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

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Allergic Rhinitis Patients of Switch Recombination in the Nasal Mucosa Local Somatic Hypermutation and Class Local Somatic Hypermutation and Class Switch Recombination in the Nasal Mucosa of Allergic Rhinitis Patients This information is current as Heather A. Coker, Stephen R. Durham and Hannah J. Gould of September 23, 2021. J Immunol 2003; 171:5602-5610; ; doi: 10.4049/jimmunol.171.10.5602 http://www.jimmunol.org/content/171/10/5602 Downloaded from References This article cites 33 articles, 7 of which you can access for free at: http://www.jimmunol.org/content/171/10/5602.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 23, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Local Somatic Hypermutation and Class Switch Recombination in the Nasal Mucosa of Allergic Rhinitis Patients Heather A. Coker,1* Stephen R. Durham,† and Hannah J. Gould2* 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 Downloaded from 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-C 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 http://www.jimmunol.org/ targeting of future therapies. The Journal of Immunology, 2003, 171: 5602–5610. llergic reactions occur mainly in the mucosal tissues of rheumatoid arthritis (3, 4). In the local mucosal environment, sig- the respiratory tract, gut, and skin. Susceptibility at these nals to initiate SHM and CSR are available (5, 6), as in vitro A sites is due to the presence of mast cells bearing the high studies have demonstrated that, in the presence of Ag, T cells have affinity IgE receptor, Fc⑀RI, sensitized by Abs of the IgE class. the ability to induce SHM and CSR by the production of cytokines Cross-linking of the receptors by allergen binding to IgE Abs trig- (such as IL-4) and also their interaction via CD40:CD40-ligand gers immediate hypersensitivity. Mast cells in the nasal mucosa of and CD80:CD28 with B cells (7). Evidence suggesting local CSR patients with allergic rhinitis are sensitized by IgE Abs that are has been presented for IgA in the murine gut mucosa (8), for IgE by guest on September 23, 2021 produced locally by resident plasma cells (1). In an allergic indi- in the human nasal mucosa of allergic rhinitics (9–11), and in the vidual, local IgE production persists for long periods in the ab- human lung mucosa in allergic asthma (12, 13). Evidence for local sence of allergen, enabling an immediate response upon re-expo- SHM has been presented for IgE in the lung mucosa of an allergic sure to allergen. However, little is known about the history of the asthmatic patient (13). We have examined the evidence for local IgE-producing B cells, in particular when and where the precursor SHM and CSR in six patients with allergic rhinitis. cells underwent class switch recombination (CSR)3 to IgE (involv- SHM results from the stepwise accumulation of predominantly ing rearrangement of the C region genes encoding the various Ab single nucleotide substitutions into the V region DNA. This step- classes, e.g., C␮ to C⑀) and affinity maturation by somatic hyper- wise accumulation of mutations enables the genealogy of a B cell mutation (SHM). to be traced, relying on the unique complementarity-determining Both SHM and CSR are stimulated by Ag in the germinal cen- region 3/framework region 4 (CDR3/FWR4) clonal signature gen- ters of lymphoid tissue (2), but it is becoming increasingly appar- erated by the VDJ recombination of the progenitor cell. It is esti- ent that these processes may also occur locally at sites of chronic mated that mutations are introduced at a rate of 10Ϫ4-10Ϫ3 per or recurrent Ag stimulation, as has been clearly demonstrated for base pair per generation (14). A single mutation may bring about as much as a 10-fold increase in Ab affinity (14, 15). Mutations are introduced at a high level across the CDRs, but additionally the *The Randall Centre, King’s College London, London, United Kingdom; and †Upper RGYW motif (in which R ϭ AorG,Yϭ CorT,Wϭ AorT, Respiratory Medicine, Imperial College School of Medicine at National Heart and and G is mutated) or the reverse complement WRCY is a frequent Lung Institute, London, United Kingdom target of mutation, particularly at the serine codons AGC and Received for publication April 21, 2003. Accepted for publication September 4, 2003. AGT (16). The molecular mechanism of SHM has not been The costs of publication of this article were defrayed in part by the payment of page fully elucidated, although errors are thought to be introduced by charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. an activation-induced cytidine deaminase (AID) and error- 1 H.A.C. is supported by a Biotechnology and Biological Sciences Research Council prone polymerase-dependent process (17–19). Several DNA PhD studentship. polymerases have been suggested as candidates, including DNA 2 Address correspondence and reprint requests to Dr. H. J. Gould, The Randall Centre, polymerase ␩, ␬, ␫, and ␨ (20–23). AID has also been shown to King’s College London, Guy’s Campus, London, SE1 1UL, United Kingdom. E-mail be required for CSR (17, 18). address: [email protected] We present evidence generated by RT-PCR and DNA sequenc- 3 Abbreviations used in this paper: CSR, class switch recombination; AID, activation- ⑀ induced cytidine deaminase; CDR, complementarity-determining region; FWR, ing of VH-C sequences from the nasal mucosa of allergic rhinitis framework region; RAST, radioallergosorbent test; SHM, somatic hypermutation. patients. Our work is the first to demonstrate in two allergic rhinitis Copyright © 2003 by The American Association of Immunologists, Inc. 0022-1767/03/$02.00 The Journal of Immunology 5603 ϩ patients the clear presence of related IgE B cell clones in the resuspended in 20 ␮l RNase-free water. The concentration of RNA was nasal mucosa, B cells that exhibit shared ancestry (judged by iden- determined from the absorbance at 260 nm. tical CDR3/FWR4 motifs), and both shared and diverse somatic ⑀ mutations. In addition, detailed investigation enabled the detection RT-PCR of VH-C transcripts ϩ of sequences from IgA B cell clones from the nasal biopsy of one RNA (5 ␮g) was included in a 40 ␮l cDNA reaction with Moloney murine patient. These sequences exhibited shared ancestry and both shared leukemia virus reverse transcriptase (Invitrogen) using an oligo(dT) primer and diverse somatic mutations with the related IgEϩ B cell clones (Invitrogen). A total of 5 ␮l of cDNA was added to a 50 ␮l PCR, which included each VH leader region class-specific primer (VH1L-VH6L) at 0.5 isolated from the same nasal biopsy sample. IgE VH-CH region ␮M and the C⑀1-specific primer (C⑀1) at 0.5 ␮M, dNTPs at 0.25 mM, and amplification from the nasal mucosa of a healthy nonatopic subject contained 1.26 U PFU DNA polymerase (Promega). The reaction was ini- with highly elevated serum IgE was negative, implying that the tially denatured at 95°C for 2 min, then subjected to 30 cycles of denatur- families of related clones seen in allergic patients were unlikely to ation at 94°C for 1 min, annealing at 56°C for 2 min, and extension at 72°C ␮ have resulted from the random migration of IgEϩ B cells from a for 2 min before a final extension at 72°C for 10 min. A total of 5 lofthe first PCR was then transferred into a second nested PCR, which differed systemic pool. only in that it included VH class-specific primers homologous to FWR1 ⑀ ⑀ Furthermore, RT-PCR analysis demonstrated the presence of (VH1F-VH6F) and an internal C 1 primer (C 2).
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