IL-33 is an emerging key factor in development of allergic diseases. The IL-33 receptor (suppressor of tumorigenicity ST2) is a differentially expressed gene in pathogenic TH2 cells, but its role in ...T-cell effector function has not been elucidated.
We investigated the role of IL-33 in modulating circulating allergen-specific T-cell responses. We hypothesized that selective ST2 expression on allergen-specific CD4+ T cells would confer susceptibility to the effects of IL-33.
PBMCs from subjects with food allergy, inhalant allergy, and no allergy were obtained on the basis of clinical history and serum IgE level. A T-cell receptor–dependent CD154 upregulation assay and direct peptide major histocompatibility complex class II tetramer staining were used to profile allergen-specific CD4+ T cells by flow cytometry. Allergen-specific CD4+ T cell cytokine production was evaluated during IL-33 exposure. ST2 expression was also tracked by using a 2-color flow-based assay.
ST2 expression on peripheral allergen-specific CD4+ T cells was confined to subjects with allergy and restricted to TH2A cells. Comparison between direct peptide major histocompatibility complex class II tetramer staining and the CD154 functional assay identified ST2 as a marker of TH2A cell activation. IL-33 exposure enhanced IL-4 and IL-5 secretion in allergen-reactive TH2A cells. Allergen-induced ST2 expression on peripheral CD4+ T cells can be used to track allergen-reactive TH2A cells from donors with allergy.
ST2 expression on circulating CD4+ T cells represents a transient phenotype associated with TH2A cell activation, allowing these cells to sense locally elicited tissue cytokines. IL-33 selectively amplifies pathogenic TH2 cell effector functions, suggesting a tissue checkpoint that may regulate adaptive allergic immunity.
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Short summary Cow’s milk allergy (CMA) is increasing in prevalence, affecting approximately 4% of children. Cow’s milk (CM) is a common cause of fatal/ near fatal anaphylactic reactions. ...Understanding of CM-specific CD4+ T-cells responses to milk allergens should help elucidate the pathological mechanisms of persistent CMA. Milk allergen epitopes specific T-cells were examined in CMA subjects. Frequencies and phenotypes of these T-cells were found to be different between older and younger subjects.
Background Allergic reactions to walnut can be life-threatening. Although IgE epitopes of walnut have been studied, CD4+ T cell–specific epitopes for walnut remain uncharacterized. In particular, the ...relationship of both phenotype and frequency of walnut-specific T cells to the disease have not been examined. Objectives We sought to provide a thorough phenotypic analysis for walnut-reactive T cells in allergic and nonallergic subjects, particularly the relationship of phenotypes and frequencies of walnut-specific T cells with the disease. Methods The CD154 upregulation assay was used to examine CD4+ T-cell reactivity toward the walnut allergens Jug r 1, Jug r 2, and Jug r 3. A tetramer-guided epitope mapping approach was used to identify HLA-restricted CD4+ T-cell epitopes in Jug r 2. Direct ex vivo staining with peptide–major histocompatibility complex class II tetramers enabled comparison of the frequency and phenotype of Jug r 2–specific CD4+ T cells between allergic and nonallergic subjects. Jug r 2–specific T-cell clones were also generated, and mRNA transcription factor levels were assessed by using quantitative RT-PCR. Intracellular cytokine staining assays were performed for further phenotypic analyses. Results Jug r 2 was identified as the major allergen that elicited CD4+ T-cell responses. Multiple Jug r 2 T-cell epitopes were identified. The majority of these T cells in allergic subjects have a CCR4+ phenotype. A subset of these T cells express CCR4+ CCR6+ irrespective of the asthmatic status of the allergic subjects. Intracellular cytokine staining confirmed these TH 2-, TH 2/TH 17-, and TH 17-like heterogenic profiles. Jug r 2–specific T-cell clones from allergic subjects mainly expressed GATA3 , nonetheless, a portion of T-cell clones both GATA3 and RAR-related orphan receptor C (RORC) or RORC alone, confirming the presence of TH 2, TH 2/TH 17, and TH 17 cells. Conclusions Jug r 2–specific responses dominate walnut T-cell responses in patients with walnut allergy. Jug r 2 central memory CD4+ cells and terminal effector T cells were detected in peripheral blood, with the central memory phenotype as the most prevalent phenotype. In addition to conventional TH 2 cells, TH 2/TH 17 and TH 17 cells were also detected in nonasthmatic and asthmatic patients with walnut allergy. Understanding this T-cell heterogeneity might render better understanding of the disease manifestation.
CD4+ T cell Responses In Cow's Milk allergy Archila, Diego, PhD; Farrington, Mary L., MD; Robinson, David M., MD ...
Journal of allergy and clinical immunology,
02/2017, Letnik:
139, Številka:
2
Journal Article
Recenzirano
Little is known about specific T-cell responses toward these allergens in adults and children with CMA and non-allergic subjects.
Rationale The immunogenicity of different Ara h components in eliciting specific CD4 T cell responses in both peanut allergic and peanut sensitized but tolerant subjects (i.e. presence of peanut ...specific IgE but non-reactive to peanut food challenge) remains unclear.
Role of T Cell Sub-Populations in Food Allergy Archila Diaz, Luis Diego, PhD; Jeong, David K., MD; Robinson, David, MD ...
Journal of allergy and clinical immunology,
02/2016, Letnik:
137, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Conclusions Highly heterogeneous T-cell responses were observed in food allergic subjects raising important questions of the pathophysiological role of each food allergen specific CD4+ T-cell subset ...in food allergy in general.
Abstract
Rationale
We aimed to evaluate the impact of daily cat exposure in cat allergic asthmatics by both clinical symptom and immunological measures.
Methods
Twenty adults with history of ...cat-induced asthma and rhinitis, positive serum cat dander-specific IgE (sIgE>0.35kU/L) and Skin Prick Test (SPT) were enrolled at a 1:1 ratio according to cat ownership. For comparison, cat extract- and Fel d1- specific basophil sensitivity test (BST), serum sIgE, sIgG4 and SPT were measured on Day 1 and 28; ambulatory spirometry and symptom measures were obtained daily. Feld1 and 4-reactive CD4+ T cells were profiled using a CD154 upregulation assay.
Results
Cat owners had higher clinical symptom scores & medication use and a trend toward lower FEV1 vs. those not living with cats. Significantly higher levels of cat dander sIgG4 were observed among cat owners, but no significant difference was observed for cat-dander sIgE or SPT. All subjects tested positive on BST to Fel d1 and cat dander. Cat-ownership was associated with reduced basophil sensitivity to Fel d1, but had positive BST to Fel d4 and 7. T-cell response to Fel d1 and 4 were differentially polarized, with Fel d1 responses strongly polarized toward Th2 in both groups. No significant correlation was observed between basophil and T cell responses against cat allergen components.
Conclusions
Cat allergic subjects living with a cat demonstrated reduced pulmonary function and greater clinical symptom severity, despite higher medication use and sIgG4. An immunological difference between cat-owners vs. non cat-owners was detected by basophil assay but not by T-cell response.
Background
The PALISADE study, an international, phase 3 trial of peanut oral immunotherapy (POIT) with AR101, resulted in desensitization in children and adolescents who were highly allergic to ...peanut. An improved understanding of the immune mechanism induced in response to food allergen immunotherapy would enable more informed and effective therapeutic strategies. Our main purpose was to examine the immunological changes in blood samples from a subset of peanut‐allergic individuals undergoing oral desensitization immunotherapy with AR101.
Methods
Blood samples obtained as part of enrollment screening and at multiple time points during PALISADE study were used to assess basophil and CD4+ T‐cell reactivity to peanut.
Results
The absence of clinical reactivity to the entry double‐blinded placebo‐controlled peanut challenge (DBPCFC) was accompanied by a significantly lower basophil sensitivity and T‐cell reactivity to peanut compared with DBPCFC reactors. At baseline, peanut‐reactive TH2A cells were observed in many but not all peanut‐allergic patients and their level in peripheral blood correlates with T‐cell reactivity to peanut and with serum peanut‐specific IgE and IgG4 levels. POIT reshaped circulating peanut‐reactive T‐cell responses in a subset‐dependent manner. Changes in basophil and T‐cell responses to peanut closely paralleled clinical benefits to AR101 therapy and resemble responses in those with lower clinical sensitivity to peanut. However, no difference in peanut‐reactive Treg cell frequency was observed between groups.
Conclusion
Oral desensitization therapy with AR101 leads to decreased basophil sensitivity to peanut and reshapes peanut‐reactive T effector cell responses supporting its potential as an immunomodulatory therapy.
CRTH2+ pTeff cells and CCR6+ pTeff cells represent two mutually exclusive, nonoverlapping cellular and molecular entities involved in food‐allergic diseases. Circulating CRTH2+ pTeff cells are mostly restricted to peanut‐allergic individuals who react to the 100 mg DBPCFC compared to those with lower clinical sensitivity to peanut. Changes in basophil and T‐cell responses to peanut closely parallel clinical benefits to POIT and resemble responses in those that did not react to the baseline 100 mg DBPCFC.Abbreviations: BAT‐EC50, concentration of allergen corresponding to 50% of maximal activation of basophils in basophil activation test; CCR6, C‐C motif chemokine receptor 6; CRTH2, chemoattractant receptor‐homologous molecule expressed on Th2 cells; DBPCFC, double‐blinded placebo‐controlled peanut challenge; FOXP3, forkhead box P3; freq, frequency; GATA3, GATA binding protein 3; HPGDS, hematopoietic prostaglandin D synthase; IFNG, interferon gamma; IL, interleukin; PALISADE, Peanut Allergy Oral Immunotherapy Study of AR101 for Desensitization in Children and Adults; POIT, peanut oral immunotherapy; PPARG, peroxisome proliferator activated receptor alpha; pTeff, peanut‐reactive T cell; RORC, RAR related orphan receptor C; ST2, suppression of tumorigenicity 2
We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication ...analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10(-10)), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10(-10)) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10(-10)) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.
Summary
Background
Allergies to cashew are increasing in prevalence, with clinical symptoms ranging from oral pruritus to fatal anaphylactic reaction. Yet, cashew‐specific T cell epitopes and T cell ...cross‐reactivity amongst cashew and other tree nut allergens in humans remain uncharacterized.
Objectives
In this study, we characterized cashew‐specific T cell responses in cashew‐allergic subjects and examined cross‐reactivity of these cashew‐specific cells towards other tree nut allergens.
Methods
CD154 up‐regulation assay was used to determine immunodominance hierarchy among cashew major allergens at the T cell level. The phenotype, magnitude and functionality of cashew‐specific T cells were determined by utilizing ex vivo staining with MHC class II tetramers. Dual tetramer staining and proliferation experiments were used to determine cross‐reactivity to other tree nuts.
Results
CD4+ T cell responses were directed towards cashew allergens Ana o 1 and Ana o 2. Multiple Ana o 1 and Ana o 2 T cell epitopes were then identified. These epitopes elicited either TH2 or TH2/TH17 responses in allergic subjects, which were either cashew unique epitope or cross‐reactive epitopes. For clones that recognized the cross‐reactive epitope, T cell clones responded robustly to cashew, hazelnut and/or pistachio but not to walnut.
Conclusions
Phylogenetically diverse tree nut allergens can activate cashew‐reactive T cells and elicit a TH2‐type response at an epitope‐specific level.
Clinical relevance
Lack of cross‐reactivity between walnut and cashew suggests that cashew peptide immunotherapy approach may not be most effective for walnut.
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