H31/42271/2017

HYPERSENITIVITY

Hypersensitivity reactions are exaggerated immune responses against an antigen. They are usually
referred to as an over-reaction of the immune system and these reactions may be damaging,
uncomfortable, or occasionally fatal. Various autoimmune disorders as well as allergies fall under the
umbrella of hypersensitivity reactions, the difference being that allergies are immune reactions to
exogenous substances whereas autoimmune diseases arise from an abnormal immune response to
endogenous antigens.

Hypersensitivity reactions usually have two phases:

(a) Sensitization phase : initial asymptomatic contact with an antigen

(b) Effector phase : harmful immune response following sensitization and subsequent antigen contact.

The Gell and Coombs classification of hypersensitivity is the most widely used, and distinguishes four
types of hypersensitivity reactions; type I,II,III and IV

Several limitations can be identified in the Gell and Coombs’s classification:

1. The variety of immune-mediated hypersensitivity reactions to drugs goes far

beyond the limited description by Gell and Coombs. This is particularly true for a variety
of rather frequent and often severe adverse drug reactions, such as toxic epidermal necrolysis ‘immuno-
allergic’hepatitis, or hypersensitivity pneumonitis.Importantly,most cutaneous hypersensitivity reactions
to drugs do not readily, if at all.

2. Allergic drug reactions can be caused by more than a single protean mechanism. For instance, it has
long been recognized that experimental contact hypersensitivity to picryl chloride in mice involves both
a typical delayed-type hypersensitivity mechanism and Ig E response.

3. One single drug can often induce a set of hypersensitivity drug reactions involving different
mechanisms. For instance, it has long been recognized that penicillin-G and probably most beta
lactamins can induce anaphylaxis, immuno-allergic hemolytic anemia, serum sick
ness (or serum sickness-like disease), and contact dermatitis.

Despite these limitations, the Gell andCoombs’s classification is still valid in a few well
defined circumstances.

Type I or Immediate type hypersensitivity.

This type of hypersensitivity occurs within minutes to less than 24 hours following re-expose to allergen.
In the sensitization phase, B-cells are stimulated (by CD4+TH2 cells) to produce Ig E antibodies specific to
an antigen. The Ig E antibodies bind to FcεRI receptors on the surface of tissue mast cells and
blood basophils. Mast cells and basophils coated by Ig E antibodies now "sensitized"
Upon re-exposure of the same antigen, the free antigen binds to two adjacent Ig E antibodies,
crosslinking which subsequently results in degranulation of pre-formed mediators and concurrent
synthesis of inflammatory mediators from lipid precursors. The net result of these mediators is
vasodilatation and smooth muscle contraction.

Release of pre-formed mediators usually occurs within minutes to two hours. Examples of pre-formed
mediators include  vasoactive amines such as histamine and serotonin as well as proteases such as
trypases and chymases. These result in increased vascular permeability, smooth muscle contraction,
increased bronchial mucus secretion, degradation of blood vessel basement membrane as well as
generation of complement split products.

The late phase mediators are usually released within 2-24 hours. Examples of late phase products are
cytokines such as IL-1, TNF-α, IL-4, IL-5, chemotactic factors as well as prostaglandins, platelet-activating
factor (PAF) and Leukotrienes. These have various effects including but not limited to platelet
aggregation, increase vascular permeability, recruitment of neutrophils and eosinophils.

Example 1: Allergic bronchial asthma, an atopic disease, characterized by bronchospasm. Histopathology

may show mucus plugs within bronchioles or bronchi. Sputum sample may show Curshmann spirals
which are desquamated epithelial cells and eosinophils that is forms spiral shaped casts. One can also
see Charcot- Leyden crystals, a histopathological finding in patients with eosinophilic inflammation
and/or proliferation. There may also be edema and congestion which appears as hyperemia of the
biopsied lung specimen.

Example 2: Eosinophilic granulomatosis with polyangitis, a multisystem disease characterized by

necrotizing granulomatous vasculitis with eosinophilia which commonly involves the lungs and the skin
but can also affect the renal cardiovascular, gastrointestinal , central and peripheral nervous system.
Lung histopathology may show asthmatic bronchitis, eosinophilic pneumonias, extravascular
granulomas or vasculitis of arteries, veins or capillaries. Vascular infiltrates are often composed of
chronic inflammatory cells, eosinophilic and epithelioid histiocytes. Diffuse pulmonary hemorrhage
maybe seen. Kidney histopathology may show necrotizing crescentic glomerulonephritis but eosinophilic
interstitial nephritis, mesangial glomerulonephritis and focal segmental glomerulosclerosis may also be
seen. Sin biopsy may show leukocytoclastic vasculitis with eosinophil infiltration.

Type II or Cytotoxic-Mediated Response.

This type of hypersensitivity occurs when antibodies (IgG or IgM) are directed against cellular or
extracellular matrix antigens with the resultant cellular destruction, functional loss, or damage to
tissues. Following exposure to the inciting agent, autoantibodies are produced (IgG and IgM) to the host
cells (sensitization phase), promoting a series of pathogenic outcomes (effector phase) within less than
24 hours.

Pathophysiology of type II hypersensitivity is as follows:

(a) Cell depletion without inflammation: Antibodies can bind to the surface of the target cell, particularly
Ig G antibodies, and through their Fc portion, they bind to their respective Fc receptor on the surface of
macrophages and thus act as an opsonin. Binding to both the target cell and the Fc receptor of the
macrophage, activates the macrophage resulting in phagocytosis of the target cell. Antibodies can also
bind to the target cell and activate the complement pathway resulting in the formation of C3b, an
opsonin that binds to receptors on the surface of macrophages. This, in turn, activates the macrophages
causing them to kill by phagocytosis. Antibodies can also bind to the target cell activating complement
pathway resulting in formation of membrane attack complex (MAC) which leads to lysis of cells.

(b) Antibody dependant cell-mediated cytotoxicity: a phenomenon by which antibodies bind to the
target cell and then the effector cells of the immune system. These are mostly natural killer cells that
attach to the Fc portion of the antibody and then are activated, releasing perforins and granzymes,
causing lysis of the target cell.

(c) Inflammation mediated by Fc receptor: Antibodies can activate the complement pathway resulting in
the formation of C3a and C5a, chemotactic factors for neutrophils, causing the recruitment of
neutrophils to the site and resulting in the activation of neutrophils.

(d) Cellular dysfunction by antibodies: Autoantibodies bind to the receptors on target cells, causing
dysfunction without causing inflammation or destruction. For example in Grave’s disease autoantibodies
bind to the thyrotropin receptor on thyroid follicular cells resulting in overproduction of thyroid
hormones. This is sometimes regarded as a Type V hypersensitivity reaction.

Example 1: Goodpasture disease, a rare autoimmune disease characterized by circulating autoantibodies

against α-3 chain of type IV collagen present in the glomerular basement membrane and pulmonary
capillary basement membranes. Histopathology of kidney biopsy may show crescentic
glomerulonephritis.

Example 2: Acute rheumatic fever with myocardium involvement, Histopathology shows densevalvular
inflammatory infiltrate and Aschoff bodies.

Type III Hypersensitivity Reaction

This type of hypersensitivity occurs when there is accumulation of immune complexes ( antigen-
antibody complexes) that have not been adequately cleared by the macrophages of the innate
immunity, giving rise to inflammatory response and attraction of leukocytes.

Following antigen re-exposure, antibodies are produced 4-10 days, the antibody reacts with antigen
forming immune complexes that circulate and diffuse into the vascular walls where they may initiate
fixation and activation of complement. These immune complexes, along with complement, produce an
influx of polymorphonuclear leukocytes into the site, where tissue damage takes place by the release of
proteolytic enzymes.

Pathophysiology:
(a) Immune complex formation: Endogenous or exogenous antigen exposure triggers an antibody
formation. The antigens bind to antibodies forming circulating immune complexes, which can later
migrate out of the plasma and deposit in host tissues.

(b) Immune complex deposition: The pathogenicity of the immune complex deposition is partly
dependent on the antigen-antibody ratio. When the antigen is excess , the aggregates are smaller and
soluble hence freely filter out of circulation in organs where the blood is transformed into other fluids
such as urine and synovial fluid. Therefore, immune complexes affect glomeruli and joints.

(c) Inflammatory reaction: After immune complexes have been deposited, there is activation of the
classical pathway, leading to the release of C3a and C5a which are chemoattractant for
macrophages and neutrophils, resulting in subsequent inflammation of the tissues. Depending on the
site of immune complex deposition, different symptoms may develop.

Example 1:Post streptococcal glomerular nephritis which is caused by prior infection with specific
nephritogenic strains of group A β-hemolytic streptococcus skin or throat infection. Histopathology
shows a diffuse proliferative and exudative glomerulonephritis with prominent endocapillary
proliferation and numerous neutrophils. Trichrome stain may show small subepithelial hump-shaped
deposits.

Example 2: Hypersensitivity pneumonitis also known as extrinsic allergic alveolitis. This is a complex
syndrome of varying intensity, clinical presentation and natural history rather than a single, uniform
disease. Histopathology of acute- subacute hypersensitivity pneumonitis appears as chronic cellular
bronchiolitis with a peribronchial infiltration of lymphocytes. Small poorly-formed noncaseating
granulomas located near respiratory or terminal bronchioles may be seen. Features of chronic
hypersensitivity pneumonitis include fibrotic nonspecific interstitial pneumonia. Sometimes features of
subacute hypersensitivity pneumonitis such as lymphocytic infiltrates, poorly-formed granulomas and
multinucleated giant cells are present in patients with chronic hypersensitivity pneumonitis.

Type IV Hypersensitivity Reaction

Often referred to as delayed type hypersensitivity since it takes several days to develop. It is a cellular
mediated type of immune response. This immune response involves T-cells, monocytes and
macrophages. In certain situations, eosinophils and neutrophils can be involved.

The pathophysiology of type four hypersensitivity depends on the underlying cause. For example, a

granuloma is formed occurs when T cells are stimulated by antigen-presenting cells that are unable to
destroy engulfed antigens. Afterward, macrophages become giant multinucleated cells, and for this to
be done, a lot of cytokines are secreted, IL-2 and TNF-α. Another mechanism occurs in contact
dermatitis when irritants or antigens are applied to the skin; this will cause an
inflammatory reaction mediated by over-expression of ICAM-1, VCAM-1, ELAM-1.
Example 1: Tuberculosis; following infection with Mycobacteria, they are phagocytosed but not killed
because they escape phagolysosome destruction, the mycobacteria continue to replicate. After a few
weeks, for reasons still unknown, the immune system ramps us and and with the help of IFN-ϒ, the
macrophages become capable of killing the mycobacteria. The hyper-activated macrophages secrete
cytokines which recruit more monocytes at site of infection. These fuse to become giant  epithelioid
cells which wall off the infected cells, but results in significant inflammation and local damage.
Histopathology, one will find casseating granulomas

Example 2: Contact dermatitis. This occurs when  antigen penetrate the skin with proximity to epidermal
and dermal cells, resulting in an inflammatory reaction. Dermal dendritic cells and Langerhans cells play
an important role in antigen presentation and sensitization of these haptens to CD4 and CD8 T-cell
lymphocytes. They secrete cytokines and other enzymes to recruit other immune cells to the site of
antigen exposure. Additionally, keratinocytes help in recruiting immune cells by secreting other groups
of cytokines such as IL-and IL-8. When a biopsy is taken from the skin, microvesicles can be seen
between the dermis and epidermis. These microvesicles are caused as a result of edema in the skin. In
irritant contact dermatitis, neutrophils are usually observed in the biopsies taken from the epidermis.

References

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