Teach me hypersensitive rxn according to microbiology

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Hypersensitivity Reactions - Microbiology

Hypersensitivity is a condition in which an exaggerated or augmented immune response occurs that is harmful to the host. It requires a presensitized state - reactions typically occur after the second encounter with a specific antigen (allergen).

In 1963, Coombs and Gell classified hypersensitivity into four types:

Types I, II, III - Antibody mediated
Type IV - T-cell mediated

Quick Reference Table

Type	Name	Onset	Mediator	Key Examples
I	Immediate / Anaphylactic	< 30 min	IgE, mast cells	Hay fever, asthma, anaphylaxis
II	Cytotoxic / Antibody-dependent	< 8 hr	IgG/IgM + complement	Transfusion reactions, Goodpasture syndrome
III	Immune Complex	< 8 hr	IgG + complement (complexes)	Serum sickness, post-streptococcal GN
IV	Delayed-Type (DTH)	24-72 hr (up to 1 week)	T cells (CD4 Th1), macrophages	Tuberculin test, contact dermatitis

(Source: Medical Microbiology 9e, Table 10.5)

Type I: Immediate Hypersensitivity (Allergy / Anaphylactic)

Mechanism

Sensitization phase: Antigen (allergen) induces formation of IgE antibody, which binds firmly via its Fc portion to high-affinity IgE receptors (FcεRI) on mast cells, basophils, and eosinophils.
Elicitation phase (second exposure): The allergen cross-links the cell-bound IgE molecules → triggering degranulation and release of pharmacologically active mediators.
Late-phase reaction (8-12 hours later): Infiltration of eosinophils and CD4 T cells + cytokine reinforcement of inflammation.

Mediators Released

Primary (preformed) mediators:

Histamine - causes vasodilation, increased capillary permeability, bronchospasm

Secondary (newly formed) mediators:

Prostaglandins - edema, bronchoconstriction
Leukotrienes: LTB4 (chemoattractant for leukocytes), LTC4 + LTD4 (vasodilation, vascular permeability)
TNF-α and IL-4
Platelet-activating factor, tryptase, kininogenase

Clinical Forms

Systemic anaphylaxis - after IV administration of heterologous proteins, bee stings, penicillin
Atopy (local reactions) - strong familial predisposition, elevated IgE levels. Includes hay fever, asthma, eczema, urticaria
- Triggered by environmental allergens (pollens, house dust) or food (shellfish)

Treatment

Acute: Epinephrine, antihistamines, corticosteroids; maintain airway
Prevention: Identify antigen (skin test or IgE serology), avoid allergen
Desensitization ("allergy shots"): Induces IgG to bind allergen and prevent allergen binding to IgE

(Source: Jawetz Melnick & Adelberg's Medical Microbiology 28e, p. 152)

Type II: Cytotoxic / Antibody-Dependent Hypersensitivity

Mechanism

IgG (or IgM) antibodies bind to cell surface antigens or extracellular matrix molecules.

Two pathways of damage:

Complement activation (IgM and IgG → C1q → classical pathway → lytic pathway) → membrane damage
ADCC (Antibody-Dependent Cellular Cytotoxicity) - IgG binds target cell; Fc receptors on ADCC effectors (neutrophils, eosinophils, macrophages/monocytes, platelets) engage → membrane damage

Type II Hypersensitivity mechanism - antibody and complement pathways leading to membrane damage

Clinical Examples

Disease	Mechanism
ABO transfusion reactions	Anti-A/B IgM → complement-mediated hemolysis of transfused RBCs
Hemolytic disease of newborn (Rh incompatibility)	Maternal IgG crosses placenta → destroys fetal RBCs
Autoimmune hemolytic anemia	Antibodies to self-RBC antigens
Goodpasture syndrome	IgG to basement membranes of kidney and lung → complement activation + leukocyte chemotaxis + severe membrane damage
Myasthenia gravis	IgG to acetylcholine receptors on neurons → blocks transmission
Graves disease	Autoantibody binds TSH receptor → stimulates thyroid (hyperthyroidism) - no cell injury but altered function
Penicillin-induced hemolysis	Penicillin (hapten) attaches to RBC surface proteins → antibody formation → hemolysis

Note: Graves disease represents a special subtype sometimes called Type V (stimulatory) hypersensitivity in Roitt's classification, where antibody stimulates rather than destroys the target cell.

(Source: Jawetz 28e, p. 152; Medical Microbiology 9e, p. 120)

Type III: Immune Complex Hypersensitivity

Mechanism

When antibody (IgG) combines with specific soluble antigens → immune complexes form. Normally cleared, but if they persist and deposit in tissues (especially kidneys, joints, blood vessels), they activate the complement cascade → inflammation and tissue injury.

Key sequence:

Abundant soluble antigen in bloodstream
Large antigen-antibody complexes form
Complexes trapped in capillaries (especially kidney, joints, vessel walls)
Classical complement cascade activated → C3a and C5a generated
Chemotaxis of neutrophils and macrophages to site
Phagocytosis frustrated by deposited complexes → enzyme release → tissue damage
Microthrombi formation, increased vascular permeability

Type III Hypersensitivity - immune complex-mediated: showing platelets, basophils, complement (C3a, C5a), neutrophils, vasoactive amines, microthrombi, and frustrated phagocytosis

Two Major Forms

Form	Description
Arthus reaction (localized)	Low dose antigen injected into skin → local IgG production + complement activation → mast cells + neutrophils release mediators → vascular permeability ↑ (within 12 hours)
Serum sickness (generalized)	Systemic disease; occurs after receiving animal immunoglobulin (e.g., antisnake venom) on multiple occasions

Clinical Examples

Acute poststreptococcal glomerulonephritis - streptococcal Ag-Ab complexes filtered by glomeruli → complement fixation → neutrophil influx → kidney damage. Low complement levels; "lumpy" IgG + C3 deposits on glomerular basement membrane (seen on immunofluorescence)
Serum sickness
Hepatitis B-associated polyarteritis nodosa (viral antigen complexes)
Malaria, staphylococcal endocarditis (microbial antigen complexes)
SLE, Rheumatoid arthritis (autoimmune complexes)
Hypersensitivity pneumonitis (persistent inhalation of mold, plant, or animal antigens)

(Source: Jawetz 28e, p. 152; Medical Microbiology 9e, p. 121)

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

Mechanism

T-cell-mediated response - no antibody involvement.

Antigen is processed and presented to circulating CD4 Th1 cells (via MHC class II on APCs)
Sensitized T cells recognize antigen upon re-exposure
T-cell proliferation + release of cytokines (IFN-γ, IL-2)
Macrophage activation → inflammatory response
Onset: typically 24-72 hours after antigen contact

Key: It takes 24-48 hours for antigen to be presented to T cells, for them to migrate to the site, and then activate neutrophils and macrophages.

Two Major Forms

A. Contact Hypersensitivity

Sensitizing agents: simple chemicals (nickel, formaldehyde, poison ivy/oak), topical medications (sulfonamides, neomycin), cosmetics, soaps
Mechanism: small molecules (haptens) enter the skin → attach to body proteins → form complete antigens → Langerhans cells in epidermis interact with CD4 Th1 cells
Re-exposure: erythema, itching, vesication, eczema, or necrosis of skin within 12-48 hours

Type IV DTH - Contact hypersensitivity: poison ivy (pentadecacatechol) modifies self-protein → Langerhans cell (APC) presents via MHC II to CD4 Th1 → IFN-γ release → macrophage recruitment → DTH response in skin

B. Tuberculin-Type Hypersensitivity (Classic DTH)

Tuberculin (PPD) skin test is the classic example
Small amount of tuberculin injected intradermally
Little immediate reaction, then induration and redness peak at 24-72 hours
Mononuclear cells (especially CD4 Th1) accumulate in subcutaneous tissue
Positive test = prior exposure to M. tuberculosis (not necessarily active disease)
A change from negative to positive = recent infection, possible current activity

C. Granulomatous Hypersensitivity (Chronic DTH)

Occurs when intracellular organism cannot be cleared (persistent stimulation)
Diseases: tuberculosis, leprosy, schistosomiasis, sarcoidosis, Crohn disease
Granulomas = epithelioid cells (chronically activated macrophages) + multinucleated giant cells + surrounding lymphocytes + fibrosis
Require sustained CD4 T cell-derived IFN-γ to restrict spread of M. tuberculosis

(Source: Jawetz 28e, p. 153; Medical Microbiology 9e, p. 121)

Summary: Key Distinguishing Features

Feature	Type I	Type II	Type III	Type IV
Mediator	IgE	IgG/IgM	IgG + soluble Ag	CD4 Th1 cells
Complement	No	Yes (classical)	Yes (classical)	No
Onset	Seconds-30 min	Hours	Hours	24-72+ hr
Effector cells	Mast cells, basophils	Complement, ADCC cells	Neutrophils	Macrophages, T cells
Antigen type	Soluble (allergen)	Cell-surface bound	Soluble (in complexes)	Intracellular / contact
Transfer	Serum (IgE)	Serum (IgG)	Serum	Cells (T cells)
Key test	Skin prick test	Direct Coombs test	Serum complement levels	Tuberculin (PPD) test

Sources:

Jawetz Melnick & Adelberg's Medical Microbiology 28e pp. 151-153 - Hypersensitivity chapter
Medical Microbiology 9e pp. 120-122 - Hypersensitivity Responses

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