Hypersensitivity Reaction

Aka: Hypersensitivity Reaction, Hypersensitivity, Gell and Coombs Classification, Coombs and Gell Classification, Type 1 Hypersensitivity, Immediate Hypersensitivity Reaction, Type 2 Hypersensitivity, Cytotoxic Antibody Reaction, Type 3 Hypersensitivity, Immune Complex Reaction, Type 4 Hypersensitivity, Delayed-Type Hypersensitivity, Stimulatory Hypersensitivity, Immune Hypersensitivity Reaction

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II. Definitions

  1. Hypersensitivity
    1. Immune System sensitization after repeated allergan exposure
  2. Allergen
    1. Exogenous Antigens (typically Proteins) that trigger an immune response
  3. Gell and Coombs Classification of Hypersensitivity Reaction
    1. Categories of Hypersensitivity Response

III. Types: 1 - Immediate Hypersensitivity Reaction (IgE Mediated)

  1. Immediate allergan immune response after repeated exposure (esp. in Atopic Patients)
  2. Most common form of Hypersensitivity Reaction
  3. Mediated by IgE Antibody to specific Antigens
    1. Sensitization
      1. B-Cells are are exposed to Antigen (e.g. pollen)
      2. T-Helper Cells (TH2) bind to B-Cells
      3. B-Cells class switch to produce IgE Antibody against Antigen (instead of IgG and IgM)
      4. B-Cells produce the IgE against the specific Antigen
      5. IgE binds blood Basophils and tissue Mast Cells at the high affinity Fc receptor (FceRI)
      6. Mast Cells are now sensitized, awaiting allergan reexposure
    2. Mast Cells and Basophils are then stimulated with repeat exposure
      1. Release secretory granules including Histamine (as well as Leukotrienes, Prostaglandins)
      2. Although there are four Histamine receptors (H1, H2, H3, H4), H1 predominates in Type I Reaction
  4. Reaction Phases
    1. Early Phase (within minutes of exposure, <1 hour)
      1. Histamine-induced vasodilation, edema, congestion
    2. Late Phase (2 to 24 hours after exposure)
      1. Inflammatory cell infiltration (Eosinophils, Neutrophils, T-Cells)
  5. Examples
    1. Anaphylaxis (e.g. Penicillin)
    2. Urticaria
    3. Angioedema
    4. Anaphylactoid Reaction (e.g. Anaphylactoid Reaction to Radiocontrast)
    5. Atopic Allergy (e.g. Allergic Rhinitis, Allergic Asthma)
    6. Food Allergy
    7. Bee sting Allergy
    8. Allergic Occupational Asthma

IV. Types: 2 - Cytotoxic Antibody Reaction (non-IgE Antibody Mediated Reaction)

  1. Mediated by IgG and IgM (on cell surface or extracellular complex) to specific Antigens
  2. Antibody-Antigen Complex destruction by one of three mechanisms
    1. Opsonization and Phagocytosis
      1. Antibody-bound Antigen (Opsonin) is destroyed by cells (PMNs, Macrophages) engulfing complex (Phagocytosis)
    2. Antibody-dependent cellular cytotoxicity (ADCC)
      1. Antibodies bind infected cells with surface Antigen, targeted for Natural Killer Cell-mediated destruction
    3. Complement Activation
      1. IgG binds Antigen and activates complement
      2. Antibody-Antigen complexes by lysis or phagocytocsis
  3. Examples
    1. Transfusion Reaction (ABO Incompatibility)
    2. Delayed transplant Graft Rejection
    3. Rhesus Incompatibility (Rh Incompatibility)
    4. Mycoplasma pneumoniae related cold Agglutinins
    5. Autoimmune Hemolytic Anemia
      1. Autoantibodies to Red Blood Cell membrane Proteins
    6. Immune Thrombocytopenic Purpura
      1. Autoantibodies to Platelet surface Proteins
    7. Hashimoto's Thyroiditis
      1. Autoantibodies to Thyroid peroxidase
    8. Pernicious Anemia
      1. Autoantibodies to gastric Intrinsic Factor (required for Vitamin B12 absorption)
    9. Grave's Disease
      1. Autoantibodies to TSH Receptors
    10. Pemphigus
      1. Autoantibodies to epidermal Proteins
    11. Myasthenia Gravis
      1. Autoantibodies to Acetylcholine receptors on Neurons
    12. Goodpasture's Syndrome
      1. Autoantibodies to renal glomeruli and pulmonary alveoli
    13. Type II Diabetes Mellitus
      1. Autoantibodies to Insulin receptors
    14. Rheumatic Fever
      1. Autoantibodies to myocardial Antigens

V. Types: 3 - Immune Complex Reaction (Antigen-Antibody Complex Deposition)

  1. Antigen-Antibody immune complexes deposit in tissue
    1. Contrast to typical immune complex processing
      1. Most immune complexes typically activate the complement system
      2. These complexes are then typically destroyed by phagocytic cells (PMNs, Macrophages)
    2. However, small complexes may be missed by Phagocytosis
      1. These complexes may instead precipitate, deposit in tissue with inflammation
    3. Other injury mechanisms triggered by immune complexes
      1. Unbridled Complement Activation
      2. Lysosomal enzyme secretion damages normal tissue
  2. Small immune complex deposition results in inflammatory reaction within 1-3 weeks of exposure
    1. Blood vessel walls resulting in Vasculitis
    2. Renal glomerular basement membrane resulting in nephritis
    3. Joint synovial membranes resulting in Arthritis
  3. Examples
    1. Serum Sickness (prototypical Immune Complex Reaction)
    2. Systemic Lupus Erythematosus
    3. Erythema Nodosum
    4. Post-Streptococcal Glomerulonephritis
    5. Arthus Reaction (e.g. Farmer's Lung)
    6. Rheumatoid Arthritis
    7. Elephantiasis (Wuchereria bancrofti reaction)
    8. Jarisch-Herxheimer Reaction
    9. Polyarteritis Nodosa
      1. Typically due to Viral HepatitisAntigen (esp. HepBsAg) and Antibody Complex

VI. Types: 4 - Delayed-Type Hypersensitivity (T Cell-Mediated)

  1. Reaction within 2-7 days after exposure
  2. Mediated by Effector T Lymphocytes (CD4+ and CD8+), activated in response to specific Antigens
    1. Triggering initial Antigens are often infectious (Mycobacteria, Protozoa, and fungi)
    2. Antigen bound to Major Histocompatibility Complex (MHC) on Antigen Presenting Cells
    3. Activated T Lymphocytes release Cytokines (e.g. Interferon-gamma) and CD8+ cells may destroy Antigen directly
    4. Cytokines trigger Phagocytosis and inflammation
  3. Examples
    1. Severe Skin Reactions
      1. Stevens Johnson Syndrome
      2. Toxic Epidermal Necrolysis
      3. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS Syndrome)
    2. Allergic Contact Dermatitis (e.g. Nickel allergy, Poison Ivy)
    3. Non-Granulomatous Disease
      1. Type I Diabetes Mellitus
        1. Autoimmune cell-mediated destruction of Insulin-Secreting pancreatic beta cells
      2. Autoimmune Viral Myocarditis
      3. Autoimmune Peripheral Neuropathy
      4. Hashimoto Thyroiditis
      5. Multiple Sclerosis
      6. Rheumatoid Arthritis
    4. Granulomatous Disease
      1. Leprosy
      2. Tuberculosis
      3. Schistosomiasis
      4. Sarcoidosis
      5. Crohn Disease
      6. Ulcerative Colitis
      7. Temporal Arteritis
    5. Mantoux Test (PPD)
      1. Immune Allergic Contact Dermatitis after prior Mycobacterium tuberculosis exposure
    6. Medications
      1. Allopurinol
      2. Lamotrigine
  4. References
    1. Vaillant (2021) Delayed Hypersensitivity Reaction, StatPearls, accessed 7/13/2021
      1. https://www.ncbi.nlm.nih.gov/books/NBK519023/

VII. Types: Other allergy mediated reactions

  1. Stimulatory Hypersensitivity
    1. Humoral Antibody activates receptor sites
    2. Example: Thyrotoxicosis (TSH autoantibodies)
  2. Fas/Fas Ligand-induced apoptosis
    1. Example: Stevens Johnson Syndrome
  3. T-Cell Activation
    1. Example: Sulfonamide induced Morbilliform rash

VIII. References

  1. Goldberg (2014) Clinical Physiology, MedMaster, Miami, FL
  2. Mahmoudi (2014) Immunology Made Ridiculously Simple, MedMaster, Miami, FL
  3. Roitt (1988) Essential Immunology, Blackwell,p. 193-214
  4. Riedl (2003) Am Fam Physician 68:1781-90 [PubMed]

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