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HYPERSENSITIVITY REACTIONS - COMPLETE 2nd MBBS ANSWER

(MUHS Exam Oriented | Apurba Shastri Pattern)

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⭐ DEFINITION OF HYPERSENSITIVITY (***)

"Hypersensitivity responses lead to tissue damage: immunopathology. The mechanisms underlying hypersensitivity reactions are the same as those normally employed by the body in combating infection - the problem is that they are occurring with much too high intensity, directed against antigens that pose no threat, and/or at inappropriate locations." - Roitt's Essential Immunology, 13th Ed.

• Requires prior sensitization
• Exaggerated immune response
• Causes tissue damage (immunopathology)
• Can be antibody-mediated or cell-mediated

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⭐⭐ CLASSIFICATION OF HYPERSENSITIVITY (Gell and Coombs, 1963)

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⭐⭐⭐ TYPE I HYPERSENSITIVITY (Immediate / Anaphylactic)

Definition

Mechanism (Step-by-step - MUHS Favorite)

• Antigen (allergen) enters the body
• Processed by APCs → presented to Th2 cells
• Th2 cells release IL-4 and IL-13 → B cells switch to produce IgE
• IgE binds via its Fc portion to high-affinity FcεRI receptors on mast cells and basophils
• Person is now "sensitized" - no symptoms yet

• Same allergen enters again
• Allergen cross-links two or more IgE molecules on mast cell surface
• This cross-linking triggers mast cell degranulation

Clinical Manifestations

• Bronchospasm, urticaria, hypotension, angioedema
• Life-threatening

• Hay fever (Allergic rhinitis) - pollens
• Bronchial asthma - house dust mites, animal dander
• Atopic dermatitis (Eczema)
• Urticaria (hives)
• Food allergy - peanuts, shellfish

Atopy = Familial predisposition to type I reactions, associated with elevated IgE levels. Strong genetic component.

Diagnosis

• Skin prick test (wheal and flare reaction - maximal at 30 minutes)
• Serum total IgE (elevated)
• RAST (radioallergosorbent test) / ELISA for specific IgE
• Blood eosinophilia

Treatment

• Epinephrine (first line for anaphylaxis)
• Antihistamines (H1 blockers)
• Corticosteroids (for late phase)
• Bronchodilators (salbutamol)
• Desensitization / Allergen immunotherapy (repeated small doses)
• Omalizumab - anti-IgE monoclonal antibody (for severe asthma)

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THREE TYPES OF IMMEDIATE HYPERSENSITIVITY WITH EXAMPLES (LAQ)

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⭐⭐ TYPE II HYPERSENSITIVITY (Cytotoxic / Antibody-dependent)

Mechanism

• IgG or IgM antibodies bind to cell surface antigens or extracellular matrix antigens
• This leads to cell destruction by:
  1. Complement activation → MAC (membrane attack complex) → cell lysis
  2. ADCC (Antibody-Dependent Cell-mediated Cytotoxicity) via NK cells (K cells)
  3. Opsonization → phagocytosis by macrophages
  4. Antibody-mediated cellular dysfunction (without cell death) - e.g. Graves' disease

Examples

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⭐⭐⭐ TYPE III HYPERSENSITIVITY (Immune Complex Mediated)

Definition

Mechanism (Pathogenesis)

• IgG (or IgM) antibodies combine with circulating soluble antigens → form immune complexes
• Normally, immune complexes are rapidly cleared by:
  • C3b attachment → erythrocyte CR1 receptor → liver/spleen macrophages for destruction
  • If this system is overloaded or defective → complexes persist

• Complexes deposit in:
  • Kidneys (glomeruli)
  • Joints (synovium)
  • Blood vessel walls
  • Skin
  • Choroid plexus
• Deposition is favored by:
  • Antigen excess (soluble complexes form)
  • Increased vascular permeability
  • Anatomical filtration sites (glomeruli)

• Immune complexes activate complement (Classical pathway via C1q)
• C5a → chemotaxis of neutrophils (the key cells in Type III)
• C3a, C5a (anaphylatoxins) → mast cell degranulation → histamine release → increased vascular permeability
• Neutrophils attempt to phagocytose complexes → release lysosomal enzymes and proteases → tissue damage
• Platelet aggregation → microthrombi → ischemia
• Macrophage activation → IL-1, TNF, ROI, NO release

Two Classic Forms

A. ARTHUS REACTION (Local Type III)

• Definition: Local immune complex reaction after intradermal injection of antigen into a hyperimmunized individual with high levels of precipitating IgG antibody
• Antigen precipitates with antibody within the venule wall → complement activation → intense neutrophil infiltration
• Peak reaction at 3-8 hours → erythema and edema → usually resolves
• Detected as: antigen + immunoglobulin + complement all demonstrable by immunofluorescence

B. SERUM SICKNESS (Systemic Type III)

• Injection of large amounts of foreign protein (e.g., heterologous serum/antitoxin)
• After 7-10 days (time needed to make antibody) → immune complexes form in antigen excess → deposit systemically
• Features: fever, urticaria, arthralgia (joint pain), lymphadenopathy, glomerulonephritis
• Self-limiting

Examples of Type III Diseases

Histological/Lab Features (MUHS exam important)

• "Lumpy-bumpy" (granular) immunofluorescence pattern on GBM (vs. linear in Goodpasture syndrome - Type II)
• Low complement levels (C3, C4) - consumed by reaction
• Detection of immune complexes in serum/tissue
• Immunofluorescence: IgG + C3 deposits along GBM

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⭐⭐⭐ TYPE IV HYPERSENSITIVITY (Delayed-Type / Cell-Mediated / DTH)

Definition

Mechanism

• Antigen is processed by Langerhans cells / dendritic cells (APCs)
• Presented to CD4+ Th1 cells via MHC Class II
• Th1 cells become sensitized (memory T cells formed)

• Antigen re-enters tissues
• Memory Th1 cells (CD4+) recognize antigen-MHC II on APCs
• T cells proliferate and release cytokines:
  • IFN-γ → macrophage activation (the most important cytokine)
  • IL-2 → T cell proliferation
  • TNF-β (Lymphotoxin) → tissue damage
  • IL-17 → neutrophil recruitment
  • MCP-1 (CCL2) → monocyte chemotaxis
• Activated macrophages form the dominant effector cells → phagocytosis, tissue damage
• If antigen not cleared → granuloma formation (epithelioid cells + multinucleated giant cells)

Histology (MUHS Exam Important)

• Predominantly mononuclear cell infiltrate (lymphocytes + macrophages) - contrast with Type III which has neutrophils
• Perivascular cuffing with mononuclear cells
• Granuloma: epithelioid cells, giant cells, caseous necrosis (in TB)

Classic Examples

Mantoux Reaction: Injection of tuberculin (PPD) intradermally → Induration + erythema at 24-48 hours → characterized by perivascular mononuclear cuffing → mononuclear infiltrate (lymphocytes + macrophages). Positive = ≥10 mm induration. Negative in advanced TB, HIV, malnutrition.

Subtypes of Type IV Hypersensitivity (Advanced)

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⭐ ANAPHYLAXIS (Brief Description)

Definition

Mechanism

• Re-exposure to antigen in a sensitized person → cross-linking of IgE on mast cells and basophils → massive systemic degranulation → release of histamine, leukotrienes, PAF, prostaglandins
• Occurs within seconds to minutes of exposure

Causes

• Injected drugs (penicillin - most common drug cause), IV contrast agents
• Insect stings (bee, wasp venom)
• Foods (peanuts, shellfish, tree nuts)
• Blood transfusion (in IgA-deficient individuals)
• Latex

Clinical Features (ABC-mnemonic)

• Airway: bronchospasm, laryngeal edema, stridor
• Breathing: dyspnea, wheeze
• Circulation: hypotension, tachycardia, cardiovascular collapse
• Skin: urticaria (hives), angioedema, flushing, pruritus
• GI: nausea, vomiting, diarrhea, abdominal cramps

Treatment (MUHS Exam - Must Know)

1. Epinephrine (Adrenaline) 1:1000 - 0.3-0.5 mg IM (thigh) - FIRST AND MOST IMPORTANT
   • Reverses bronchospasm (β2), vasoconstriction (α1), inhibits further mediator release
2. Oxygen + airway management
3. IV fluids (for hypotension)
4. Antihistamines (H1 + H2 blockers - diphenhydramine + ranitidine)
5. Corticosteroids (IV hydrocortisone) - for late/biphasic reactions
6. Bronchodilators (salbutamol nebulization)

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COMPARISON TABLE - ALL FOUR TYPES (MUHS Favorite Summary)

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KEY EXAM POINTS FOR MUHS (⭐ Star items)

1. Sensitization requires prior exposure - first exposure sensitizes, second exposure causes reaction
2. Type I = IgE + Mast cells + Histamine - immediate (seconds); anaphylaxis treated with epinephrine
3. Type II = IgG/IgM + complement - example: Goodpasture (linear IF), hemolytic anemia
4. Type III = Immune complexes + Complement + Neutrophils - "lumpy-bumpy" IF; Arthus reaction (local), serum sickness (systemic); low complement levels
5. Type IV = T cells, NO antibody, NO complement - delayed 24-72h; ONLY type transferable by lymphocytes (not serum); Mantoux test; granuloma formation
6. Mantoux positive = ≥10mm induration at 48-72h
7. SRS-A = Slow Reacting Substance of Anaphylaxis = Leukotrienes C4+D4+E4
8. Atopy = familial predisposition to Type I; elevated total IgE
9. Arthus reaction = LOCAL Type III; Serum sickness = SYSTEMIC Type III
10. Omalizumab = anti-IgE monoclonal antibody - treatment for severe asthma
11. Type IV granuloma: epithelioid cells + multinucleated Langhans giant cells + central caseation (TB)

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