Search

Allergic asthma is largely dominated by Th2 lymphocytes. Micropeptides in Th2 cells and asthma remain unmasked. Here, we aimed to demonstrate a micropeptide, T-cell regulatory micropeptide (TREMP), in Th2 cell differentiation in asthma. TREMP translated from lincR-PPP2R5C was validated using Western blotting and mass spectrometry. TREMP knockout mice were generated using CRISPR/Cas9. Coimmunoprecipitation revealed that TREMP targeted pyrroline-5-carboxylate reductase 1 (PYCR1), which was further explored in vitro and in vivo. The levels of TREMP and PYCR1 in Th2 cells from clinical samples were determined by flow cytometry. TREMP, encoded by lincR-PPP2R5C, was in the mitochondrion. The lentivirus encoding TREMP promoted Th2 cell differentiation. In contrast, Th2 differentiation was suppressed in TREMP−/− CD4+ T cells. In the HDM-induced model of allergic airway inflammation, TREMP was increased in pulmonary tissues. Allergic airway inflammation was relieved in TREMP−/− mice treated with HDM. Mechanistically, TREMP interacted with PYCR1, which regulated Th2 differentiation via glycolysis. Glycolysis was decreased in Th2 cells from TREMP−/− mice and PYCR1−/− mice. Similar to TREMP−/− mice, allergic airway inflammation was mitigated in HDM-challenged PYCR1−/− mice. Moreover, we measured TREMP and PYCR1 in asthma patients. And we found that, compared with those in healthy controls, the levels of TREMP and PYCR1 in Th2 cells were significantly increased in asthmatic patients. The micropeptide TREMP encoded by lincR-PPP2R5C promoted Th2 differentiation in allergic airway inflammation by interacting with PYCR1 and enhancing glycolysis. Our findings highlight the importance of neglected micropeptides from noncoding RNAs in allergic diseases. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to investigate the changes of T lymphocyte subsets (Th1, Th2, Tc1, Tc2, and Th17) and memory T lymphocyte subsets (Tcm and Tem) in patients with multiple myeloma (MM) at different stages of the disease. Methods: In total, 25 newly diagnosed patients with MM were selected as the study subjects and 30 healthy people were selected as the control group. The subsets of T lymphocytes such as Th1, Th2, Tc1, Tc2, Th17, Tcm, and Tem in the peripheral blood were detected by flow cytometry at the time of initial diagnosis, infection, and remission. Results: Th1, Tem, and Tcm cells in MM patients showed a significant decrease compared to the control group. Th2 and Th17 cells in MM patients showed a significant increase compared to the control group. Total Th1 cells and memory Th1 cells in MM patients with bacterial infection were significantly higher than at initial diagnosis (p < 0.05). The Tcm of Th2 cells in the remission stage were significantly higher than those in MM patients with no remission. Conclusions: MM patients have decreased Th1 cells and increased Th2 and Th17 cells. The changes in memory Th1 cells were related to bacterial infection in MM patients. The increase of Tcm of Th2 cells may be associated with disease remission. The balance of T lymphocyte subsets plays an important role in the pathogenic course of MM. [ABSTRACT FROM AUTHOR]

Background: Improvement is needed in the remedies used to control Th2 polarization. Bioengineering approaches have modified immune cells that have immunosuppressive functions. This study aims to generate modified eosinophils (Meos) in vivo and use Meos to balance Th2 polarization and reduce airway allergy. Methods: A cell editor was constructed. The editor contained a peptide carrier, an anti-siglec F antibody, MHC II, ovalbumin, and LgDNA (DNA extracted from a probiotic, Lactobacillus rhamnosus GG). Which was designated as Cedit. Meos are eosinophils modified using Cedits. An airway Th2 polarization mouse model was established used to test the effect of Meos on suppressing airway allergy. Results: The Cedits remained physically and chemically stable in solution (pH7.2) for at least 96 h. Cedits specifically bound to eosinophils, which are designated as Meos. Meos produced programmed death ligand-1 (PD-L1); the latter induced antigen specific CD4+ T cell apoptosis. Administration of Cedits through nasal instillations generated Meos in vivo, which significantly reduced the frequency of antigen specific CD4+ T cells in the airways, and mitigated airway Th2 polarization. Conclusions: We constructed Cedit, which could edit eosinophils into Meos in vivo. Meos could induce antigen specific CD4+ T cell apoptosis, and reconcile airway Th2 polarization. [ABSTRACT FROM AUTHOR]

CD: cluster of differentiation; Th: T helper; Treg: T regulatory; MDD: major depressive disorder; HC: healthy controls; DSM: The Diagnostic and Statistical Manual of Mental Disorders; ICD: International Classification of Diseases. [Display omitted] • This meta -analysis aims to assess the alterations of peripheral CD4+ Th cells in MDD. • MDD patients may exhibit higher levels of CD4+ Th cells and CD4+/CD8+ ratio. • MDD patients may exhibit lower levels of Th1, Th2 and Treg cells. Previous research has shown that patients with major depressive disorder (MDD) develop immune dysfunction. However, the exact alterations of cluster of differentiation (CD)4+ T helper (Th) lymphocytes in MDD remains unclear. This meta -analysis aimed to examine the specific changes in CD4+ Th cells. A comprehensive search of PubMed, EMBASE, Web of Science, and PsycINFO databases was conducted to identify studies investigating CD4+ Th, Th1, Th2, Th17, and T regulatory (Treg) cell counts in the peripheral blood of MDD patients and healthy controls (HCs), covering the period up to June 22, 2024. Our findings revealed that patients with MDD might exhibit higher CD4+ Th cells (SMD=0.26, 95 %CI, 0.02 to 0.50), CD4+/CD8+ cell ratios (SMD=0.51, 95 %CI, 0.14 to 0.89), Th1/Th2 cell ratios (SMD=0.15, 95 %CI, 0.01 to 0.30) and lower Th1 (SMD=-0.17, 95 %CI, -0.30 to -0.03), Th2 (SMD=-0.25, 95 %CI, -0.40 to -0.11), and Treg cells (SMD=-0.69, 95 %CI, -1.27 to -0.11). However, no significant difference was observed in terms of Th17 cells and Th17/Treg cell ratios between MDD patients and the HCs. Heterogeneity was large (I2:18.1–95.2 %), and possible sources of heterogeneity were explored (e.g., age, depression scale, country, and antidepressant use). Our findings indicate that peripheral CD4+ T cells in depressed patients exhibit features of adaptive immune dysfunction, as evidenced by increased CD4+ Th cells and CD4+/CD8+ and decreased Treg cells. These findings offer insights into the underlying mechanism of MDD. [ABSTRACT FROM AUTHOR]

Introduction: After mild COVID-19 that does not require hospitalization, some individuals develop persistent symptoms that may worsen over time, producing a multisystemic condition termed Post-COVID condition (PCC). Among other disorders, PCC is characterized by persistent changes in the immune system that may not be solved several months after COVID-19 diagnosis. Methods: People with PCC were recruited to determine the distribution and functionality of CD4+ T helper (Th) subsets in comparison with individuals with mild, severe, and critical presentations of acute COVID-19 to evaluate their contribution as risk or protective factors for PCC. Results: People with PCC showed low levels of Th1 cells, similar to individuals with severe and critical COVID-19, although these cells presented a higher capacity to express IFNg in response to stimulation. Th2/Th1 correlation was negative in individuals with acute forms of COVID-19, but there was no significant Th2/Th1 correlation in people with PCC. Th2 cells from people with PCC presented high capacity to express IL-4 and IL-13, which are related to low ventilation and death associated with COVID-19. Levels of proinflammatory Th9 and Th17 subsets were significantly higher in people with PCC in comparison with acute COVID-19, being Th1/Th9 correlation negative in these individuals, which probably contributed to a more pro-inflammatory than antiviral scenario. Th17 cells from approximately 50% of individuals with PCC had no capacity to express IL-17A and IL-22, similar to individuals with critical COVID-19, which would prevent clearing extracellular pathogens. Th2/Th17 correlation was positive in people with PCC, which in the absence of negative Th1/Th2 correlation could also contribute to the proinflammatory state. Finally, Th22 cells from most individuals with PCC had no capacity to express IL-13 or IL-22, which could increase tendency to reinfections due to impaired epithelial regeneration. Discussion: People with PCC showed skewed polarization of CD4+ Th subsets with altered functionality that was more similar to individuals with severe and critical presentations of acute COVID-19 than to people who fully recovered from mild disease. New strategies aimed at reprogramming the immune response and redirecting CD4+ Th cell polarization may be necessary to reduce the proinflammatory environment characteristic of PCC. [ABSTRACT FROM AUTHOR]

The activation of CD4+ T‐cells in a T cell receptor (TCR)‐dependent antigen‐specific manner is a central characteristic of the adaptive immune response. In addition to ensuring that CD4+ T‐cells recognise their cognate antigen during activation, TCR‐mediated signalling can also direct the outcome of differentiation. In both in vivo and in vitro model systems, strong TCR signalling has been demonstrated to drive Th1 differentiation, whereas weak TCR signalling drives Th2 responses. During the process of differentiation, TCR signal strength acts as a quantitative component in combination with the qualitative effects imparted by cytokines to polarise distinct T‐helper lineages. Here, we investigated the role of interleukin 2 (IL‐2) signalling in determining the outcome of TCR‐dependent differentiation. IL‐2 production was initiated as an early response to TCR‐induced activation and was regulated by the strength of TCR signalling initially received. In the absence of IL‐2, TCR dependent differentiation was found to be abolished. However, proliferative responses and early markers of activation were maintained, including the upregulation of GATA3, Tbet and Foxp3 at 24 h post‐stimulation. Demonstrating that IL‐2 signalling has a key role in stabilising and amplifying lineage‐specific transcirption factor expression during differentiation. Further, activation of IL‐2‐deficient T‐cells in the presence of exogenous cytokines was sufficient to restore differentiation whilst maintaining transcriptional signatures imparted during initial TCR signalling. Combined, our data demonstrate that the integration of quantitative TCR‐dependent signalling and qualitative IL‐2 signalling is essential for determining the fate of CD4+ T‐cells during differentiation. [ABSTRACT FROM AUTHOR]

[Display omitted] Previous studies implied that local M2 polarization of macrophage promoted mucosal edema and exacerbated T H 2 type inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP). However, the specific pathogenic role of M2 macrophages and the intrinsic regulators in the development of CRS remains elusive. We sought to investigate the regulatory role of SIRT5 in the polarization of M2 macrophages and its potential contribution to the development of CRSwNP. Real-time reverse transcription–quantitative PCR and Western blot analyses were performed to examine the expression levels of SIRT5 and markers of M2 macrophages in sinonasal mucosa samples obtained from both CRS and control groups. Wild-type and Sirt5 -knockout mice were used to establish a nasal polyp model with T H 2 inflammation and to investigate the effects of SIRT5 in macrophage on disease development. Furthermore, in vitro experiments were conducted to elucidate the regulatory role of SIRT5 in polarization of M2 macrophages. Clinical investigations showed that SIRT5 was highly expressed and positively correlated with M2 macrophage markers in eosinophilic polyps. The expression of SIRT5 in M2 macrophages was found to contribute to the development of the disease, which was impaired in Sirt5 -deficient mice. Mechanistically, SIRT5 was shown to enhance the alternative polarization of macrophages by promoting glutaminolysis. SIRT5 plays a crucial role in promoting the development of CRSwNP by supporting alternative polarization of macrophages, thus providing a potential target for CRSwNP interventions. [ABSTRACT FROM AUTHOR]

Background: This study aimed to explore the changes in Th cells and cytokines in the peripheral blood of patients with multiple myeloma before and after treatment and at the time of the bacterial infection. Methods: In total, 23 newly diagnosed MM patients admitted to the Hospital and 23 healthy individuals were selected as the study group and the control group, respectively. Flow cytometry was used to detect the Th1 and Th2 lymphocytes and cytokines, such as IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, INF-γ, IL-17A, IL-1b, TNF-α, TNF-β, and IL-12P70, in the peripheral blood of the patients at initial diagnosis, before and after treatment, and at the time of the bacterial infection. Results: The Th1% and Th1/Th2 ratio at the time of the initial diagnosis were lower in the MM patients than in the control group, whereas the Th2% at initial diagnosis was higher in the MM patients than in the control group. The levels of IL-6, IL-8, IL-10, and IL-17A at initial diagnosis were higher in the MM patients than in the control group. After 4 cycles of treatment, the Th2% in the patients was lower than before the treatment and the Th1/Th2 ratio in the patients was higher than before the treatment. The Th1% and the levels of IL-6, IL-8, IL-10, and INF-γ increased, while the level of IL-12P70 decreased, when MM patients got a bacterial infection. The abovementioned differences were statistically significant (p < 0.05). Conclusions: The Th1/Th2 deviation affects the immune function of the MM patients. There were significant changes in the Th1 and Th2 lymphocytes and cytokines in newly diagnosed MM patients after the treatment. The changes in the Th lymphocytes and cytokines may be an indicator of bacterial infection. [ABSTRACT FROM AUTHOR]

Malnutrition, which includes macro- and micronutrient deficiencies, is common in individuals with allergic dermatitis, food allergies, rhinitis, and asthma. Prolonged deficiencies of proteins, minerals, and vitamins promote Th2 inflammation, setting the stage for allergic sensitization. Consequently, malnutrition, which includes micronutrient deficiencies, fosters the development of allergies, while an adequate supply of micronutrients promotes immune cells with regulatory and tolerogenic phenotypes. As protein and micronutrient deficiencies mimic an infection, the body's innate response limits access to these nutrients by reducing their dietary absorption. This review highlights our current understanding of the physiological functions of allergenic proteins, iron, and vitamin A, particularly regarding their reduced bioavailability under inflamed conditions, necessitating different dietary approaches to improve their absorption. Additionally, the role of most allergens as nutrient binders and their involvement in nutritional immunity will be briefly summarized. Their ability to bind nutrients and their close association with immune cells can trigger exaggerated immune responses and allergies in individuals with deficiencies. However, in nutrient-rich conditions, these allergens can also provide nutrients to immune cells and promote health. [ABSTRACT FROM AUTHOR]

Background: A definition of the immunological features of COVID-19 pneumonia is needed to support clinical management of aged patients. In this study, we characterized the humoral and cellular immune responses in presence or absence of SARS-CoV-2 vaccination, in aged patients admitted to the IRCCS San Raffaele Hospital (Italy) for COVID-19 pneumonia between November 2021 and March 2022. Methods: The study was approved by local authorities. Disease severity was evaluated according to WHO guidelines. We tested: (A) anti-SARS-CoV-2 humoral response (anti-RBD-S IgG, anti-S IgM, anti-N IgG, neutralizing activity against Delta, BA1, BA4/5 variants); (B) Lymphocyte B, CD4 and CD8 T-cell phenotype; (C) plasma cytokines. The impact of vaccine administration and different variants on the immunological responses was evaluated using standard linear regression models and Tobit models for censored outcomes adjusted for age, vaccine doses and gender. Result: We studied 47 aged patients (median age 78.41), 22 (47%) female, 33 (70%) older than 70 years (elderly). At hospital admission, 36% were unvaccinated (VACno), whilst 63% had received 2 (VAC2) or 3 doses (VAC3) of vaccine. During hospitalization, WHO score > 5 was higher in unvaccinated (14% in VAC3 vs. 43% in VAC2 and 44% VACno). Independently from vaccination doses and gender, elderly had overall reduced anti-SARS-CoV-2 humoral response (IgG-RBD-S, p = 0.0075). By linear regression, the anti-RBD-S (p = 0.0060), B (p = 0.0079), CD8 (p = 0.0043) and Th2 cell counts (p = 0.0131) were higher in VAC2 + 3 compared to VACno. Delta variant was the most representative in VAC2 (n = 13/18, 72%), detected in 41% of VACno, whereas undetected in VAC3, and anti-RBD-S production was higher in VAC2 vs. VACno (p = 0.0001), alongside neutralization against Delta (p = 0141), BA1 (p = 0.0255), BA4/5 (p = 0.0162). Infections with Delta also drove an increase of pro-inflammatory cytokines (IFN-α, p = 0.0463; IL-6, p = 0.0010). Conclusions: Administration of 3 vaccination doses reduces the severe symptomatology in aged and elderly. Vaccination showed a strong association with anti-SARS-CoV-2 humoral response and an expansion of Th2 T-cells populations, independently of age. Delta variants and number of vaccine doses affected the magnitude of the humoral response against the original SARS-CoV-2 and emerging variants. A systematic surveillance of the emerging variants is paramount to define future vaccination strategies. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Alopecia areata (AA) is a chronic, nonscarring hair‐loss disorder associated with significant quality‐of‐life impairment and limited treatment options. AA has been recently linked to atopy and shown to exhibit both Th1‐ and Th2‐driven inflammation. However, a comprehensive molecular and cellular characterization across blood and scalp compartments in both atopic and nonatopic patients is lacking.Lesional and nonlesional scalp biopsies obtained from AA patients with (n = 16) or without (n = 20) atopic history, and 17 demographically matched healthy controls were analyzed with RNA‐seq, RT‐PCR, and immunohistochemistry. Flow cytometry was also performed on peripheral blood mononuclear cells (PBMCs) from a subset of patients. Differential expression was defined using |fold‐change| > 1.5 and false‐discovery rate <0.05.AA scalp exhibited robust upregulation of Th1‐ (IFNG, CXCL9, CXCL10, CXCL11) and Th2‐related products (CCL26, CCR4, IL10, IL13, TSLP, TNFRSF4/OX40) and shared downregulation of hair keratins, regardless of atopic background, with variable Th17/Th22 modulation. AA patients with atopy exhibited greater inflammatory tone and Th2‐skewing (IL10, IL13, IL33, CCR4, CCL26). Disease severity correlated significantly with immune and hair keratin biomarkers and with perifollicular cellular infiltrates. Cutaneous OX40/OX40L upregulation was paralleled by increases in circulating OX40+ and OX40L+ leukocytes, regardless of atopic background.Our results suggest some atopy‐associated immune differences in AA and highlight the OX40 axis as a potential novel therapeutic target that may broadly benefit AA patients. [ABSTRACT FROM AUTHOR]

Background: Allergic asthma is largely dominated by Th2 lymphocytes. Micropeptides in Th2 cells and asthma remain unmasked. Here, we aimed to demonstrate a micropeptide, T-cell regulatory micropeptide (TREMP), in Th2 cell differentiation in asthma. Methods: TREMP translated from lincR-PPP2R5C was validated using Western blotting and mass spectrometry. TREMP knockout mice were generated using CRISPR/Cas9. Coimmunoprecipitation revealed that TREMP targeted pyrroline-5-carboxylate reductase 1 (PYCR1), which was further explored in vitro and in vivo. The levels of TREMP and PYCR1 in Th2 cells from clinical samples were determined by flow cytometry. Results: TREMP, encoded by lincR-PPP2R5C, was in the mitochondrion. The lentivirus encoding TREMP promoted Th2 cell differentiation. In contrast, Th2 differentiation was suppressed in TREMP−/− CD4+ T cells. In the HDM-induced model of allergic airway inflammation, TREMP was increased in pulmonary tissues. Allergic airway inflammation was relieved in TREMP−/− mice treated with HDM. Mechanistically, TREMP interacted with PYCR1, which regulated Th2 differentiation via glycolysis. Glycolysis was decreased in Th2 cells from TREMP−/− mice and PYCR1−/− mice. Similar to TREMP−/− mice, allergic airway inflammation was mitigated in HDM-challenged PYCR1−/− mice. Moreover, we measured TREMP and PYCR1 in asthma patients. And we found that, compared with those in healthy controls, the levels of TREMP and PYCR1 in Th2 cells were significantly increased in asthmatic patients. Conclusions: The micropeptide TREMP encoded by lincR-PPP2R5C promoted Th2 differentiation in allergic airway inflammation by interacting with PYCR1 and enhancing glycolysis. Our findings highlight the importance of neglected micropeptides from noncoding RNAs in allergic diseases.

Abstract Background Improvement is needed in the remedies used to control Th2 polarization. Bioengineering approaches have modified immune cells that have immunosuppressive functions. This study aims to generate modified eosinophils (Meos) in vivo and use Meos to balance Th2 polarization and reduce airway allergy. Methods A cell editor was constructed. The editor contained a peptide carrier, an anti-siglec F antibody, MHC II, ovalbumin, and LgDNA (DNA extracted from a probiotic, Lactobacillus rhamnosus GG). Which was designated as Cedit. Meos are eosinophils modified using Cedits. An airway Th2 polarization mouse model was established used to test the effect of Meos on suppressing airway allergy. Results The Cedits remained physically and chemically stable in solution (pH7.2) for at least 96 h. Cedits specifically bound to eosinophils, which are designated as Meos. Meos produced programmed death ligand-1 (PD-L1); the latter induced antigen specific CD4+ T cell apoptosis. Administration of Cedits through nasal instillations generated Meos in vivo, which significantly reduced the frequency of antigen specific CD4+ T cells in the airways, and mitigated airway Th2 polarization. Conclusions We constructed Cedit, which could edit eosinophils into Meos in vivo. Meos could induce antigen specific CD4+ T cell apoptosis, and reconcile airway Th2 polarization.

Abstract Objective To explore the role of different cells and molecules in the pathogenesis of allergic rhinitis (AR) with positive Artemisia allergen by detecting their expression levels. Methods From January 2021 to December 2022,200 AR patients diagnosed in the Otolaryngology Clinic of Ordos Central Hospital were selected as the AR group, and 50 healthy people who underwent physical examination in the hospital during the same period were randomly selected as the healthy control (HC) group. The levels of GATA-3mRNA, RORγtmRNA and FoxP3mRNA in peripheral blood mononuclear cells were detected by real-time fluorescence quantitative PCR (qRT-PCR). The proportions of Th2, Th17 and Treg cells were detected by flow cytometry. The concentrations of IL-4, IL-5, IL-17 and IL-10 in serum were detected by enzyme-linked immunosorbent assay. The differences of transcription gene level, immune cell ratio and cytokine concentration between the two groups were analyzed. Results There was no difference in age and gender between the two groups. The levels of GATA-3mRNA and RORγtmRNA transcription genes in peripheral blood mononuclear cells, the percentage of Th2, Th17 and Treg immune cells, the levels of eosinophils and basophils in peripheral blood, the concentrations of IL-4, IL-5, IL-17, IL-10 cytokines and IgE in serum of AR patients were significantly higher than those in HC group (P

Objective: To evaluate the immunological response elicited by an inactivated bacterial vector carrying the K39 antigen of Leishmania infantum, and a purified antigen. Methods: Mice were subjected to the following treatments: (1) Purified recombinant K39 (rK39) protein at a 20 μg dose with complete Freund’s adjuvant; (2) Inactivated Escherichia coli (BL21 DE3) carrying the K39 protein at an equivalent total protein content of 200 μg; (3) Inactivated bacteria lacking the K39 protein; (4) Non-immunized control animals. Serological monitoring was performed. All groups were challenged by intraperitoneal injection of 107 Leishmania infantum promastigotes. After euthanasia, the liver and spleen were collected to analyze the levels of TNF, IFN-γ, IL-12, IL-4, and IL-10. Results: Mice immunized with purified rK39 or the inactivated bacterial vector carrying the K39 antigen of Leishmania infantum showed a long-lasting immune response with high levels of polyclonal antibodies specifically recognizing the recombinant proteins. The IgG1 subclass was the predominant immunoglobulin; however, the induction of IgG2a and the profile of cytokines produced were indicative of the induction of a mixed-type response. Conclusions: The inactivated bacterial vector carrying the K39 antigen, as well as the purified antigen can induce a long-lasting immune response in immunized mice, predominantly favouring a Th2 profile response.

Objective: To explore the role of different cells and molecules in the pathogenesis of allergic rhinitis (AR) with positive Artemisia allergen by detecting their expression levels. Methods: From January 2021 to December 2022,200 AR patients diagnosed in the Otolaryngology Clinic of Ordos Central Hospital were selected as the AR group, and 50 healthy people who underwent physical examination in the hospital during the same period were randomly selected as the healthy control (HC) group. The levels of GATA-3mRNA, RORγtmRNA and FoxP3mRNA in peripheral blood mononuclear cells were detected by real-time fluorescence quantitative PCR (qRT-PCR). The proportions of Th2, Th17 and Treg cells were detected by flow cytometry. The concentrations of IL-4, IL-5, IL-17 and IL-10 in serum were detected by enzyme-linked immunosorbent assay. The differences of transcription gene level, immune cell ratio and cytokine concentration between the two groups were analyzed. Results: There was no difference in age and gender between the two groups. The levels of GATA-3mRNA and RORγtmRNA transcription genes in peripheral blood mononuclear cells, the percentage of Th2, Th17 and Treg immune cells, the levels of eosinophils and basophils in peripheral blood, the concentrations of IL-4, IL-5, IL-17, IL-10 cytokines and IgE in serum of AR patients were significantly higher than those in HC group (P < 0.05). IL-4 and IL-17 were positively correlated with total IgE level. Conclusion: The secretion of immune cells and cytokines in peripheral blood of AR patients is abnormal. Th2, Th17, Treg specific transcription factors and related cells and cytokines are involved in the occurrence and development of allergic rhinitis. [ABSTRACT FROM AUTHOR]

This mathematical model delves into the dynamics of the immune system during Chronic Myeloid Leukemia (CML) therapy with imatinib. The focus lies in elucidating the allergic reactions induced by imatinib, specifically its impact on T helper (Th) cells and Treg cells. The model integrates cellular interactions, drug pharmacokinetics, and immune responses to unveil the mechanisms underlying the dominance of Th2 over Th1 and Treg cells, leading to allergic manifestations. Through a system of coupled delay differential equations, the interplay between healthy and leukemic cells, the influence of imatinib on T cell dynamics, and the emergence of allergic reactions during CML therapy are explored. [ABSTRACT FROM AUTHOR]

Vaccines are the most effective and feasible way to control pathogen infection. Helminths have been reported to jeopardize the protective immunity mounted by several vaccines. However, there are no experimental data about the effect of helminth infection on the effectiveness of COVID-19 vaccines. Here, a mouse model of trichinosis, a common zoonotic disease worldwide, was used to investigate effects of Trichinella spiralis infection on the RBD protein vaccine of SARS-CoV-2 and the related immunological mechanism, as well as the impact of albendazole (ALB) deworming on the inhibitory effect of the parasite on the vaccination. The results indicated that both the enteric and muscular stages of T. spiralis infection inhibited the vaccine efficacy, evidenced by decreased levels of IgG, IgM, sIgA, and reduced serum neutralizing antibodies, along with suppressed splenic germinal center (GC) B cells in the vaccinated mice. Pre-exposure to trichinosis promoted Th2 and/or Treg immune responses in the immunized mice. Furthermore, ALB treatment could partially reverse the inhibitory effect of T. spiralis infection on the efficiency of the vaccination, accompanied by a restored proportion of splenic GC B cells. Therefore, given the widespread prevalence of helminth infections worldwide, deworming therapy needs to be considered when implementing COVID-19 vaccination strategies. [ABSTRACT FROM AUTHOR]

Introduction: We investigated the function of type 2 innate lymphoid cells (ILC2s) and IL-33 in pulmonary tuberculosis (PTB). Methodology: Peripheral blood samples were collected from PTB patients and healthy controls. The cytometric bead array was used to detect plasma IL-33, TGF-β, IL-4, IL-5, IL-6, IL-10, IL-13, and soluble ST2 (sST2). ILC2s, Th2, and Treg cells were detected with flow cytometry. Quantitative real-time PCR was used to measure mRNA levels. ILC2s were co-cultured with peripheral blood mononuclear cells and then intervened with IL-33 or anti-ST2 antibody + IL-33 in vitro. IL-4, IL-6, IL-5, IL-10, IL-13, and TGF-β levels were measured by enzyme-linked immunosorbent assay. Results: Compared with healthy controls, the levels of IL-33, sST2, TGF-β, IL-10, and IL-6 in the plasma of PTB patients were significantly higher. No significant difference was found in the plasma IL-4, IL-5, and IL-13 levels. Patients with PTB had significantly increased ILC2s proportion and mRNA levels of RAR-related orphan receptor α and GATA binding protein 3. After 48 h of IL-33 stimulation in vitro, Treg cell proportion significantly increased and the IL-10 level was significantly elevated. Treatment with anti-ST2 abolished these effects. No significant difference was found in cytokines of IL-4, IL-6, IL-5, IL-13, and TGF-β, or Th2 cells before and after IL-33 treatment. ILC2s proportion in peripheral blood was increased and plasma IL-33 was upregulated in PTB patients. Conclusions: IL-33 may promote the growth of ILC2s and the production of Treg-related cell cytokines, but not Th2-related cell cytokines, to participate in immune response to PTB. [ABSTRACT FROM AUTHOR]

The relationship between allergic inflammation and gut microbiota has been elucidated, and the effect of probiotics on immune disorders has been studied as well. Identifying the role of probiotics in individual diseases and immune responses and selecting and applying specific microorganisms based on these findings can be an effective strategy for using probiotics. Herein, lactobacilli isolated from kimchi were investigated in depth, focusing on their immune regulatory effects and the mechanisms involved. Lactic acid bacteria (LAB) effectively diminished the increased secretion of T helper 2 cytokines, such as IL‐4, IL‐5, and IL‐13, from ovalbumin (OVA)‐sensitized mouse splenocytes. The gene expression of GATA3, IL‐4, IL‐5, IL‐9, and IL‐13 was confirmed to be regulated by LAB. LAB also suppressed IL‐2 production and STAT5 phosphorylation. An IL‐10‐neutralizing antibody attenuated these effects, indicating that LAB‐induced upregulation of IL‐10 in antigen‐presenting cells was responsible at least partially for the increased IL‐2 production and STAT5 phosphorylation in CD4+ T cells. In conclusion, the current study identified one immunomodulatory mechanism that allows LAB to regulate allergic immune reactions and the potential of LAB from kimchi to modulate various immune reactions. [ABSTRACT FROM AUTHOR]

IntroductionAfter mild COVID-19 that does not require hospitalization, some individuals develop persistent symptoms that may worsen over time, producing a multisystemic condition termed Post-COVID condition (PCC). Among other disorders, PCC is characterized by persistent changes in the immune system that may not be solved several months after COVID-19 diagnosis.MethodsPeople with PCC were recruited to determine the distribution and functionality of CD4+ T helper (Th) subsets in comparison with individuals with mild, severe, and critical presentations of acute COVID-19 to evaluate their contribution as risk or protective factors for PCC.ResultsPeople with PCC showed low levels of Th1 cells, similar to individuals with severe and critical COVID-19, although these cells presented a higher capacity to express IFNγ in response to stimulation. Th2/Th1 correlation was negative in individuals with acute forms of COVID-19, but there was no significant Th2/Th1 correlation in people with PCC. Th2 cells from people with PCC presented high capacity to express IL-4 and IL-13, which are related to low ventilation and death associated with COVID-19. Levels of proinflammatory Th9 and Th17 subsets were significantly higher in people with PCC in comparison with acute COVID-19, being Th1/Th9 correlation negative in these individuals, which probably contributed to a more pro-inflammatory than antiviral scenario. Th17 cells from approximately 50% of individuals with PCC had no capacity to express IL-17A and IL-22, similar to individuals with critical COVID-19, which would prevent clearing extracellular pathogens. Th2/Th17 correlation was positive in people with PCC, which in the absence of negative Th1/Th2 correlation could also contribute to the proinflammatory state. Finally, Th22 cells from most individuals with PCC had no capacity to express IL-13 or IL-22, which could increase tendency to reinfections due to impaired epithelial regeneration.DiscussionPeople with PCC showed skewed polarization of CD4+ Th subsets with altered functionality that was more similar to individuals with severe and critical presentations of acute COVID-19 than to people who fully recovered from mild disease. New strategies aimed at reprogramming the immune response and redirecting CD4+ Th cell polarization may be necessary to reduce the proinflammatory environment characteristic of PCC.

BackgroundAmbient air pollutant (AAP) exposure is associated with adverse pregnancy outcomes, such as preeclampsia, preterm labor, and low birth weight. Previous studies have shown methylation of immune genes associate with exposure to air pollutants in pregnant women, but the cell-mediated response in the context of typical pregnancy cell alterations has not been investigated. Pregnancy causes attenuation in cell-mediated immunity with alterations in the Th1/Th2/Th17/Treg environment, contributing to maternal susceptibility. We recruited women (n = 186) who were 20 weeks pregnant from Fresno, CA, an area with chronically elevated AAP levels. Associations of average pollution concentration estimates for 1 week, 1 month, 3 months, and 6 months prior to blood draw were associated with Th cell subset (Th1, Th2, Th17, and Treg) percentages and methylation of CpG sites (IL4, IL10, IFNγ, and FoxP3). Linear regression models were adjusted for weight, age, season, race, and asthma, using a Q value as the false-discovery-rate-adjusted p-value across all genes.ResultsShort-term and mid-term AAP exposures to fine particulate matter (PM2.5), nitrogen dioxide (NO2) carbon monoxide (CO), and polycyclic aromatic hydrocarbons (PAH456) were associated with percentages of immune cells. A decrease in Th1 cell percentage was negatively associated with PM2.5 (1 mo/3 mo: Q

Allergies affect approximately 10–30% of people worldwide, with an increasing number of cases each year; however, the underlying mechanisms are still poorly understood. In recent years, extracellular vesicles (EVs) have been suggested to play a role in allergic sensitization and skew to a T helper type 2 (Th2) response. The aim of this review is to highlight the existing evidence of EV involvement in allergies. A total of 22 studies were reviewed; 12 studies showed EVs can influence a Th2 response, while 10 studies found EVs promoted a Th1 or Treg response. EVs can drive allergic sensitization through up-regulation of pro-Th2 cytokines, such as IL-4 and IL-13. In addition, EVs from MRSA can induce IgE hypersensitivity in mice towards MRSA. On the other hand, EVs can induce tolerance in the immune system; for example, pre-exposing OVA-loaded EVs prevented OVA sensitization in mice. The current literature thus suggests that EVs play an essential role in allergy. Further research utilizing human in vitro models and clinical studies is needed to give a reliable account of the role of EVs in allergy. [ABSTRACT FROM AUTHOR]

Background: Acute respiratory distress syndrome (ARDS) is respiratory failure that commonly occurs in critically ill patients, and the molecular mechanisms underlying its pathogenesis and severity are poorly understood. We evaluated mRNA and miRNA in patients with ARDS and elucidated the pathogenesis of ARDS after performing mRNA and miRNA integration analysis. Methods: In this single-center, prospective, observational clinical study of patients with ARDS, peripheral blood of each patient was collected within 24 hours of admission. Sequencing of mRNA and miRNA was performed using whole blood from the ARDS patients and healthy donors. Results: Thirty-four ARDS patients were compared with 15 healthy donors. Compared with the healthy donors, 1233 mRNAs and 6 miRNAs were upregulated and 1580 mRNAs and 13 miRNAs were downregulated in the ARDS patients. For both mRNA and miRNA-targeted mRNA, canonical pathway analysis showed that programmed death-1 (PD-1) and programmed cell death ligand 1 (PD-L1) cancer immunotherapy pathway was most activated and the Th2 pathway was most suppressed. For mRNA, the Th1 pathway was most suppressed. miR-149-3p and several miRNAs were identified as upstream regulators. Conclusion: miRNAs regulated the PD-1 and PD-L1 cancer immunotherapy pathway and Th2 pathway through miRNA interference action of mRNA. Integrated analysis of mRNAs and miRNAs showed that T cells were dysfunctional in ARDS patients. [ABSTRACT FROM AUTHOR]

As an inflammatory disease with a disrupted immune system, cytokine disorders in atopic dermatitis (AD) are closely related to the abnormal activation of JAKSTAT signal pathway. The critical relevance of the JAK-STAT signaling pathway to the pathogenesis of AD provides a strong rationale for JAK inhibitor research. Baricitinib, a small-molecule oral JAK inhibitor, has been proven to inhibit JAKSTAT signaling in a variety of diseases, including AD. It is currently available in China for off-label use. However, its efficacy in China and its mechanism are rarely reported. In our study, we found that the immune status of patients with moderate and severe AD was hyperactive. Among the 49 known immunotherapy targets, JAK1 and JAK2 genes on lymphocytes of AD patients were significantly upregulated, which was closely related to the symptom severity in moderate and severe AD patients. Baricitinib can improve immune hyperresponsiveness and clinical symptoms in moderate and severe AD by inhibiting the activation of Th2 cell subsets and the secretion of Th2-type cytokines through MAPK, mTOR and PI3K-Akt signaling pathways, providing an important theoretical basis for clinical off-label use of Baricitinib to treat moderate and severe AD. [ABSTRACT FROM AUTHOR]

CD19 deficiency is a rare, predominantly antibody deficiency, and there are few studies showing that it can be seen in autoimmune diseases. The aim of study was evaluated to transcription factor and cytokine expressions of helper T (Th)-cell subsets in CD19 deficiency and the possible mechanism role of this factor expression in autoimmune disease. Transcription factor and cytokine expressions of Th1, Th2, Th17, and regulatory T (Treg) cells were investigated by real-time polymerase chain reaction (qPCR) method. In the study, in the patient/control comparison, transcription factor and cytokine expressions of Th1 (T-bet, STAT1, and STAT4) were found to be significantly downregulated, but IFN-γ was significantly upregulated in patients. Th2 factor GATA3, STAT6, IL-4, and IL-5 were significantly downregulated. For Th17, RORγt was downregulated while IL-22 was upregulated. In the heterozygous/control comparison, there was no significant change in gene expressions other than IL-5. T-bet, STAT1, GATA3, IL-4, RORγt, FoxP3, and TGF-β were significantly downregulated in the patient/heterozygous comparison. It was revealed for the first time that the expression of the transcription factors and cytokines in CD19 deficiency. These findings might be showing the predominance of Th1 factors and suppressed Treg factors which could be related with autoimmunity in CD19 deficiency. [ABSTRACT FROM AUTHOR]

Cigarette smoke (CS) facilitates adverse effects on the airway inflammation and treatment of asthma. Here, we investigated the mechanisms by which CS exacerbates asthma. The roles of IL-33 and IL-35 in asthma development were examined by treatment with IL-33 knockout (IL-33 KO) or transfection of adenovirus encoding IL-35 (Ad-IL-35) in a murine model of cigarette smoke-exposure asthma. Furthermore, the involvement of IL-33 and IL-35 in regulating DCs and Th2/Th17 cells was examined in a coculture system of DCs with CD4+ T cells. Additionally, we observed the effect of CpG-ODNs on the balance of IL-33 and IL-35. We show that CS and house dust mite (HDM) exposure induced IL-33 and suppressed IL-35 levels in cigarette smoke-exposure asthma in vivo and in vitro. Treatment with IL-33 KO or Ad-IL-35 significantly attenuated airway hyperreactivity, goblet hyperplasia, airway remodelling, and eosinophil and neutrophil infiltration in the lung tissues from asthmatic mice. Furthermore, we demonstrated reciprocal regulation between CS and HDM-modulated IL-33 and IL-35. Mechanistically, IL-33 KO (or anti-ST2) and Ad-IL-35 attenuated Th2- and Th17-associated inflammation by downregulating TSLP-DC signalling. Finally, administration of CpG-ODNs suppressed the expression of IL-33/ST2 and elevated the levels of IL-35, which is mainly derived from CD4+Foxp+ Tregs, to alleviate Th2- and Th17-associated inflammation by inhibiting the activation of BMDCs. Taken together, the IL-33/ST2 pathway drives the DC-Th2 and Th17 responses of cigarette smoke-exposure asthma, while IL-35 has the opposite effect. CpG-ODNs represent a potential therapeutic strategy for modulating the balance of IL-33 and IL-35 to suppress allergic airway inflammation. [ABSTRACT FROM AUTHOR]

Visceral leishmaniasis (VL) is a parasitic zoonosis caused by Leishmania spp. that usually manifests itself in immunocompromised subjects. It is a rare and neglected disease, and it is not endemic in the province of Brescia (Italy). Three cases of human VL occurred in Brescia from October to December 2021 in immunocompetent patients. We evaluated the patients looking for signs of underlying immunodeficiencies and conducted further epidemiological evaluations in the province of Brescia without success. An analysis of the sera levels of the main cytokines involved in the immune response to VL was performed. All patients presented a significant augmentation of CXCL-10, CCL-4, and IL-6. The patients tested during the acute phase showed an elevation of IL-1α, IL-5, IL-10, and IL-12, while in the recovery phase, higher levels of TNF-α and IL-7 were detected. Altogether, a predominant activation of the T-helper-2 pathway emerged during the acute phase of the parasite infection, while the cytokines associated with the T-helper-1 pathway were less represented. This imbalanced immune response to the parasite infection might play a crucial role in the development of VL in immunocompetent patients. [ABSTRACT FROM AUTHOR]

Abstract Immune cells, such as macrophages, B cells, neutrophils and T cell subsets, have been implicated in the context of obesity. However, the specific role of Th2 cells in adipose tissue function has remained elusive. Eight-week-old male CD3ε─/─ mice were randomly divided into two groups (≥ 5 mice per group): one received intravenous injection of Th2 cells isolated from LATY136F mice, while the other receiving PBS as a control. Both of groups were subjected to a high-fat diet (HFD). The adoptive transfer of polarized Th2 cells led to a significant reduction in obesity following a HFD. This reduction was accompanied by improvements in hepatic steatosis, glucose intolerance, and insulin resistance. Mechanistically, Th2 cell treatment promoted oxidative phosphorylation of adipocytes, thereby contributing to a reduction of lipid droplet accumulation. These findings suggest that Th2 cell therapy represents a novel approach for treating diet-induced obesity and other diseases involving lipid droplet accumulation disorders.

Immune cells, such as macrophages, B cells, neutrophils and T cell subsets, have been implicated in the context of obesity. However, the specific role of Th2 cells in adipose tissue function has remained elusive. Eight-week-old male CD3ε─/─ mice were randomly divided into two groups (≥ 5 mice per group): one received intravenous injection of Th2 cells isolated from LATY136F mice, while the other receiving PBS as a control. Both of groups were subjected to a high-fat diet (HFD). The adoptive transfer of polarized Th2 cells led to a significant reduction in obesity following a HFD. This reduction was accompanied by improvements in hepatic steatosis, glucose intolerance, and insulin resistance. Mechanistically, Th2 cell treatment promoted oxidative phosphorylation of adipocytes, thereby contributing to a reduction of lipid droplet accumulation. These findings suggest that Th2 cell therapy represents a novel approach for treating diet-induced obesity and other diseases involving lipid droplet accumulation disorders. [ABSTRACT FROM AUTHOR]

Objective: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for Coronavirus Disease 2019 (COVID-19), elicits a strong immune response similar to that seen in other viral infections. The predominant cell type in this immune response also influences the disease prognosis. This study, conducted between 2022 and May 2023, aimed to evaluate the transcription factors and cytokine expressions of Th (helper T) cell subsets at the time of diagnosis and after discharge in patients with nonsevere COVID-19. Materials and Methods: Forty-eight patients with non-severe COVID-19 were included in the study. Transcription factor and cytokine expressions of Th cell subsets were evaluated using the quantitative polymerase chain reaction (qPCR) method, and the results were compared at the time of diagnosis and after discharge. Results: It was determined that the cytokines and transcription factors of T helper 1 (Th1) cells (T-box expressed in T cells [T-bet], 2.71-fold, p<0.001; Interferon-gamma [IFN-γ], 1.42- fold, p=0.010) and T helper 17 (Th17) cells (RAR-related orphan receptor gamma [RORγt], 1.06-fold, p=0.946; Interleukin-22 [IL-22], 1.01-fold, p=0.599) decreased, whereas the expression of T helper 2 (Th2) cells (GATA binding protein 3 [GATA3], 2.56-fold, p<0.001; Interleukin-4 [IL-4], 1.34-fold, p=0.012; Interleukin-5 [IL-5], 1.02-fold, p=0.649; Interleukin-13 [IL-13], 2.06-fold, p=0.0119) and regulatory T (Treg) cells (Forkhead box P3 [FoxP3], 3.56-fold, p<0.001; Transforming growth factor-beta [TGF-β], 1.03-fold, p=0.670; Interleukin-10 [IL-10], 1.40-fold, p=0.010) increased. Conclusion: Our study in non-severe COVID-19 patients demonstrated significant changes in the transcription factor and cytokine expressions of Th cell subsets at the time of diagnosis compared to discharge. We think that even if the patients do not exhibit severe clinical and laboratory findings, Th cell immune responses may be strong, warranting careful consideration. [ABSTRACT FROM AUTHOR]

The type Ⅱ inflammatory response is primarily mediated by type 2 immune cells and cytokines, such as helper 2 cells （Th2） and group 2 innate lymphoid cells (ILC2), along with IL-4, IL-5 and IL-13. This response plays crucial roles in humoral immunity, parasite defense, toxin neutralization, tissue damage repair and regeneration. However, type-Ⅱ immune response can also contribute to the development of diseases. Currently, type Ⅱ inflammation is recognized to have physiological and pathological implications in the skin, respiratory tract, digestive tract and adipose tissues. Moreover, it serves as a major cause of allergic diseases. Due to its unique immune microenvironment, the respiratory tract exhibits a high prevalence of type Ⅱ inflammation encompassing chronic sinusitis, allergic rhinitis, allergic asthma, allergic bronchopulmonary aspergillosis, and chronic obstructive pulmonary disease with eosinophilia among others. This review will focus on the research progress concerning Th2 and ILC2 cells in allergic pulmonary inflammation as well as targeted therapy for allergic diseases. [ABSTRACT FROM AUTHOR]

Vaccines have demonstrated remarkable effectiveness in protecting against COVID‐19; however, concerns regarding vaccine‐associated enhanced respiratory diseases (VAERD) following breakthrough infections have emerged. Spike protein subunit vaccines for SARS‐CoV‐2 induce VAERD in hamsters, where aluminum adjuvants promote a Th2‐biased immune response, leading to increased type 2 pulmonary inflammation in animals with breakthrough infections. To gain a deeper understanding of the potential risks and the underlying mechanisms of VAERD, we immunized ACE2‐humanized mice with SARS‐CoV‐2 Spike protein adjuvanted with aluminum and CpG‐ODN. Subsequently, we exposed them to increasing doses of SARS‐CoV‐2 to establish a breakthrough infection. The vaccine elicited robust neutralizing antibody responses, reduced viral titers, and enhanced host survival. However, following a breakthrough infection, vaccinated animals exhibited severe pulmonary immunopathology, characterized by a significant perivascular infiltration of eosinophils and CD4+ T cells, along with increased expression of Th2/Th17 cytokines. Intracellular flow cytometric analysis revealed a systemic Th17 inflammatory response, particularly pronounced in the lungs. Our data demonstrate that aluminum/CpG adjuvants induce strong antibody and Th1‐associated immunity against COVID‐19 but also prime a robust Th2/Th17 inflammatory response, which may contribute to the rapid onset of T cell‐mediated pulmonary immunopathology following a breakthrough infection. These findings underscore the necessity for further research to unravel the complexities of VAERD in COVID‐19 and to enhance vaccine formulations for broad protection and maximum safety. [ABSTRACT FROM AUTHOR]

The concept of DNA vaccination was introduced in the early 1990s. Since then, advancements in the augmentation of the immunogenicity of DNA vaccines have brought this technology to the market, especially in veterinary medicine, to prevent many diseases. Along with the successful COVID mRNA vaccines, the first DNA vaccine for human use, the Indian ZyCovD vaccine against SARS-CoV-2, was approved in 2021. In the current review, we first give an overview of the DNA vaccine focusing on the science, including adjuvants and delivery methods. We then cover some of the emerging science in the field of DNA vaccines, notably efforts to optimize delivery systems, better engineer delivery apparatuses, identify optimal delivery sites, personalize cancer immunotherapy through DNA vaccination, enhance adjuvant science through gene adjuvants, enhance off-target and heritable immunity through epigenetic modification, and predict epitopes with bioinformatic approaches. We also discuss the major limitations of DNA vaccines and we aim to address many theoretical concerns. [ABSTRACT FROM AUTHOR]

Hereditary hemorrhagic telangiectasia (HHT) is a rare inherited disease due to heterozygous loss-of-function mutations on the BMP9/10 pathway (ENG, ACVRL1 or MADH4 mainly). HHT endothelial cells are prone to lose their quiescence, leading to progressive appearance of numerous telangiectases on skin and mucosa (complicated by epistaxis and anemia), and to larger arteriovenous malformations in lungs, liver and brain. HHT is also associated with T lymphocyte abnormalities, which are currently poorly understood. We quantified by flow-cytometry the main T lymphocyte circulating subsets in 40 HHT patients and 20 matched healthy controls. Immunostaining was done on 2 HHT skin telangiectases. Disruptions in T lymphocyte homeostasis was observed, characterized by increases in subsets known to promote angiogenesis: Th2 (1.38% vs 1.15%, p=0.021), Th17 (0.32% vs 0.22%, p=0.019 2) and Treg (4.94% vs 3.51%, p= 0.027). T angiogenic lymphocytes (Tang), defined as CD3+CD31+CXCR4+ T cells, were at similar levels in both groups, but the proportion of VEGF-A+ Tang after stimulation was higher in the HHT group compared to controls (68.2% vs 44.9%, p=0.012). The global HHT T lymphopenia predominantly affected the effector memory T-helper cells (200 vs 270 cells/mm³, p=0.017), and the lymphocytic infiltrate around HHT telangiectases consisted of memory T-helper cells. The Th17 circulating subset was positively correlated with the monthly epistaxis duration (r coefficient: +0,431, p=0.042), prospectively assessed. HHT T-helper lymphocytes are affected by several pro-angiogenic changes, potentially resulting from their recruitment by abnormal endothelial cells. They could constitute a biologically relevant source of VEGF-A and a valuable therapeutic target in HHT. [ABSTRACT FROM AUTHOR]

Mice develop pathology in the lungs as they age and this may be accelerated by a high calorie diet (HCD). ES-62 is a protein secreted by the parasitic worm Acanthocheilonema viteae that is immunomodulatory by virtue of covalently attached phosphorylcholine (PC) moieties. In this study, we show that weekly treatment of C57BL/6J mice with ES-62 protected against pathology in the lungs in male but not female mice fed a HCD from 10 weeks of age as shown by reductions in cellular infiltration and airway remodelling, particularly up to 160 days of age. ES-62 also reduced gene expression of the cytokines IL-4 and IL-17 and in addition the TLR/IL-1R adaptor MyD88, in the lungs of male mice although HCD-induced increases in these inflammatory markers were not detected until between 340 and 500 days of age. A combination of two drug-like ES-62 PCbased small molecule analogues (SMAs), produced broadly similar protective effects in the lungs of male mice with respect to both lung pathology and inflammatory markers, in addition to a decrease in HCD-induced IL-5 expression. Overall, our data show that ES-62 and its SMAs offer protection against HCDaccelerated pathological changes in the lungs during ageing. Given the targeting of Th2 cytokines and IL-17, we discuss this protection in the context of ES-62’s previously described amelioration of airway hyper-responsiveness in mouse models of asthma. [ABSTRACT FROM AUTHOR]

Autoimmune bullous disease autoantibodies, particularly including bullous pemphigoid (BP)-related anti-BP180-NC16A IgG, have been reported in a small subset of healthy individuals, but information about associated factors is lacking. We hypothesized that an abnormal status of immunomodulatory vitamin D could play a role in anti-BP180-NC16A autoantibody reactivity in healthy persons. In addition, we aimed to evaluate the cytokine profile associated with these autoantibodies. Plasma samples from 34 anti-BP180-NC16A IgG-reactive and 85 anti-BP180-NC16A IgG-negative healthy blood donors were tested for levels of 25-hydroxyvitamin D [25(OH)D] and a wide range of cytokines (IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17A, IL-17F, IL-21, IL-22, IFN-γ, and TNF-α). We observed that anti-BP180-NC16A IgG-reactive healthy subjects had significantly lower plasma 25(OH)D levels and about a two-fold higher rate of vitamin D deficiency (< 20 ng/ml) compared to anti-BP180-NC16A IgG-negative healthy persons. In addition, anti-BP180-NC16A IgG-positive samples were characterized by significantly higher levels of IL-2, IL-5, IL-9, IL-10, and IL-13 which were, however, not significantly associated with the vitamin D levels. Our results indicate that healthy individuals with BP autoantibody reactivity share similarities with BP patients regarding the vitamin D status and cytokine profile (i.e., marked hypovitaminosis D and Th2 predominance), which may have pathophysiologic implications. [ABSTRACT FROM AUTHOR]

Copyright of China Tropical Medicine is the property of China Tropical Medicine Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Pregnenolone (P5) is synthesized as the first bioactive steroid in the mitochondria from cholesterol. Clusters of differentiation 4 (CD4+) and Clusters of differentiation 8 (CD8+) immune cells synthesize P5 de novo; P5, in turn, play important role in immune homeostasis and regulation. However, P5’s biochemical mode of action in immune cells is still emerging. We envisage that revealing the complete spectrum of P5 target proteins in immune cells would have multifold applications, not only in basic understanding of steroids biochemistry in immune cells but also in developing new therapeutic applications. We employed a CLICK-enabled probe to capture P5-binding proteins in live T helper cell type 2 (Th2) cells. Subsequently, using highthroughput quantitative proteomics, we identified the P5 interactome in CD4+ Th2 cells. Our study revealed P5’s mode of action in CD4+ immune cells. We identified novel proteins from mitochondrial and endoplasmic reticulum membranes to be the primary mediators of P5’s biochemistry in CD4+ and to concur with our earlier finding in CD8+ immune cells. Applying advanced computational algorithms and molecular simulations, we were able to generate near-native maps of P5–protein key molecular interactions. We showed bonds and interactions between key amino acids and P5, which revealed the importance of ionic bond, hydrophobic interactions, and water channels. We point out that our results can lead to designing of novel molecular therapeutics strategies. [ABSTRACT FROM AUTHOR]

The dysfunction of regulatory T cell (Treg) is associated with the pathogenesis of many immune diseases. The regiments used to re‐establish Treg's function are currently unsatisfactory and need to be improved. The purpose of this study is to elucidate the synergistic effects of cortisol and endoplasmic reticulum (ER) stress on impairing regulatory T cell functions. In this study, blood samples were collected from patients with food allergy (FA). Immune cells were purified from blood specimens by flow cytometry. A mouse model of FA was established with ovalbumin as a specific antigen. We observed that serum cortisol levels of FA patients were negatively correlated with peripheral Treg counts. Overwhelmed ER stress status was detected in Tregs of FA patients. The antigen‐specific immune response induced ER stress in Tregs, which was exacerbated by concurrent cortisol exposure. ER stress mediated the effects of cortisol on impairing the immune suppressive ability of Tregs. The expression of Rnf20 was observed in Tregs upon exposure to cortisol. Rnf20 reduced the expression of Foxp3 and transforming growth factor (TGF)‐β in Tregs. Rnf20 inhibition re‐established the immunosuppressive functions of Tregs obtained in patients with FA. The experimental FA in mice was attenuated by inhibition of Rnf20 in Tregs. In summary, specific immune response in synergy with cortisol to induce the expression of Rnf20 in Tregs. Rnf20 reduces the levels of Foxp3 and TGF‐β to impair the immune suppressive function. Inhibition of Rnf20 can restore the immune suppressive ability of Tregs obtained from FA patients. [ABSTRACT FROM AUTHOR]

Over the last years, technological advances in the field of asthma have led to the identification of two disease endotypes, namely, type 2‐high and type 2‐low asthma, characterized by different pathophysiologic mechanisms at a cellular and molecular level. Although specific immune cells are important contributors to each of the recognized asthma endotype, the lung epithelium is now regarded as a crucial player able to orchestrate responses to inhaled environmental triggers such as allergens and microbes. The impact of the epithelium goes beyond its physical barrier. It is nowadays considered as a part of the innate immune system that can actively respond to insults. Activated epithelial cells, by producing a specific set of cytokines, trigger innate and adaptive immune cells to cause pathology. Here, we review how the epithelium contributes to the development of Th2 sensitization to allergens and asthma with a "type 2‐high" signature, in both murine models and human studies of this asthma endotype. We also discuss epithelial responses to respiratory viruses, such as rhinovirus, respiratory syncytial virus, and SARS‐CoV‐2, and how these triggers influence not only asthma development but also asthma exacerbation. Finally, we also summarize the results of promising clinical trials using biologicals targeting epithelial‐derived cytokines in asthmatic patients. [ABSTRACT FROM AUTHOR]