24.1: Type I Hypersensitivities

Learning Objectives

• Compare the distinguishing characteristics, mechanisms, and major examples of type I, II, III, and IV hypersensitivities
• Identify the cells that cause a type I hypersensitivity reaction
• Describe the differences between immediate and late-phase type I hypersensitivity reactions
• List the signs and symptoms of anaphylaxis

In Adaptive Specific Host Defenses, we discussed the mechanisms by which adaptive immune defenses, both humoral and cellular, protect us from infectious diseases. However, these same protective immune defenses can also be responsible for undesirable reactions called hypersensitivity reactions. Hypersensitivity reactions are classified by their immune mechanism.

• Type I hypersensitivity reactions involve immunoglobulin E (IgE) antibody against soluble antigen, triggering mast cell degranulation.
• Type II hypersensitivity reactions involve IgG and IgM antibodies directed against cellular antigens, leading to cell damage mediated by other immune system effectors.
• Type III hypersensitivity reactions involve the interactions of IgG, IgM, and, occasionally, IgA¹ antibodies with antigen to form immune complexes. Accumulation of immune complexes in tissue leads to tissue damage mediated by other immune system effectors.
• Type IV hypersensitivity reactions are T-cell–mediated reactions that can involve tissue damage mediated by activated macrophages and cytotoxic T cells.

Type I Hypersensitivities

When a presensitized individual is exposed to an allergen, it can lead to a rapid immune response that occurs almost immediately. Such a response is called an allergy and is classified as a type I hypersensitivity. Allergens may be seemingly harmless substances such as animal dander, molds, or pollen. Allergens may also be substances considered innately more hazardous, such as insect venom or therapeutic drugs. Food intolerances can also yield allergic reactions as individuals become sensitized to foods such as peanuts or shellfish (Figure \(\PageIndex{1}\)). Regardless of the allergen, the first exposure activates a primary IgE antibody response that sensitizes an individual to type I hypersensitivity reaction upon subsequent exposure.

Figure \(\PageIndex{1}\): (a) Allergens in plant pollen, shown here in a colorized electron micrograph, may trigger allergic rhinitis or hay fever in sensitive individuals. (b) Skin rashes are often associated with allergic reactions. (c) Peanuts can be eaten safely by most people but can provoke severe allergic reactions in sensitive individuals.

Mechanism of Type I Hypersensitivity 

For susceptible individuals, a first exposure to an allergen activates a strong T_H2 cell response (Figure \(\PageIndex{2}\)). Cytokines interleukin (IL)-4 and IL-13 from the T_H2 cells activate B cells specific to the same allergen, resulting in clonal proliferation, differentiation into plasma cells, and antibody-class switch from production of IgM to production of IgE. The fragment crystallizable (Fc) regions of the IgE antibodies bind to specific receptors on the surface of mast cellsthroughout the body. It is estimated that each mast cell can bind up to 500,000 IgE molecules, with each IgE molecule having two allergen-specific fragment antigen-binding (Fab) sites available for binding allergen on subsequent exposures. By the time this occurs, the allergen is often no longer present and there is no allergic reaction, but the mast cells are primed for a subsequent exposure and the individual is sensitized to the allergen.

On subsequent exposure, allergens bind to multiple IgE molecules on mast cells, cross-linking the IgE molecules. Within minutes, this cross-linking of IgE activates the mast cells and triggers degranulation, a reaction in which the contents of the granules in the mast cell are released into the extracellular environment. Preformed components that are released from granules include histamine, serotonin, and bradykinin (Table \(\PageIndex{1}\)). The activated mast cells also release newly formed lipid mediators (leukotrienes and prostaglandins from membrane arachadonic acid metabolism) and cytokines such as tumor necrosis factor (Table \(\PageIndex{2}\)).

Table \(\PageIndex{1}\): Selected Preformed Components of Mast Cell Granules

Granule Component	Activity
Heparin	Stimulates the generation of bradykinin, which causes increased vascular permeability, vasodilation, bronchiole constriction, and increased mucus secretion
Histamine	Causes smooth-muscle contraction, increases vascular permeability, increases mucus and tear formation
Serotonin	Increases vascular permeability, causes vasodilation and smooth-muscle contraction

The chemical mediators released by mast cells collectively cause the inflammation and signs and symptoms associated with type I hypersensitivity reactions. Histamine stimulates mucus secretion in nasal passages and tear formation from lacrimal glands, promoting the runny nose and watery eyes of allergies. Interaction of histamine with nerve endings causes itching and sneezing. The vasodilation caused by several of the mediators can result in hives, headaches, angioedema (swelling that often affects the lips, throat, and tongue), and hypotension (low blood pressure). Bronchiole constriction caused by some of the chemical mediators leads to wheezing, dyspnea (difficulty breathing), coughing, and, in more severe cases, cyanosis (bluish color to the skin or mucous membranes). Vomiting can result from stimulation of the vomiting center in the cerebellum by histamine and serotonin. Histamine can also cause relaxation of intestinal smooth muscles and diarrhea.

Table \(\PageIndex{2}\): Selected Newly Formed Chemical Mediators of Inflammation and Allergic Response

Chemical Mediator	Activity
Leukot riene	Causes smooth-muscle contraction and mucus secretion, increases vascular permeability
Prostaglandin	Causes smooth-muscle contraction and vasodilation
TNF-α (cytokine)	Causes inflammation and stimulates cytokine production by other cell types

Figure \(\PageIndex{2}\): On first exposure to an allergen in a susceptible individual, antigen-presenting cells process and present allergen epitopes with major histocompatibility complex (MHC) II to T helper cells. B cells also process and present the same allergen epitope to T_H2 cells, which release cytokines IL-4 and IL-13 to stimulate proliferation and differentiation into IgE-secreting plasma cells. The IgE molecules bind to mast cells with their Fc region, sensitizing the mast cells for activation with subsequent exposure to the allergen. With each subsequent exposure, the allergen cross-links IgE molecules on the mast cells, activating the mast cells and causing the release of preformed chemical mediators from granules (degranulation), as well as newly formed chemical mediators that collectively cause the signs and symptoms of type I hypersensitivity reactions.

Query \(\PageIndex{1}\)

 

Types of Type I Hypersensitivity 

Type I hypersensitivity reactions can be either localized or systemic. Localized type I hypersensitivity reactions include hay fever rhinitis, hives, and asthma (Table \(\PageIndex{3}\)). Systemic type I hypersensitivity reactions are referred to as anaphylaxis or anaphylactic shock. Although anaphylaxis shares many symptoms common with the localized type I hypersensitivity reactions, the swelling of the tongue and trachea, blockage of airways, dangerous drop in blood pressure, and development of shock can make anaphylaxis especially severe and life-threatening. In fact, death can occur within minutes of onset of signs and symptoms.

Late-phase reactions in type I hypersensitivities may develop 4–12 hours after the early phase and are mediated by eosinophils, neutrophils, and lymphocytes that have been recruited by chemotactic factors released from mast cells. Activation of these recruited cells leads to the release of more chemical mediators that cause tissue damage and late-phase symptoms of swelling and redness of the skin, coughing, wheezing, and nasal discharge.

Individuals who possess genes for maladaptive traits, such as intense type I hypersensitivity reactions to otherwise harmless components of the environment, would be expected to suffer reduced reproductive success. With this kind of evolutionary selective pressure, such traits would not be expected to persist in a population. This suggests that type I hypersensitivities may have an adaptive function. There is evidence that the IgE produced during type I hypersensitivity reactions is actually meant to counter helminth infections². Helminths are one of few organisms that possess proteins that are targeted by IgE. In addition, there is evidence that helminth infections at a young age reduce the likelihood of type I hypersensitivities to innocuous substances later in life. Thus it may be that allergies are an unfortunate consequence of strong selection in the mammalian lineage or earlier for a defense against parasitic worms.

Table \(\PageIndex{3}\): Type I Hypersensitivities

Common Name	Cause	Signs and Symptoms
Allergy-induced asthma	Inhalation of allergens	Constriction of bronchi, labored breathing, coughing, chills, body aches
Anaphylaxis	Systemic reaction to allergens	Hives, itching, swelling of tongue and throat, nausea, vomiting, low blood pressure, shock
Hay fever	Inhalation of mold or pollen	Runny nose, watery eyes, sneezing
Hives (urticaria)	Food or drug allergens, insect stings	Raised, bumpy skin rash with itching; bumps may converge into large raised areas

Query \(\PageIndex{1}\)

 

The Hygiene Hypothesis

In most modern societies, good hygiene is associated with regular bathing, and good health with cleanliness. But some recent studies suggest that the association between health and clean living may be a faulty one. Some go so far as to suggest that children should be encouraged to play in the dirt—or even eat dirt³—for the benefit of their health. This recommendation is based on the so-called hygiene hypothesis, which proposes that childhood exposure to antigens from a diverse range of microbes leads to a better-functioning immune system later in life.

The hygiene hypothesis was first suggested in 1989 by David Strachan⁴, who observed an inverse relationship between the number of older children in a family and the incidence of hay fever. Although hay fever in children had increased dramatically during the mid-20th century, incidence was significantly lower in families with more children. Strachan proposed that the lower incidence of allergies in large families could be linked to infections acquired from older siblings, suggesting that these infections made children less susceptible to allergies. Strachan also argued that trends toward smaller families and a greater emphasis on cleanliness in the 20th century had decreased exposure to pathogens and thus led to higher overall rates of allergies, asthma, and other immune disorders.

Other researchers have observed an inverse relationship between the incidence of immune disorders and infectious diseases that are now rare in industrialized countries but still common in less industrialized countries.⁵ In developed nations, children under the age of 5 years are not exposed to many of the microbes, molecules, and antigens they almost certainly would have encountered a century ago. The lack of early challenges to the immune system by organisms with which humans and their ancestors evolved may result in failures in immune system functioning later in life.

Query \(\PageIndex{1}\)

 

Key Concepts and Summary

• An allergy is an adaptive immune response, sometimes life-threatening, to an allergen.
• Type I hypersensitivity requires sensitization of mast cells with IgE, involving an initial IgE antibody response and IgE attachment to mast cells. On second exposure to an allergen, cross-linking of IgE molecules on mast cells triggers degranulation and release of preformed and newly formed chemical mediators of inflammation. Type I hypersensitivity may be localized and relatively minor (hives and hay fever) or system-wide and dangerous (systemic anaphylaxis).

Footnotes

1. 1 D.S. Strayer et al (eds). Rubin’s Pathology: Clinicopathologic Foundations of Medicine. 7th ed. 2Philadelphia, PA: Lippincott, Williams & Wilkins, 2014.
2. 2 C.M. Fitzsimmons et al. “Helminth Allergens, Parasite-Specific IgE, and Its Protective Role in Human Immunity.” Frontier in Immunology 5 (2015):47.
3. 3 S.T. Weiss. “Eat Dirt—The Hygiene Hypothesis and Allergic Diseases.” New England Journal of Medicine 347 no. 12 (2002):930–931.
4. D.P. Strachan “Hay Fever, Hygiene, and Household Size.” British Medical Journal 299 no. 6710 (1989):1259.
5. H. Okada et al. “The ‘Hygiene Hypothesis’ for Autoimmune and Allergic Diseases: An Update.” Clinical & Experimental Immunology 160 no. 1 (2010):1–9.