Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions are mediated by IgE, and T and B cells play important roles in the development of these antibodies. CD4+ T cells are subdivided into classes: effector T cells (TH1, TH2, TH17 cells), memory T cells, and regulatory T cells (Tregs). TH1 cells produce interferon-gamma and interleukin (IL)-2, and promote a cell-mediated immune response. TH2 cells produce IL-4 and IL-13, which then act on B cells to promote the production of antigen-specific IgE. TH17 cells produce IL-17, IL-21, and IL-22 to help fight extracellular pathogens, to produce antimicrobial peptides, and to promote neutrophil inflammation essential for immunity at the skin and mucosal surfaces. ^[8]  Memory T cells rapidly differentiate into effector T cells in secondary immune responses. CD4+CD25+FOXP3+ Tregs are essential in peripheral tolerance and serve to suppress dysregulated immune responses. CD4+CD25+FOXP3+Tregs inhibit TH2 cytokine production through the secretion and action of IL-10 and TGF-β. Proper function of CD4+CD25+FOXP3+ Tregs has been shown to be important in the tolerance of allergens. ^[7]  Abnormalities in the CD4+CD25+FOXP3+ Treg population may play a role in the development of allergic disease.

The allergic reaction first requires sensitization to a specific allergen, and it occurs in genetically predisposed individuals. The allergen is typically introduced through the respiratory tract (inhaled), the gastrointestinal tract (ingested), or contact of the integument (on the skin). The allergen/antigen is then processed by an antigen-presenting cell (APC), such as a dendritic cell, macrophage, or B cell. ^[9]  The antigen-presenting cell(s) then migrate to lymph nodes, where they prime naïve T-helper cells that bear receptors for the specific antigen.

After antigen priming, naïve T-helper cells differentiate into TH1, TH2, or TH17 cells based upon antigen and cytokine signaling. In the case of allergen sensitization, the differentiation of naïve T-helper cells is skewed toward a TH2 phenotype. These allergen-primed TH2 cells then release IL-4, IL-5, IL-9, and IL-13. IL-5 plays a role in eosinophil development, recruitment, and activation. IL-9 plays a regulatory role in mast cell activation. IL-4 and IL-13 act on B cells to promote production of antigen-specific IgE antibodies.

In order for B cells to produce antigen-specific IgE, the B cells must internalize the recognized antigen. The antigen is then processed via the major histocompatibility complex (MHC) class II antigen processing pathway where the MHC class II molecule presents the antigenic peptide on the B cell surface to the TH2 cell. The peptide:MHC class II complex is then recognized by the T-cell receptor (TCR) on the TH2 cell. This interaction requires costimulation where CD40 on the B cell interacts with CD40L on the TH2 cell surface to activate the signaling cascade in the TH2 cell to produce IL-4 and IL-13. The CD40:CD40L interaction is essential for the activation of the activation-induced cytosine deaminase (AICD) enzyme in B cells for isotype switching from IgM to IgE in the presence of IL-4 and IL-13 (see image below).

The antigen-specific IgE antibodies produced can then bind to high-affinity IgE receptors located on the surfaces of mast cells and basophils. Re-exposure to the antigen can then result in the antigen binding to and crosslinking the bound IgE antibodies on the mast cells and basophils. This causes the release and formation of chemical mediators from these cells. These mediators include preformed mediators, newly synthesized mediators, and cytokines. The major mediators and their functions are described as follows: ^{[10, 11]}

Preformed mediators

See the list below:

• Histamine: This mediator acts on histamine 1 (H1) and histamine 2 (H2) receptors to cause contraction of smooth muscles of the airway and GI tract, increased vasopermeability and vasodilation, enhanced mucous production, pruritus, cutaneous vasodilation, and gastric acid secretion. ^[12]

• Tryptase: Tryptase is a major protease released by mast cells. It has many roles where it degrades allergens and cross-linked IgE, potentiates histamine release, increases heart rate and airway smooth muscle contractility, activates TGF-β, generates C3a and bradykinin and plays a role in airway remodeling through the stimulation of collagen and fibroblast proliferation. ^{[13, 7, 12]}  Tryptase is found in all human mast cells but in few other cells, thus is a good marker of mast cell activation.

• Proteoglycans: Proteoglycans include heparin and chondroitin sulfate. The role of the latter is unknown; heparin seems to be important in storing the preformed proteases and may play a role in the production of α-tryptase.

• Chymase: Chymase plays a role in mucous secretion; degradation of IL-4 and extracellular matrix; decrease T-cell adhesion to airway smooth muscle; and releasing stem cell factor. ^[12]

Newly formed mediators

Arachidonic acid metabolites

Leukotrienes - Produced via the lipoxygenase pathway:

• Leukotriene B4 - Neutrophil chemotaxis and activation, augmentation of vascular permeability

• Leukotrienes C4 and D4 - Potent bronchoconstrictors with airway smooth muscle proliferation, increase vascular permeability to cause tissue edema, enhance tissue fibrosis and arteriolar constriction

• Leukotriene E4 - Enhances bronchial responsiveness and increases vascular permeability

• Leukotrienes C4, D4, and E4 - Comprise what was previously known as the slow-reacting substance of anaphylaxis

Cyclooxygenase products:

• Prostaglandin D2 - Produced mainly by mast cells; bronchoconstrictor, peripheral vasodilator to cause tissue edema, coronary and pulmonary artery vasoconstrictor, platelet aggregation inhibitor, neutrophil and eosinophil chemoattractant, and enhancer of histamine release from basophils 

• Prostaglandin F2-α - Bronchoconstrictor, peripheral vasodilator, coronary vasoconstrictor, and platelet aggregation inhibitor

• Thromboxane A2 - Causes vasoconstriction, platelet aggregation, and bronchoconstriction

Platelet-activating factor (PAF): PAF is synthesized from membrane phospholipids via a different pathway from arachidonic acid. It aggregates platelets but is also a very potent mediator in allergic reactions. It increases vascular permeability, causes bronchoconstriction, and causes chemotaxis and degranulation of eosinophils and neutrophils.

Adenosine: This is a bronchoconstrictor that also potentiates IgE-induced mast cell mediator release.

Bradykinin: Kininogenase released from the mast cell can act on plasma kininogens to produce bradykinin. An additional (or alternative) route of kinin generation, involving activation of the contact system via factor XII by mast cell–released heparin, has been described. ^{[14, 15]} Bradykinin increases vasopermeability, vasodilation, hypotension, smooth muscle contraction, pain, and activation of arachidonic acid metabolites. However, its role in IgE-mediated allergic reactions has not been clearly demonstrated. ^[4]

Cytokines

See the list below:

• IL-4: IL-4 stimulates and maintains TH2 cell differentiation and proliferation as well as switches B cells to IgE synthesis. ^[12]

• IL-5: IL-5 is key in the maturation, chemotaxis, activation, and survival of eosinophils. IL-5 primes basophils for histamine and leukotriene release. ^[12]

• IL-6: IL-6 promotes mucus production, increases IgE secretion, and enhances the survival of mast cells. ^[12]

• IL-13: IL-13 has many of the same effects as IL-4. ^[12]

• Tumor necrosis factor-α: Tumor necrosis factor-α is a pro-inflammatory cytokine which activates neutrophils and eosinophils; increases monocyte chemotaxis; promotes histamine and tryptase secretion from mast cells; upregulation of MHC class II and IL2R expression. ^{[16, 7, 12]}

The collective biological activities of the aforementioned mediators can cause variable clinical responses depending on which organ systems are affected, as follows:

• Urticaria/angioedema: Release of the above mediators in the superficial layers of the skin can cause pruritic wheals with surrounding erythema. If deeper layers of the dermis and subcutaneous tissues are involved, angioedema results. Angioedema is swelling of the affected area; it tends to be painful rather than pruritic.

• Allergic rhinoconjunctivitis: Release of the above mediators in the upper respiratory tract can result in sneezing, itching, nasal congestion, rhinorrhea, and itchy or watery eyes.

• Allergic asthma: Release of the above mediators in the lower respiratory tract can cause bronchoconstriction, mucus production, and inflammation of the airways, resulting in chest tightness, cough, shortness of breath, and wheezing.

• Anaphylaxis: Systemic release of the above mediators, resulting in symptoms in two or more organ systems, is considered anaphylaxis. In addition to the foregoing symptoms, the GI system can also be affected with nausea, abdominal cramping, bloating, and diarrhea. Systemic vasodilation and vasopermeability can result in significant hypotension and is referred to as anaphylactic shock. Anaphylactic shock is one of the two most common causes for death in anaphylaxis; the other is throat swelling and asphyxiation. ^{[4, 11]}

Allergic reactions can occur as immediate reactions, late-phase reactions, and/or chronic allergic inflammation. Immediate or acute-phase reactions occur within seconds to minutes after allergen exposure. Some of the mediators released by mast cells and basophils cause eosinophil and neutrophil chemotaxis. Attracted eosinophils and resident lymphocytes are activated by mast cell mediators.

These and other cells (eg, monocytes, T cells) are believed to cause the late-phase reactions that can occur hours after antigen exposure and after the signs or symptoms of the acute-phase reaction have resolved. The signs and symptoms of the late-phase reaction can include redness and swelling of the skin, nasal discharge, airway narrowing, sneezing, coughing, and wheezing. These effects can last a few hours and usually resolve within 24–72 hours.

Finally, continuous or repeated exposure to an allergen (eg, a cat-allergic patient who owns a cat) can result in chronic allergic inflammation. Tissue from sites of chronic allergic inflammation contains eosinophils and T cells (particularly TH2 cells). Eosinophils can release many mediators (eg, major basic protein), which can cause tissue damage and thus increase inflammation. Collectively, this results in structural and functional changes to the affected tissue. Furthermore, a repeated allergen challenge can result in increased levels of antigen-specific IgE, which ultimately can cause further release of IL-4 and IL-13, thus increasing the propensity for TH2 cell/IgE–mediated responses. ^[11]

Frequency

The prevalence of atopic diseases (ie, asthma, allergic rhinitis, food allergy, and atopic dermatitis) has increased over the last two decades. ^{[7, 17]}

According to 2021 data from the CDC's National Center for Health Statistics, nearly one in three US adults and more than one in four US children reported experiencing a seasonal allergy, eczema, or food allergy. Approximately 6% of both adults and children in the United States have a food allergy, with Black, non-Hispanic individuals being among the most likely to report this condition. ^[18]

Allergic rhinitis is the most prevalent allergic disease. It affects more than 400 million people worldwide, with prevalence rates between 10% and 30% among adults and more than 40% among children. ^[19]

From 2001 to 2021, the prevalence of asthma in the United States increased from 7.4% to 7.7%. ^[20]  Overall, about 25 million (7.7% of the US population) had asthma in 2021, an increase from 20.3 million, or 7.4% who had asthma in 2001 among all ages. In 2019, an estimated 262.41 million people had asthma globally. ^[21]

The prevalence of severe anaphylaxis is estimated between 0.05% and 2%. ^[22]

Mortality/Morbidity

Mortality from allergic diseases occurs primarily from anaphylaxis and asthma, although fatal anaphylaxis constitutes less than 1% of total mortality risk. ^[23]  Approximately 1500 people die annually from anaphylaxis in the United States. ^[22]

Deaths from asthma are relatively rare. The rate of asthma deaths decreased from 15 per million in 2001 (n = 4269) to 10.6 per million (n = 3517) in 2021. Notably, asthma-related deaths were higher in 2020 compared to 2019 and 2021, potentially influenced by the increased mortality associated with the COVID-19 pandemic. The death rate was higher in females and non-Hispanic blacks and nearly six times higher for adults than children. ^[24]  

Race

The reason for the differences in the prevalence of allergic diseases with respect to race are complex and not completely understood. There are significant disparities in asthma prevalence, with American Indian/Alaska Native and Black non-Hispanic populations experiencing the highest rates, while Asians and individuals of Mexican origin report the lowest prevalence. ^[25]  Asthma prevalence also increases with increasing poverty. ^[25]  Thus, it is likely that differences in allergic diseases among different racial or ethnic groups is multifactorial and includes genetic, environmental, and socioeconomic factors.

Sex

Some unexplained differences exist in the prevalence of allergic diseases between the sexes. Asthma is more prevalent in boys from birth to age 17 years, but females have a higher prevalence overall. ^[25]

Women are more likely than men to experience severe asthma, multiple comorbidities, poorer quality of life, and higher rates of exacerbations, hospitalizations, and mortality. ^{[26, 27]}

Skin test reactivity in women can fluctuate with the menstrual cycle, but this is not clinically significant. ^[10]

Age

In general, allergic rhinitis symptoms (and skin test reactivity) tend to wane with increasing age. ^[19]

Food allergies and subsequent anaphylaxis are more prevalent in children; IgE-mediated food allergy is also on the rise. It is unclear the reason(s) for the increase in IgE-mediated food allergy, but a landmark article, the LEAP trial, published in 2015 showed sustained early introduction of peanut (first 11 months of life) into the diet of high-risk infants significantly reduced risk of peanut allergy by 5 years of age. ^[28] Subsequently, the LEAP-on trial studied the same high-risk children from the LEAP trial. The children who tolerated peanut at age 5 avoided peanut protein consumption for 12 months without an increase in peanut allergy prevalence with reintroduction at age 6 years. ^[29]  These studies have shifted the paradigm to early introduction and sustained consumption of peanut protein. Furthermore the results of these studies could possibly be extrapolated to all highly allergenic foods being introduced into the diet of children. When IgE-mediated food allergy develops, some children may outgrow their allergies to certain foods, such as milk, soy, and egg allergy. However, anaphylaxis from food and other triggers is still a threat in adults. Some food allergies, such as allergy to shellfish, tree nuts, and finned fish, may last a lifetime.

In 2019, 7.0% of US children under age 18 years had current asthma. The percentage of current asthma was higher in children aged 10–17 years (9.1%) and children aged 5–9 years (7.8%) than in children aged 0–4 years (2.6%). Childhood asthma is more prevalent in boys and can often resolve by adulthood. However, females tend to develop asthma later in life and can also have asthma that is more severe. ^[30]

Patients with a known inciting agent should be advised in avoidance techniques, including immunologic cross-reactivity as is encountered in latex allergies.

Patients must be educated in the proper use of their maintenance and rescue medications.