Local Somatic Hypermutation and Class Switch Recombination in the Nasal Mucosa of Allergic Rhinitis Patients

Abstract

Immunoglobulin E is produced by nasal B cells in response to allergen. We have analyzed IgE VH region sequences expressed in the nasal mucosa of patients suffering from allergic rhinitis. VH region sequences were amplified by RT-PCR from IgE+ B cells from nasal biopsies. In two of six patients, sequence analysis clearly demonstrated the presence of closely related IgE+ B cell clones: cells displaying identical signature regions across CDR3/FWR4, indicating a common clonal ancestry, but a mixture of shared and diverse somatic mutations across the VH region. Furthermore, in one of the two patients exhibiting related IgE+ B cell clones, five IgA+ B cell clones, related to the IgE+ B cell family, were also isolated from the patient’s nasal mucosa. This evidence, combined with the local expression of mRNA transcripts encoding activation-induced cytidine deaminase, suggests that local somatic hypermutation, clonal expansion, and class switch recombination occur within the nasal mucosa of allergic rhinitics. The presence of related B cells in the nasal mucosa does not appear to result from the random migration of IgE+ cells from the systemic pool, as analysis of a nonatopic subject with highly elevated serum IgE did not exhibit any detectable VH-Cε transcripts in the nasal mucosa. We have provided evidence that suggests for the first time that the nasal mucosa of allergic rhinitics is an active site for local somatic hypermutation, clonal expansion, and class switch recombination, making it of major significance for the targeting of future therapies.

Allergen Drives Class Switching to IgE in the Nasal Mucosa in Allergic Rhinitis

“…As mentioned above, such evidence has been presented in asthma (31,32). Another type of indirect evidence comes from the observations of clonal families of V H regions comprising IgE together with other isotypes in the nasal mucosa in allergic rhinitis (36) and asthma (37). We may extrapolate further to autoimmune diseases in which similar indirect evidence of CSR has been reported in rheumatoid and reactive arthritis (28,38), Sjögren's syndrome (39), ankylosing spondilitis (40), and diabetes (41).…”

Isoallergen Variations Contribute to the Overall Complexity of Effector Cell Degranulation: Effect Mediated through Differentiated IgE Affinity

“…In the fairly limited number of papers (19)(20)(21)(22)(23), including this one, in which human allergenspecific IgE Ab fragments have been isolated, combinatorial libraries have always been cloned from peripheral blood samples. However, an essential aspect of the evolving IgE response is the accumulating evidence that both class-switch recombination (24)(25)(26)(27) and somatic hypermutation (25) followed by clonal expansion and IgE production (28,29) occur in local airway mucosa under the influence of the inflamed tissue (reviewed in Ref. 30).…”

Mechanisms of Peptide Immunotherapy in Allergic Airways Disease

“…However, no decreases in allergen-specific IgE were observed in the sera of these animals. Because local IgE production in the respiratory mucosa has been demonstrated in samples from subjects with allergy (25)(26)(27), it is possible that reduced numbers of B cells may result in lower local concentrations of IgE.…”