Hypersensitivity Reactions - Complete Notes (Robbins Pathology)

DEFINITION

"Immune responses that normally are protective are also capable of causing tissue injury. Injurious immune reactions are grouped under hypersensitivity." - Robbins Basic Pathology

CAUSES OF HYPERSENSITIVITY

1. Self antigens (Autoimmunity) - failure of self-tolerance; e.g., SLE, rheumatoid arthritis
2. Microbial antigens - excessive/persistent responses to microbes; e.g., post-streptococcal glomerulonephritis, TB granulomas
3. Environmental antigens (Allergy) - reactions to pollens, dust mites, animal dander, drugs; ~20% of the population in high-income countries

CLASSIFICATION OF HYPERSENSITIVITY REACTIONS

TYPE I HYPERSENSITIVITY (IMMEDIATE / ANAPHYLACTIC)

Definition

Pathogenesis - Sequence of Events

1. Allergen enters the body and is processed by dendritic cells
2. Dendritic cells present antigen to naive CD4+ T cells in lymph nodes
3. Epithelial cells release IL-25, IL-33, and TSLP in response to allergen injury
4. These cytokines drive naive T cells to differentiate into Th2 cells
5. Th2 cells secrete IL-4, IL-5, and IL-13:
   • IL-4 + IL-13 → stimulate B cells to undergo class switching to IgE
   • IL-5 → activates eosinophils
   • IL-13 → stimulates mucus secretion from epithelium
6. IgE antibodies are produced and bind to high-affinity FcεRI receptors on mast cells and basophils → Sensitized mast cells

1. On re-exposure, allergen cross-links adjacent IgE molecules on mast cell surface
2. Cross-linking of IgE-FcεRI triggers intracellular signal transduction
3. Results in mast cell activation and release of mediators

Fig. 6.13A - Kinetics of the immediate and late-phase reactions. Peak reaction within 1 hour of allergen exposure; late-phase reaction at 8-12 hours. (Robbins Pathologic Basis of Disease)

Mediators Released by Mast Cells

Fig. 6.15 - Mast cell mediators responsible for immediate and late-phase reactions. (Robbins Pathologic Basis of Disease)

• Histamine - most important; causes smooth muscle contraction, increases vascular permeability, stimulates mucus secretion
• Enzymes (tryptase, chymase, acid hydrolases) - cause tissue damage; generate kinins and C3a
• Proteoglycans (heparin, chondroitin sulfate) - package and store amines in granules

• Prostaglandin D2 - intense bronchoconstriction, vasodilation
• Leukotrienes C4, D4, E4 - most potent bronchoconstricting agents known; increase vascular permeability
• Leukotriene B4 - chemotactic for neutrophils, eosinophils, monocytes
• Platelet-activating factor (PAF) - platelet aggregation, bronchoconstriction, vasodilation

• TNF, IL-1, IL-4, IL-5, IL-13 → leukocyte recruitment
• Chemokines (eotaxin) → recruit eosinophils

Two Phases of Type I Reaction

Fig. 6.13 B,C - (B) Immediate reaction: mast cells, vascular congestion, edema. (C) Late-phase reaction: eosinophil-rich infiltrate. (Robbins Pathologic Basis of Disease)

Characteristics

• Antibody: IgE
• Cells: Mast cells, basophils, eosinophils, Th2 cells
• Complement: NOT involved
• Genetic predisposition: Atopy (susceptibility to mount Th2/IgE responses)
• Transfer: Passive transfer with serum (Prausnitz-Küstner reaction)

Clinical Examples

TYPE II HYPERSENSITIVITY (ANTIBODY-MEDIATED / CYTOTOXIC)

Definition

Pathogenesis - Three Mechanisms

Fig. 5.12 - Mechanisms of antibody-mediated injury. (A) Opsonization and phagocytosis. (B) Complement- and Fc receptor-mediated inflammation. (C) Antibody-mediated cellular dysfunction (Graves disease). (Robbins Basic Pathology)

• IgG or IgM antibodies coat (opsonize) cell surface antigens
• Phagocytes recognize IgG via Fc receptors
• Complement is activated (classical pathway) → generates C3b → recognized by C3b receptors on macrophages/neutrophils
• Result: phagocytosis and destruction of the opsonized cell
• Complement activation also forms Membrane Attack Complex (MAC) → osmotic lysis

• Antibody deposits on tissues (not cells) → activates complement → generates C5a, C3a (anaphylatoxins) + C5a (neutrophil chemotaxis)
• Complement fragments and Fc receptors recruit and activate neutrophils and macrophages
• Neutrophils release lysosomal enzymes and reactive oxygen species → tissue damage and fibrinoid necrosis

• Antibodies against cell surface receptors impair or dysregulate function
• No complement, no inflammation - purely functional disorder
• Example: In Graves disease, anti-TSH receptor antibodies stimulate the receptor → hyperthyroidism
• Example: In Myasthenia gravis, anti-ACh receptor antibodies block receptor → muscle weakness

• Cells coated with IgG are killed by NK cells and macrophages binding via Fc receptors
• No phagocytosis required

Characteristics

• Antibody: IgG (mainly), IgM
• Complement: Classical pathway activated
• Time: Minutes to hours
• Cells: Neutrophils, macrophages, NK cells
• Complement: YES (classical)

Clinical Examples

TYPE III HYPERSENSITIVITY (IMMUNE COMPLEX-MEDIATED)

Definition

Pathogenesis - Three Phases

Fig. 6.17 - Sequential phases of systemic immune complex disease (Type III hypersensitivity). (Robbins Pathologic Basis of Disease)

• Protein antigen enters body → immune response → antibodies produced (IgG/IgM) ~1 week later
• Antibodies react with antigen still in circulation → form antigen-antibody complexes
• Most pathogenic: complexes of intermediate size formed under slight antigen excess (not too large to be cleared, not too small to deposit)

• Complexes circulate in blood and deposit in tissues
• Preferential sites: kidney (glomeruli), joints (synovium), skin, small blood vessels
• Why these sites? Organs where blood is filtered at high pressure (urine, synovial fluid) → complexes concentrate; also fenestrated endothelium promotes passage
• Large complexes → cleared efficiently by phagocytes in spleen/liver
• Small complexes → remain in circulation, do not deposit well
• Intermediate-sized complexes → deposit in vessel walls and cause disease

• Deposited complexes activate complement (classical pathway) → C3a, C5a (anaphylatoxins)
• C5a is chemotactic → recruits neutrophils and monocytes
• Neutrophils attempt to phagocytose complexes → frustrated phagocytosis → release lysosomal enzymes and ROS → tissue damage
• Complement consumption → ↓ serum C3 levels (useful disease marker)
• Platelet aggregation → microthrombi formation → ischemia

Morphology

Types

• Systemic immune complex disease (Serum sickness): single large antigen exposure → complexes form → deposit systemically → fever, urticaria, joint pain, proteinuria at ~10 days
• Local immune complex disease (Arthus reaction): intracutaneous antigen injection in immunized individual with circulating antibodies → large complexes form locally → fibrinoid necrosis of vessel wall + thrombosis

Characteristics

• Antibody: IgG (primarily), IgM
• Complement: YES (classical pathway) - C3 levels fall
• Key feature: Granular (lumpy-bumpy) immunofluorescence (vs. linear in Goodpasture)
• Time: 6-12 hours (or ~10 days for serum sickness)
• Sites: Kidney, joints, skin, blood vessels

Clinical Examples

TYPE IV HYPERSENSITIVITY (CELL-MEDIATED / DELAYED-TYPE)

Definition

Pathogenesis - Two Mechanisms

• APC (dendritic cell) presents antigen via MHC class II to naive CD4+ T cells
• If APC produces IL-12 → T cells differentiate into Th1 cells
• If APC produces IL-1, IL-6, IL-23 → T cells differentiate into Th17 cells
• These effector T cells enter circulation as memory cells

• Re-exposure to antigen → Th1 cells release IFN-γ (key cytokine)
• IFN-γ activates macrophages ("classical activation") → macrophages:
  • Enhanced phagocytosis and killing ability
  • Express more MHC class II → amplify antigen presentation
  • Secrete TNF, IL-1, chemokines → promote inflammation
  • Produce more IL-12 → amplify Th1 response (positive feedback loop)
• Th17 cells secrete IL-17, IL-22 → recruit neutrophils and monocytes
• Result: Perivascular mononuclear infiltrate (lymphocytes + macrophages)

• With persistent or nondegradable antigens (e.g., M. tuberculosis), macrophages transform into epithelioid cells → aggregate into granulomas surrounded by lymphocytes
• This is granulomatous inflammation, driven by Th1 + IFN-γ

• CD8+ CTLs recognize antigen presented via MHC class I on target cells
• Kill target cells directly by perforin-granzyme pathway
• Also secrete IFN-γ
• Important in: viral infections, graft rejection, type 1 diabetes (destruction of islet cells)

Histology of DTH Reaction

Fig. 6.19 - Delayed-type hypersensitivity in skin. (A) H&E: perivascular "cuffing" of mononuclear cells, dermal edema, fibrin deposition. (B) Anti-CD4 immunoperoxidase: predominantly CD4+ perivascular infiltrate. (Robbins Pathologic Basis of Disease)

Classic Test: Tuberculin (Mantoux) Reaction

• Intracutaneous injection of PPD (purified protein derivative of M. tuberculosis)
• In previously sensitized individual: redness and induration appear at 8-12 hours, peak at 24-72 hours
• Morphology: accumulation of CD4+ T cells and macrophages around venules ("perivascular cuffing"), marked endothelial hypertrophy

Characteristics

• No antibody involved (purely cellular)
• Key cells: CD4+ Th1 and Th17 cells, CD8+ CTLs, macrophages
• Key cytokines: IFN-γ (most important), IL-17, TNF, IL-12
• Time: 24-72 hours (hence "delayed")
• Complement: NOT involved
• Cannot be transferred with serum (only with T cells)

Clinical Examples

TYPE V HYPERSENSITIVITY (STIMULATORY)

Characteristics

• Antibody: IgG
• Mechanism: Antibody mimics the natural ligand → constitutive receptor activation
• No complement activation, no cell destruction
• Sometimes classified within Type II (antibody-mediated cellular dysfunction)

Prototypic Example: Graves Disease (Hyperthyroidism)

• Antibodies against TSH receptor on thyroid cells
• Antibody binds and continuously stimulates TSH receptor (acts like TSH)
• → Continuous production of thyroid hormones → hyperthyroidism
• Clinically: weight loss, tachycardia, exophthalmos, goiter

Other Examples

• Myasthenia gravis (traditionally Type II - receptor blockade, but sometimes listed here)

SUMMARY COMPARISON TABLE

KEY MNEMONICS FOR EXAM

• Type I - "IMMEDIATE" ANAPHYLAXIS: IgE, Instant, mast cell Irritation → histamine
• Type II - "CYTOTOXIC": antibodIes kIll Cells (the letter "II" reminds you of two direct targets: complement + Fc receptor)
• Type III - "IMMUNE COMPLEX": Complex disease, III = Triple trouble (form, deposit, inflame)
• Type IV - "DELAYED" (D = Days; DTH): T-cell mediated, no antibody, needs 24-72h
• Type V - "STIMULATORY": antibody mimics Stimulant → receptor overactivation