Hypersensitivity Reactions

Hypersensitivity Reaction Types

Classification on the basis of immunological mechanisms that mediate the disease:

Immediate hypersensitivity (type I)

Antibody mediated hypersensitivity (type II)

Immune complex mediated hypersensitivity (type III)

Cell mediated hypersensitivity (type IV)

Hypersensitivity Reaction Type I

Immediate Hypersensitivity

Production of IgE antibody with immediate release of vasoactive amines and other mediators from mast cells and recruitment of inflammatory cells particularly eosinophils, (latter is termed the late phase reaction).

Examples of Immediate Hypersensitivity

Anaphylaxis, Bronchial asthma and Atopy.

Antibody Mediated Hypersensitivity Type II

Production of IgG and IgM that binds to an antigen on a target cell or tissue causing phagocytosis or lysis of target cell mediated by activated complement or Fc receptors from the antibody. This recruits leukocytes. Overall, 3 types of mechanisms are seen:
1. Opsonisation by antibody and C’ complement and Fc receptor mediated phagocytosis.
When cells opsonised by IgG, they are recognised by phagocyte Fc receptors and phagocytosed and destroyed.
Ag-Ab complexes trigger C complement activation and the by-products generated, mainly C3b and C4b are deposited on the surface of the cells and are recognised by phagocytes that express receptors for these proteins. Proteins are phagocytosed and destroyed.
C complement activation also leads to the formation of MAC membrane attack complex that creates holes on cells that disrupt membrane integrity and cause osmotic lysis of the cells.

Antibody dependent cellular cytotoxicity (ADCC)

Cells are coated by IgG and killed by effector cells, which express receptors for Fc fragment of IgG antibodes. These effector cells are monocytes, eosinophils, neutrophils and natural killer cells. When cytotoxicity is mediated against parasites IgE is involved. In ADCC cell lysis occurs without C complement activation or phagocytosis.

Examples of Antibody Mediated Hypersensitivity Type II

Examples of Antibody mediated cell destruction and phagocytosis

Transfusion reaction, erythroblastosis fetalis AIHA and certain drug reactions

C Complement and Fc Receptor mediated inflammation

Antibody is deposited on extra cellular tissue such as the basement membrane causing injury by inflammation and not by phagocytosis or lysis. C complement activation generates C5a (also C3a and C4a) which leads to the recruitment of neurophils and monocytes which are activated. Release of enzymes and reactive oxygen occurs leading to damage to tissues.
Examples: Good pastures (GN) and vascular rejection in organ grafts.

Antibody mediated cellular dysfunction

Antibodies directed against cell surface receptors impair or dysregulate function without causing cell injury or inflammation.
Examples include:

a) Myasthenia gravis in which an antibody reacts with acetyl choline receptors in the motor end plate in skeletal muscle and impairs neuromuscular transmission.
b) Pemphigus vulgaris: antibody against desmosomes disrupts intercellular junctions.
c) Graves disease: antibodies against thyroid stimulating hormone (TSH) receptor on thyroid epithelial cells stimulate the cells

Immune Complex Mediated Hypersensitivity

Type III Hypersensitivity Reaction

Antigen-antibody (Ag-Ab) complexes produce tissue injury by eliciting inflammation at the site of deposition.
Immune complexes are formed within the circulation and get deposited in vessel walls or in extra-vascular tissue. Also, complexes have been formed in extra vascular sites where antigen may be deposited.

Two types of antigens: Exogenous (example: bacteria, virus) or endogenous (example: circulating antigens present in the blood, such as an individuals own cells and tissue).

a) Generalised: Immune complexes are formed in the circulation and deposited in several organs.
b) Localised: If complexes are formed and deposited locally in one particular organ such as the kidney.
Examples:

Acute serum sickness

Systemic immune complex disease

Acute serum sickness is the prototype.

Three phases:
1. Formation of Ag-Ab complexes.
2. Deposition of complexes: depends on Ag excess or Ab excess. In Ab excess, larger complexes are formed and engulfed by macrophages. In Ag excess, smaller complexes are formed which bind less avidly to phagocytes and therefore present in the circulation for longer time. Other factors like avidity, affinity, valency and charges also determine the deposition.
3. Inflammatory reaction at the site of deposition. Two mechanisms are involved in the development of inflammation: Activation of C cascade by immune complex and activation of neutrophils and macrophages through their Fc receptors.

Arthus reaction

Local immune complex disease

Localised area of tissue necrosis resulting from acute immune complex vasculitis usually elicited in skin.
Example: Intra cutaneous injection of Ag in an immune animal having circulating Ab against that. Ag diffuses into the vessel wall binds the pre formed Ab, forms large complexes which precipitate in the vessel wall and trigger an inflammatory reaction. This develops within a few hours (in contrast to Type I Hypersensitivity Reactions) and reaches a peak in 4 to 10 hours.

Cell Mediated Hypersensitivity

Type IV Hypersensitivity Reaction

Delayed type hypersensitivity CD4 T cell mediated
T cell mediated cytolysis CD8 T cell mediated

Delayed type hypersensitivity

Tuberculin reaction

Tuberculin reaction mechanism: When an individual is first exposed to Antigens of tubercle bacilli, naïve CD4+ T cells recognise them in association with class II molecules on the surface of the antigen presenting cells. This encounter drives the CD4+ T cells to differentiate to T helper type 1 cells which remain in the memory pool. T helper type 1 cells are of great importance in delayed type hypersensitivity (the effector cell). On subsequent intracutaneous injection of tuberculin protein they recognise the antigen and secrete cytokines mainly IFN-γ. They also secrete TNF and IL-2.
IFN-γ causes activation of macrophages which leads to phagocytosis. Eexpression of more class II molecules and more antigen presentation
leads to the secretion of PDGF leading to fibroblast proliferation and collgen formation.
TNF facilitates extravasation of lymphocytes and monocytes
IL-2 leads to autocrine and paracrine proliferation of T cells.

Other examples of delayed type hypersensitivity are fungal infections, parasitic infections, transplant rejection and contact dermatitis.

T cell mediated cytolysis

Graft rejection and virus infected cell

Mechanism: Viral peptides associate with class I molecules within the cell and both are transported to the cell surface in the form of a complex. This is recognised by the T cell receptor (TCR) of the CD8 cytotoxic T lymphocytes. Lysis occurs to eliminate the infection.

Two mechanisms of T-cell mediated damage

1. Perforin – granzyme dependent killing.
2. FAS-FAS ligand dependent killing.

Perforins and granzymes are preformed mediators found within lysosome like granules in the CTL. When come into contact with the target, perforins are released; they are polymerized and drill holes on the surface of the target. Granzymes are inserted through perforin – induced pores. Inside the target cell granzymes activate caspases to induce apoptosis of the target cells. In addition, water enters in and thus causes osmotic lysis.

Activated CTLs express FAS-FAS ligand, a molecule similar to TNF, that can bind to FAS expressed on the surface. This leads to apoptosis.

Hypersensitivity Reaction Histology and Pathology

Type I Hypersensitivity Reaction

Bronchial asthma

Bronchi and bronchioles are occluded by thick and tenacious mucus plugs which contain whorls of shed epithelium which gives rise to the Curschmann spirals. Numerous eosinophils and Charcot – Leyden crystals are present, the latter are collections of crystalloid made up of eosinophil membrane protein.
Other features: – Thickened basement membrane
- Edema and inflammatory infiltrate in the bronchial wall, with prominent eosinophils and mast cells.
- Increase in size of the sub mucosal glands
- Hypertrophy of bronchial wall muscle.
(The above features are seen in status asthmaticus and at autopsy. A better example for histological features of Type I hypersensitivity. is urticaria which is given below).

Urticaria

Hives

- Sparse perivenular infiltrate consisting of mononuclear cells and rare neutrophils and eosinophils.
- Edema of superficial dermis.
- Dilated superficial lymphatics.

Type II Hypersensitivity Reaction

Pemphigus vulgaris

- Acantholysis of supra basal layer
- Presence of round acanthocytes within the bullous
- Tombstone appearance of the single cell basal layer..
- Superficial dermis will show lymphocytes, Eos and histiocytes.

Type III Hypersensitivity Reaction

Systemic immune complex disease

Vasculitis

Examples: SLE, PAN, AGN and several other vasculitis. Morphology of immune complex disease:
Necrotizing vasculitis with necrosis of vessel wall and intense neutrophilic infiltration.
- Fibrinoid necrosis: Necrotic tissue, deposition of immune complexes, complement and plasma proteins produce a smudgy eosinophilic deposit.
Acute glomerular nephritis in kidneys:
- Glomeruli are hyper cellular, because, following deposition of immune complexes in the glomeruli, there is swelling and proliferation of endothelial and mesangial cells accompanied by infiltration of neutrophils and monocytes.

Arthus reaction

Local immune complex disease

Fibrinoid necrosis and micro thrombi, usually in venules.

Type IV Hypersensitivity Reaction

Cell Mediated Hypersensitivity

Delayed type Hypersensitivity

Example Tuberculous granuloma
- Central caseous necrosis surrounded by epithelioid histiocytes and MNG.
- Surrounded by cuff of lymphocytes and fibroblasts.

References:

Robbins Basic Pathology 7th ed, edited by Vinay Kumar, Ramzi S. Cotran, and Stanley J. Robbins, 873 pp, Philadelphia, Pa, Sounders, 2003.