Published: September, 2014
Hay fever is a seasonal type of allergic rhinitis, which spreads misery in the pollen season. The immediate reaction to airborne allergens, such as grass pollen, is triggered by immunoglobulin E (IgE) antibodies, which recognize specific allergens and sensitize mast cells in the nose to pollen allergens. When provoked by allergens, the sensitized mast cells release a torrent of potent mediators of inflammation. But how do these IgE antibodies differ from all the others in the body, which appear quite innocuous, or indeed from those of healthy people? This is the question that YC. Wu and colleagues sought to address in an article recently featured in The Journal of Allergy and Clinical Immunology.
The authors’ efforts centered on the repertoire of immunoglobulin heavy-chain genes (IGH) in search of a cause for immediate hypersensitivity to allergens in hay fever sufferers. They exploited the “next-generation sequencing (NGS)” technology to capture and record in a massively parallel fashion the IGH sequences in the nasal mucosa and peripheral blood. This pioneering study encompassed a total of 97610 IGH sequences, including 8135 IGH sequences derived from IgE-expressing B cells, in 7 pairs of matched specimens from grass-pollen hay fever patients, with 3 pairs sampled out of season and 4 pairs sampled in season, and in 3 pairs from healthy subjects. Subsequently, their bioinformatics pipeline explored in the sea of IGH sequences the changes elicited by seasonal allergen provocation.
It emerged that more somatic mutations were detected in the nasal IgE repertoire (i) in hay fever patients than in healthy subjects and (ii) in hay fever patients in the pollen season than out of it. Because somatic hypermutation (SHM) of immunoglobulin genes is an indispensible mechanism that diversifies the repertoire of antibodies to recognize an essentially infinite array of antigens and optimizes their affinity for antigens, the authors suggest that the resident B cells in the nasal mucosa of people with hay fever may be more prone to SHM than those of healthy people. Furthermore, their mathematical models revealed that IgE-expressing B cells were more positively selected and the IgE population became more diverse in the nasal mucosa of hay fever patients during the pollen season. These local changes in the IgE repertoire therefore uncovered a molecular basis for the hypersensitivity to seasonal pollen in hay fever patients.
B cells originate in the bone marrow as IgM but only those that actually encounter an antigen may undergo switching to another class, thereby keeping their specificity for antigens but changing their function: IgM+ cells may switch directly to IgE (IgM, IgE) or indirectly by way of IgG or IgA intermediates (IgM, IgG/IgA, IgE). In between these events, the cell in its intermediate isotype may proliferate and undergo SHM, so that the IgE inherits these mutations from its precursor cell. By identifying IGH sequences from cells of the same precursor origin and tracing their mutation footprints to construct “family trees”, the authors of the featured article found that IgE and IgG were more likely to be positioned in the same family tree in hay fever patients than in healthy controls. Therefore, they conjecture that mutated IgG “memory” B cells in the nose of hay fever patients may undergo cell proliferation and rapid switching to IgE upon allergen exposure, accounting for the increased mutations observed in local IgE in hay fever patients.
Wu and colleagues’ work, regardless of its modest cohort size, has provided proof of principle for the potential of NGS in future asthma and allergy research and in the development of immunotherapies. Their observations imply that the nasal mucosa constitutes a uniquely favorable microenvironment for allergy-initiating antibodies to thrive in hay fever. Therapies to suppress the development of IgE-expressing B cells locally in the nose, and thereby prevent the symptoms of hay fever, may be envisaged.
The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.