestive tract, leading to nausea, vomiting, diarrhea, and potentially skin reactions (due to allergen being absorbed by intestinal cells and into surrounding capillaries to spread through body causing immune reactions that are symptomatic in the cutaneous tissues.
     • Food allergens can cause anaphylactic reactions, leading to swelling of respiratory tract, leading to severe breathing difficulties.
     • Allergens absorbed from the GI tract can spread through the bloodstream, causing skin rashes (urticaria).
     • Contact allergies, like dermatitis from laundry soap, can lead to skin rashes and eczema.
     • Atopic allergies have a genetic component and can be triggered by various factors like ingested food or irritating fabrics.

• Symptoms are dependent on location of hypersensitivity reaction:
  • Respiratory Tract: The mechanisms of Type I Hypersensitivity Reactions within the Respiratory Tract due to inhaled allergens can lead to the development or respiratory allergies and/or Extrinsic Asthma.
    • Inhalation Exposure
      • Allergen inhaled (e.g., pollen, cat hair).
      • Mast cells in the respiratory tract release histamine.
      • Effects on the respiratory system:
        • Bronchoconstriction (smooth muscles constrict)
        • Difficulty breathing
        • Increased exudate (fluid in bronchioles)
        • Increased mucus production.
    • 1. Respiratory Allergies (e.g., Hay fever (allergic rhinitis)):  sneezing, itchy, watery eyes, runny nose.  In terms of signs and symptoms, the difference between allergic rhinitis and infection with the common cold virus is the lack of fever which usually accompanies the common cold.
    • 2. Extrinsic Asthma: Bronchoconstriction, mucus production, coughing, difficulty breathing.
      • Asthma is not an allergy, but can be triggered by allergens.
      • Asthma attacks can be triggered by specific allergens like pollen.
      • Mast cells and basophils in the respiratory mucosa are involved in asthma attacks.
      • Asthma is characterized by inflammation of the respiratory tract, leading to breathing difficulties.
      • Asthma has a genetic component and can run in families.
      • Susceptibility to allergies has a genetic component.
      • Exposure to allergens triggers helper T cells to recruit eosinophils and stimulate B cells.
      • Macrophages present allergens to helper T cells via MHC class II.
      • Helper T cells stimulate B cells, which produce IgE antibodies.
      • IgE antibodies bind to mast and basophils.
      • In an extrinsic asthmatic attack, contact with allergens triggers a massive release of histamine, prostaglandin, and bradykinin, leading to excessive inflammation swelling and mucous production in the respiratory tract and stimulation of bronchiole smooth muscles resulting in bronchoconstriction.  The symptoms of an asthmatic attack are generally far more pronounced that with those of hay fever due to the amount of pro-inflammatory cytokines that are released.  Additionally, hay fever (and other forms of allergic rhinitis) are typically limited to the upper airway, whereas asthma involves the lower airways as well.  Excessive mucus can lead to air trapping within the alveoli and bronchoconstriction and swelling can reduce airflow.  This leads to coughing, wheezing, dyspnea (difficulty) breathing.
      • Poor oxygenation of blood stimulates the sympathetic response in the central nervous system triggering feelings of anxiety, fear and reduced neuron function causing weakness, dizziness, and loss of consciousness.
      • Can be fatal if not treated.
  • Skin: Contact with allergens (e.g., bee stings, lotions, soaps, pet dander, poison ivy, latex) trigger Type I Hypersensitivity Reactions in the GI tract, which lead to the following signs and symptoms:
    • Allergen enters through the skin (subcutaneous exposure)
    • Dermatitis: Rash, itching, hives, redness, and/or wheel-and-flare reactions from contact with allergens.
    • Eczema: Chronic rash on face, trunk, extremities, often linked to genetic factors.
  • Intravenous Exposure
    • Allergen introduced directly into the bloodstream (e.g., injected drug).
    • Triggers mast cells and basophils covered in IgE antibodies.
    • Massive histamine release causes:
      • Vasodilation
      • Severe hypotension (low blood pressure)
      • Risk of anaphylactic shock, cardiac arrest, respiratory arrest, organ failure.
  • Digestive Tract:  Ingested food, drink, or oral medication allergens trigger Type I Hypersensitivity Reactions in the GI tract, which lead to the following signs and symptoms:
• Gastrointestinal Exposure
  • Allergen ingested (e.g., nuts, shellfish, strawberries).
  • Mast cells in gastric mucosa release histamine.
  • Effects on the gastrointestinal system:
    • Intestinal smooth muscle constriction
    • Vomiting
    • Diarrhea
  • Rapid entry into blood supply can cause:
    • Systemic hives
    • Anaphylaxis and anaphylactic shock.
    • Nausea, vomiting, diarrhea.
    • Quick absorption through intestinal cells into bloodstream spreads allergens throughout body, causing skin rashes (urticaria), hives, swelling.
  • Allergens (particularly when ingested or injected into the bloodstream) can lead to Systemic Signs and Symptoms which can lead to anaphylactic shock:
    • Anaphylaxis: Severe, life-threatening reaction. Symptoms include:
      • Massive vasodilation, hypotension, fainting, confusion, irritability.
      • Bronchoconstriction, respiratory distress, hypoxia.
      • Generalized itching, hives, swelling.

• Example of Anaphylaxis:

• • Trigger: Systemic exposure to allergens (e.g., nuts, shellfish, insect stings, various drugs).
  • Pathophysiology:
    • Massive release of histamine and other mediators.
    • Systemic vasodilation and increased capillary permeability lead to drop in blood pressure, leading to shock (defined as insufficient flow of oxygenated blood to tissues).
    • Bronchoconstriction, airway obstruction, respiratory acidosis (due to build up of carbon dioxide and carbonic acid in the blood),  metabolic acidosis (due to switch from aerobic cellular respiration to anaerobic cellular respiration, and the production of lactic acid) and hypoxia.
    • Anaphylaxis results in severe hypoxia very quickly because of combined respiratory (airway obstructions) and cardiovascular (shock) impairment, leading to loss of consciousness and potential cardiac or respiratory arrest. Immediate treatment is essential.
  • Symptoms of Anaphylaxis:
    • Itching, hives, swelling, coughing, difficulty breathing, dizziness, fainting, loss of consciousness.
    • Low blood pressure, sense of fear, panic, anxiety, rapid weak pulse.
    • Gastrointestinal distress: nausea, vomiting, diarrhea.
    • Edema around eyes, lips, tongue, hands, feet
  • Treatment:
    • Immediate administration of epinephrine.
    • Medical attention: call 911.
    • Supportive care: positioning, CPR if needed.
    • Supplemental oxygen, glucocorticoids

Management of Allergies:

• • Medications: Antihistamines (e.g., Claritin, Reactin) to block histamine effects, Corticosteroids.
  • Emergency:
    • Epinephrine (EpiPen): Bronchodilation, vasoconstriction to reverse symptoms.
    • Call 911, CPR if necessary.
  • Prevention of allergic and/or asthmatic attacks:
    • Avoid known allergens.
    • Carry emergency medication (e.g., asthma inhalers containing bronchodilators and/or corticosteroids).
    • While allergy testing is limited in what can be tested for, it can be helpful in some cases when it is possible to determine allergens (and then avoiding allergens)
• Risk Factors for the development of Allergies:

• • Genetics: Allergies and asthma tend to run in families.
  • Environment: Exposure to allergens such as dust, mold, pollen, foods, medications, bees, soaps, etc.

This overview provides a structured outline of type I hypersensitivity reactions, their mechanisms, symptoms, and management.

Signs and Symptoms Based on Allergen Contact Location

• Skin: Edema, redness, warmth, itching, hives.
• Respiratory Tract: Bronchoconstriction, difficulty breathing, increased mucus.
• Gastrointestinal Tract: Vomiting, diarrhea, potential systemic effects like hives and anaphylaxis.

Immediate and Late Phase Reactions

Immediate Phase as the name suggests is depicted by immediate signs and symptoms.  The immediate phase is due to mast cell activation releasing histamine, PGs & other preformed mediators of vascular permeability & vasodilation.  Often in allergy tests, potential allergens are injected into the subcutaneous tissue of the arm.  After 1-30minutes, the arm is examined for “Wheal and Flare” allergic reactions, which involves signs of inflammation (redness, warmth, swelling, itching).  After 8 hours, the late phase reaction of increased inflammation may take place if the injected substance is an allergen for the individual.

Late Phase is characterized by signs and symptoms that develop 8-12 hours after exposure to the allergen.  The late phase response is due to synthesis of more mast cell cytokines including leukotrienes, which have a long half life.  These cytokines recruit other leukocytes such as Eosinophils which leads to sustained edema and inflammation (and in asthma more bronchoconstriction and difficulty breathing) → sustained irritation and inflammation can cause more tissue destruction over time.

Physiologic Effects of Repeated Type I Hypersensitivity Reactions

1. Physiologic Effects
   • Inflammation and inflammatory reactions are significant, especially in asthma.
   • Repeated allergic or asthmatic attacks lead to white blood cells releasing toxic chemicals, causing collateral damage to host cells, which can lead to permanent loss of functional tissue and fibrosis (scarring within lungs).

Seriousness Based on Entry Portal (inhalation, ingestion, injection, skin contact)

• Intravenous Exposure: Most serious due to rapid systemic distribution and potential for anaphylactic shock.
• Inhalation and Gastrointestinal Exposures: Serious due to potential for respiratory distress or systemic reactions.
• Subcutaneous Exposure: Generally, less serious than gastrointestinal, inhalation, or injection exposures, localized skin reactions.