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

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 epsilon immunoglobulin heavy-chain germline gene transcripts (GLTs; epsilonGLTs), epsilon circle transcripts (CTs; Ivarepsilon-Cmu CT or Ivarepsilon-Cgamma CT), and mRNA encoding the heavy chain of IgE (epsilon 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 varepsilonGLT and AID mRNA were detectable in the bronchial mucosa of subjects in all 4 groups. In contrast, Iepsilon-Cmu CT, Ivarepsilon-Cgamma CT, and epsilon 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 epsilonGLT 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.

Allergen drives class switching to IgE in the nasal mucosa in allergic rhinitis.

IgE-expressing B cells are over 1000 times more frequent in the nasal B cell than the peripheral blood B cell population. We have investigated the provenance of these B cells in the nasal mucosa in allergic rhinitis. It is generally accepted that expression of activation-induced cytidine deaminase and class switch recombination (CSR) occur in lymphoid tissue, implying that IgE-committed B cells must migrate through the circulation to the nasal mucosa. Our detection of mRNA for activation-induced cytidine, multiple germline gene transcripts, and epsilon circle transcripts in the nasal mucosa of allergic, in contrast to nonallergic control subjects, however, indicates that local CSR occurs in allergic rhinitis. The germline gene transcripts and epsilon circle transcripts in grass pollen-allergic subjects are up-regulated during the season and also when biopsies from allergic subjects are incubated with the allergen ex vivo. These results demonstrate that allergen stimulates local CSR to IgE, revealing a potential target for topical therapies in allergic rhinitis.

The biology of IGE and the basis of allergic disease.

Allergic individuals exposed to minute quantities of allergen experience an immediate response. Immediate hypersensitivity reflects the permanent sensitization of mucosal mast cells by allergen-specific IgE antibodies bound to their high-affinity receptors (FcepsilonRI). A combination of factors contributes to such long-lasting sensitization of the mast cells. They include the homing of mast cells to mucosal tissues, the local synthesis of IgE, the induction of FcepsilonRI expression on mast cells by IgE, the consequent downregulation of FcgammaR (through an insufficiency of the common gamma-chains), and the exceptionally slow dissociation of IgE from FcepsilonRI. To understand the mechanism of the immediate hypersensitivity phenomenon, we need explanations of why IgE antibodies are synthesized in preference to IgG in mucosal tissues and why the IgE is so tenaciously retained on mast cell-surface receptors. There is now compelling evidence that the microenvironment of mucosal tissues of allergic disease favors class switching to IgE; and the exceptionally high affinity of IgE for FcepsilonRI can now be interpreted in terms of the recently determined crystal structures of IgE-FcepsilonRI and IgG-FcgammaR complexes. The rate of local IgE synthesis can easily compensate for the rate of the antibody dissociation from its receptors on mucosal mast cells. Effective mechanisms ensure that allergic reactions are confined to mucosal tissues, thereby minimizing the risk of systemic anaphylaxis.

Local IgE synthesis in allergic rhinitis and asthma.

Local IgE production has been a contentious concept for over 40 years. Although a host of clinical observations suggested a local source of IgE, co-localization of IgE to B cells in the nasal mucosa could not be demonstrated. In contrast, igE-producing B cells were observed in local lymphoid tissue. Definitive proof of local IgE synthesis in the nasal mucosa has now become available. Here, we review the recent developments in local IgE research in allergic rhinitis and asthma within their historical context, and speculate on the implications of both local IgE synthesis and ongoing research into local immunoglobulin isotype switching for patient therapy.

Increases in allergen-specific IgE in BAL after segmental allergen challenge in atopic asthmatics.

IgE is important in both early and late allergic responses. Increases in the numbers of RNA transcripts coding for IgE have been observed in the bronchial mucosa of asthmatics and in the nasal mucosa of hay fever patients both during natural allergen exposure and after nasal allergen challenge, suggesting that IgE may be synthesized locally in the mucosa. In this study we have examined bronchoalveolar lavage (BAL) taken before and 24 h after bronchoscopic segmental allergen challenge from 18 atopic asthmatic patients, looking for evidence of increases in IgE protein. Allergen-specific IgG and total and allergen-specific IgE were measured in BAL using a fluoroenzyme immunoassay. There was a significant increase in allergen-specific IgE (Ku/L) in the BAL after allergen challenge [before [median (interquartile range)] 0 (0, 0); after 0.35 (0, 1.87): p = 0.009] which was not observed for allergen-specific IgG (p = 1.0) or for IgE specific to an allergen to which the subject was sensitized but was not used for provocation (p = 1.0). Correction for corresponding increases in total IgE, albumin, and urea in BAL did not affect the observed changes in allergen-specific IgE. These data indicate that allergen provocation results in a selective local accumulation of isotype-specific and allergen-specific IgE antibody within the bronchi, independent of alterations in circulating IgE.