Introduction
Hypersensitivity immune responses to allergens and other environmental factors, including helper T cell cytokine responses and the production of mmunoglobulin E (IgE) antibodies, are key immunologic features of allergic diseases [
1]. Memory B cells, plasmablasts and antibody-producing cells arise during adaptive humoral immune responses in germinal center (GC) [
2‐
4]. Regulatory CD24
hiCD27
+ B cells and CD24
hiCD38
hi transitional B cells have been identified to down-regulate allergic and auto-immune inflammation, suppress pro-inflammatory Th1/Th17 responses and induce regulatory T cells (Tregs) by producing IL-10 and/or TGF-β [
5‐
7]. Sumimoto K et al. [
8] found that circulating CD24
hiCD27
+ B cells decreased while CD24
hiCD38
hi B cells increased in patients with type I autoimmune pancreatitis. However, circulating CD24
hiCD27
+ B cells and CD24
hiCD38
hi B cells decreased and functionally impaired in psoriatic arthritis and systemic sclerosis [
9,
10]. Van der Vlugt LE et al. [
11] found that CD24
hiCD27
+ B cells from patients with allergic asthma have impaired regulatory function in response to lipopolysaccharide. Investigations have also revealed that the IgE level can be regulated by regulatory B cells by producing IL-10 [
12]. However, the fundamental question of whether B cell response and IgE antibody production are regulated by the same immunological pathway in allergic asthma is still a matter of debate.
T follicular helper (Tfh) cells are distinguished from other CD4
+ T cells by their selective role in orchestrating GC responses and in promoting the development of memory B cells and long-lived plasma cells. Previous studies demonstrated that Tfh cells orchestrated systemic IgE production in patients with allergic asthma [
11,
13]. Yao Y et al. [
14] also found a positive correction between Tfh2 subtypes and IgE in patients with allergic asthma. Achour A et al. [
15] found human regulatory B cells control Tfh cell development and maturation, and further suppress the antibody secretion. However, understanding the role of Tfh cells in the regulation of IgE antibodies in allergic immune responses to allergens remains limited.
Recently, T peripheral helper (Tph) cells were found in the peripheral blood to possess B cell help functions like Tfh cells [
16,
17]. Tph cells possess phenotypic characteristics similar to Tfh cells, such as inducible T-cell costimulator (ICOS), programmed cell death 1-positive (PD-1), the cytokines interleukin (IL)-21, chemokine (C-X-C motif) ligand 13, thus having the ability to regulate B-cell differentiation [
18]. However, Tph cells are distinguished from Tfh cells by their lacking the expression of chemokine C-X-C receptor (CXCR) 5. Interestingly, CXCR5
− Tph cells have hitherto been divided into three subtypes based on differential expression of CXCR3 and C–C receptor 6 (CCR6): CXCR3
+CCR6
− Tph1, CXCR3
−CCR6
− Tph2, and CXCR3
−CCR6
+ Tph17 [
19]. Recently, studies found increased peripheral blood circulation Tph cells in patients with IgG4-related disease (IgG4-RD) [
20,
21], rheumatoid arthritis (RA) [
18,
22], systemic lupus erythematosus (SLE) [
23,
24] and Sjögren's Syndrome (SS) [
25]. Further, Tph cells in patients with IgG4-RD contribute to B cell reaction and plasma cell formation [
21,
26,
27]. Moreover, the increased circulating Tph cells is positively related to the disease activity of SLE [
23,
24,
28]. However, whether circulating Tph cell subsets contributes to the regulation of IgE antibodies in allergic immune responses deserves further investigation.
Accordingly, to better understand the contribution of B cell subsets, Tph cell subsets and Tfh cell subsets to the production of IgE antibodies in response to allergens and to elucidate their roles in allergic immune responses, we analyze circulating B cell subsets, Tph cell subsets and Tfh cell subsets in children with allergic asthma using multicolor flow cytometry in the current study. Our observations suggest that CD24hiCD38hi transitional B cells, CD24hiCD27+ B cells, CXCR5− Tph, CXCR5−ICOS+PD-1+ Tph, Tph2 subtypes and Tfh2 subtypes could play a key role in the regulation of IgE antibody production. Our observations suggest CD24hiCD38hi transitional B cells, CD24hiCD27+ B cells, CXCR5−ICOS+PD-1+ Tph and Tph2 subtypes indreased in children with allergic asthma. Hence, allergic immune responses might be mediated by CD24hiCD38hi transitional B cells, CD24hiCD27+ B cells, CXCR5−ICOS+PD-1+ Tph and Tph2 subtypes.
Discussion
Allergic asthma is IgE-mediated type I hypersensitivity reaction to allergens [
29]. Efforts are being made to understand the dysregulation of IgE production in patients with allergic asthma. In the current study, we analyzed changes in circulating B cell subsets, Tfh cell subsets, and Tph cell subsets in children with allergic asthma. A novel concept derived from our study was IgE antibody production was closely related to CD27
+CD38
+ plasmablasts, CD24
hiCD38
hi transitional B cells, CXCR5
− Tph, CXCR5
−ICOS
+PD-1
+ Tph, Tph2 subtypes and Tfh2 subtypes. In the current study, we sought to obtain a better understanding of B cell response in children with allergic asthma.
CD27 is a recognized surface marker of memory B cells [
30]. We found increased CD19
+ B cells, CD27
+ memory B cells and CD27
+CD38
+ plasmablasts while decreased CD27
− naïve B cells in children with allergic asthma. Moreover, we found a weak positive correlation between CD27
+CD38
+ plasmablasts and serum total IgE level. These results demonstrated that the allergen induced B cell activation and a high plasmablasts response, consistent with previous studies [
4,
31,
32]. Currently, Flores-Borja Fet al. [
33] and Noble A et al. [
34] reported that CD24
hiCD38
hi B cells in asthmatic mice induced CD4
+CD25
− T effector cells transform into Tregs, so as to inhibit allergic airway inflammation. Our observations, for the first time, demonstrated that increased CD24
hiCD38
hi transitional B cells in children with allergic asthma were weakly positively correlated with serum total IgE level, indicating that CD24
hiCD38
hi transitional B cells may emerged after exposure to allergens.
We also found significantly decreased CD24
hiCD27
+ B cells in children with allergic asthma, consistent with previous study [
1,
2,
4,
6,
11]. Therefore, together with our findings, indicate that CD27
+CD38
+ plasmablasts and CD24
hiCD38
hi transitional B cells could play an important role in IgE antibody production.
Tph cells hardly express CXCR5 [
24,
35], and can promote B cell differentiation and the production of autoantibodies [
28,
36,
37]. Previous studies have shown that Tph cells regulate B cell response and plasma cell differentiation in rheumatoid arthritis [
18]. Ekman I et al
. found increased circulating Tph cells in children with newly diagnosed type I diabetes, which has the potential to further become a biomarker of disease progress, and monitor the effect of immunotherapy [
38]. Recent study have shown that Tph cells are associated with serum IgG level and may be a biomarker for monitoring disease activity [
26]. In the current study, we observed increased frequency of CXCR5
− Tph, CXCR5
−ICOS
+ Tph, CXCR5
−ICOS
+PD-1
+ Tph, Tph2 and Tph17 subtypes in children with allergic asthma. Most interestingly, CXCR5
− Tph, CXCR5
−ICOS
+PD-1
+ Tph and Tph2 subtypes were weakly positively correlated with serum total IgE level, suggesting that CXCR5
− Tph, CXCR5
−ICOS
+PD-1
+ Tph and Tph2 subtypes may play an important role in the excessive accumulation of serum total IgE in allergic asthma.
Previous reports have demonstated that a skewed distribution of circulating Tfh2 subtypes contributes to the pathogenesis of inflammatory airway diseases such as allergic rhinitis and asthma, and that Tfh2 subtypes promote the polarization of IgE production in patients with allergic asthma [
14,
39‐
43]. We found a lower frequency of CXCR5
+ Tfh or Tfh1 subtypes and a higher frequency of CXCR5
+ICOS
+ Tfh, CXCR
+ICOS
+PD-1
+ Tfh, Tfh2 or Tfh17 subtypes in children with allergic asthma. Our data also showed that Tfh2 subtypes were positively correlated with serum total IgE level in children with allergic asthma. Achour A et al. [
15] found that humans regulate B cells to control Tfh maturation and inhibit Tfh cell-mediated antibody secretion. Thus, decreased CD24
hiCD27
+ B cells could bring about excessive Tfh cell-dependent humoral responses and might lead to aberrant immune responses.
In summary, it has become clear that the increased CD24hiCD38hi transitional B cell, CXCR5−ICOS+PD-1+ Tph, Tph2 and Tfh2 subtypes may contribute to the development of aberrant immune responses in children with allergic asthma. Although this study was conducted in a small number of subjects, a deeper understanding of human Tph or Tfh and B cell subsets interrelations is worthy of pursuit to elaborate new therapeutic strategies in allergic asthma. Further research is required to elucidate the role of various B cell subsets, Tph and Tfh in allergic asthma.
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