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Title: Regulatory B cells in seasonal allergic rhinitis and the influence of grass pollen immunotherapy
Author: Charlesworth, James
ISNI:       0000 0004 5922 7023
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Introduction: Interleukin (IL)-10-producing B cells (Bregs) regulate immune responses in autoimmune disease; however their role in allergy is unclear. Allergen exposure in predisposed atopic individuals results in the induction of IgE-secreting B cells, crucial in the immunopathophysiology of allergic rhinitis. Allergen-specific immunotherapy (AIT) is the only disease-modifying treatment for allergic rhinitis. AIT results in long-term clinical and immunological tolerance; however, whether Bregs contribute towards AIT-induced tolerance remains unclear. Hypotheses: 1. In vitro induced IL-10-producing B cells regulate allergen-driven Th2 inflammation, 2. Bregs are present in fewer numbers in seasonal grass pollen allergic (SAR) individuals compared with healthy controls, which is restored during AIT. Methods: B cells were isolated and subjected to flow cytometry to detect surface markers and IL-10 capacity following CpG stimulation. FluoroSpot, ELISA or qPCR were used to confirm IL-10. Suppression of T cell proliferation (by CFSE) and cytokine production (by ELISA) were carried out in co-cultures. Regulatory B cells in SAR (n=14), AIT (n=18) and healthy (n=14) donors were compared. Nasal allergen challenge (NAC) was carried out, with blood taken pre and post challenge for flow cytometry. Results: CpG significantly enhanced proportions of Bregs, with enrichment particularly within CD24hiCD27+, CD5hi, PD-L1+ and CD24hiCD38hi populations. Bregs suppressed both polyclonally- and grass pollen allergen-stimulated T cells. Ex vivo, proportions of IL-10+ B cells from SAR and healthy donors matched, but were significantly greater amongst AIT donors (particularly sublingual immunotherapy - SLIT) compared to SAR. Following NAC, proportions of B cells within CD24hiCD38hi, CD5hi, CD24hiCD27hi and CD25+ subsets were significantly increased amongst non-allergic and AIT groups, but not amongst SAR donors. Conclusion: Bregs are capable of suppressing allergen induced, Th2-driven inflammation in vitro and may be involved in the induction of tolerance during allergen immunotherapy in vivo, particularly following SLIT.
Supervisor: Durham, Stephen ; Cousins, David ; Shamji, Mohamed Sponsor: Medical Research Council ; Asthma UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available