Hypersensitivity Reactions - Pathology

Summary Table (Robbins)

Type I - Immediate (IgE-mediated) Hypersensitivity

1. First antigen exposure: APCs present allergen peptides to naive CD4+ T cells, which differentiate into Th2 cells under IL-4 signaling
2. Th2 cells produce IL-4 and IL-13, which act on B cells to class-switch to IgE production
3. IgE binds to FcεRI receptors on mast cells and basophils - the individual is now sensitized

• Antigen cross-links IgE on mast cell surface → mast cell degranulation
• Primary (preformed) mediators: histamine, heparin, proteases (tryptase, chymase), eosinophil/neutrophil chemotactic factors
• Secondary (newly synthesized) mediators: prostaglandins, leukotrienes (LTC4, LTD4, LTE4), PAF, cytokines (IL-4, IL-5, IL-13, TNF)

• Immediate reaction (within minutes): vasodilation, increased vascular permeability, smooth muscle spasm, glandular secretions - subsides within hours
• Late-phase reaction (2-24 hours later, without re-exposure): tissue infiltration with eosinophils, neutrophils, basophils, monocytes, CD4+ T cells; epithelial damage - persists for days

Type II - Antibody-Mediated (Cytotoxic) Hypersensitivity

1. Complement-mediated lysis: IgG/IgM activates classical complement → MAC formation → cell lysis; C3b/C4b opsonization → phagocytosis
2. ADCC (Antibody-Dependent Cell-mediated Cytotoxicity): NK cells, neutrophils, macrophages with FcR bind IgG-coated cells and kill them
3. Functional alteration without tissue injury: antibodies against receptors alter normal cell signaling (e.g., anti-TSH receptor in Graves disease stimulates thyroid; anti-AChR in myasthenia gravis blocks neurotransmission)

• Autoimmune hemolytic anemia, immune thrombocytopenic purpura
• Goodpasture syndrome (anti-GBM antibodies)
• Graves disease (stimulatory - sometimes classified Type V)
• Myasthenia gravis (blocking)
• Hemolytic transfusion reactions, erythroblastosis fetalis
• Rheumatic fever (anti-streptococcal Ab cross-reacts with cardiac myosin)

Type III - Immune Complex-Mediated Hypersensitivity

1. Immune complex formation: antigen excess favors small, soluble complexes that evade phagocytosis; slight antigen excess produces intermediate-sized complexes that are the most pathogenic
2. Immune complex deposition: high-pressure filtration sites (glomeruli, joints, choroid plexus, skin) concentrate complexes - explains organ tropism
3. Inflammation and injury: complement activation generates C3a/C5a (anaphylatoxins) → mast cell degranulation + neutrophil recruitment → release of lysosomal enzymes and ROS → tissue destruction

• Serum sickness: 5-10 days after single large antigen exposure; fever, urticaria, joint pain, lymphadenopathy, proteinuria; serum C3 levels fall due to complement consumption
• Arthus reaction: localized skin necrosis after intradermal antigen injection in a pre-immunized individual; large complexes precipitate in vessel walls → fibrinoid necrosis + thrombosis

Type IV - Cell-Mediated (Delayed-Type) Hypersensitivity

IVa - Delayed-Type Hypersensitivity (DTH) via CD4+ T Cells

• Sensitization (1-2 weeks): antigen presented on MHC II → Th1/Th17 differentiation
• Elicitation (re-exposure, 48-72 hours later - hence "delayed"):
  • Th1 cells release IFN-γ → macrophage activation → release of lysosomal enzymes, ROS, nitric oxide
  • Th17 cells release IL-17 → neutrophil recruitment
• Persistent antigen → granuloma formation (hallmark of chronic DTH): epithelioid macrophages, multinucleated giant cells, surrounded by CD4+ T cells and fibroblasts

IVb - Direct Cytotoxicity via CD8+ CTLs

• Antigen presented on MHC I → CD8+ CTLs kill target cells directly via perforin/granzyme and Fas-FasL

• Contact dermatitis (poison ivy, nickel, latex) - prototype
• Tuberculosis - caseating granulomas
• Type 1 diabetes mellitus - CTL destruction of beta cells
• Multiple sclerosis - Th1/Th17 attack on myelin
• Transplant rejection (cellular component)
• Tuberculin skin test (PPD reaction at 48-72 hours)

Type V - Stimulatory Hypersensitivity (Addition to original classification)

• Graves disease: anti-TSH receptor IgG acts as TSH agonist → continuous thyroid stimulation → hyperthyroidism
• Contrasted with myasthenia gravis (Type II blocking) where the antibody inhibits receptor function

Key Distinctions to Remember

Hypersensitivity - Definition (Robbins)

"Injurious immune reactions, called hypersensitivity, are responsible for the pathology associated with immunologic diseases. This term arose from the idea that individuals who have been previously exposed to an antigen will manifest detectable reactions to that antigen and are therefore said to be sensitized. Hypersensitivity implies an excessive or harmful reaction to an antigen."

1. Antigens can be exogenous or endogenous. Exogenous antigens include dust, pollen, food, drugs, microbes, and chemicals - reactions to these range from trivial (skin itching) to fatal (anaphylaxis). Reactions to self (autologous) antigens cause autoimmune diseases.
2. Hypersensitivity results from an imbalance between the effector mechanisms of immune responses and the control mechanisms that normally limit them. In many hypersensitivity diseases, the underlying cause is suspected to be a failure of normal regulation.
3. Genetic susceptibility plays a role. Development of hypersensitivity diseases (allergic and autoimmune) is often associated with inheritance of particular susceptibility genes - including HLA and non-HLA genes.
4. The mechanisms of tissue injury are the same as normal immune defense. The problem in hypersensitivity is that these reactions are poorly controlled, excessive, or misdirected - for example, against normally harmless environmental antigens or self antigens.