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This study provides the first detailed characterization of allergen-specific B cells before and after bee venom tolerance induction. The observed B-cell responses in both venom immunotherapy-treated patients and naturally exposed beekeepers suggest a similar functional immunoregulatory role for B cells in allergen tolerance in both groups. These findings can be investigated in other AIT models to determine their potential as biomarkers of early and successful AIT responses.

Background: Long-term follow-up of allergen-specific B cells in terms of immunoglobulin isotype expression, plasmablast differentiation, and regulatory B (Breg) cell development during allergen-specific immunotherapy (AIT) has not been reported. Objective: Allergen-specific B-cell responses during 2 years of house dust mite AIT were compared between responder and nonresponder patients. Methods: B cells specific for Der p 1 were detected by using the fluorochrome-labeled allergen method. The frequency of IgA-, IgG 1-and IgG 4-switched Der p 1-specific B cells, plasmablasts, and IL-10and IL-1 receptor antagonist (IL-1RA)-producing Breg cells were investigated and correlated to clinical response to AIT. Results: Sixteen of 25 patients completed the 2-year study. Eleven responder patients showed a successful response to AIT, as measured by a decrease in symptom-medication scores from 13.23 6 0.28 to 2.45 6 0.24 (P 5 .001) and a decrease in skin prick test reactivity to house dust mite from 7.0 6 1.3 to 2.7 6 0.5 mm (P 5 .001). IgG 4 1 and IgA 1 Der p 1-specific B cells showed a significant increase after AIT, with a significantly greater frequency in responders compared with nonresponders in the IgG 4 1 but not the IgA 1 fraction. The frequency of plasmablasts and IL-10-and/or IL-1RA-producing Breg cells was greater among responders compared with nonresponders after 2 years. The increased frequency of Der p 1-specific IgG4 1 B cells, plasmablasts, and IL-10 1 and dual-positive IL-10 1 IL-1RA 1 Breg cells significantly correlated with improved clinical symptoms over the course of AIT. Conclusion: Allergen-specific B cells in patients responding to AIT are characterized by increased numbers of IgA-and IgG 4expressing Der p 1-specific B cells, plasmablasts, and IL-10 1 and/or IL-1RA 1 Breg cells.

Summary B cells thwart antigenic aggressions by releasing immunoglobulin M (IgM), IgG, IgA and IgE, which deploy well-understood effector functions. In contrast, the role of secreted IgD remains mysterious. We found that some B cells generated IgD-secreting plasma cells following early exposure to external soluble antigens such as food proteins. Secreted IgD targeted basophils by interacting with the CD44-binding protein galectin-9. When engaged by antigen, basophil-bound IgD incresed basophil secretion of interleukin-4 (IL-4), IL-5 and IL-13, which facilitated the generation of T follicular helper type-2 cells expressing IL-4. These germinal center T cells enhanced IgG1 and IgE but not IgG2a and IgG2b responses to the antigen initially recognized by basophil-bound IgD. In addition, IgD ligation by antigen attenuated allergic basophil degranulation induced by IgE co-ligation. Thus, IgD may link B cells with basophils to optimize humoral T helper type-2-mediated immunity against common environmental soluble antigens.

Background: Allergen-specific immunotherapy (AIT) is the only available treatment for allergic diseases that can induce specific immune tolerance to allergens. The key mechanisms involved in this process include changes in allergen-specific regulatory T (Treg) cells. Methods:We studied 25 allergic rhinitis patients undergoing subcutaneous house dust mite-specific immunotherapy. Peripheral blood mononuclear cells were studied before and after 10, 30 weeks, and 3 years of AIT. Der p 1-specific T regulatory cell responses were investigated by characterization of Der p 1-MHC class II tetramerpositive cells and correlated with nasal symptom score. Results: Twelve of 25 AIT patients matched with their MHC class II expression to the Der p 1 peptide-MHC class II tetramers. A significant increase in the numbers of Der p 1-specific FOXP3 + Helios + CD25 + CD127 − Treg cells after 30 weeks was observed, which slightly decreased after 3 years of AIT. In contrast, Der p 1-specific immunoglobulin-like transcript 3 (ILT3) + CD25 + Treg cells decreased substantially from baseline after 3 years of AIT. ILT3 + Treg cells displayed compromised suppressive function and low FOXP3 expression. In addition, Der p 1-specific IL-10 and IL-22 responses have increased after 30 weeks, but only IL-10 + Der p 1-specific Treg cells remained present at high frequency after 3 years of AIT. Increased number of FOXP3 + Helios + and IL-10 + and decreased ILT3 + Treg cell responses correlated with improved allergic symptoms. Conclusion: The results indicate that AIT involves upregulation of the activated allergen-specific Treg cells and downregulation of dysfunctional allergen-specific Treg cell subset. Correction of dysregulated Treg cells responses during AIT is associated with improved clinical response. K E Y W O R D Sallergen-specific T cells, antigen-specific immunotherapy, house dust mite allergy, Treg Abbreviations: AIT, antigen-specific immunotherapy; AR, allergic rhinitis; HDM, house dust mite; ILT3, immunoglobulin-like transcript 3; Treg, T regulatory.

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Background: Asthma patients present with distinct immunological profiles, with a predominance of type 2 endotype. The aim of this study was to investigate the impact of high-altitude treatment on the clinical and immunological response in asthma. Methods: Twenty-six hospitalized asthma patients (nine eosinophilic allergic; EA, nine noneosinophilic allergic; NEA and eight noneosinophilic nonallergic; NN) and nine healthy controls in high altitude for 21 days were enrolled in the study. We assessed eosinophils, T cells, Tregs, and innate lymphoid cells (ILC) from peripheral blood using flow cytometry. Results: The number of eosinophils (both resting and activated) and chemoattractant receptor homolog expressed on Th2 cells (CRTH2)-expressing CD4 + and CD8 + T cells decreased significantly in EA patients after altitude treatment. The frequency of CRTH2 + Tregs as decreased significantly in all the asthma phenotypes as well as the frequency of ILC2 was significantly reduced in EA after altitude treatment. After 21 days of altitude therapy, CRTH2-expressing ILC2, CD4 + and CD8 + T cells and Treg cells showed attenuated responses to exogenous PGD2. Furthermore, PGD2 signaling via CRTH2 was found to diminish the suppressive function of CRTH2 + Tregs which partially normalized during high-altitude treatment. Improved asthma control was particularly evident in allergic asthma patients and correlated with decreased frequencies of CRTH2 + Treg cells in EA patients. Serum IL-5 and IL-13 decreased during climate treatment in asthma patients with high baseline levels. Conclusions: Asthma treatment in high altitude reduced the type 2 immune response, corrected the increased CRTH2 expression and its dysregulated functions. | 85 BOONPIYATHAD eT Al.