Th2 Lymphocytes Research Articles

RORC overexpression as a sign of Th17 lymphocytes accumulation in multiple myeloma bone marrow

The role of the bone marrow microenvironment in supporting the proliferation and survival of the abnormal plasma cells in multiple myeloma (MM) is well established. Such microenvironment is rich of cytokines like IL-6, TGF-β, IL-1 and IL-23 which are known to promote the differentiation of Th17 lymphocytes, a T helper subpopulation. Th17 cells secrete IL-17, a cytokine involved in the pathophysiology of several auto-immune diseases. Yet, its involvement in cancers remains unclear. Herein, we aimed to try to understand the role of Th17 lymphocytes in multiple myeloma.Bone marrow samples were prospectively collected from 29 MM patients and 23 healthy bone marrow donors for allograft. Mononuclear bone marrow cells were isolated by Ficoll-Hypaque gradient and CD138+ plasma cells were depleted using magnetic beads. The quantification of Th17 cells was performed by flow cytometry in the CD138 negative cells. The mRNA expression of IL17 and RORc was quantified using real time PCR in the same subset. The mRNA expression of IL17R was analyzed in plasma cells (CD138+ cells). Data obtained from patients and healthy donors were compared by both non-parametric Mann-Whitney U test and Spearman test.A significant increase of IL17 and RORC mRNA expression was found in the bone marrow microenvironment of MM patients compared to healthy donors. Th17 cells were also increased in the bone marrow of MM patients compared to healthy donors. Interestingly, the mRNA expression of IL17R was significantly decreased in MM patients. Yet, no correlation was found between the gene expression IL17, RORC and IL17R and the bone marrow infiltration or the stage of the disease. Collectively, our results suggest the involvement of Th17 cells in the pathophysiology of MM. Such data further support the use of anti-IL-17 antibodies as a therapeutic approach in MM.

Irbesartan may relieve renal injury by suppressing Th22 cells chemotaxis and infiltration in Ang II-induced hypertension

Angiotensin II (Ang II) as an important pathogenic factor, has been implicated in the pathogenesis of hypertension and associated renal injury, and inhibition of Ang II can reduce renal inflammation and exert renal protective effects. In the present study, we determine the infiltration of Th22 cells in kidney and serum IL-22 level in hypertensive renal injury, and explore the effects and mechanisms of a widely used angiotensin II type 1 receptor blocker irbesartan on Th22 cells infiltration and related renal injury. Hypertension was induced by administering 1.5 mg/kg Ang II subcutaneously daily in C57BL/6 mice for 28 days. The mice were additionally treated by irbesartan or amlodipine. Renal Th22 lymphocytes frequency was evaluated through flow cytometry, serum IL-22 was detected by ELISA, and renal histopathological changes were also detected. The levels of renal chemokines (CCL20, CCL22, CCL27) and serum proinflammatory factors (IL-1β, IL-6, TNF-α) were measured by ELISA. Renal expression of alpha-smooth muscle actin (α-SMA), Fibronectin (FN) and collagen I (Col I) were evaluated by western blot. Chemotaxis assay and co-culture assay were conducted to clarify the effect of irbesartan on Th22 cells chemotaxis and differentiation in vitro. Our results showed in Ang II-infused hypertension mice, irbesartan suppressed renal Th22 cells accumulation as well as CCL20, CCL22, CCL27 expression. Serum IL-22, IL-1β, IL-6 and TNF-α concentrations wasere also reduced, in addition to inhibited renal expression of α-SMA, FN and Col I. Irbesartan treatment lowered blood pressure, urinary protein and renal pathological damage. In vitro, irbesartan could abrogate the Th22 cells chemotaxis and differentiation, compared to control and amlodipine groups. Our study reveals a new pharmacological mechanism that irbesartan ameliorates inflammation and fibrosis in hypertensive renal injury induced by Ang II, maybe through inhibiting Th22 cells chemotaxis and infiltration, which provides a new theoretical basis and therapeutic target for hypertensive renal injury.

Th17 lymphocytes in atypical cutaneous leishmaniasis caused by Leishmania (L.) infantum chagasi in Central America

Skin lesions in nonulcerated cutaneous leishmaniasis (NUCL) caused by Leishmania (L.) infantum chagasi are characterized by a mononuclear inflammatory infiltrate in the dermis, which is composed mainly of lymphocytes, followed by macrophages, few plasma cells and epithelioid granulomas with mild tissue parasitism. Previous studies have shown that the main population of lymphocytes present in the dermal infiltrate is CD8+ T cells, followed by CD4+ T cells, which are correlated with IFN-γ+ cells. To improve the knowledge of cellular immune responses in NUCL, skin biopsies were submitted to immunohistochemistry using anti-ROR-γt, anti-IL-17, anti-IL-6, anti-TGF-β, and anti-IL-23 antibodies to characterize the involvement of Th17 cells in the skin lesions of patients affected by NUCL. ROR-γt+ , IL-17+ , IL-6+ , TGF-β+ and IL-23+ cells were observed in the dermal inflammatory infiltrate of NUCL skin lesions. A positive correlation between CD4+ T-lymphocytes and ROR-γt+ and IL-17+ cells suggests that some of the CD4+ T-lymphocytes in NUCL could be Th17 lymphocytes. Moreover, a positive correlation between ROR-γt+ cells and TGF-β+ , IL-6+ , IL-17+ and IL-23+ cells could indicate the role of these cytokines in the differentiation and maintenance of Th17 lymphocytes. Our findings improve knowledge of the pathogenesis of this rare and atypical clinical form of leishmaniasis.

Identification of Novel Molecular Markers of Human Th17 Cells.

Th17 cells are important players in host defense against pathogens such as Staphylococcus aureus, Candida albicans, and Bacillus anthracis. Th17 cell-mediated inflammation, under certain conditions in which balance in the immune system is disrupted, is the underlying pathogenic mechanism of certain autoimmune disorders, e.g., rheumatoid arthritis, Graves’ disease, multiple sclerosis, and psoriasis. In the present study, using transcriptomic profiling, we selected genes and analyzed the expression of these genes to find potential novel markers of Th17 lymphocytes. We found that APOD (apolipoprotein D); C1QL1 (complement component 1, Q subcomponent-like protein 1); and CTSL (cathepsin L) are expressed at significantly higher mRNA and protein levels in Th17 cells than in the Th1, Th2, and Treg subtypes. Interestingly, these genes and the proteins they encode are well associated with the function of Th17 cells, as these cells produce inflammation, which is linked with atherosclerosis and angiogenesis. Furthermore, we found that high expression of these genes in Th17 cells is associated with the acetylation of H2BK12 within their promoters. Thus, our results provide new information regarding this cell type. Based on these results, we also hope to better identify pathological conditions of clinical significance caused by Th17 cells.

Human Microbiome and Allergic Diseases in Children: Pathogenetic Role and Therapeutic Options.

The recent and extensive study of the microbiome has provided an enormous amount of data concerning the type and possible functions of microorganisms present in the gut, airways, genital tract, and skin. These data showed interpersonal differences in the composition of the microbiome and these differences suggest a link between the microbiome, the immune modulation, and the pathogenesis of allergic diseases. This research is particularly relevant in paediatrics, since allergic diseases are constantly increasing and there is evidence in the paediatric age that shows that the composition of the microbiome in the foetal and neonatal period plays a key role in the development of the immune system: vaginal delivery, breastfeeding, childhood spent in rural environments and/or in contact with animals result in a greater biodiversity of the microbiome with the presence of protective species that reduce the activation of Th2 lymphocytes, involved in allergic reactions. Further studies are necessary to better understand the microbiota role in the pathogenesis of atopy in order to understand if specific probiotics and prebiotics, administered orally or topically, can affect the microbiota composition and modulate immune system functions, producing a therapeutic effect in the treatment of allergic diseases. This narrative review analysed the available literature regarding the correlation between the microbiome and the development of allergic diseases and with special focus on paediatric studies. The skin, gut or lung dysbiosis can be a cofactor in the pathogenesis of allergies and the remodulation of the microbiome becomes an important therapeutic challenge.

Relationship between chemokines and T lymphocytes in the context of respiratory allergies (Review).

Allergic diseases have been classified in the last decades using various theories. The main classes of the newest classification in allergic respiratory diseases focus on the characterization of the endotype (which takes into account biomarkers related to determinant pathophysiological mechanisms) and of the phenotype (based on the description of the disease). Th2, Th1 and Th17 lymphocytes and the type of inflammatory response mediated by them represent the basis for Th2 and non-Th2 endotype classification. In addition, new lymphocytes were also used to characterize allergic diseases: Th9 lymphocytes, Th22 lymphocytes, T follicular helper cells (TFH) lymphocytes and invariant natural killer T (iNKT) lymphocytes. In the last decade, a growing body of evidence focused on chemokines, chemoattractant cytokines, which seems to have an important contribution to the pathogenesis of this pathology. This review presents the interactions between chemokines and Th lymphocytes in the context of Th2/non-Th2 endotype classification of respiratory allergies.

Polarization of Immune Cells in the Pathologic Response to Inhaled Particulates.

Polarization of immune cells is commonly observed in host responses associated with microbial immunity, inflammation, tumorigenesis, and tissue repair and fibrosis. In this process, immune cells adopt distinct programs and perform specialized functions in response to specific signals. Accumulating evidence indicates that inhalation of micro- and nano-sized particulates activates barrier immune programs in the lung in a time- and context-dependent manner, including type 1 and type 2 inflammation, and T helper (Th) 17 cell, regulatory T cell (Treg), innate lymphoid cell (ILC), and myeloid-derived suppressor cell (MDSC) responses, which highlight the polarization of several major immune cell types. These responses facilitate the pulmonary clearance and repair under physiological conditions. When exposure persists and overwhelms the clearance capacity, they foster the chronic progression of inflammation and development of progressive disease conditions, such as fibrosis and cancer. The pulmonary response to insoluble particulates thus represents a distinctive disease process wherein non-infectious, persistent exposures stimulate the polarization of immune cells to orchestrate dynamic inflammatory and immune reactions, leading to pulmonary and pleural chronic inflammation, fibrosis, and malignancy. Despite large variations in particles and their associated disease outcomes, the early response to inhaled particles often follows a common path. The initial reactions entail a barrier immune response dominated by type 1 inflammation that features active phagocytosis by M1 macrophages and recruitment of neutrophils, both of which are fueled by Th1 and proinflammatory cytokines. Acute inflammation is immediately followed by resolution and tissue repair mediated through specialized pro-resolving mediators (SPMs) and type 2 cytokines and cells including M2 macrophages and Th2 lymphocytes. As many particles and fibers cannot be digested by phagocytes, resolution is often extended and incomplete, and type 2 inflammation becomes heightened, which promotes interstitial fibrosis, granuloma formation, and tumorigenesis. Recent studies also reveal the involvement of Th17-, Treg-, ILC-, and MDSC-mediated responses in the pathogenesis caused by inhaled particulates. This review synopsizes the progress in understanding the interplay between inhaled particles and the pulmonary immune functions in disease pathogenesis, with focus on particle-induced polarization of immune cells and its role in the development of chronic inflammation, fibrosis, and cancer in the lung.

Innate Lymphocyte Th1 and Th17 Responses in Elderly Hospitalised Patients with Infection and Sepsis.

Background: the role of innate immunity in human sepsis must be fully clarified to identify potential avenues for novel immune adjuvant sepsis therapies. Methods: A prospective observational study was performed including patients with sepsis (septic group), infection without sepsis (infection group), and healthy controls (control group) in the setting of acute medical wards and intensive care units in a 1000-bed university hospital. A total of 42 patients with sepsis, 30 patients with infection, and 30 healthy controls were studied. The differentiation states of circulating mucosal associated invariant T (MAIT) cells and Natural Killer T (NKT) cells were characterised as naive (CD45RA+, CD197+), central memory (CD45RA−, CD197+), effector memory (CD45RA−, CD197−), or terminally differentiated (CD45RA+, CD197−). The differentiation states of circulating gamma-delta T lymphocytes were characterised as naive (CD45RA+, CD27+), central memory (CD45RA−, CD27+), effector memory (CD45RA−, CD27−), or terminally differentiated (CD45RA+, CD27−). The expression of IL-12 and IL-23 receptors, the transcription factors T-Bet and RORγt, and interferon-γ and IL-17a were analysed. Results: MAIT cell counts were lower in the septic group (p = 0.002) and the infection group (p < 0.001) than in the control group. The MAIT cell T-Bet expression in the infection group was greater than in the septic group (p = 0.012). The MAIT RORγt expression in the septic group was lower than in the control group (p = 0.003). The NK cell counts differed in the three groups (p < 0.001), with lower Natural Killer (NK) cell counts in the septic group (p < 0.001) and in the infection group (p = 0.001) than in the control group. The NK cell counts increased in the septic group in the 3 weeks following the onset of sepsis (p = 0.028). In lymphocyte stimulation experiments, fewer NK cells expressed T-Bet in the septic group than in the infection group (p = 0.002), and fewer NK cells expressed IFN-γ in the septic group than in the control group (p = 0.002). The NKT cell counts were lower in the septic group than both the control group (p = 0.05) and the infection group (p = 0.04). Fewer NKT cells expressed T-Bet in the septic group than in the infection group (p = 0.004). Fewer NKT cells expressed RORγt in the septic group than in the control group (p = 0.003). Fewer NKT cells expressed IFN-γ in the septic group than in both the control group (p = 0.002) and the infection group (p = 0.036). Conclusion: The clinical presentation of infection and or sepsis in patients is linked with a mosaic of changes in the innate lymphocyte Th1 and Th17 phenotypes. The manipulation of the innate lymphocyte phenotype offers a potential avenue for immune modulation in patients with sepsis.

Microenvironmental Th9 and Th17 lymphocytes induce metastatic spreading in lung cancer.

Immune microenvironment plays a critical role in lung cancer control versus progression and metastasis. In this investigation, we explored the effect of tumor-infiltrating lymphocyte subpopulations on lung cancer biology by studying in vitro cocultures, in vivo mouse models, and human lung cancer tissue. Lymphocyte conditioned media (CM) induced epithelial-mesenchymal transition (EMT) and migration in both primary human lung cancer cells and cell lines. Correspondingly, major accumulation of Th9 and Th17 cells was detected in human lung cancer tissue and correlated with poor survival. Coculturing lung cancer cells with Th9/Th17 cells or exposing them to the respective CM induced EMT in cancer cells and modulated the expression profile of genes implicated in EMT and metastasis. These features were reproduced by the signatory cytokines IL-9 and IL-17, with gene regulatory profiles evoked by these cytokines partly overlapping and partly complementary. Coinjection of Th9/Th17 cells with tumor cells in WT, Rag1-/-, Il9r-/-, and Il17ra-/- mice altered tumor growth and metastasis. Accordingly, inhibition of IL-9 or IL-17 cytokines by neutralizing antibodies decreased EMT and slowed lung cancer progression and metastasis. In conclusion, Th9 and Th17 lymphocytes induce lung cancer cell EMT, thereby promoting migration and metastatic spreading and offering potentially novel therapeutic strategies.

Th17 cell frequency and IL-17A production in peripheral blood of patients with non-small-cell lung cancer.

ObjectiveThis study investigated the frequency of T-helper (Th)17 lymphocytes and production of cytokine interleukin (IL)-17 in peripheral blood of patients with non-small-cell lung cancer (NSCLC) and their use as a marker of clinical value.MethodsSixty patients with NSCLC and 60 healthy volunteers were enrolled in the study. Flow cytometry was used to detect the frequency of Th17 lymphocytes in peripheral blood, and enzyme-linked immunosorbent assay (ELISA) was used to detect serum levels of IL-17. We analyzed the association of Th17 lymphocytes and IL-17 levels in the peripheral blood of patients with their clinicopathological features.ResultsFrequency of Th17 lymphocytes and production of IL-17 were significantly higher in the NSCLC group than in the control group and were higher in patients with a smoking history compared with non-smokers. Moreover, Th17 lymphocyte and IL-17 expression levels were higher in patients with squamous cell carcinoma than in patients with adenocarcinoma, and significantly higher in patients with stage III and IV cancers than in patients at stage I or II.ConclusionTh17 lymphocytes and IL-17 play an important role in the development of NSCLC in patients and may have clinical value as markers for treatment of NSCLC.

THU0325 REDUCED OF TREG CELLS ASSOCIATED WITH THE DISEASE ACTIVITY OF ANCA-ASSOCIATED VASCULITIS

Background:Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of autoimmune disease that can cause systemic organ damage, characterized with the presence of abnormal antibodies (ANCAs) in the circulation and the small- and medium-vessel vasculitis[1].However,the etiology of AAV remained unclear. Several observations have showed that the breakdown of immune tolerance caused by many complex interactions was involved in the pathogenesis of AAV[2].It has been confirmed that the disorder of the CD4+T cell,especially the imbalance of Th17 and Treg cells can destroy the immune tolerance and cause many autoimmune disease[3]. But the relationship between the Th17/Treg and AAV is unknown.Objectives:We investigated the absolute numbers of CD4+T subsets cells in peripheral blood of patients with AAV and healthy adults,and then compared them in different disease activity of AAV to explore the role of CD4+T subsets cells in the pathogenesis and development of AAV.Methods:49 patients with AAV,hospitalized at the Second Hospital of Shanxi Medical University from the May 2016 to the November 2019 were enrolled, and 31 age and gender-matched healthy adults were anticipated as controls.According to BVAS, the patients were divided into disease-activity group (BVAS≥15, n=27) and non-disease-activity group (BVAS&lt;15, n=22). The absolute numbers of CD4+T subsets cells including Th17 and Tregs in peripheral blood of these individuals were detected by flow cytometry.We analyzed whether there was difference of CD4+T subsets between the patients and healthy controls,and between disease-activity group and non-disease-activity group.Results:There was significant decreased level of Treg cells in the patients with AAV compared with healthy controls,especially in the disease-activity group. The absolute numbers of Treg cells was decreased in the patients with AAV compared with healthy controls (P&lt;0.001) leading to a higher Th17/Treg ratio in the patients (P&lt;0.01).Similarly,the absolute number of Treg cells was decreased in the disease- activity group (P&lt;0.01) compared with the non-disease-activity group, and the absolute number of Treg cells was significant negative correlation with the disease activity indexes such as BVAS (r=-0.342,P=0.016), erythrocyte sedimentation rate(ESR) (r=-0.315,P=0.027) and C-reactive protein(CRP) (r=-0.305,P=0.033). But there was no statistically significant in the absolute number of Th17 cells between the patients and healthy controls, and between disease-activity group and non-disease-activity group.Conclusion:The results we investigated here suggested that the decreased number of Treg cells failed to control autoimmune inflammatory response and maintain immune tolerance, and the disease activity of AAV was associated with the reduced number of Treg cells.Figure 1.(A-C) Characteristics of the absolute number of Th17 cells and Treg cells in peripheral blood of healthy controls (n=31) and the patients with AAV (n=49). There was significant decreased level of Treg cells in the patients with AAV compared with healthy controls leading to a higher Th17/Treg ratio in the patients with AAV. (D-F) The absolute number of Treg cells was decreased in the disease- activity group (n=27) compared with the non-disease-activity group (n=21). The absolute number of Th17 cells and Treg cells was detected by flow cytometry. Statistical analyses were performed by the Mann-Whitney U test. *p&lt;0.05,**p&lt;0.01, ***p&lt;0.001.

SAT0278 LOW-DOSE IL-2 RESTORES TREG-MEDIATED IMMUNE TOLERANCE IN PATIENTS WITH ANCA-ASSOCIATED VASCULITIS

Background:Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of autoimmune disease that can cause systemic organ damage, including granulomatosis with polyangiitis(GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis(EGPA)[1]. Several observations have showed that the breakdown of immune tolerance was involved in the pathogenesis of AAV [2], furthermore, a single, open and clinical trial demonstrates that IL-2 can be used to treat patients with GPA [3]. But there is still a lack of understanding of the relationship between Th17 / Treg and AAV and evidence for the therapeutic effect of IL-2 on AAV, which needs further exploration.Objectives:We first measured the absolute number of CD4+T subsets in peripheral blood of patients to explore the pathogenesis of AAV, and then investigated the effects of short-term and low-dose recombinant human IL-2 (rhIL-2) on CD4+T subsets of patients to analyze the regulatory effect of IL-2 on AAV.Methods:49 patients with AAV, hospitalized at the Second Hospital of Shanxi Medical University from the May 2016 to the November 2019 were enrolled, including 36 patients who were only received conventional glucocorticoids and DMARDs, and other 13 patients who were not only received these treatments but were also injected subcutaneously rhIL-2(50WIU/day for a 5-day course). 31 age and gender-matched healthy adults were selected as controls. The absolute number of Th17 and Treg cells in peripheral blood of health controls and the patients before and after treatment was detected by flow cytometry.Results:There was significant decreased level of Treg cells in the patients with AAV compared with healthy controls (P&lt;0.001) leading to a higher Th17/Treg ratio in the patients with AAV, but there was no statistically significant in the absolute number of Th17 cells between the patients and healthy controls. After the treatment of short-term and low-dose IL-2, there was a significant increase in the absolute number of Treg cells (P&lt;0.01) leading to a decrease in the ratio of Th17 and Treg (p&lt;0.05).The absolute number of Th17 had a trend towards higher values but was not statistical significance.Conclusion:The difference of Treg cells between the patients and healthy controls suggested that the decreased number of Treg cells failed to control autoimmune inflammatory response contributing to the pathogenesis of AAV. After the treatment of short-term and low-dose rhIL-2, there was a more significant increase in the absolute number of Treg cells showing that IL-2 could selectively stimulate the growth of Treg cells and restore the Treg-mediated immune tolerance in patients with AAV to achieve disease remission.

Cholinergic anti-inflammatory pathway plays negative regulatory role in early inflammatory and immune responses in septic rats

To investigate the role of cholinergic anti-inflammatory pathway (CAP) in neuro-regulation of inflammatory and immune response in the early stage of sepsis. Sixty-four SD rats were randomly divided into control Group (n=8) with normal feeding without any treatment; sham operation group (n=8) with laparotomy but without cecal ligation and puncture (CLP), followed by intraperitoneal injection 50 mg/kg piperacillin 3 times a day for 3 consecutive days; and sepsis group (n=48) with CLP-induced sepsis. The rat models of sepsis were randomized into model groups (n=16) with intraperitoneal injection of piperacillin (50 mg/kg) and normal saline (1 mL/100 g) for 3 times a day for 3 days; GTS-21 group (n=16) with additional intraperitoneal injection of 4 mg/kg GTS-21 (once a day for 3 days); and methyllycaconitine (MLA) group (n=16) with intraperitoneal injection of MLA (4.8 mg/kg) in addition to piperacillin (once a day for 3 days). Murine Sepsis Score (MSS) of the rats and short-range HRV analysis were recorded. Three days later, the rats were sacrificed and serum levels of TNF-α, IL-1α, IL-10, IL-6, HMGB1, and sCD14 were measured with ELISA. The percentages of CD4+CD25+ Treg and TH17 lymphocytes and their ratios were measured using flow cytometry. Compared with the control rats, the septic rats had significantly increased MSS scores and lowered HRV indexes (SDNN, RMSSD, HF, SD1, and SD2; P &lt; 0.05); treatment with GTS-21 significantly decreased while MLA increased MSS scores (P &lt; 0.05), but neither of them obviously affected HRV of the rats. Serum levels TNF-α, IL-1α, IL-10, IL-6, HMGB1, and sCD14 and the percentages of CD4+CD25+ Treg and TH17-positive lymphocytes were significantly higher and Treg/TH17 ratio was significantly lower in the septic rats compared with those in the control group (P &lt; 0.05); treatment with GTS-21 significantly decreased the levels of serum levels of TNF-α, IL-1α, IL-6, HMGB1, and sCD14 and TH17 lymphocyte percentage (P &lt; 0.05), whereas MLA treatment significantly increased serum levels of TNF-α, IL-1α, IL-10, IL-6, HMGB1, and sCD14 and the percentages of CD4+ CD25+ Treg and TH17-positive lymphocytes and decreased Treg/TH17 ratio in the septic rats (P &lt; 0.05). CAP plays negative regulatory role in early inflammatory and immune response to sepsis, and some of the HRV indicators can well reflect the regulatory effect of CAP on inflammation and immunity in the septic rats.

CD2 Regulates Pathogenesis of Asthma Induced by House Dust Mice Extract

Characteristic of allergic asthma, CD4+Th2 lymphocytes secrete Th2 cytokines, interleukin (IL)-4, IL-13, and IL-5 that mediate the inflammatory immune response. Surface expression of CD2 and its ligand, CD58, is increased on the monocytes and eosinophils of asthma patients, which correlate with elevated serum IgE levels, suggesting that CD2 may contribute to allergic airway inflammation. Using a murine model of asthma, we observed that house dust mice extract (HDME)-exposed Balb/c mice have increased airway hyperresponsiveness (AHR), lung inflammation, goblet cell hyperplasia, and elevated levels of Th2 cytokines in the lungs, as well as increased serum IgE levels as compared to the control mice. In contrast, with the exception of serum IgE levels, all the other parameters were significantly reduced in HDME-treated Cd2−/− mice. Interestingly, Il13 but not Il4 or Il5 gene expression in the lungs was dramatically decreased in HDME-exposed Cd2−/− mice. Of note, the gene expression of IL-13 downstream targets (Muc5b and Muc5ac) and high affinity IL-13Rα2 were upregulated in the lungs of HDME-exposed Balb/c mice but were significantly reduced in HDME-exposed Cd2−/− mice. Consistently, gene expression of microRNAs regulating mucin production, inflammation, airway smooth muscle cell proliferation and IL-13 transcripts were increased in the lungs of HDME-exposed Cd2−/− mice. Given the established role of IL-13 in promoting goblet cell hyperplasia, lung inflammation and AHR in allergic asthma, our studies reveal a unique role for CD2 in the regulation of Th2-associated allergic asthma.

Aberrant peripheral blood CD4+ CD25+ FOXP3+ regulatory T cells/T helper-17 number is associated with the outcome of patients with lymphoma.

Little is known about the clinical significance of the peripheral blood CD4+ CD25+ FOXP3+ regulatory T cells (Tregs) and T helper-17 (Th17) cells in lymphoma patients. In this study, the prognostic and clinical significance of peripheral blood Tregs and Th17 cells were evaluated in lymphoma patients during different phases. The frequency of Tregs and Th17 lymphocytes was measured by flow cytometry method in 47 classical Hodgkin's lymphoma (cHL) and 48 diffuse large B cell lymphoma (DLBCL) patients. Our results showed that the frequency of Tregs and absolute Treg count was significantly reduced in relapsed patients compared to patients at the remission phase, as well as with newly diagnosed untreated patients in both groups. Patients who reached complete remission had elevated frequency of CD4+ FOXP3+ lymphocytes, Tregs, absolute Treg count, Treg/CD4 and Treg/Th17 ratio in the cHL group and CD4+ CD25+ cells in DLBCL group. The frequency of Tregs, absolute Treg count and Treg/Th17 ratio in cHL patients and CD4+ FOXP3+ and CD4+ CD25+ cells in DLBCL patients positively associated with survival rate. Moreover, the percentage of Tregs and absolute Treg count positively correlated with white blood cell, platelet count and ESR level in cHL patients and with white blood cell count in DLBCL patients. The initial number of Tregs/Th17 cells and also the Treg/Th17 ratio was not associated with changes in disease-free survival (DFS) in both groups. Therefore, higher frequency of peripheral blood Tregs and Treg/Th17 ratio might be associated with a favorable outcome in lymphoma patients, better response to chemotherapy and lower rate of relapse.

Red Wine Extract Disrupts Th17 Lymphocyte Differentiation in a Colorectal Cancer Context.

Scope: It is well established that immune response and inflammation promote tumoral progression. Immune cells communicate through direct contact or through cytokine secretion, and it is the pro-inflammatory status that will tip the balance toward tumor progression or anti-tumor immunity. It is demonstrated here that a red wine extract (RWE) can decrease inflammation through its action on the inflammasome complex. This study determines whether an RWE could impact other key actors of inflammation, including T helper 17 (Th17) immune cells in particular. Methods and results: Using an RWE containing 4.16g of polyphenols/liter of wine, it is shown that RWE decreases colorectal cancer cells in vitro and induces a reduction in colorectal tumor growth associated with a decrease in tumor-infiltrating lymphocytes in vivo. The process of T-lymphocyte differentiation in Th17 cells is altered by RWE, as revealed by the decrease in the expression of key actors controlling this process, such as signal transducer and activator of transcription 3 and retinoid acid-related orphan receptor γt. This disruption is associated with an inhibition of inflammatory interleukin 17 secretion. The data highlights the major involvement of Th17 immune cells in the biological effects of an RWE.

Human Microbiome and Allergic Diseases in Children: Pathogenetic Role and Therapeutic Options

The recent and extensive study of the microbiome has provided an enormous amount of data concerning the type and possible functions of microorganisms present in the gut, airways, genital tract, and skin. These data showed interpersonal differences in the composition of the microbiome and these differences suggest a link between the microbiome, the immune modulation, and the pathogenesis of allergic diseases. This research is particularly relevant in paediatrics, since allergic diseases are constantly increasing and there is evidence in the paediatric age that shows that the composition of the microbiome in the foetal and neonatal period plays a key role in the development of the immune system: vaginal delivery, breastfeeding, childhood spent in rural environments and/or in contact with animals result in a greater biodiversity of the microbiome with the presence of protective species that reduce the activation of Th2 lymphocytes, involved in allergic reactions. Further studies are necessary to better understand the microbiota role in the pathogenesis of atopy in order to understand if specific probiotics and prebiotics, administered orally or topically, can affect the microbiota composition and modulate immune system functions, producing a therapeutic effect in the treatment of allergic diseases. This narrative review analysed the available literature regarding the correlation between the microbiome and the development of allergic diseases and with special focus on paediatric studies. The skin, gut or lung dysbiosis can be a cofactor in the pathogenesis of allergies and the remodulation of the microbiome becomes an important therapeutic challenge.

Surgical Infection Society Guidance for Operative and Peri-Operative Care of Adult Patients Infected by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2).

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-associated viral infection (coronavirus disease 2019, COVID-19) is a virulent, contagious viral pandemic that is affecting populations worldwide. As with any airborne viral respiratory infection, surgical and non-surgical patients may be affected. Methods: Review and synthesis of pertinent English-language literature pertaining to COVID-19 infection among adult patients. Results: COVID-19 disease that requires hospitalization results in critical illness approximately 25% of the time and requires mechanical ventilation with positive airway pressure. Acute kidney injury, a marked hypercoagulable state, and sometimes myocarditis can be features of COVID-19 in addition to the characteristic severe acute lung injury. Even if not among the most seriously afflicted, older patients with medical comorbidities are both predisposed to infection and risk increased morbidity and mortality, however, all persons presenting for surgical intervention should be suspected of infection (and thus transmissibility) even if asymptomatic. Although most elective surgery has been curtailed by administrative or governmental fiat, patients will still need urgent or emergency operative intervention for time-sensitive disease processes such as malignant neoplasia or for true emergencies such as perforated viscus or traumatic injury. It is possible to provide safe surgical care for SARS-CoV-2-positive patients and minimize nosocomial transmission to healthcare workers. Conclusions: This guidance will facilitate appropriate protection of patients and staff, and maintenance of infection control measures to assist surgical personnel and facilities to prepare for COVID-19-infected adult patients requiring urgent or emergent operative intervention and to provide optimal patient care.

Glycolysis - a key player in the inflammatory response.

The inflammatory response involves the activation of several cell types to fight insults caused by a plethora of agents, and to maintain the tissue homoeostasis. On the one hand, cells involved in the pro‐inflammatory response, such as inflammatory M1 macrophages, Th1 and Th17 lymphocytes or activated microglia, must rapidly provide energy to fuel inflammation, which is essentially accomplished by glycolysis and high lactate production. On the other hand, regulatory T cells or M2 macrophages, which are involved in immune regulation and resolution of inflammation, preferentially use fatty acid oxidation through the TCA cycle as a main source for energy production. Here, we discuss the impact of glycolytic metabolism at the different steps of the inflammatory response. Finally, we review a wide variety of molecular mechanisms which could explain the relationship between glycolytic metabolites and the pro‐inflammatory phenotype, including signalling events, epigenetic remodelling, post‐transcriptional regulation and post‐translational modifications. Inflammatory processes are a common feature of many age‐associated diseases, such as cardiovascular and neurodegenerative disorders. The finding that immunometabolism could be a master regulator of inflammation broadens the avenue for treating inflammation‐related pathologies through the manipulation of the vascular and immune cell metabolism.

Macrophage Activity and Histopathological Differences of Lung Tissue on Sequential Co-infections of Heligmosomoides Polygyrus Nematode on Mycobacterium Tuberculosis Infection

Background: Tuberculosis is a chronic infection caused by Mycobacterium tuberculosis, a facultative intracellular parasite, that can be eliminated by cellular immunity played by macrophages. It has become a debate whether the co-infection of nematodes will affect the immune response of macrophages towards mycobacterium infection. Objective: To reveal macrophage activity and histopathological difference of lung tissue in sequential coinfection of Heligmosomoides Polygyrus towards Mycobacterium tuberculosis infection. Method: This study used 49 mice divided into 7 treatment groups with Mycobacterium tuberculose infection by inhalation and Heligmosomoides polygyrus orally within 8 and 16 weeks, and observed by immunohistochemical staining. Result: Infection for 8 weeks showed polarization of macrophages towards M1 macrophage, whereas in 16 weeks, the macrophage polarization more towards M2 macrophages, supported by histopathological changes of lung tissue: peribronchiolitis, perivaskulitis, alveolitis, and granuloma formation with counts of acid-resistant germs +3. There was a difference of expression of arginase1 to each group (p &lt;0.001) and there was a difference of T CD4+ Th1 lymphocyte (p &lt;0.001). Conclusion: There is a difference in macrophage activity in lung tissue; however, it does not cause different levels of histopathological changes in lung tissue and does not affect the immune response to Mycobacterium tuberculosis infection.