What Determines an Antigen‐Specific IgE Isotypic Response?—A Hypothesis

Abstract

Two models to account for an antigen-specific IgE isotypic response are proposed. Both models assume a first-tiered IgE production induced by antigen and IL-4; however, the processed IgE or Ag-IgE immune complexes stimulate T epsilon cells differently in the two models. In Model I, we propose that T epsilon cells express conventional T-cell receptors which recognize IgE isotypic determinants. Model IA proposes that IgE fragments are processed and recognized along with class II MHC molecules, and T epsilon cell preferentially act on antigen-activated IgE-committed B epsilon cells via recognition of processed membrane IgE determinants but not antigens; thus T epsilon cells are in principle capable of modulating non-antigen-specific polyclonal IgE responses. Model IB proposes that IgE function as a class-restriction determinant for nominal antigens analogous to that of class II molecules, and T epsilon cells exert stringent antigen-specific IgE isotypic responses by recognizing nominal antigens restricted to IgE. T epsilon cells thus exert antigen-specific and IgE concerted immunoregulation, and do not participate in modulating polyclonal IgE production. Model II proposes a heterotypic interaction of IgE with a cell interaction receptor (or IgE Fc receptor) on T cells. T epsilon cells modulate antigen-specific IgE isotypic responses via ligation with IgE-antigen immune complexes on B-cell surface; thus, T epsilon cells in principle contribute to polyclonal IgE responses.

Abrogation and homeostatic restoration of IgE responses by a universal IgE allergy CTL vaccine—The three signal self/non‐self/self (S/NS/S) theory

“…In the current applied vaccinology, prolonged effector CD8 CTLs against the nECPs on IgE committed B cells and plasma cells risks deletion of IgE system resulting in the long-term IgE deficiency as observed in experimental perinatal IgE immunization via the breaking of IgEclass-restricted central tolerance in the laboratory [1,[3][4][5][6][7]. As shown in Figure 6 Noticeably, the nECP tetramer-specific CD4+ Tregs converted from CD8+ CTLs maintained the expression of the cytokine biomarkers CD127/IFN-γ on CTLs, leaving the footprint of their origin (Figure 1c).…”

“…IgE is a critical class of immunoglobulin playing a crucial gatekeeper function to amplify IgE‐mediated defence to parasites and other functions in the mucosal respiratory and the GI tract microenvironment. [1, 2] On the other hand, dysregulated IgE production is the central culprit for mediating type 2 immediate hypersensitivity, accounting for allergic asthma, rhinitis, urticaria, peanut allergy and food allergy in more than 40% of the worldwide population.…”

Abrogation and Homeostatic Restoration of IgE Responses by a Universal IgE Allergy CTL Vaccine—The Three Signal Self/Non-Self/Self (S/NS/S) Model

“…In the current applied vaccinology, prolonged effector CD8 CTLs against the nECPs on IgE committed B cells and plasma cells risks deletion of IgE system resulting in the long-term IgE deficiency as observed in experimental perinatal IgE immunization via the breaking of IgE-class-restricted central tolerance in the laboratory 1, 3-7 . As shown in Fig.…”

“…During the perinatal period in rodents, IgE system, not other isotypes, is highly autoreactive, and pre-mature exposure to IgE or externally in soluble form without adjuvant or conjugated on splenic APCs in particular to newborn to up to 72 h perinates lead to anti-IgE, and suppressive cell-mediated immunity that result in life-long lack of allergen-specific IgE production and profound life-long total IgE deficiency, while natural tolerance to IgE is completed within one week after birth concordant with the appearance of endogenous IgE in the laboratory 1, 3-7 . Dampening the levels of IgE in allergen-sensitized patients regardless of allergen specificity is considered the goal of a universal allergy therapy.…”

“…Therefore, by disrupting self-IgE tolerance via costimulation, the cytotoxic T lymphocytes (CTLs) induced by nECPs can serve as universal allergy vaccines (UAVs) in humans to dampen IgE production mediated by diverse allergen-specific IgE- secreting B cells and plasma cells expressing surface nECP-MHCIa as targets. The study herein has enabled the identification of nECPs produced through the correspondence principle 1, 2 . Furthermore, nECP-tetramer-specific CTLs were found to be converted into CD4 Tregs that restored IgE competence via the homeostatic principle, mediated by SREBP-1c suppressed DCs.…”