Immediate hypersensitivity is the hallmark of allergic disease and encompasses disorders such as asthma, anaphylaxis, and allergic rhinitis. Central to this process are mast cells and IgE. This chapter provides a brief overview of the immunology underlying allergic reactions and allergic inflammation.
Mast cells are metachromatic effector cells found near portals of entry, including lung and skin, that are critical for both innate and acquired defense mechanisms. They associate with blood vessels and nerves as well as inflammatory and malignant foci and are most notable for their abundant cytoplasmic granules and mediators that are released by immune and nonimmune stimuli. They are stimulated through the surface high-affinity receptor for IgE, termed FceRI. Antigen binding and cross-linking of cell surface-bound IgE result in mast cell degranulation and activation. This interaction is what drives hypersensitivity and atopic reactions.
Developing Mast Cells
Developing mast cells arise from CD34+ bone marrow progenitors. Maturation and granule acquisition occur in the periphery near blood vessels.
Mast Cell Granules
Mast cell granules contain several preformed mediators, enzymes, and cytokines including histamine, chymase, heparin, tryptase, and tumor necrosis factor alpha(TNF-alpha), that are released within minutes of cross-linking of surface-bound IgE Newly formed Mediators, including lipid mediators, made through the lipoxygenase pathway are synthesized de novo at the time of mast cell activation.
Histamine increases vascular permeability and causes smooth muscle contraction and vasodilation. Clinically, histamine mediates pruritus, increases airway secretions, and causes the cutaneous wheal and flare reaction.
Tryptase is a neutral protease and major granule component that has several forms:
The constitutively secreted alpha isoform. Blood levels of alpha-tryptase are indivative of overall mast cell numbers and are markedly increased in patients with mastocytosis
The beta isoform. Blood levels of beta typtase are normally quite low. It is released primarily during mast cell degranulation and therefore is a marker of a recent mast cell.
Newly formed Mediators
Newly formed mediators, such as leukotrienes(LTC, LTD, LTE), prostaglandin D2 (PGD2), platelet activating factor(PAF), and cytokines, such as TNF-alpha, are synthesized de novo after mast cell degranulation.
Their effect are seen in both the early and late phases of allergic reactions.
Cytokines contribute primarily to late-phase allergic reactions. Cytokine dependent mechanisms are through to be bridge between mast cell activation by IgE and subsequent late-phase reactions that result in inflammatory cell recruitment.
Stimuli for Mast Cell Degranulation
Stimuli for mast cell degranulation include
Allergens, via cross-linking of surface IgE molecules.
Antibodies that bind IgE or the FceRI receptor and result in cross-linking.
Clinical effects produced by mast cell mediators include urticaria, angioedema , ecseme, rhinitis, conjunctivitis, asthma, laryngeal edema, and anaphylaxis.
Immediate allergic response: The reaction begins when IgE already bound to mast cells via its high-affinity receptor (FceRI) is cross-linked by an antigen. This stimulates the immediate release of mast cell granules containing performed medators such as tryptase, chymase, and histamine.
Late-phase allergic response: The late-phase response(LPR) is mediated in part by newly formed lipid mediators(Includig PGD2, PAF, and leukotrienes LTC4/D4/E4) produced by mast cells and basophils.
IgE is a 190-kd immunoglobulin that exists in minute concentrations in the serum. It does not activate the complement pathway, nor is it involved in opsonization and neutralization of antigens. Mechanistically, its activity occurs through its interaction with IgE receptors located on mast and other cells of the immune system.
Serum IgE often found in higher concentrations in allergic individuals, but measurement of serum IgE has very limited clinical value.
Biological activity of IgE occurs by interacting with receptors found on mast cells, basophils, and to a lesser extent, Langerhans’ cells, dendritic cells and monocytes.
The high-affinity receptor (FceRI) has three subunits. The alpha subunit binds the ligand. The Beta and gamma subunits are required for signal amplification and transduction, respectively.
The FceRI on moncytes and dendritic and langerhans’ cells does not have the beta subunit-amplification component.
Mast cell degranulation occurs when a threshold level of antigens binds and cross links surface-bound IgE molecules.
Low-Affinity Receptor (FceRll)
The low-affinity receptor(FceRll) is a single-chain transmembrane protein with two isoforms.
The A isoform is found on B cells, and the B isoform is found on B cells, T cells monocytes, and eosinophils.
FceRll mediates cytotoxis responses by monocytes, macrophages, platelets, and eosinophils and is able to down-regulate its own expression.
IgE sysnthesis is regulated by a complex pathway that causes B cells to differentiate into IgE producing cells. B cells require IL-4 to undergo istype switch to produce IgE. The IL-4 is a ‘helper signal’ derived from CD4+ Th2 helper T lymphocytes.
Antigen presentation to T cells usually results in a low-grade inflammatory process whereby IgG is produced by B cells. This is accomplished when the T-cell activation response to an antigen involves the sercretion of gamma-interferon(gamma-IFN) and IL-2.
When a macrophage engulfs an antigen by phagocytosis or pinocytosis, it begins to secrete IL-12. This promotes the differentiation of activated T lymphocytes toward the Th1 phenotype, resulting in the production of gamma-IFN
Hypersensitivity reactions are well described in the medical literature and are an essential part of basic pathology. They are mechanisms by which the immune system causes injury to tissues. Normally, an antigen encountered by various cells of the immune system stimulates an inflammatory response that protects the body from the environment. Inflamation, therefore, is both protective and damaging. Hypersensitivity reactions describe the many ways that tissue damage can occur. Table 2-2 describes these reactions according to the classification by Gell and Coombs.
Cross-linking of IgE molecules anchored on mast cells by antigen triggers mast cell degranulation, mediator release, and de novo synthesis of lipid-derived mediators.
The immediate allergic response is mediated by mast cells, whereas the latephase allergic response is mediated by other inflammatory cells, including CD4 T lymphocytes, basophils and eosinophils.