The immune system regulates itself to establish an appropriate immune response to potentially harmful pathogens while tolerating harmless environmental antigens and self-antigens. A central role in this balance is played by regulatory T cells (Tregs) through various ways of actions. By means of molecule secretion and cell-cell contact mechanisms, Tregs may have the capacity to modulate effector T cells and suppress the action of proinflammatory cytokines across a broad range of cell types. As a result, abnormal regulatory T cell function has been pointed as a main cause in the development of allergic diseases, a major public health problem in industrialized countries, with a high socioeconomic impact. This prevalence and impact have created an international interest in improving the allergy diagnosis and therapy. Additionally, research has sought to gain a better understanding of the molecular mechanisms underlining this kind of disease, in order to a better management. At this respect, the role of Treg cells is one of the most promising areas of research, mainly because of their potential use as new immunotherapeutical approaches. Therefore, the aim of this review is to update the existing knowledge of the role of Tregs in this pathology deepening in their implication in allergen-specific therapy (AIT).

Asthma is a complex and heterogeneous respiratory disorder characterized by chronic airway inflammation. It has generally been associated with allergic mechanisms related to type 2 airway inflammation. Nevertheless, between 10 and 33% of asthmatic individuals have nonallergic asthma (NA). Several targeted treatments are in clinical development for patients with Th2 immune response, but few biomarkers are been defined for low or non-Th2-mediated inflammation asthma. We have recently defined by gene expression a set of genes as potential biomarkers of NA, mainly associated with disease severity: IL10, MSR1, PHLDA1, SERPINB2, CHI3L1, IL8, and PI3. Here, we analyzed their protein expression and specificity using sera and isolated peripheral blood mononuclear cells (PBMCs). First, protein quantification was carried out using ELISA (in sera) or Western blot (proteins extracted from PBMCs by Trizol procedure), depending on the biomarker in 30 healthy controls (C) subjects and 30 NA patients. A receiver operating characteristic curve analysis was performed by using the R program to study the specificity and sensitivity of the candidate biomarkers at a gene- and protein expression level. Four kinds of comparisons were performed: total NA group vs C group, severe NA patients vs C, moderate–mild NA patients vs C, and severe NA patients vs moderate–mild NA patients. We found that all the single genes showed good sensitivity vs specificity for some phenotypic discrimination, with CHI3L1 and PI3 exhibiting the best results for C vs NA: CHI3L1 area under the curve (AUC) (CI 95%): 0.95 (0.84–1.00) and PI3 AUC: 0.99 (0.98–1.00); C vs severe NA: PI3 AUC: 1 (0.99–1.00); and C vs moderate–mild NA: CHI3L1 AUC: 1 (0.99–1.00) and PI3 AUC: 0.99 (0.96–1.00). However, the results for discriminating asthma disease and severity with protein expression were better when two or three biomarkers were combined. In conclusion, individual genes and combinations of proteins have been evaluated as reliable biomarkers for classifying NA subjects and their severity. These new panels could be good diagnostic tests.

Asthma is a complex disease comprising various phenotypes and endotypes, all of which still need solid biomarkers for accurate classification. In a previous study, we defined specific genes related to asthma and respiratory allergy by studying the expression of 94 genes in a population composed of 4 groups of subjects: healthy control, nonallergic asthmatic, asthmatic allergic, and nonasthmatic allergic patients. An analysis of differential gene expression between controls and patients revealed a set of statistically relevant genes mainly associated with disease severity, i.e., CHI3L1, IL-8, IL-10, MSR1, PHLDA1, PI3, and SERPINB2. Here, we analyzed whether these genes and their proteins could be potential asthma biomarkers to distinguish between nonallergic asthmatic and asthmatic allergic subjects. Protein quantification was determined by ELISA (in serum) or Western blot (in protein extracted from peripheral blood mononuclear cells or PBMCs). Statistical analyses were performed by unpaired t-test using the Graph-Pad program. The sensitivity and specificity of the gene and protein expression of several candidate biomarkers in differentiating the two groups (and the severity subgroups) was performed by receiver operating characteristic (ROC) curve analysis using the R program. The ROC curve analysis determined single genes with good sensitivity and specificity for discriminating some of the phenotypes. However, interesting combinations of two or three protein biomarkers were found to distinguish the asthma disease and disease severity between the different phenotypes of this pathology using reproducible techniques in easy-to-obtain samples. Gene and protein panels formed by single biomarkers and biomarker combinations have been defined in easily obtainable samples and by standardized techniques. These panels could be useful for characterizing phenotypes of asthma, specifically when differentiating asthma severity.

Olive-pollen allergy is one of the leading causes of respiratory allergy in Mediterranean countries and some areas of North America. Currently, allergen-specific immunotherapy is the only etiophatogenic treatment. However, this approach is not fully optimal, safe, or effective. Thus, efforts continue in the search for novel immunotherapy strategies, being one of the most promising the use of peptides derived from major allergens. This work tries to determine the therapeutic potential and safety of 5 dodecapeptides derived from the main allergen of olive-pollen allergy, Ole e 1. The immunomodulatory capacity of these peptides was studied using peripheral blood mononuclear cells (PBMCs) obtained from 19 olive-pollen-allergic patients and 10 healthy controls. We determined the capacity of these peptides to inhibit the proliferative response toward olive-pollen allergenic extract and to induce the regulatory cytokines, IL-10 and IL-35. To test the safety and absence of allergenicity of the peptides, the basophil activation was analyzed by flow-cytometry, using peripheral blood. The results showed that two of five peptides inhibited near to 30% the proliferative response against the total olive-pollen allergenic extract in olive-pollen-allergic patients. Inhibition increased to nearly 35% when the 5 peptides were used in combination. In both cases, a statistically significant induction of IL-10 and IL-35 secretion was observed in the supernatants of allergic patients PBMCs cultures. None of the 5 peptides induced basophil activation and cross-link inflammatory cell-bound IgE. In conclusion, these results open up new possibilities in the treatment of olive-pollen allergy, which could solve some of the problems facing current therapy approaches.