Hypersensitivity

Snapshot

A 12-year-old boy presents to the emergency department with dyspnea and urticaria. His symptoms began approximately 30 minutes after being stung by bee. Medical history is significant for asthma and an allergy to shellfish. On physical exam, breathing is labored, and wheezes are appreciated on pulmonary auscultation. Airway, breathing, and circulation is intact. The boy is immediately started on intramuscular epinephrine. (Anaphylaxis)

Introduction – Hypersensitivity

Hypersensitivity reactions (HSR) can be considered as an overreactive immune response
HSR can be classified into four categories
- type I, II, III, and IV
  - type I, II, and III are antibody mediated
  - type IV is cell mediated
Speed of reaction
- type I HSR is immediate (fastest)
- type IV HSR is delayed (slowest)

Type I HSR (Anaphylactic and Atopic)

Mechanism of action
- initial exposure to an allergen causes
  - Th2 cells to stimulate (via IL-4 and -13) B-cells to produce
    - IgE antibodies which attaches to
      - mast cells and basophils (these are said to be sensitized)
- second exposure to the allergen causes
  - IgE cross-linking on mast cells and basophil which results in
    - the immediate release of vasoactive amines (e.g., histamine and heparin) that can cause
      - vascular leakage
      - bronchoconstriction
      - intestinal hypermotility
      - inflammation
- since the antibodies are pre-formed, the reaction is immediate
  - a few hours after the immediate response ensues, a late-phase reaction occurs
    - which is mediated by downstream products of the arachidonic acid cascade such as
      - prostaglandins
      - leukotrienes
Clinical disorders
- refer to chart
Diagnostic testing
- allergen-specific IgE can be assessed with
- skin testing for allergic disease

Type II HSR (Cytotoxic)

Mechanism of action
- antibodies are directed against tissue specific antigens which can result in
  - opsonization
  - complement activation
  - neutrophil and macrophage recruitment
  - NK cell killing
  - impair cell function if targetting a cellular receptor
Clinical disorders
- refer to chart
- Diagnostic testing

direct Coombs test
- assesses antibodies that are attached directly to the erythrocyte surface
indirect Coombs test
assesses antibodies that are unbound in the serum

Type III HSR (Immune-Complex)

Mechanism of action
- antibodies bind to self or foreign antigen forming immune complexes
  - immune complexes activate the complement cascade and results in
    - systemic manifestations
Clinical disorders
refer to chart

Type IV HSR (Cell-Mediated)

Mechanism of action
- T-cell-mediated tissue injury resulting from
  - CD8+ T-cells directly killing a target cell
  - pre-sensitized CD4+ helper T-cells are exposed to the insult, which results in
    - cytokine release (delayed-type HSR), which leads to
      - macrophage activation and
        
        inflammation
Clinical disorders
refer to chart

Summary

Hypersensitivity Reactions
Hypersensitivity Reaction Type	Pathophysiology	Clinical Examples
Type I (anaphylactic and atopic)	ImmediateAntigens cross-link IgE antibodies triggeringvasoactive amine release (e.g., histamine)	Anaphylaxisallergensbee stingfood (e.g., peanuts)drugsAsthmaallergensinhaled materialsAllergic rhinitisallergensanimalstrees
Type II (cytotoxic)	Antibodies are directed against cell-surface antigens resulting inopsonizationcomplement activationneutrophil and macrophage recruitingNK cell killingimpairment of cellular function	Autoimmune hemolytic anemiaantigenerythrocyte membrane proteinsAcute rheumatic fever antigenmyocardial antigens via cross-reacting with S. pyogenes M proteinGoodpasture syndromeantigentype IV collagenImmune thrombocytopenic purpuraantigenplatelet membrane proteinsMyasthenia gravis antigenacetylcholine receptorsGraves’ diseaseantigenTSH receptorsErythroblastosis fetalis antigenRh antigenPemphigus vulgaris antigendesmosomes
Type III (immune-complex)	IgG antibodies complexes with self or foreign antigens resulting incomplement activation	Serum sickness Arthus reactionSystemic lupus erythematosisPolyarteritis nodosaPoststreptococcal glomerulonephritis
Type IV (cell mediated)	CD8+ T-cells directly destroy the target cellPre-sensitized CD4+ helper T-cell releases cytokines when re-exposed to the offending materialNotice this does NOT involve antibodies	Type I diabetes meilltusContact dermatitis Tuberculin testSympathetic ophthalmia

Function and Clinical Significance:

Hypersensitivity reactions can range from mild to severe and may have significant clinical implications:

Allergic Rhinitis: Type I hypersensitivity to airborne allergens can cause allergic rhinitis, with symptoms like sneezing, nasal congestion, and itchy eyes.
Anaphylaxis: Anaphylaxis is a severe, life-threatening allergic reaction characterized by sudden-onset symptoms such as difficulty breathing, low blood pressure, and hives. It requires immediate medical intervention with epinephrine.
Autoimmune Diseases: Certain hypersensitivity reactions can lead to autoimmune diseases, where the immune system mistakenly attacks the body’s own tissues. Examples include rheumatoid arthritis and multiple sclerosis.

Diagnostic Studies:

Skin Prick Test: In Type I hypersensitivity, skin prick tests involve introducing small amounts of allergens under the skin to identify specific allergens triggering an allergic response.
Blood Tests: Blood tests can measure the levels of IgE antibodies specific to particular allergens, aiding in the diagnosis of allergic conditions.

Treatment Approaches:

Allergen Avoidance: The primary approach in managing hypersensitivity is to identify and avoid allergens triggering the immune response.
Medications: Antihistamines, corticosteroids, and decongestants are commonly used to manage allergic symptoms and reduce inflammation.
Immunotherapy: Allergen immunotherapy, commonly known as allergy shots, involves exposing individuals to increasing doses of allergens to desensitize the immune system over time.

Clinical Significance and Anaphylaxis Management:

Emergency Management: Anaphylaxis is a medical emergency requiring prompt treatment with epinephrine, followed by supportive care in a hospital setting.
Epinephrine Auto-Injectors: Individuals with a history of severe allergies are often prescribed epinephrine auto-injectors (e.g., EpiPen) to self-administer in case of anaphylaxis.

Conclusion:

Hypersensitivity encompasses a range of immune responses that can cause various allergic reactions and clinical conditions. Understanding the types of hypersensitivity reactions, their underlying immune mechanisms, and potential triggers is essential for medical professionals to diagnose and manage allergic conditions effectively.

Timely diagnosis, allergen avoidance, and appropriate treatments, including immunotherapy and epinephrine administration, are essential for improving patient outcomes and preventing severe allergic reactions such as anaphylaxis. Ongoing research in immunology continues to advance our understanding of hypersensitivity, paving the way for more targeted and personalized approaches in allergy and immunology care.

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