Despite the efficacy of allergen-specific immunotherapy (AIT), the role of trained immunity and tolerance in this process has not been elucidated.
Here, we have performed a comprehensive longitudinal ...analysis of the systemic innate immune cell repertoire during the course of AIT.
Patients with allergy received standard preseasonal subcutaneous AIT with allergoids to birch and/or grass. Healthy controls were monitored without any intervention. Flow cytometry of innate lymphoid cell (ILC), natural killer cell, monocyte cell, and dendritic cell (DC) subsets was performed at baseline, 3 months (birch season), 6 months (grass seasons), and 12 months after the therapy in patients or at similar seasonal time points in controls. Additional analyses were performed in the third-year birch and grass season.
We observed a durable decrease in group 2 ILCs and an increase of group 1 ILCs after AIT, with dynamic changes in their composition. We found that an expansion of CD127+CD25++ clusters caused observed shifts in the heterogeneity of group 1 ILCs. In addition, we observed development of CD127+CD25++c-Kit+ group 3 ILC clusters. Moreover, we found an increase in the number of intermediate monocytes in parallel with a reduction in nonclassical monocytes during the first year after AIT. Classical and intermediate monocytes presented significant heterogeneity in patients with allergy, but AIT reduced the HLA-DR++ clusters. Finally, an increase in plasmacytoid DCs and CD141+ myeloid DCs was observed in individuals with allergy, whereas the number of CD1c+ myeloid DCs was reduced during the first year of AIT.
AIT induces changes in the composition and heterogeneity of circulating innate immune cells and brings them to the level observed in healthy individuals. Monitoring of ILCs, monocytes, and DCs during AIT might serve as a novel biomarker strategy.
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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.
Allergen-specific B-cell responses during 2 years of house dust mite AIT were compared between responder and nonresponder patients.
B cells specific for Der p 1 were detected by using the fluorochrome-labeled allergen method. The frequency of IgA-, IgG1- and IgG4-switched Der p 1–specific B cells, plasmablasts, and IL-10– and IL-1 receptor antagonist (IL-1RA)–producing Breg cells were investigated and correlated to clinical response to AIT.
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 ± 0.28 to 2.45 ± 0.24 (P = .001) and a decrease in skin prick test reactivity to house dust mite from 7.0 ± 1.3 to 2.7 ± 0.5 mm (P = .001). IgG4+ and IgA+ Der p 1–specific B cells showed a significant increase after AIT, with a significantly greater frequency in responders compared with nonresponders in the IgG4+ but not the IgA+ 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+ B cells, plasmablasts, and IL-10+ and dual-positive IL-10+IL-1RA+ Breg cells significantly correlated with improved clinical symptoms over the course of AIT.
Allergen-specific B cells in patients responding to AIT are characterized by increased numbers of IgA- and IgG4-expressing Der p 1–specific B cells, plasmablasts, and IL-10+ and/or IL-1RA+ Breg cells.
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Group 2 innate lymphoid cells (ILC2s) have been implicated in the pathogenesis of allergic disease. However, the effect of allergen-specific immunotherapy (AIT) on ILCs remains to be clarified. The ...aim of this study was to evaluate the levels of ILC subsets in allergic rhinitis (AR) patients in response to house dust mite (HDM)-specific immunotherapy.
We enrolled 37 AR patients undergoing AIT (16 responders and 11 non-responders) for 2 years, 35 HDM AR patients and 28 healthy subjects. Peripheral blood mononuclear cells (PBMCs) were analyzed by flow cytometry to identify ILC subsets. Stimulation of ILC2s with recombinant allergen-specific protein was used to determine ILC2's activation (CD69 expression).
Responder AIT patients and healthy subjects had a decreased frequency of circulating ILC2s compared to non-responder AIT and AR patients. Conversely, ILC1s from responder AIT patients and healthy subjects showed increased frequency compared to non-responder AIT and AR patients. The frequency of ILC3s natural cytotoxicity receptor (NCR)⁺ and NCR⁻ in responder AIT patients was significantly lower compared to AR patients and healthy subjects. The ILC1: ILC2 proportion in responder AIT patients was similar to that of healthy subjects. PBMCs from patients who were responders to AIT had a significantly lower expression of the activation marker CD69 on ILC2s in response to allergen re-stimulation compared to AR patients, but no difference compared to non-responder AIT patients and healthy subjects.
We propose that AIT might affect ILC responses. The activation of ILC2s was reduced in AR patients treated with AIT. Our results indicate that a relative ILC1/ILC2 skewed response is a possible key to successful AIT.
Abstract
Inborn errors of immunity are known to cause not only immunodeficiencies and allergies but also autoimmunity. Leukocyte immunoglobulin-like receptor B1 (LILRB1) is a receptor on leukocytes ...playing a role in regulating immune responses. No phenotypes have been reported to be caused by germline mutations in
LILRB1
. We aimed to identify the causative variant in a three-generation family with nine members suffering from one of the three autoimmune diseases—Graves’ disease, Hashimoto's thyroiditis, or systemic lupus erythematosus. Whole-genome linkage study revealed a locus on chromosome 19q13.4 with the maximum LOD score of 2.71. Whole-exome sequencing identified a heterozygous missense variant, c.479G > A (p. G160E) in
LILRB1
, located within the chromosomal-linked region, in all nine affected members. The variant has never been previously reported. Jurkat cells transfected with the mutant
LILRB1
, compared with those with the wild-type
LILRB1
, showed decreased phosphorylation of both LILRB1 and its downstream protein, SHP-1. Flow cytometry was used to study immunophenotype and revealed that LILRB1 was significantly lower on the surface of activated regulatory T lymphocytes (Treg) cells of patients. Single-cell RNA sequencing showed substantially increased M1-like monocytes in peripheral blood mononuclear cells of affected individuals. This study, for the first time, implicates
LILRB1
as a new disease gene for autoimmunity.
Allergic rhinitis (AR) is an IgE-mediated disease that is characterized by Th2 joint inflammation. Allergen-specific immunotherapy (AIT) is indicated for AR when symptoms remain uncontrolled despite ...medication and allergen avoidance. AIT is considered to have been effective if it alleviated allergic symptoms, decreased medication use, improved the quality of life even after treatment cessation, and prevented the progression of AR to asthma and the onset of new sensitization. AIT can be administered subcutaneously or sublingually, and novel routes are still being developed, such as intra-lymphatically and epicutaneously. AIT aims at inducing allergen tolerance through modification of innate and adaptive immunologic responses. The main mechanism of AIT is control of type 2 inflammatory cells through induction of various functional regulatory cells such as regulatory T cells (Tregs), follicular T cells (Tfr), B cells (Bregs), dendritic cells (DCregs), innate lymphoid cells (IL-10
ILCs), and natural killer cells (NKregs). However, AIT has a number of disadvantages: the long treatment period required to achieve greater efficacy, high cost, systemic allergic reactions, and the absence of a biomarker for predicting treatment responders. Currently, adjunctive therapies, vaccine adjuvants, and novel vaccine technologies are being studied to overcome the problems associated with AIT. This review presents an updated overview of AIT, with a special focus on AR.
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