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Blocking IgD, a potential novel therapeutic strategy for eosinophilic CRSwNP

Published online: August 10, 2018

Chronic rhinosinusitis (CRS) is a highly prevalent chronic inflammatory disease of the paranasal sinuses. Clinically, it is classified into two subgroups, chronic rhinosinusitis (CRSwNP) with and without nasal polyps (CRSsNP). Based on the extent of eosinophilic inflammation, CRSwNP is further subclassified into eosinophilic and non-eosinophilic types. Generally, eosinophilic CRSwNP is characterized by a TH2-biased immune response and local IgE production, whereas non-eosinophilic CRSwNP and CRSsNP are more neutrophilic and type 1/ type 17 response dominant. Current treatment approaches for CRS include medical treatments and endoscopic sinus surgery. However, a significant number of patients respond poorly to the current treatments, especially those with eosinophilic CRSwNP. Previous studies have implicated an involvement of local immunoglobulin (Ig), including IgE, IgG, IgA and IgD, in the pathogenesis of CRS. Compared to other Igs, IgD remains an enigmatic antibody class. Although up-regulation of IgD in sinonasal mucosa has been reported in CRS, its function remains unclear.

In a recent study published in The Journal of Allergy & Clinical Immunology (JACI), Zhai and colleagues provided new insight into the pathogenesis of eosinophilic CRSwNP by characterizing the regulatory function of IgD-activated mast cells on B cell antibody production, particularly IgE production. The researchers explored the expression, specificity, and function of secreted IgD in CRS. The expression of IgD was analyzed by RT-PCR (reverse transcription polymerase chain reaction) and ELISA (enzyme-linked immunosorbent assay). IgD+ cells and IgD+ cell subsets were detected by immunohistochemistry, immunofluorescence, and flow cytometry. HMC-1 cells, a human mast cell line, and nasal mast cells purified from eosinophilic polyps were co-cultured with naïve B cells to study the effect of IgD-activated mast cells on B cell Ig production. The antigen specificity of nasal IgD was investigated by ELISA.

The authors found that the mRNA expression of the immunoglobulin heavy constant delta gene, the numbers of IgD+ cells, and the protein levels of secretory IgD were increased locally, but not systemically, in both CRSsNP and CRSwNP, indicating a localized IgD response in CRS. Eosinophilic CRSwNP demonstrated the highest levels of local IgD production, suggesting a role of IgD in the pathogenesis. In addition to IgD+IgM- plasmablasts, the study found that IgD-bound mast cells constituted the second largest population of IgD+ cells in eosinophilic CRSwNP. Crosslinking IgD induced serum pre-incubated HMC-1 cells and polyp mast cells to produce B-cell activating factor, IL-21, IL-4 and IL-13, and to promote IgM, IgG, IgA, and IgE production from B cells. In eosinophilic nasal polyps, the expression of those B cell-stimulating factors in mast cells and close contacts between mast cells and B cells also were found. Moreover, positive correlations of total IgD with total IgE and eosinophilia were discovered in eosinophilic CRSwNP. IgD with binding activity to lipopolysaccharide was upregulated in both eosinophilic and non-eosinophilic CRSwNP, whereas up-regulation of specific IgD against house dust mites was only discovered in eosinophilic CRSwNP.

Overall, the authors showed an enhanced localized IgD response in both CRSsNP and CRSwNP, potentially induced by bacteria or aeroallergens. IgD-activated mast cells facilitate local IgE production and exaggerate eosinophilic inflammation in CRSwNP, and thereby contribute to disease progression. Blocking IgD represents a potential novel therapeutic strategy to alleviate local IgE production and eosinophilic inflammation in CRSwNP.

The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.

Immunoglobulin D-activated mast cells induce IgE synthesis in B cells in nasal polyps