Local somatic hypermutation and class switch recombination in the nasal mucosa of allergic rhinitis patients.
Immunoglobulin E is produced by nasal B cells in response to allergen. We have analyzed IgE V(H) region sequences expressed in the nasal mucosa of patients suffering from allergic rhinitis. V(H) 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 V(H) 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 V(H)-Cepsilon 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.
Coker
Heather A
HA
The Randall Centre, King's College London, London, United Kingdom.
Durham
Stephen R
SR
Gould
Hannah J
HJ
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D002999:Clone Cells; D003564:Cytidine Deaminase / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007070:Immunoglobulin A / Q000096:biosynthesis; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007127:Immunoglobulin Constant Regions / Q000096:biosynthesis / Q000235:genetics; D007073:Immunoglobulin E / Q000096:biosynthesis; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000276:immunology; D009297:Nasal Mucosa / Q000276:immunology* / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D011995:Recombination, Genetic / Q000276:immunology*; D012221:Rhinitis, Allergic, Perennial / Q000201:enzymology / Q000235:genetics* / Q000276:immunology*; D017422:Sequence Analysis, DNA; D027041:Somatic Hypermutation, Immunoglobulin
D007070:Immunoglobulin A; D007127:Immunoglobulin Constant Regions; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D012333:RNA, Messenger; D007073:Immunoglobulin E; D003564:Cytidine Deaminase