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MI 2.5 - Hypersensitivity Reactions (Gell & Coombs Classification)

---

DEFINITION

Hypersensitivity = Exaggerated or augmented immune response that is harmful to the host.

• Requires a presensitized state (prior exposure)
• Symptoms occur after 2nd encounter with the antigen (allergen)

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GELL & COOMBS CLASSIFICATION (1963)

┌─────────────────────────────────────────────────────────────────┐
│           GELL & COOMBS CLASSIFICATION (1963)                   │
│                                                                 │
│  TYPE I       TYPE II      TYPE III     TYPE IV                 │
│  Immediate    Cytotoxic    Immune        Delayed /              │
│  (Anaphylactic) (Ab-       Complex      Cell-mediated          │
│               mediated    (Deposition)                          │
│               lysis)                                            │
│                                                                 │
│  ←────────── ANTIBODY (IgE/IgG/IgM) MEDIATED ──────→ T-CELL    │
└─────────────────────────────────────────────────────────────────┘

• Anaphylactic (Type I)
• Cytotoxic (Type II)
• Immune Complex (Type III)
• Delayed / Cell-mediated (Type IV)

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TYPE I - IMMEDIATE HYPERSENSITIVITY (Anaphylactic / Allergic)

Key Facts

MECHANISM FLOWCHART:

FIRST EXPOSURE (Sensitization)
        │
        ▼
Antigen (Allergen) enters body
        │
        ▼
B cells produce IgE antibodies
        │
        ▼
IgE binds to Fc receptors (FcεRI) on
MAST CELLS & BASOPHILS  ← (Sensitized state)
        │
════════╪════ SECOND EXPOSURE ════════╪════
        │
        ▼
Same Antigen enters again
        │
        ▼
Cross-linking of cell-bound IgE molecules
        │
        ▼
DEGRANULATION of Mast Cells
        │
        ├─→ PRIMARY MEDIATORS (Preformed)
        │       ├── Histamine → Vasodilation, ↑permeability, bronchospasm
        │       └── Eosinophil chemotactic factor (ECF-A)
        │
        └─→ SECONDARY MEDIATORS (Newly formed from Arachidonic acid)
                ├── Prostaglandins → Edema, bronchoconstriction
                ├── Leukotrienes C4, D4 → Vasodilation, ↑permeability
                ├── Leukotriene B4 → Chemotaxis of leukocytes
                └── TNF-α, IL-4

Mnemonic for Mediators: "HELP"

• Histamine (Primary - preformed)
• Eosinophil chemotactic factor
• Leukotrienes (Secondary - newly formed)
• Prostaglandins (Secondary)

Clinical Examples:

ATOPY:

• Strong familial/genetic predisposition
• Associated with elevated IgE levels
• Antigens: Environmental (pollen, ragweed, house dust) or Foods (shellfish)
• Positive skin test (immediate wheal and flare)

Treatment:

• Epinephrine (first line for anaphylaxis)
• Antihistamines (block H1 receptors)
• Corticosteroids
• Best prevention = antigen avoidance / desensitization

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TYPE II - CYTOTOXIC HYPERSENSITIVITY

Key Facts

MECHANISM FLOWCHART:

IgG/IgM antibodies bind to
CELL SURFACE ANTIGENS
        │
        ├─→ Path 1: COMPLEMENT ACTIVATION
        │       │
        │       ▼
        │   MAC (Membrane Attack Complex) → Cell LYSIS
        │
        ├─→ Path 2: ADCC (Antibody-Dependent Cell Cytotoxicity)
        │       │
        │       ▼
        │   NK cells, Macrophages attack opsonized cell
        │
        └─→ Path 3: RECEPTOR STIMULATION/BLOCKADE
                │
                ▼
            Altered cell function (no cell death)

Clinical Examples - Mnemonic: "GRHT" (Good Reactions Harm Tissues)

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TYPE III - IMMUNE COMPLEX HYPERSENSITIVITY

Key Facts

MECHANISM FLOWCHART:

Antigen + IgG Antibody
        │
        ▼
IMMUNE COMPLEX FORMATION
        │
        ├─→ Normally: Phagocytosed and cleared
        │
        └─→ EXCESS ANTIGEN or DEFECTIVE CLEARANCE
                │
                ▼
        Immune complexes DEPOSITED in tissues
        (Kidneys, Joints, Blood vessels)
                │
                ▼
        COMPLEMENT ACTIVATION
                │
                ▼
        Neutrophil & Macrophage migration
                │
                ▼
        Release of LYSOSOMAL ENZYMES
                │
                ▼
        TISSUE DAMAGE & INFLAMMATION

Two Major Forms:

TYPE III REACTIONS
       │
       ├── LOCAL (Arthus Reaction)
       │     - Low dose antigen injected into skin
       │     - Local IgG + complement activation
       │     - Onset: 12 hours
       │     - Features: Local edema, necrosis at injection site
       │
       └── SYSTEMIC (Serum Sickness)
             - Large antigen load in circulation
             - Example: Post-streptococcal GN
             - Features: Arthritis, Nephritis, Vasculitis

Clinical Examples - Mnemonic: "SCRAP"

Diagnosis of Type III:

• Low serum complement (C3 consumed)
• Lumpy/granular immunofluorescence on basement membrane (vs. linear in Type II)
• "Lumpy-bumpy" pattern = Immune complex disease

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TYPE IV - DELAYED TYPE HYPERSENSITIVITY (DTH) / Cell-Mediated

Key Facts

MECHANISM FLOWCHART:

SENSITIZATION PHASE (1st exposure)
        │
        ▼
Antigen processed by APCs (Macrophages/Dendritic cells)
        │
        ▼
Presented to CD4+ T cells → T cell proliferation
        │
        ▼
Formation of SENSITIZED T cells (memory)

════════════════ 2nd EXPOSURE ════════════════
        │
        ▼
Antigen re-enters → activates sensitized T cells
        │
        ▼
CD4+ Th1 cells release cytokines:
├── IFN-γ → activates macrophages
├── IL-2 → T cell proliferation
└── TNF-α → inflammatory response
        │
        ▼
Activated Macrophages release:
├── Lysosomal enzymes
├── Reactive oxygen species
└── More cytokines
        │
        ▼
TISSUE DAMAGE (peaks 24-72 hrs)

Two Subtypes:

TYPE IV
  │
  ├── A) CONTACT HYPERSENSITIVITY
  │      - Haptens (nickel, formaldehyde, poison ivy, neomycin)
  │      - Attach to skin proteins → complete antigen
  │      - Langerhans cells interact with CD4 Th1 cells
  │      - Reaction: Erythema, itching, vesication, eczema
  │      - Onset: 12-48 hours
  │
  └── B) TUBERCULIN-TYPE (Classic DTH)
         - Intradermal tuberculin (PPD) injection
         - Prior TB exposure → CD4 Th1 accumulation
         - Induration + redness peaks at 24-72 hours
         - Positive test = prior exposure (NOT current disease)

Clinical Examples - Mnemonic: "THICK"

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MASTER COMPARISON TABLE

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SUPER MNEMONIC: "I CAST"

• I = IgE (Type I - Immediate)
• C = Complement + IgG (Type II - Cytotoxic)
• A = Antigen-Antibody complexes (Type III - Arthus/Serum sickness)
• S = Sensitized T-cells (Type IV)
• T = Time order: Seconds → Hours → 6-12h → 24-72h

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MI 2.6 - AUTOIMMUNE DISEASES: Mechanisms and Examples

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DEFINITION

Key point: Low-level autoimmunity (natural autoantibodies) is NORMAL. Disease occurs only when tolerance fails and pathogenic anti-self responses arise.

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PREREQUISITE: NORMAL TOLERANCE

Normal Immune System
        │
        ├── Central Tolerance (Thymus / Bone Marrow)
        │       ├── Negative selection → apoptosis of self-reactive T cells
        │       └── Receptor editing → eliminates autoreactive B cells
        │
        └── Peripheral Tolerance
                ├── Clonal anergy (no costimulation)
                ├── Regulatory T cells (Tregs) suppress self-reactive cells
                └── Fas/FasL → apoptosis of activated self-reactive cells

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MECHANISMS OF TOLERANCE FAILURE (How Autoimmunity Develops)

FLOWCHART - Pathogenesis of Autoimmunity:

GENETIC PREDISPOSITION
(HLA associations, complement deficiencies)
        +
ENVIRONMENTAL TRIGGER
(Infection, UV light, drugs, smoking)
        │
        ▼
┌─────────────────────────────────────────────┐
│   MECHANISMS OF TOLERANCE BREAKDOWN        │
│                                             │
│  1. MOLECULAR MIMICRY                      │
│     Microbial antigen resembles self →      │
│     T/B cells activated against self        │
│     Example: Rheumatic fever (Strep M        │
│     protein vs cardiac myosin)              │
│                                             │
│  2. BYSTANDER ACTIVATION                   │
│     Infection → local inflammation →        │
│     APCs present sequestered self antigens  │
│     → activation of self-reactive T cells   │
│                                             │
│  3. EPITOPE SPREADING                      │
│     Initial response to one epitope →       │
│     spreads to other self epitopes          │
│                                             │
│  4. POLYCLONAL ACTIVATION                  │
│     Superantigens/LPS activate many T/B     │
│     clones including self-reactive ones     │
│                                             │
│  5. LOSS OF Treg FUNCTION                  │
│     Regulatory T cells fail →               │
│     self-reactive cells go unchecked        │
│                                             │
│  6. CRYPTIC EPITOPES                       │
│     Antigens not expressed in thymus →      │
│     self-reactive T cells escape deletion   │
└─────────────────────────────────────────────┘
        │
        ▼
PATHOGENIC AUTOIMMUNE RESPONSE
        │
        ├── Autoantibodies (Type II or III mechanism)
        ├── Autoreactive CD4+ T cells (Type IV mechanism)
        └── Autoreactive CD8+ CTLs (direct tissue killing)
        │
        ▼
AUTOIMMUNE DISEASE

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CLASSIFICATION: Organ-Specific vs Non-Organ-Specific

AUTOIMMUNE DISEASES
        │
        ├── ORGAN-SPECIFIC
        │   (Autoantigen restricted to one organ)
        │       ├── Hashimoto's thyroiditis (thyroid)
        │       ├── Graves' disease (thyroid)
        │       ├── Type 1 Diabetes Mellitus (pancreatic β-cells)
        │       ├── Multiple Sclerosis (myelin in CNS)
        │       └── Myasthenia gravis (NMJ - ACh receptors)
        │
        └── NON-ORGAN-SPECIFIC (SYSTEMIC)
            (Autoantigen widespread in body)
                ├── SLE (anti-dsDNA, anti-Sm antibodies)
                ├── Rheumatoid Arthritis (anti-IgG = RF, anti-CCP)
                ├── Sjögren's syndrome (anti-Ro, anti-La)
                └── Antiphospholipid syndrome

• Hashimoto's
• Graves'
• Myasthenia gravis
• MS (multiple sclerosis)
• Type 1 DM

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DETAILED EXAMPLES

1. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

SLE - KEY FEATURES
│
├── Prevalence: Predominantly women (F:M = 9:1), childbearing age
│
├── AUTOANTIBODIES (pathognomonic):
│       ├── Anti-dsDNA ← Most specific (95%)
│       ├── Anti-Sm (anti-Smith) ← Most specific single marker
│       ├── ANA (Antinuclear antibodies) ← Most sensitive (screening)
│       ├── Anti-histone ← Drug-induced lupus
│       └── Anti-Ro, Anti-La
│
├── MECHANISM:
│       ├── Failure to clear apoptotic debris (cell nuclei)
│       ├── Self-reactive B cells produce anti-nuclear antibodies
│       ├── Immune complexes (Type III) deposited in:
│       │       ├── Kidneys → Lupus nephritis (glomerulonephritis)
│       │       ├── Skin → Butterfly rash
│       │       ├── Joints → Arthritis
│       │       └── Blood vessels → Vasculitis
│       └── Type II mechanism → hemolytic anemia, thrombocytopenia
│
└── MANIFESTATIONS - Mnemonic: "DOPAMINE RASH"
        D - Discoid rash
        O - Oral ulcers
        P - Photosensitivity
        A - Arthritis (non-erosive)
        M - Malar (butterfly) rash
        I - Immunological (anti-dsDNA, anti-Sm)
        N - Neurological (seizures, psychosis)
        E - Elevated ANA
        R - Renal (nephritis, proteinuria)
        A - Anemia (hemolytic), Alopecia
        S - Serositis (pleuritis, pericarditis)
        H - Hematological (thrombocytopenia, lymphopenia)

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2. RHEUMATOID ARTHRITIS (RA)

RA - KEY FEATURES
│
├── Prevalence: F > M (3:1), any age (peak 30-50 years)
│
├── AUTOANTIBODIES:
│       ├── Rheumatoid Factor (RF) - IgM anti-IgG
│       └── Anti-CCP (anti-cyclic citrullinated peptide) ← Most specific
│
├── HLA ASSOCIATION: HLA-DR4 (shared epitope)
│
├── MECHANISM:
│       ├── Synovial membrane infiltrated by:
│       │       ├── CD4+ T cells (Th1, Th17)
│       │       ├── Macrophages
│       │       └── Plasma cells (produce RF)
│       ├── Cytokine cascade: TNF-α, IL-1, IL-6, IL-17
│       ├── Pannus formation (invasive granulation tissue)
│       │       └── Erodes cartilage and bone
│       └── Type III (immune complex in joint) + Type IV (T-cell)
│
└── MANIFESTATIONS:
        - Symmetric small joint arthritis (hands, wrists)
        - Morning stiffness > 1 hour
        - Pannus → cartilage/bone erosion
        - Extra-articular: Rheumatoid nodules, vasculitis, lung disease

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3. HASHIMOTO'S THYROIDITIS

Mechanism:
CD4+ T cells (Th1) sensitized to thyroid antigens
        │
        ▼
CD8+ CTLs directly kill thyroid follicular cells
        +
Antibodies to thyroid peroxidase (Anti-TPO)
        +
Antibodies to thyroglobulin (Anti-Tg)
        │
        ▼
Lymphocytic infiltration + germinal center formation
        │
        ▼
Hypothyroidism (progressive thyroid destruction)

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4. GRAVES' DISEASE

Mechanism (Type II - Stimulatory):
Antibody (Anti-TSH receptor Ab = TRAb)
        │
        ▼
Binds TSH receptor on thyroid follicular cells
        │
        ▼
STIMULATES thyroid (mimics TSH action)
        │
        ▼
Hyperthyroidism (unregulated T3/T4 production)

• This is unique: autoantibody that STIMULATES (not destroys) - Type II variant

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5. MYASTHENIA GRAVIS (MG)

Mechanism (Type II - Blocking):
Anti-AChR antibodies (IgG)
        │
        ├── Block Ach binding to receptor
        ├── Complement-mediated destruction of NMJ
        └── Receptor internalization (downregulation)
        │
        ▼
Failure of neuromuscular transmission
        │
        ▼
Muscle weakness (proximal muscles, ocular, bulbar)
Worsens with activity, improves with rest

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INDICATIONS A DISEASE IS AUTOIMMUNE (Criteria)

1. High titer autoantibodies and/or autoreactive lymphocytes in vivo
2. Autoantibody binding or T-cell reactivity to autoantigen in vitro
3. Transfer of disease with autoreactive serum/lymphocytes (animal models)
4. Immunopathology consistent with autoimmune-mediated processes
5. Beneficial effect of immunosuppressive interventions
6. Exclusion of other causes
7. MHC association
8. Animal model mirroring the human disease

• Pathology consistent
• Autoantibodies/autoreactive lymphocytes present
• Transfer of disease (experimental)
• Immunosuppression beneficial
• Exclusion of other causes
• Animal model exists
• MHC association present

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MASTER FLOWCHART - HOW AUTOIMMUNE DISEASE DEVELOPS

GENETIC RISK
(HLA-DR3, DR4, complement deficiency)
        +
ENVIRONMENTAL TRIGGER
(Infection, UV, drugs, hormones)
        │
        ▼
TOLERANCE BREAKDOWN
        │
        ├─ Central: Incomplete negative selection (cryptic epitopes)
        └─ Peripheral: Loss of Tregs / Bystander activation / Molecular mimicry
        │
        ▼
AUTOIMMUNE EFFECTOR MECHANISMS
        │
        ├── Autoantibody-mediated (Types II & III)
        │       ├── Stimulatory (Graves')
        │       ├── Blocking (MG)
        │       ├── Cytotoxic (Hemolytic anemia, Goodpasture)
        │       └── IC deposition (SLE, RA)
        │
        └── T-cell mediated (Type IV)
                ├── Th1 + Macrophage activation (RA, Hashimoto's, MS)
                └── CD8+ CTL killing (Type 1 DM)
        │
        ▼
CHRONIC INFLAMMATION → ORGAN DAMAGE

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SUMMARY TABLE: AUTOIMMUNE DISEASES

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FINAL MNEMONIC: "SHIELD" for Autoimmune Pathogenesis

• S - Self-tolerance breakdown
• H - HLA / MHC predisposition
• I - Infection as trigger (molecular mimicry)
• E - Epitope spreading
• L - Loss of Treg control
• D - DNA/nuclear debris accumulation (as in SLE)

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• Jawetz Melnick & Adelberg's Medical Microbiology 28E (Chapter on Immunity and Hypersensitivity, p. 150-155)
• Roitt's Essential Immunology (Chapter 17 - Autoimmune Disease, p. 520-535)
• Cellular and Molecular Immunology (SLE mechanisms)

Note: Apurba Sastry's Review of Microbiology and Immunology is not available in the library, but the content above follows the same framework used in Indian medical education and covers all MI 2.5 and MI 2.6 competencies as per NMC guidelines.