Regulatory B cells in allergic rhinitis and allergen immunotherapy
File(s)
Author(s)
Palmer, Elizabeth
Type
Thesis or dissertation
Abstract
Regulatory B cells (Breg) are a subset of B cells with enhanced propensity for IL-10 production that play essential roles in maintaining peripheral tolerance. Allergic diseases (AD), such as allergic rhinitis (AR), arise due to loss of tolerance to sensitising allergen in predisposed atopic individuals, resulting in induction of IgE+ B cells and T helper 2 (TH2) and allergen specific TH2A cellular responses. Allergen immunotherapy (AIT) remains the only disease-curative treatment for AD, however, the exact role of IL-10+ Breg cells in AR pathophysiology and AIT, remains unclear. This thesis aims to evaluate IL-10+ Breg cellular subsets in AR, non-atopic controls (NAC), and AIT-treated patients, and assess the capability of IL-10+ Breg cells to modulate allergen-driven TH2, TH2A and regulatory T cell (Treg) responses.
Frequency and IL-10 propensity of heterogenous peripheral IL-10+ Breg cell subsets were significantly dysregulated in AR compared to NAC. Enumeration of IL-10+ Breg cells in a cross-sectional study demonstrated the ability of AIT to significantly restore IL-10+ Breg frequencies in GPA. Moreover, preclinical studies revealed novel AIT approaches utilising allergen-carrier systems demonstrated significant immunogenicity through the induction of IL-10+ Breg cells. Alternative short-term AIT regimens substantially induced systemic and local blocking IgA and IgG antibody responses during a Phase III clinical study, indirectly evidencing AIT-mediated induction of B cell isotype switch towards protective antibodies. Additionally, functional co-culture systems revealed IL-10+ Breg cells suppressed allergen-driven TH2/TH2A cells in parallel to promotion of Treg cellular responses, partially mediated by IL-10.
Collectively, these findings demonstrate attenuation of IL-10+ Breg cells contribute towards AR disease pathophysiology and highlight this dearth may result in loss of regulation of TH2/TH2A-orchestrated allergic inflammation. Allergen-carrier systems and short-term AIT regimens demonstrate capability to induce IL-10+ B cells and protective antibody production, giving prominence to their potential therapeutic use for the treatment of AD.
Frequency and IL-10 propensity of heterogenous peripheral IL-10+ Breg cell subsets were significantly dysregulated in AR compared to NAC. Enumeration of IL-10+ Breg cells in a cross-sectional study demonstrated the ability of AIT to significantly restore IL-10+ Breg frequencies in GPA. Moreover, preclinical studies revealed novel AIT approaches utilising allergen-carrier systems demonstrated significant immunogenicity through the induction of IL-10+ Breg cells. Alternative short-term AIT regimens substantially induced systemic and local blocking IgA and IgG antibody responses during a Phase III clinical study, indirectly evidencing AIT-mediated induction of B cell isotype switch towards protective antibodies. Additionally, functional co-culture systems revealed IL-10+ Breg cells suppressed allergen-driven TH2/TH2A cells in parallel to promotion of Treg cellular responses, partially mediated by IL-10.
Collectively, these findings demonstrate attenuation of IL-10+ Breg cells contribute towards AR disease pathophysiology and highlight this dearth may result in loss of regulation of TH2/TH2A-orchestrated allergic inflammation. Allergen-carrier systems and short-term AIT regimens demonstrate capability to induce IL-10+ B cells and protective antibody production, giving prominence to their potential therapeutic use for the treatment of AD.
Version
Open Access
Date Issued
2024-04-28
Date Awarded
2024-08-01
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Shamji, Mohamed
Durham, Stephen
Kappen, Jasper
Layhadi, Janice
Sponsor
National Heart and Lung Institute
Publisher Department
National Heart and Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)