Human Leukocyte Antigen-G and Regulatory T Cells during Specific Immunotherapy for Pollen Allergy

Abstract

Background: T_H2-biased immune responses are important in allergy pathogenesis. Mechanisms of allergen-specific immunotherapy (SIT) might include the induction of regulatory T cells (Tregs) and immunoglobulin (Ig) G₄ blocking antibodies, a reduction in the number of effector cells, and skewing of the cytokine profile towards a T_H1-polarized immune response. We investigated the effects of SIT on T cells, on immunomodulation of human leukocyte antigen (HLA)-G, which has been associated with allergy, on regulatory cytokine expression, and on serum allergen-specific antibody subclasses (IgE and IgG₄). Methods: Eleven birch and/or grass pollen-allergic patients and 10 healthy nonatopic controls were studied before and during SIT. Tregs, chemokine receptors, soluble HLA-G (sHLA-G), Ig-like transcript (ILT) 2, specific IgE, and IgG₄ were studied. Peripheral blood mononuclear cells (PBMCs) were stimulated with pollen extract in vitro and immune factors were evaluated. Results: During SIT, the main changes in the peripheral blood were an increase in CXCR3⁺CD4⁺CD25⁺CD127^low/- Tregs and a decrease in CCR4⁺CD4⁺CD25⁺CD127^low/- Tregs, an increase in allergen-specific IgG₄, and a decrease in sHLA-G during the first half of the treatment period. In the PBMC in vitro experiments, the following changes were observed upon allergen-stimulation: an increase in CD4⁺CD25⁺CD127^low/- Tregs and ILT2⁺CD4⁺CD25⁺CD127^low/- Tregs, an increase in IL-10 and IL-2 levels, and an increase in sHLA-G that was most pronounced at the start of SIT. Conclusions: The changes in CXCR3⁺CD4⁺CD25⁺CD127^low/- Treg, IgG₄, and sHLA-G levels in the peripheral blood and in ILT2⁺ Treg, IL-10, IL-2, and sHLA-G levels upon in vitro allergen stimulation suggest an upregulation in immunomodulatory factors and, to some degree, a shift towards T_H1 during SIT.

Allergen-driven HLA-G expression and secretion in peripheral blood mononuclear cells from allergic rhinitis patients

“…When considering allergic diseases, elevated levels of sHLA-G molecules have been detected in plasma and bronchoalveolar lavage fluid of atopic asthmatics [42][43][44][45] and in plasma from AR patients, where their levels correlated with clinical severity and response to pharmacological therapy [48,49]. Of interest, specific immunotherapy is able to reduce the sHLA-G antigen levels in serum [50] and in the supernatant from PBMCs stimulated in vitro with allergen [47]. More recently, it has been reported that patients with seasonal allergic rhinitis had significantly higher sHLA-G serum levels than patients with perennial allergic rhinitis [52].…”

“…ported that elevated levels of sHLA-G molecules are detected in plasma and bronchoalveolar lavage fluid of atopic asthmatics [42][43][44][45], that the production of sHLA-G in unstimulated PBMC cultures is significantly higher in subjects with occupational isocyanate-induced asthma as compared with asymptomatic-exposed controls [46] and that the amount of sHLA-G detected in the medium from PBMC stimulated with allergen in vitro is reduced after specific immunotherapy [47]. Moreover, previous studies in allergic rhinitis (AR) patients indicated that sHLA-G serum levels were: i) significantly increased in comparison with normal subjects; ii) elevated both outside and during the pollen season in patients with seasonal allergy; and iii) correlated with clinical severity, drug use, allergen-specific IgE levels, type of allergy and response to immunotherapy [48][49][50][51][52].…”

HLA-G in Allergy: Does It Play an Immunoregulatory Role?

“…The measurement of sHLA-G in culture supernatants confirmed that high amounts of sHLA-G molecules are found when the causal allergen is used as stimulus. Soluble molecules detected in culture supernatants mainly belong to the HLA-G5 isoform suggesting that they are actively secreted by immune cells after incubation with allergen ( 69 , 70 ).…”

Expanding Diversity and Common Goal of Regulatory T and B Cells. II: In Allergy, Malignancy, and Transplantation

“…Some years ago, Tregs appeared to be a good marker for such assessment. In many studies, clinically successful ASIT went together with increased proportion of Tregs, increased population of IL-10 + cells, and/or hypomethylation of forkhead box P3 (Foxp3) (Fujimura et al 2011 ; Lou et al 2012 ; Scadding et al 2010 ; Sørensen et al 2013 ; Suárez-Fueyo et al 2014 ; Swamy et al 2012 ; Syed et al 2014 ). However, other authors did not demonstrate any alterations in the number of Tregs after ASIT (Kim et al 2011 ; Lou et al 2012 ; Moed et al 2013 ; Schubert et al 2009 ; Stelmaszczyk-Emmel et al 2015 ; Thunberg et al 2010 ).…”