Basic and clinical immunology
Class switch recombination to IgE in the bronchial mucosa of atopic and nonatopic patients with asthma

https://doi.org/10.1016/j.jaci.2006.09.045Get rights and content

Background

Class switching from IgM/IgG/IgA to IgE is required for B cells to express IgE. This requires class switch recombination in the Ig heavy-chain gene locus. It is generally believed that class switch recombination occurs in lymphoid tissue, but it was recently shown that class switching to IgE occurs in the nasal mucosa in allergic rhinitis.

Objective

We aimed to determine whether class switching to IgE also occurs in the bronchial mucosa in asthma, and to look for possible differences/similarities between atopic and nonatopic asthma.

Methods

We have used RT-PCR to examine ɛ immunoglobulin heavy-chain germline gene transcripts (GLTs; ɛGLTs), ɛ circle transcripts (CTs; Iɛ-Cμ CT or Iɛ-Cγ CT), and mRNA encoding the heavy chain of IgE (ɛ mRNA) and activation-induced cytidine deaminase (AID) in bronchial biopsies from atopic patients with asthma, nonatopic patients with asthma, atopic controls without asthma, and nonatopic controls without asthma (10 subjects in each group).

Results

The ɛGLT and AID mRNA were detectable in the bronchial mucosa of subjects in all 4 groups. In contrast, Iɛ-Cμ CT, Iɛ-Cγ CT, and ɛ mRNA were detectable in the bronchial mucosa of the majority of both atopic and nonatopic patients with asthma, but rarely in the controls without asthma.

Conclusion

The bronchial mucosa is a site primed in all individuals for class switching to IgE, because of B-cell expression of ɛGLT and AID mRNA. However, it is only in patients with asthma, regardless of atopic status, that class switching to IgE occurs.

Clinical implications

Our findings reveal prospects for local targeting of the Ig class switch mechanism in the management of atopic and nonatopic asthma.

Section snippets

Clinical protocol

Bronchial biopsies were obtained at fiberoptic bronchoscopy from atopic patients with asthma (AAs), nonatopic patients with asthma (NAs), atopic controls without asthma (ACs), and nonatopic controls without asthma (NCs; n = 10 in each group). Asthma was defined as a clear history of relevant symptoms with either reversible airways obstruction (≥15% variability in the FEV1 either spontaneously or after inhaled albuterol, 200 μg), and/or a histamine PC20 provocation test result <8 mg/mL

ɛGLT expression in the bronchial mucosa

ɛ Germline transcription marks the first step in the commitment of B cells to the synthesis of IgE. We sought ɛGLT in bronchial mucosal biopsies from 10 patients in each of the 4 subject groups. As shown in Fig 1, A, and Table II, ɛGLT expression was detected in 8 of 10 AAs, 7 of 10 NAs, 5 of 10 ACs, and 1 of 10 NCs.

ɛCT expression in the bronchial mucosa

DNA recombination, producing ɛCT, marks the irreversible step in the commitment of B cells to the synthesis of IgE. We sought ɛCT in the same biopsies used to detect GLT. IgM to IgE

Discussion

We have investigated B-cell IgE switching and synthesis in the bronchial mucosa of patients with asthma, and provide the first direct and definitive evidence that bronchial mucosal B cells undergo class switch recombination from IgM and IgG to IgE in situ. Our data would suggest that this phenomenon is a particular feature of asthma, and occurs irrespective of the atopic status of the patients with asthma as assigned by conventional SPT or in vitro testing to detect allergen-specific IgE. The

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    Supported by Asthma UK Grant #03/055 and MRC Cooperative Component Grant #G0200485.

    Disclosure of potential conflict of interest: H. J. Gould and P. Takhar have received grant support from Asthma UK and the Medical Research Council. L. Smurthwaite is now employed by Asthma UK but at the time of contributing to this article was not in their employment. B. J. O'Connor has consulting arrangements with GlaxoSmithKline, AstraZeneca, Altana, Celgene, Pfizer, Boehringer Ingelheim, Inflazyme, NiCox, Theravance, Pharmadigm, and Inverseon; has received grant support from GlaxoSmithKline, AstraZeneca, Altana, Aventis, Novartis, Pfizer, Inflazyme, NiCox, Pharmadigm, and Oxagen; and is on the speakers' bureau for AstraZeneca, GlaxoSmithKline, Pfizer, Bushranger Ingelheim, and Altana. S. R. Durham has consulting arrangements with ALK-Abelló, GlaxoSmithKline, and Novartis, has received grant support from ALK-Abelló, GlaxoSmithKline, and UCB; and is on the speakers' bureau for ALK-Abelló and Allergy Therapeutics. The rest of the authors have declared that they have no conflict of interest.

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