Hypersensitivity Reactions

Advanced Pharmacology - University Long Answer (10 Marks)

Introduction

The effectors for Types I, II, and III hypersensitivity are antibody molecules; Type IV is mediated by antigen-specific effector T cells.

• Goldman-Cecil Medicine, Table 36-1

Classification (Gell and Coombs)

• Roitt's Essential Immunology, 13th Ed.

TYPE I - Immediate (Anaphylactic) Hypersensitivity

Mechanism

1. First exposure to the allergen stimulates B cells to produce IgE antibodies (via Th2 cells and IL-4, IL-13).
2. IgE binds via its Fc portion to FcεRI receptors on mast cells and basophils - these cells become "sensitized."

Type I: Soluble antigen cross-links IgE on mast cell FcεRI receptors, triggering degranulation - Goldman-Cecil Medicine

Mediators of Type I

• Histamine - vasodilation, increased vascular permeability, smooth muscle contraction, increased mucus secretion
• Proteolytic enzymes (tryptase, chymase, carboxypeptidase)
• Heparin - anticoagulant

• Leukotrienes (LTC4, LTD4, LTE4) - potent bronchospasm (1000x more potent than histamine), increased vascular permeability
• Prostaglandins (PGD2) - bronchoconstriction, vasodilation
• Platelet-Activating Factor (PAF) - platelet aggregation, bronchoconstriction
• Cytokines: IL-4, IL-5 (eosinophil activation), IL-13, TNF-α, GM-CSF
• Chemokines: IL-8 (neutrophil recruitment)
• Major basic protein (from eosinophils) - toxic granular protein causing epithelial damage

Clinical Examples

• Systemic anaphylaxis (bee sting, penicillin, peanuts)
• Bronchial asthma (inhaled allergens causing bronchoconstriction)
• Allergic rhinitis / hay fever (pollen)
• Urticaria and angioedema (food, drugs)
• Atopic dermatitis / eczema
• Food allergies (GI tract: diarrhea, vomiting)

"The main targets of this type of reaction are the GI tract (food allergies), the skin (urticaria and atopic dermatitis), the respiratory system (rhinitis and asthma), and the vasculature (anaphylactic shock)."

• Goodman & Gilman's The Pharmacological Basis of Therapeutics

TYPE II - Cytotoxic (Cytolytic) Hypersensitivity

Mechanism

1. An antigen is present on a cell surface (either naturally, or a drug hapten bound to a cell surface).
2. IgG or IgM antibodies are produced against these cell-surface or matrix-associated antigens.
3. Antibody binding triggers cell destruction via three mechanisms:
   • Complement activation (classical pathway) → membrane attack complex (MAC) → cell lysis
   • Opsonization and phagocytosis - C3b and IgG coat the cell; FcγR+ macrophages phagocytose it
   • Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) - NK cells with FcγRIII (CD16) kill antibody-coated targets
4. Target cells are mainly in the circulatory system (RBCs, platelets, WBCs).

Mediators

• IgG / IgM antibodies
• Complement proteins (C1q, C3b, C5-C9 - MAC)
• FcγR-bearing cells: macrophages, NK cells

Clinical Examples

• Penicillin-induced hemolytic anemia - penicillin binds RBC surface as a hapten → IgG forms → complement-mediated lysis
• Quinidine-induced thrombocytopenic purpura
• Sulfonamide-induced granulocytopenia
• Rh incompatibility - Rh-negative mother develops anti-Rh IgG against Rh-positive fetal RBCs
• ABO transfusion reactions - preformed IgM antibodies lyse incompatible donor RBCs
• Autoimmune hemolytic anemia
• Myasthenia gravis (antibodies to acetylcholine receptors - blocking subtype)
• Goodpasture's syndrome (anti-GBM antibodies)

"Type II allergies are mediated by both IgG and IgM antibodies and usually are attributed to their capacity to activate the complement system."

• Goodman & Gilman's

TYPE III - Immune Complex (Arthus) Hypersensitivity

Mechanism

1. Soluble antigen-antibody (IgG) immune complexes are formed in circulation.
2. Under normal conditions, complexes are cleared; in Type III, excessive complexes overwhelm the clearance system.
3. Complexes are deposited in vascular endothelium (kidneys, joints, skin, blood vessels).
4. Deposited complexes activate complement → C3a and C5a (anaphylatoxins) are generated.
5. C5a acts as a chemoattractant for neutrophils (PMNs) to the site.
6. Neutrophils attempt phagocytosis of complexes but release lysosomal enzymes (proteases, collagenase) and reactive oxygen species into the surrounding tissue, causing inflammation and damage.
7. Platelet aggregation and mast cell activation also contribute.

Mediators

• IgG immune complexes
• Complement fragments (C3a, C5a - anaphylatoxins)
• Neutrophil lysosomal enzymes (proteases, collagenase)
• Reactive oxygen species

Clinical Examples

• Serum sickness (e.g., antiserum administration, some drugs) - urticaria, arthralgia, lymphadenopathy, fever; lasts 6-12 days
• Arthus reaction - local immune complex deposition after repeated intradermal injections of antigen
• Subacute bacterial endocarditis - circulating bacterial antigen-antibody complexes deposit in kidneys, joints
• Post-streptococcal glomerulonephritis
• Systemic lupus erythematosus (SLE) - widespread immune complex deposition in kidneys, skin, joints
• Rheumatoid arthritis (partially)
• Hypersensitivity pneumonitis (Farmer's lung, pigeon fancier's lung)

"Type III allergic reactions are mediated predominantly by IgG; the mechanism involves generation of antigen-antibody complexes that subsequently fix complement. The complexes are deposited in the vascular endothelium, where a destructive inflammatory response called serum sickness occurs."

• Goodman & Gilman's

TYPE IV - Delayed-type (Cell-mediated) Hypersensitivity

Mechanism

1. Antigen is processed and presented on MHC class II by antigen-presenting cells (APCs) to CD4+ T cells (or MHC class I to CD8+ T cells).
2. T cells become sensitized and expand into memory T cells.

• Th1-mediated - contact dermatitis, tuberculin reaction (macrophage activation)
• Th2-mediated - chronic allergic inflammation (eosinophil activation)
• Th17-mediated - contact/atopic dermatitis, rheumatoid arthritis (neutrophil/macrophage activation)
• CTL-mediated - direct cytotoxicity (virus-infected cells, graft rejection)

Mediators

• IFN-γ - activates macrophages
• TNF-α / TNF-β (lymphotoxin) - inflammatory; recruits leukocytes
• IL-2 - T cell proliferation
• IL-17 (Th17) - neutrophil recruitment
• Perforin / Granzyme B (CTLs) - direct cell killing
• Activated macrophages release: IL-1, IL-6, reactive oxygen species, lysosomal enzymes

Clinical Examples

• Allergic contact dermatitis - poison ivy/oak (urushiol), nickel, latex
• Tuberculin reaction (Mantoux test) - PPD injection → indurated reaction at 48-72 hours
• Granulomatous hypersensitivity - tuberculosis, sarcoidosis, leprosy (Hansen's disease), schistosomiasis
• Graft rejection (organ/skin transplant)
• Type 1 diabetes mellitus - CD8+ CTLs destroy pancreatic beta cells
• Multiple sclerosis - Th1/Th17 attack on myelin

"These reactions are mediated by sensitized T lymphocytes and macrophages. When sensitized cells come in contact with an antigen, an inflammatory reaction is generated by the production of lymphokines and the subsequent influx of neutrophils and macrophages."

• Goodman & Gilman's

TYPE V - Stimulatory Hypersensitivity (Addition to Gell-Coombs)

• Graves' disease - anti-TSH receptor antibodies stimulate thyroid overactivity (hyperthyroidism)
• Neonatal Graves' disease - maternal IgG crosses placenta

Summary Comparison Table

Pharmacological Relevance

1. Antihistamines (H1-blockers) - target histamine in Type I (urticaria, allergic rhinitis)
2. Epinephrine - first-line for Type I anaphylaxis; reverses bronchoconstriction and vasodilation via β2 and α1 receptors
3. Corticosteroids - suppress inflammation in all types; particularly Type IV
4. Leukotriene receptor antagonists (Montelukast) - block CysLT1 receptors, used in asthma (Type I late phase)
5. Anti-IgE (Omalizumab) - binds free IgE, prevents FcεRI binding; approved for severe asthma/urticaria (Type I)
6. Immunosuppressants (Cyclosporine, Tacrolimus) - suppress T cell activation, used in Type IV graft rejection
7. NSAIDs - block prostaglandin synthesis (Type I mediators)
8. Corticosteroids in serum sickness (Type III) - reduce immune complex-mediated inflammation

Conclusion

• Identifying the etiology of adverse drug reactions
• Selecting appropriate pharmacological interventions (antihistamines, steroids, epinephrine, biologics)
• Predicting cross-reactivity patterns in drug hypersensitivity

• Goodman & Gilman's The Pharmacological Basis of Therapeutics, Chapter 9
• Goldman-Cecil Medicine (International Edition), Chapter 36
• Jawetz, Melnick & Adelberg's Medical Microbiology, 28th Ed.
• Janeway's Immunobiology, 10th Ed., Chapter 14
• Roitt's Essential Immunology, 13th Ed., Chapter 14