Expression of IgE Heavy Chain Transcripts in the Sinus Mucosa of Atopic and Nonatopic Patients with Chronic Sinusitis

Abstract

We have recently shown the increased mRNA expression of interleukin (IL)-4 and IL-13 in sinus biopsies from allergic subjects with chronic sinusitis (ACS), whereas only IL-13 mRNA was elevated in biopsies obtained from nonallergic subjects with chronic sinusitis (NCS). In the lymph nodes and spleen, these cytokines may promote IgE production through transcriptional activation of the germline IgE heavy chain promoter, an event which precedes immunoglobulin isotype switching to IgE in B cells. We hypothesized that local expression of IL-4 and/or IL-13 might act by inducing germline IgE heavy chain transcript expression locally in the sinus mucosa of chronic sinusitis patients. Mucosal sinus biopsies were obtained from 13 patients with ACS, 12 subjects with NCS, and 11 normal control individuals. The numbers of B cells in the sinus mucosa were studied by immunocytochemistry with anti-CD20 monoclonal antibodies. In situ hybridization was performed using antisense radiolabeled riboprobes complementary to the IgE epsilon -heavy chain germline (Iepsilon) and heavy chain constant region (Cepsilon) gene transcripts. Riboprobes specific for the IgG gamma-heavy chain constant region (Cgamma) were used as an isotype control. Immunocytochemical analysis indicated augmented numbers of CD20-positive B cells in the biopsies obtained from ACS patients compared with NCS subjects (P < 0.05) and normal control subjects (P < 0.01). Statistically significant increases were observed in the numbers of cells expressing Iepsilon and Cepsilon transcripts in the sinus mucosa of ACS patients compared with those with NCS (P < 0. 001) and normal controls (P < 0.001), while Cgamma RNA expression did not differ significantly between the groups. In three randomly selected ACS biopsies, 92-100% of cells expressing Cepsilon transcripts and 100% of Iepsilon RNA-positive cells coexpressed CD20 immunoreactivity. Cells expressing Cepsilon transcripts were also significantly increased in NCS compared with normal controls (P < 0. 05). The results of this study suggest that local IgE class switching occurs in the pathogenesis of ACS and that ACS and NCS are both associated with increased expression of Cepsilon transcripts.

SεSμ and SεSγ Switch Circles in Human Nasal Mucosa Following Ex Vivo Allergen Challenge: Evidence for Direct as Well as Sequential Class Switch Recombination

“…The IgE self-sufficiency of the nasal mucosa may also explain how many individuals diagnosed as nonatopic, based on skin prick tests and low serum IgE levels, nevertheless manifest allergy-like symptoms. Indeed, elevated levels of ⑀ GL transcripts and mature ⑀ mRNA have been observed within the ethmoid sinus and the lung even in individuals diagnosed with nonatopic sinusitis and asthma (23,24). Interestingly, these data parallel observations of IgA isotype switching within the gut lamina propria (38), suggesting that local synthesis of Igs may be a property of peripheral tissues strategically located at the site of Ag entry.…”

“…Although isotype switching has classically been considered an event restricted to germinal centers within lymph nodes and spleen, ⑀ GL transcripts have been observed within nasal (22), ethmoidal (23), and bronchial (24) biopsies of individuals with rhinitis, sinusitis, and asthma following in vivo allergen exposure. Furthermore, the nasal mucosa from individuals with allergic rhinitis produces ⑀ GL transcripts following ex vivo allergen challenge (25).…”

Local IgE and the Future of Allergy Care

“…In 1998, Ghaffar et al, while studying individuals with chronic rhinosinusitis (CRS) with and without evidence of atopic disease on SPT, determined by immunocytochemistry of the nasal mucosa that the B cell population was significantly higher in the atopic CRS group [11]. In this study, in situ hybridization was used to analyze mRNA transcripts as an early indicator of class switching to IgE in B cells, which were found to be elevated in both atopic and non-atopic CRS individuals, compared to that in healthy controls, though significantly higher in atopic individuals.…”

“…Likewise, levels of IgE in the serum may need to also reach a threshold before they can be transported to a predetermined local region. Studies have demonstrated that local IgE in the sinonasal mucosa is more likely to be detected when total IgE levels in the serum are elevated or if the SPT grade is higher [7,11,47 •• ]. Currently, the signals which are orchestrating this complex transit system for antigen-specific IgE are largely unknown.…”

Local and Systemic IgE in the Evaluation and Treatment of Allergy

“…It has been suggested that prior work evidencing local IgE synthesis in nasal tissue is applicable to the pulmonary system as well. 8,76,77 ANTIGEN SPECIFICITY OR DISORDERED PRODUCTION?…”