Type 2 hypersensitive reaction

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Type II Hypersensitivity (Antibody-Mediated Cytotoxic Hypersensitivity)

Definition

Type II hypersensitivity reactions are caused by antibodies (IgG or IgM) directed against target antigens on the surface of cells or other tissue components. The antigens may be:

Normal molecules intrinsic to cell membranes or the extracellular matrix (as in autoimmune diseases)
Adsorbed exogenous antigens - e.g., a drug metabolite bound to a cell surface (as in drug reactions)

It is also called antibody-mediated cytotoxic hypersensitivity in the Gell-Coombs classification.

Robbins & Kumar Basic Pathology, p. 169

Three Core Mechanisms of Tissue Injury

Mechanisms of antibody-mediated injury - Robbins Fig 5.12

Fig 5.12 - Mechanisms of antibody-mediated (Type II) injury: (A) Opsonization and phagocytosis, (B) Complement- and Fc receptor-mediated inflammation, (C) Antibody-mediated cellular dysfunction. (Robbins & Kumar Basic Pathology)

1. Opsonization and Phagocytosis

When circulating cells (red cells, platelets) are coated (opsonized) with autoantibodies, with or without complement proteins, they become targets for phagocytosis by neutrophils and macrophages. Phagocytes express:

Fc receptors (for IgG antibody tails)
C3b receptors (for complement breakdown products)

Opsonized blood cells are usually eliminated by macrophages in the spleen - this is why splenectomy is clinically beneficial in some antibody-mediated diseases.

2. Complement- and Fc Receptor-Mediated Inflammation

Antibodies bound to tissue antigens activate the complement cascade. This generates:

C3b - promotes opsonization
C5a, C3a - anaphylatoxins that recruit and activate neutrophils and macrophages
MAC (C5b-C9) - membrane attack complex causing direct lysis

Leukocytes recruited via Fc receptors and complement products release proteases, reactive oxygen intermediates, and cytokines causing local tissue damage. C1 through C9 activation can cause intravascular lysis of red cells.

3. Antibody-Mediated Cellular Dysfunction (without direct cell killing)

Antibodies directed at cell surface receptors can:

Block the receptor (e.g., anti-acetylcholine receptor antibodies in myasthenia gravis block neuromuscular transmission)
Stimulate the receptor inappropriately (e.g., anti-TSH receptor antibodies in Graves' disease cause hyperthyroidism)
Strip receptors from the cell surface
Robbins & Kumar Basic Pathology, p. 169-170

Immunoglobulin Classes Involved

IgG (most common) - activates complement via classical pathway, binds Fc receptors on phagocytes, mediates ADCC
IgM - very efficient at activating complement; involved in ABO transfusion reactions and cold hemagglutinin disease

Classic Clinical Examples

Disease	Target Antigen	Mechanism	Manifestation
Autoimmune hemolytic anemia	Red cell membrane proteins	Opsonization, phagocytosis	Hemolysis, anemia
Autoimmune thrombocytopenic purpura (ITP)	Platelet glycoproteins (GpIIb:IIIa)	Opsonization, phagocytosis	Bleeding
Goodpasture syndrome	Type IV collagen (GBM, alveolar BM)	Complement + Fc receptor-mediated inflammation	Nephritis, lung hemorrhage
Myasthenia gravis	Acetylcholine receptor	Receptor blockade, stripping, complement	Muscle weakness, paralysis
Graves' disease	TSH receptor	Receptor stimulation	Hyperthyroidism
Pemphigus vulgaris	Desmoglein 3 (intercellular junctions)	Protease activation, disruption of cell adhesion	Skin bullae
Acute rheumatic fever	Streptococcal antigen cross-reacting with myocardium	Inflammation, macrophage activation	Myocarditis, arthritis
ANCA vasculitis	Neutrophil granule proteins	Neutrophil degranulation	Vasculitis

Robbins & Kumar Basic Pathology, Table 5.4, p. 169

Goodpasture Syndrome - Immunofluorescence Pattern

Immunofluorescence in glomerulonephritis

Figure 14.19 (Roitt's Essential Immunology): (a) Goodpasture syndrome (Type II) - LINEAR IgG deposition along the glomerular basement membrane. (b) SLE (Type III) - GRANULAR/lumpy-bumpy immune complex deposition. This distinction is diagnostically important.

Drug-Induced Type II Reactions

Drugs can act as haptens - they bind covalently to the surface of circulating blood cells (red cells, platelets, neutrophils), creating new epitopes. The immune system recognizes these conjugates as foreign and generates IgG/IgM antibodies. Upon drug withdrawal, the reaction resolves.

Mechanism steps:

Drug binds to red cell surface protein
Penicillin-specific IgG binds to the drug-protein conjugate
Complement activated (C1 through C9), C3b deposited on the red cell
Red cells susceptible to phagocytosis in spleen/liver, or intravascular lysis by MAC

Examples:

Penicillin, quinidine, methyldopa - hemolytic anemia and/or thrombocytopenia
Amidopyrine, quinidine - agranulocytosis
Chlorpromazine, phenacetin - hemolytic anemia
Heparin-induced thrombocytopenia (HIT) - involves heparin + platelet factor 4 complex, anti-PF4-heparin IgG, and FcγRIIA-mediated platelet activation; affects 1-3% of heparin-exposed patients
Goldman-Cecil Medicine, p. 1552-1554; Roitt's Essential Immunology, p. 441

Comparison with Other Types (Gell-Coombs)

Feature	Type I	Type II	Type III	Type IV
Mediator	IgE	IgG, IgM	IgG, IgM (complexes)	T cells
Antigen location	Soluble	Cell surface / ECM	Soluble (circulating)	Cell-associated / soluble
Complement	No	Yes	Yes	No
Onset	Minutes	Minutes-hours	Hours-days	48-72 hours
Example	Anaphylaxis	Goodpasture, MG, Graves'	SLE, serum sickness	Contact dermatitis, TB

Key Diagnostic Points

Linear immunofluorescence on basement membrane = Type II (e.g., Goodpasture) vs. granular = Type III (e.g., SLE)
Coombs' (DAT) test detects antibodies or complement on red cell surfaces - used for autoimmune hemolytic anemia and hemolytic transfusion reactions
Splenectomy helps in ITP and autoimmune hemolytic anemia because the spleen is the major site where opsonized cells are cleared

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