Glossary
Allergen-specific immunotherapy (AIT): also known as
desensitization or hyposensitization; the most common form of specific
immunotherapy; involves a course of injections that build up tolerance
to particular allergens through small, controlled doses.Allergens: proteins that trigger the immune system of an
allergic person to produce unwanted symptoms. Allergy: a
chronic condition involving an exaggerated reaction to an otherwise
harmless substance, called an allergen. B cells: differentiate
into clones of antibody-producing plasma cells; have a central role in
allergen tolerance through the production of IgG-blocking antibodies.FcƐRI: a high-affinity IgE receptor expressed on the cell
surface of mast cells and basophils; triggers the IgE-mediated allergic
cascade. FcγRIIb: a low-affinity IgG receptor. IgG antibodies
can inhibit IgE-mediated mast cell activation through direct allergen
neutralization or through the inhibitory receptor FcγRIIb.Germinal center: a specialized microstructure that forms in
secondary lymphoid tissues, producing long-lived antibody-secreting
plasma cells and memory B cells, which can provide protection against
reinfection; IgE: primary antibody mediator in the allergic
response. IgG: most common antibody in the body; used to treat
a range of diseases. Mast cells: similar to basophils, mast
cells become activated by antigen crosslinking of FcƐRI receptor-bound
IgE to undergo rapid degranulation and release of the inflammatory
substance histamine, causing an allergic reaction.Pathogen-associated structural pattern (PASP): a
pathogen-associated molecular pattern (PAMP). Cells of the innate immune
system utilize pattern recognition receptors to identify viral pathogens
by engaging PAMPs e.g. viral structures, Toll-like receptor ligands such
as RNA. Toll-like receptors: The Toll-like receptors are
Pathogen recognition receptors that have a unique and essential function
in animal immunity.
1 Introduction
The discovery of IgE-mediated allergic disease as an indication of
hay-fever, or allergic rhinitis, was first described in 1819 by John
Bostock, a medical doctor who himself suffered from hay
fever1. He called the
disease catarrhus aestivus, summer catarrh, as it was invariably absent
in winter time. Catarrhus aestivus was a rare disease in the early
nineteenth century, and after reporting his own case, it took him more
than nine years to identify another 28 cases for publishing a second
article2. At the
beginning of the 20th century, allergens were
considered being
toxins3. Only with the
discovery of IgE
antibodies4,5,
it became evident that allergen-specific antibodies are the reason for
the aberrant response of the body against pollen.
In clinical practice, there are several possibilities to avoid the
activity of IgE and many pharmaceutical interventions aim to prevent IgE
production and/or make the immune system more tolerant to allergens by
inducing a shift in Th cell responses from Th2 to Th1 or regulatory T
cells6,7;
more recently, the concept of mAbs targeting and blocking IgE directly
by monoclonal anti-IgE antibodies has been introduced8. Alternatively, it may
be possible to block the action of IgE indirecty by induction of
allergen-specific IgG through passive9 or active
vaccination10,11.
This approach is supported by the clinical observation that successful
specific immunotherapy may correlate with an increase of the IgG/IgE
ratio, and more recently, that polyclonal and monoclonal allergen
specific IgG antibodies were able to curb allergic immune responses both
in mice and humans as a form of passive vaccination12-14. Hence, it seems
reasonable to conclude that the overarching goal of immunotherapy should
be the induction of allergen-specific IgG antibodies.
This raises the question of antibody specificity and quality. Which are
the key parameters driving or inhibiting allergic responses? As outlined
below, the answer is complex and different for IgE mediated activation
by allergen versus IgG mediated neutralization of allergen versus
FcγRIIb-mediated inhibition of allergic responses (Figure 1). The same
is true for antibody specificity, as rules for IgE-mediated activation
versus IgG-mediated blockade or FcγRIIb-mediated inhibition are
fundamentally different. Perhaps unexpectedly, IgG subclasses plays only
a minor role in inhibiting the allergic response.