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.