Peptides derived from IgE heavy chain constant region induce profound IgE isotype‐specific tolerance

Abstract

(BALB/c x SJL)F1 mice, perinatally injected with peptide-N-glyconase F-treated, deglycosylated IgE heavy chain or recombinant IgE heavy chain (CH epsilon 2-CH epsilon 4), were profoundly inhibited in antigen-specific IgE production. There exist minimally two tolerogenic IgE peptides, residing in the CH epsilon 2 and CH epsilon 4 domains. Peptide I, generated by V8 protease, comprises 39 amino acids within CH epsilon 2, beginning at amino acid 103. Peptide E begins at amino acid 312 of the CH epsilon 4 domain and extends through the CH epsilon 4 domain. The total lack of antigen-specific IgE responses in IgE peptide-treated mice was not due to overproduction of interferon-gamma, nor lack of interleukin (IL)-4, as predicted by the Th2/IL-4 paradigm for IgE production. IgE-tolerant mice exhibited comparable levels of circulating anti-IgE antibodies to those of PBS-treated control mice. IgG obtained from sera of both sources failed to inhibit IgE responses in vitro. Moreover, IgE responses of spleen cells from IgE peptides-treated mice were restored by CD4+ T cells from PBS-treated control mice. We hypothesize that regulation of antigen-specific IgE responses is mediated by CD4+ T cells which normally recognize IgE peptides on IgE precursor B cells, and can be rendered tolerant by perinatal IgE peptide treatment.

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).…”

“…The concept of using unique IgE selfbiomarkers on the IgE-producing B cells and plasma cells as CTL targets was first validated in rodents. IgE production was inhibited by CTLs in adult vaccinated with bone marrow-derived dendritic cells (BMDCs) co-presenting rodent natural IgE peptides, peptide I [7] restricted to K d / D b along with a conventional helper peptide in the laboratory [10,11].…”

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.…”

“…The concept of using unique IgE self-biomarkers on the IgE-producing B cells and plasma cells as CTL targets was first validated in rodents. IgE production was inhibited by CTLs in adult vaccinated with bone marrow-derived dendritic cells (BMDCs) co-presenting rodent natural IgE peptides, peptide I 7 restricted to K d /D b along with a conventional helper peptide in the laboratory 10, 11 .…”