Sensitization and synthesis of allergic antibodies
The development of an allergy begins with initial contact with the allergen. In the mucous membranes, type 2 dendritic cells (DC2) capture the antigen. Unlike classical inflammation, DC2 produce IL-4. They migrate to the lymph node and present the allergen to CD4+ T cells, directing their differentiation pathway into Th2 lymphocytes.
Epithelial cells secrete the cytokine TSLP, which induces the expression of the costimulatory molecule OX40L on dendritic cells. The interaction via the OX40 receptor specifically generates "allergic" Th2 cells that, in addition to classical cytokines, secrete pro-inflammatory TNFα.
Under the influence of IL-4, gene switching occurs in B lymphocytes to synthesize IgE. This class switch (bringing V and Cε genes together while looping out and excising DNA) can proceed in a single-step or two-step manner. As a result, the IgE molecule is synthesized.
Structural features of IgE and receptor binding
The IgE molecule (molecular weight 190 kDa) has four C domains in its heavy chain, which provides an extensive contact surface for receptor binding. It is extremely unstable: it is destroyed at 56 °C, extreme pH values, and by reducing agents.
Most IgE is secreted in the mucous membranes. Through its Cε3 domain, the antibody binds tightly to the high-affinity receptor FcεRI on the mast cell membrane. This receptor consists of three chains: α (binds IgE), β, and a signaling γ-chain with activation ITAM motifs. Important: mere settling of IgE on the receptor does not trigger cellular activation.
Mast cell activation: intracellular cascades
Upon re-exposure, the allergen cross-links FcεRI receptors. This activates the tyrosine kinase Lyn, and subsequently the kinase Syk, which triggers three parallel signaling branches:
- Rapid response (degranulation). Syk activates phospholipase C (PLC), which cleaves PIP2 into diacylglycerol and inositol trisphosphate (IP3). The latter induces the release of calcium ions, which together with diacylglycerol activate protein kinase C. The result is cytoskeletal contraction and release of preformed granules.
- Intermediate response. Phospholipase A2 (PLA2) is activated, releasing arachidonic acid. Lipid mediators—eicosanoids—are synthesized from it.
- Late response. The MAP kinase cascade is triggered (involving Ras and transcription factors), turning on cytokine genes.
Reaction phases and mediator effects
Clinically, immediate-type hypersensitivity proceeds in several stages:
- Early phase (minutes): Mediated by preformed factors in mast cell granules. The main mediator is histamine. Through H1 receptors, it causes bronchial smooth muscle spasm, vasodilation (edema), abundant mucus secretion, and pruritus.
- Second wave: Secretion of eicosanoids. Leukotrienes cause the slow phase of bronchospasm, while prostaglandin D2 causes vasodilation.
- Late phase (4–6 hours later): Released chemokines and cytokines attract leukocytes into the tissues, primarily eosinophils. These cells release tissue-toxic proteins (e.g., major basic protein MBP and eosinophil cationic protein ECP) and also synthesize their own cytokines, sustaining local inflammation.
Briefly: answers to topical questions
What are the structure and functions of the high-affinity FcεRI receptor?
The high-affinity FcεRI receptor binds free IgE antibody molecules and, upon cross-linking, triggers cell activation and degranulation. The receptor is expressed on mast cells, B lymphocytes, dendritic cells, and eosinophils. The receptor structure includes three types of chains:
- α-chain — binds IgE antibodies (molecular weight 29.6 kDa).
- β-chain — spans the cell membrane four times (26.5 kDa).
- γ-chain — a signaling chain with a mass of 9.7 kDa containing three ITAM activation motifs.
IgE binding is driven by the high affinity of the antibody Fc region for the receptor (Kd = 10⁻⁹–10⁻¹⁰ M). Receptor cross-linking induces conformational changes in the α-chain, which are detected by the tyrosine kinase Lyn, initiating the intracellular cascade.
What is the role of type 2 dendritic cells (DC2) in the development of the allergic response?
Type 2 dendritic cells (DC2) present the allergen and direct CD4+ T lymphocyte differentiation down the Th2 pathway. The main functions of DC2 in the allergic response are:
- Cytokine production — DC2 secrete interleukin-4 (IL-4), which is the primary inducer of the Th2 response.
- Migration — cells move to the regional lymph node for the primary immune response.
- Antigen presentation — in the lymph node, DC2 present the antigen to CD4+ T lymphocytes in the presence of IL-4.
Upon re-exposure to the allergen, DC2 present it to memory T cells locally, predominantly in the mucous membranes, promoting the development of local allergic reactions.
How does antibody class switching to IgE synthesis occur in B lymphocytes?
Antibody class switching to IgE occurs via the replacement of immunoglobulin C genes with the Cε gene under the control of interleukin-4 (IL-4). The process at the DNA level includes the following steps:
- Gene approximation — V and Cε genes are brought into proximity, forming a DNA loop of intermediate genes that is subsequently excised.
- Transcription and translation — the resulting V and Cε gene tandem is transcribed into mRNA, which is translated into the IgE heavy H chain.
The switching mechanism can be single-step (from the Cμ to the Cε gene) or two-step (via the Cγ4 gene). Additionally, the process is stimulated by the interaction of the soluble form of the CD23 receptor with the CD21 molecule on B lymphocytes, which triggers an intracellular signal via the tyrosine kinase Lyn.
What are the main physicochemical properties and the half-life of the IgE molecule?
The IgE molecule is an 8S monomeric immunoglobulin with a molecular weight of 190 kDa, consisting of two heavy (ε) and two light chains. The half-life of serum IgE is 2.5 days. The main physicochemical properties are:
- ε-chain structure — contains four C domains, providing a larger surface area for interaction with the Fc receptor.
- Glycosylation — the molecule has a high degree of C-domain glycosylation (up to 12% carbohydrates, 6 sites).
- Stability — IgE is highly sensitive to heat treatment at 56 °C, extreme acidity (pH 11), and reduction by β-mercaptoethanol.
The three cascades inside the mast cell are easy to remember by timing: "Degranulation, Lipids, Genes." First (in seconds), the cell releases preformed histamine granules, then (in minutes) synthesizes lipids (e.g., eicosanoids) from the membrane, and only afterwards (in hours) reads genes to assemble new cytokines.
Class and exam questions
Why do symptoms not occur during the first contact with an allergen?
Primary contact is required for sensitization: Th2 cell differentiation, IgE production, and their fixation on mast cell FcεRI receptors. Symptoms appear only upon re-exposure when the allergen cross-links antibodies already fixed on the cell.
Can a mast cell be activated without an allergen and IgE antibodies?
Yes, mast cell degranulation directly depends on an increase in intracellular calcium levels. This process can also be triggered by anaphylatoxins (e.g., complement component C5a), calcium ionophores, and certain pharmacological agents.
What is the difference between the effects of histamine and leukotrienes in asthma?
Histamine is released instantly and accounts for the acute, early phase of bronchial spasm. Leukotrienes, in contrast, are synthesized during the reaction (e.g., eicosanoid pathway) and drive the slow, more protracted phase of bronchospasm.
What else to study on this topic
- Humoral regulation of IgE production involving low-affinity CD23 receptors.
- The role of the microenvironment (including the role of dihydroxyvitamin D) in promoting Th2 differentiation.
- The detailed mechanism of genetic isotype switching to the Cε gene.
- Morphological changes in mast cells during active degranulation.
- Characteristics of the 4 main proteins of eosinophil specific granules.
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