Part of the TeachMe Series

Hypersensitivity Reactions

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Original Author(s): Jess Speller
Last updated: 19th January 2020
Revisions: 3

Original Author(s): Jess Speller
Last updated: 19th January 2020
Revisions: 3

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Hypersensitivity reactions are an overreaction of the immune system to an antigen which would not normally trigger an immune response. The antigen may be something which would in most people be ignored – peanuts, for example, or it may originate from the body. In either case, the damage and clinical symptoms result from the body’s response to the substance rather than damage caused by the substance itself.

The vulnerability of an individual to these reactions can have a genetic link – overreaction to innocuous antigens are linked to changes in the CD regions of T-helper cell membranes, explaining why things like peanut allergies can commonly run in families. Overreaction to self-antigens is normally due to a failure in central tolerance, and this failure can also have genetically-inheritable features.

As is the case for many immune reactions, hypersensitivity reactions require two separate interactions of the immune system with the antigen. The first time an antigen enters the body, it is picked up by antigen-presenting cells (macrophages or dendritic cells) and taken to the nearest lymph node, where it is presented to naïve T-cells. Cross-linking of the antigen with T-cells, as well as co-stimulatory molecules, can lead to activation of that T-cell and subsequent differentiation into “primed” Th1, Th2, or Th17 cells, which are specific to that antigen and can stimulate further immune responses if they meet the antigen again.

Types of Hypersensitivity Reaction

There are four main types of hypersensitivity reaction (NB some models include a fifth type, similar but slightly distinct to Type 2- this is beyond the scope of this article).

Type 1

In Type 1 hypersensitivity reactions, initial exposure to the antigen causes the priming of T-cells described above. These newly primed Th2 cells are CD4+, and their release of IL-4 causes the B cells to switch their production of IgM to IgE antibodies which are specific to the antigen. The IgE antibodies bind to mast cells and basophils, sensitising them.

When the antigen enters the body again, it cross links the IgE bound to the sensitised cells, causing the release of preformed mediators including histamine, leukotrienes and prostaglandins. This leads to widespread vasodilation, bronchoconstriction, and increased permeability of vascular endothelium.

The reaction can be divided into two stages – immediate, in which release of pre-formed mediators causes the immune response, and the late-phase response 8-12 hours later, where cytokines released in the immediate stage activate basophils, eosinophils, and neutrophils even though the antigen is no longer present.

Fig 1.0 – Summary diagram of IgE mediated mast cell activation in allergy

Clinical Relevance – Anaphylaxis

Anaphylaxis is a systemic response to an antigen, leading to bronchoconstriction and vasodilation. This decline in oxygen transportation and can lead to anaphylactic shock and possibly death. It is usually treated with adrenaline, to dilate the bronchioles and constrict the blood vessels, antihistamines, to reduce the inflammatory effects of histamine, and corticosteroids, to reduce systemic inflammation.

Type 2

In Type 2 hypersensitivity reactions, a failure in the mechanism of central tolerance leads to the escape of self-reactive T and B cells. When self or innocuous antigens are presented to the T cells, an immune response is started, targeting the host cells to which the antigens are attached.

Activation of complement leads to degranulation of neutrophils, a release of oxygen radicals, and eventual formation of membrane attack complex – all of which lead to destruction of the host cell. Parts of the complement activation can also opsonise the target cell, marking it for phagocytosis.

All of these mechanisms would be normal and healthy if the cell they were targeting was a foreign antigen – however, the destruction of host cells leads to tissue-specific damage.

Type 2 is distinguished from Type 3 by the location of the antigens – in Type 2, the antigens are cell bound, whereas in Type 3 the antigens are soluble.

Clinical Relevance – Acute Transfusion Reactions

Acute transfusion reactions are when an inappropriate blood transfusion is administered and a patient is given blood not matching their ABO type. This leads to activation of complement and widespread haemolysis by tumour necrosis factor and other interleukins, which can be fatal.

Fig 2.0 – Summary table of ABO blood groups

Type 3

In Type 3 sensitivity reactions, an excess of antigen means that small antigen-antibody complexes are present in circulation. The small size of the complexes mean that they are not particularly immunogenic and so are free to circulate, usually becoming lodged in the basement membranes of tissues which have particularly high rates of blood filtration – the kidney and synovial joints being common targets.

Once lodged, the immune complexes rapidly and significantly activates the complement chain, causing local inflammation and attraction of leukocytes beyond the immune response which would normally be expected for a complex of this size. Activation of complement results in increased vasopermeability, the attraction and degranulation of neutrophils, and the release of oxygen free radicals which can severely damage surrounding cells.

Clinical Relevance – Rheumatoid Arthritis

Rheumatoid arthritis can occur when antigen-antibody complexes circulate in the bloodstream end up lodging in the complex filtration systems responsible for maintaining the levels of synovial fluids at synovial joints. The lodged immune complexes can cause a local inflammatory response, leading to stiffness and pain in affected joints.

Type 4

Type 4 hypersensitivity reactions are the only kind that do not involve antibodies in any way- instead, they are mediated by T-cells. When the antigen enters the system, it is picked up by an antigen-presenting cell and presented on the MHC region to a T-helper cell.

If the T-helper cell recognises the antigen, it will differentiate into a Th1 cell and release IL-2 and interferon-gamma, leading to proliferation of further Th1 cells and also causing the activation of macrophages and their differentiation in CD4+ and CD8+ cells.

Activated macrophages release pro-inflammatory factors, leading to local swelling, oedema, warmth, and redness. They also secrete lysosomal elements and reactive oxygen species, again leading to local tissue damage.

This type of hypersensitivity reaction takes longer than the others because of the length of time required to recruit Th1 cells to the site of exposure – around 48-72 hours.

Clinical Relevance – Contact Dermatitis

Contact dermatitis can result from a wide variety of innocuous substances, such as nickel, poison ivy, or household cleaning products. Because of the delay in transporting Th1 cells to the site of infiltration, symptoms can develop several days after initial exposure to the substance, but redness, itching, swelling, and heat are all common.

Fig 3.0 – Image showing contact dermatitis resulting from a buprenorphine transdermal patch

Summary Table

Type Type 1 Type 2 Type 3 Type 4
Reactant IgE IgG IgG Th1, Th2
Mechanism Mast-cell activation releases histamines and other mediators Antigens embedded in host cells cause complement activation and destruction by MAC. Antibody binds to soluble antigen, forming a circulating immune complex lodges in a vessel wall and causes a local inflammatory response. Helper T cells are activated by an APC. On second presentation, memory T cells will activate macrophages and cause an inflammatory response.
Time course Minutes Days
Example Anaphylaxis Acute Transfusion Reaction Rheumatoid Arthritis Contact Dermatitis