Biomedical Engineering Reference
In-Depth Information
C
ε
1
C ε 2
Binding site
for F c ε RI
C ε 3
FIGURE 20.2
Structure of IgE. (Modified from Hamelmann E,
Rolinck-Werninghaus C and Wahn U 2002. From
IgE to Anti-IgE: Where do we stand? Allergy 57:
983-994.)
C ε 4
was published in 1919 by Ramirez (8), where the author reported on an incident during
which a man entering a horse-drawn carriage experienced an acute asthmatic episode two
weeks after having received a blood transfusion from a man with a known horse allergy
(7). It was not until 1921, however, that Prausnitz and Küster gave the first scientific
description of the mechanism of the allergic reaction, showing that hypersensitivity could
be transferred from an allergic patient to a nonallergic patient through a serum factor (7).
Type I hypersensitivity reactions, in which IgE plays a central role, include wheal and flare
eruptions of the skin, sneezing, rhinorrhea, and conjunctival irritation (9). More serious
conditions include asthma and anaphylaxis, which are believed to share a similar patho-
genesis (9).
The production of IgE is mainly under control of T cells and T cell cytokines. T cells can
undergo two separate differentiation pathways, namely Th1 and Th2, in response to dis-
tinct stimuli, and are characterized by the type of cytokines predominantly produced (7).
Th1 cells secrete, amongst others, interleukin (IL)-2, interferon-
(IFN-
), tumor necrosis
factor-
), and lymphotoxin (LT). These cytokines mobilize the cellular and
humoral defense mechanisms against intracellular pathogens and antagonise IgE
responses (9). The cytokines secreted by Th2 cells include IL-4, IL-5, IL-6, IL-9, and IL-13.
These cytokines coordinate the host defense against large, extracellular pathogens (9).
The hypersensitivity cascade pathway, depicted in Figure 20.3, begins with the presen-
tation of an antigen/allergen to a T helper cell by an antigen-presenting cell (APC) and, in
this case, native T cells undergo differentiation along the Th2 pathway, defined by the pro-
duction of Th2 cytokines (7), as described above. IL-4 and IL-13 then direct the differenti-
ation of B cells to IgE-producing plasma cells (10). This differentiation also requires
interaction between the CD40 antigen, a cell-surface receptor expressed on B cells, and its
ligand (CD154) on the T-cell surface (9). The biological activities of the free circulating IgE
are then mediated through specific receptors (7): the high-affinity receptor (F c
(TNF-
RI) (see
Figure 20.2) is mainly expressed on mast cells and basophiles, whereas the low-affinity
receptor (F c
RII) is expressed on B cells. Following binding of IgE to the high-affinity
receptors, mast cells remain sensitized for up to 12 weeks, thereby greatly increasing the
half-life of free-circulating serum IgE, which is of 2½ days (7). Reexposure of sensitized
patients to the allergen leads to specific binding of the allergen to the IgE-F c
RI complexes
on the mast cells. Crosslinking of the receptors then triggers the release of inflammatory
cytokines, chemokines, and mediators, such as histamine and heparin (7). It is these mol-
ecules that cause the symptoms observed in the allergic response. IgE is thus the “gate-
keeper” of immediate type I hypersensitivity.
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