Decrease in CD38⁺ TH2A cell frequencies following immunotherapy with house dust mite tablet correlates with humoral responses

Abstract

Background In line with evidence for a role of pathogenic TH2A in seasonal allergies, we previously showed that individuals suffering from food allergy exhibited a decrease in circulating TH2A cells following multi‐food immunotherapy. Herein, we aim to confirm the decline of TH2A cells in individuals undergoing house dust mite immunotherapy (HDM‐AIT) and extend our observation to a new subset of CD38 expressing activated TH2A cells. Methods The frequencies of TH2A and CD38+ TH2A cells were analysed by flow cytometry in blood cells from 182 Japanese HDM‐allergic individuals included in a 1‐year clinical trial assessing the efficacy of HDM tablets. Interrelationship between these cellular responses and humoral mite‐specific IgE and IgG4 levels was further explored. Results A decrease in TH2A cells was observed in both active and placebo groups. Interestingly, CD38+ TH2A cell frequencies significantly decreased only in active groups. In younger individuals (16–30 years), both TH2A and CD38+ TH2A cells were significantly reduced in active groups but not in the placebo group. Significant inverse correlations were observed in the course of HDM‐AIT between changes in TH2A or CD38+ TH2A frequencies and IgG4 antibody levels. Conclusions We confirm the value of monitoring TH2A cell frequencies in allergic individuals and extend this observation to perennial allergy to HDM. We highlight the interest of CD38 to better identify the subset of TH2A cell down‐regulated by AIT. Finally, correlated cellular and humoral responses observed in immunoreactive individuals stress that coordinated pathways occur in the adaptive responses during AIT.

Coordinated IgG2 and IgE responses as a marker of allergen immunotherapy efficacy

“…The search for surrogate biomarkers of AIT efficacy has raised great interest but not yet resulted in validated candidates 14,24 . Immunological changes in peripheral blood or mucosal tissues of patients have been well‐documented in various AIT studies and include a boost of regulatory responses (e.g., innate immune markers, B and Treg cells, IgA, IgG4, and blocking factors) and a concomitant decrease of pro‐allergenic immune responses (e.g., basophils, mastocytes, innate markers, pathogenic Th2A cells, Tfh cells, and IgE) 10‐13,25‐28 . Furthermore, the induction of innate immune regulatory markers associated with dendritic cells (e.g., induction of C1q and Stabilin‐1) and detected in peripheral blood mononuclear cells (PBMCs) correlates with early onset of AIT clinical efficacy, thus emphasizing a critical role for Tregs in AIT 29‐31 …”

“…Coordinated IgG2 and IgE responses may be transient, and we may speculate that only the increase of allergen‐specific IgG2 responses will be sustained beyond the first year of HDM AIT. Such questions as well as the coordination with other humoral (e.g., IgA) 27,28 or cellular (e.g., ILC2, TH2A) 25,26 immune responses during AIT will need to be addressed in further dedicated AIT studies.…”

“…14,24 Immunological changes in peripheral blood or mucosal tissues of patients have been well-documented in various AIT studies and include a boost of regulatory responses (e.g., innate immune markers, B and Treg cells, IgA, IgG4, and blocking factors) and a concomitant decrease of pro-allergenic immune responses (e.g., basophils, mastocytes, innate markers, pathogenic Th2A cells, Tfh cells, and IgE). [10][11][12][13][25][26][27][28] Furthermore, the induction of innate immune regulatory markers associated with dendritic cells (e.g., induction of C1q and Stabilin-1) and detected in peripheral blood mononuclear cells (PBMCs) correlates with early onset of AIT clinical efficacy, thus emphasizing a critical role for Tregs in AIT. [29][30][31] Monitoring of innate immune cellular responses during AIT also indicated a decrease of pro-inflammatory monocytes as well as type 2 and 3 innate lymphoid cells (ILC2s/ILC3s) confirming the importance of innate immunity in the development of allergy inflammation and its resolution.…”

“…[29][30][31] Monitoring of innate immune cellular responses during AIT also indicated a decrease of pro-inflammatory monocytes as well as type 2 and 3 innate lymphoid cells (ILC2s/ILC3s) confirming the importance of innate immunity in the development of allergy inflammation and its resolution. 32 The increase of regulatory IL-10-producing ILC2s, likely associated with the maintenance of the epithelial cell integrity, 33 Such questions as well as the coordination with other humoral (e.g., IgA) 27,28 or cellular (e.g., ILC2, TH2A) 25,26 immune responses during AIT will need to be addressed in further dedicated AIT studies.…”

Th2A cells: The pathogenic players in allergic diseases

“…Meanwhile, Luce et al. observed the frequency of CD38 + Th2A cells to be only significantly decreased in patients who received the treatment of HDM tablets, demonstrating the potential value of CD38 + Th2A cells as the new biomarker of asthma ( 37 ). In the meantime, Morgan et al.…”