Higher Percentage Of Th17 Cells Research Articles

Immunological Profiles in Parry-Romberg Syndrome: A Case-Control Study.

Background: Parry-Romberg syndrome (PRS) is a rare craniofacial disorder. The aim of this study is to provide information on the immunological profile of this pathology. Since PRS can be included in a wider spectrum of sclerodermic diseases, we propose a case-control study comparing a patient affected by PRS with one with a diagnosis of scleroderma, herein used as control (CTR). Methods: B lymphocyte, T lymphocyte, and monocyte phenotypes and functions were assessed by flow cytometry in influenza (Flu)- or anti cluster differentiation (CD)3/CD28-stimulated peripheral blood mononuclear cells (PBMCs). Cytokine concentration was evaluated as well in PBMC supernatants, plasma, and saliva by Luminex assay. Results: T and B lymphocytes were similarly activated in unstimulated PRS and CTR cells but differed following antigen stimulation. T helper (Th)17 lymphocytes were expanded in PRS compared to CTR; this increase correlated with higher interleukin (IL)-17 concentration. Conclusions: Our case-control study is the first to compare the immunological profiles of PRS and scleroderma patients. The higher percentage of Th17 cells in PRS suggests the use of anti-IL17 receptor monoclonal antibody in this rare disease; however, further studies with larger numbers of patients are needed to confirm our findings.

CyTOF analysis for differential immune cellular profiling between latent tuberculosis infection and active tuberculosis

Limited data exist about the comparative immune cell population profile determined by cytometry by time-of-flight (CyTOF) analysis between active tuberculosis (TB) and latent TB infection (LTBI). In this study, we performed CyTOF analysis using peripheral blood mononuclear cells (PBMCs) to compare the differential immune cellular profile between active TB and LTBI. A total of 51 subjects (active TB [n = 34] and LTBI [n = 17]) were included. CyTOF analysis of 16 subjects (active TB [n = 8] and LTBI [n = 8]) identified a significantly higher Th17-like cell population in active TB than in LTBI. This finding was validated in the remaining 35 subjects (active TB [n = 26] and LTBI [n = 9]) using flow cytometry analysis, which consistently reveals a higher percentage of Th17 cell population in active TB (p = 0.032). The Th1/Th17 ratio represented good ability to discriminate between active TB and LTBI (AUC = 0.812). Among patients with active TB, the Th17 cell percentage was found to be lower in more advanced forms of the disease. Additionally, Th17 cell percentage positively correlated with the levels of IL-6 and neutrophil-lymphocyte ratio, respectively. In conclusion, CyTOF analysis of PBMCs showed a significantly higher percentage of Th17 cells in active TB although fairly similar immune cell populations between active TB and LTBI were observed.

Interleukin-17-Producing CD4+ T Cells Promote Inflammatory Response and Foster Disease Progression in Hyperlipidemic Patients and Atherosclerotic Mice.

Atherosclerosis is a chronic inflammatory disease. Interleukin-17-producing CD4+ T cells (Th17 cells) play important roles in the progression of atherosclerosis. However, most of the studies were focused on the advanced stage of atherosclerosis. In the current study, we investigated the roles of Th17 cells, relevant mechanisms in hyperlipidemic patients, and different stages of atherosclerotic mice. Human blood samples were collected, and percentages of Th17 cells, macrophages, and neutrophils were analyzed by flow cytometry. ApoE−/− mice were fed with high-fat diet (HFD) and sacrificed at different time points to evaluate the infiltration of inflammatory cells at different stages of atherosclerosis. Furthermore, essential mechanisms of IL-17A in atherosclerotic inflammatory milieu formation were studied in vivo by intraperitoneal injection with monoclonal anti-murine IL-17 antibody. Our study reveals the higher percentages of Th17 cells, monocytes, and neutrophils in hyperlipidemic patients compared to healthy donors. Meanwhile, we also identify an infiltration of Th17 cells in the early stage of atherosclerosis (4 weeks after HFD), which maintains at high level until late stage of atherosclerosis (20 weeks after HFD). What is more, inflammatory cells including macrophages and neutrophils were also accumulated in atherosclerotic lesions. Neutralization of IL-17 in ApoE−/− mice resulted in less infiltration of macrophages and neutrophils and smaller atherosclerotic lesions. Importantly, in accordance with what is found in the mouse model, positive correlations between Th17 cells and macrophages or neutrophils were observed in hyperlipidemic patients. In conclusion, our clinical and mouse model data together reveal a pro-atherogenic role of Th17 cells through the promotion of inflammation in hyperlipidemic conditions and different stages of atherosclerosis, which further supports the notion that IL-17 may be a therapy target for the treatment of atherosclerosis.

Upregulated microRNA-132 in T helper 17 cells activates hepatic stellate cells to promote hepatocellular carcinoma cell migration in vitro.

MicroRNAs play an important role in the modulation of the immune system. T helper 17 (Th17) cells are involved in the modulation of the tumour microenvironment. However, the function of miRNA in Th17 cells in the tumour microenvironment is unclear. In this study, we analysed miR-132 expression in Th17 cells and assessed the function of miR-132 on Th17 cell differentiation. In addition, the effect of miR-132 on Th17 cells in the tumour microenvironment, especially hepatic stellate cells (HSCs), was confirmed. CD4+ IL-17∓cells were isolated from hepatocellular carcinoma (HCC) tumour tissues. The expression of miR-132 was higher in CD4+ IL-17+cells than in CD4+ IL-17- cells. Human primary CD4+ T cells were used for Th17 cell differentiation. Compared with primary CD4+ T cells, Th17 cells expressed high levels of miR-132. During Th17 cell differentiation, a miR-132 mimic and inhibition were applied. After treatment with the miR-132 mimic, the differentiation of Th17 cells accelerated, showing a a higher percentage of Th17 cells and the expression and secretion of IL-17 and IL-22. Smad nuclear interacting protein 1 (SNIP1), as one of the targets of miR-132, decreased during Th17 cell differentiation-related Th17 differentiation and IL-17 expression. The conditioned medium of miR-132-overexpressing Th17 cells could increase the activation of the HSCs, which strongly promoted HCC cell migration and epithelial-mesenchymal transition (EMT). In summary, miR-132 positively regulates Th17 cell differentiation and improves the function of Th17 on HSCs for their tumour-promoting effects.

Mannan-binding lectin regulates Treg/Th17 cell balance in mice with Candida albicans infection

Objective To investigate the regulation of Treg/Th17 axis by mannan-binding lectin (MBL) in mice with Candida albicans (C.albicans) infection. Methods MBL gene-knockdown (MBL-/-) C57BL/6 mice and wild-type (WT) C57BL/6 mice were divided into four groups. C. albicans strains (2×107 CFU) were injected intraperitoneally into the mice of infection groups. Paraffin sections of mouse liver and kidney tissues were prepared on 3 d. Histopathological changes were observed with hematoxylin and eosin (HE) and Periodic acid-Schiff (PAS) staining. Flow cytometry was performed to analyze Th17 and Treg cells in mice on 7 d. The levels of IL-10 and IL-17A were measured by ELISA. CD4+ T cells were obtained from spleen cells by magnetic sorting. Expression of Foxp3 and RORγt at mRNA and protein levels were detected by qRT-PCR and Western blot, respectively. Results The mouse model of C. albicans infection was established successfully. After infection, the MBL-/- mice had higher percentages of Th17 cells, but lower percentages of Treg cells than the WT mice. ELISA results showed that compared with the WT mice with C. albicans infection, the MBL-/- mice had significantly increased IL-17A and decreased IL-10 after infection. Moreover, the expression of RORγt at both mRNA and protein levels was up-regulated, while that of Foxp3 was down-regulated in the MBL-/- mice than in the WT mice following infection. Conclusions MBL regulates the immune balance of Treg/Th17 cells in mice infected with C. albicans through promoting the differentiation of CD4+ T cells into Treg cell subsets and inhibiting the differentiation into Th17 cell subsets. Key words: Mannan-binding lectin (MBL); MBL gene-knockdown mice; Candida albicans; Th17 cell; Regulatory T cell

Th17 cells in Bulgarian children with chronic obstructive lung diseases

Introduction and objectivesTh17 lymphocytes are now widely believed to be critical in various chronic pulmonary diseases. However, there is still a small number of investigations regarding children. We aimed to assess the percentage of Th17 lymphocytes and IL-17A in peripheral blood of children with chronic obstructive lung diseases. Patients and methodsWe included a total of 42 children: 20 with bronchial asthma (BA), 12 with cystic fibrosis (CF) and 10 healthy children without a history of allergies, aged 4–17 years. Th17 cells (CD3+CD4+CD161+CCR6+) were determined in peripheral blood by flow cytometry. The concentration of serum IL-17A was measured by ELISA. ResultsThe BA patients had a significantly higher percentage of Th17 (12.40±1.16%) compared to the CF children (7.64±0.87%, p=0.0035) and healthy (7.25±0.45%, p=0.008). Stratifying the BA group, we found higher levels of Th17 in patients with severe BA (p=0.03), whereas patients with moderate BA had Th17 cells close to those in CF and healthy children. We found that patients with better control of BA had Th17 closer to those with CF (p=0.98) than BA children with poor control (p<0.001) (post hoc, Bonferroni correction). CF patients with concomitant P. aeruginosa infection showed slightly higher percentages of Th17 cells than those without infection (8.08±3.09% vs. 6.25±2.42%, p=0.294). ConclusionsThe percentage of Th17 cells was significantly increased in the peripheral blood of children with severe BA compared to the children with moderate BA, which suggests that the former could possibly benefit from future target therapies.

Effects of human mesenchymal stem cells on airway inflammation in allergic asthma mice and the underlying mechanism

Objectives: To investigate the effects of human umbilical cord mesenchymal stem cells (hUC-MSCs) on airway inflammation in an ovalbumin (OVA) induced asthma mouse model and the underlying mechanism. Methods: Twenty-four BALB/c mice were randomly divided into four equal groups: normal control group, OVA-induced asthmatic model group, hUC-MSCs treated group (50 μl of hUC-MSCs was transplanted into the trachea of asthmatic mice ) and hUC-MSCs control group (50 μl of hUC-MSCs was transplanted into the trachea of control mice). Human umbilical cord mesenchymal stem cells from umbilical cord of healthy new born babies were used as the source of hUC-MSCs for this study. The asthmatic conditions of the airways and the lungs were assessed by examining: (1) histopathological changes of the airways and the lungs; (2) expression of cytokines IL-6 and TGF-β mRNA by real-time PCR; (3) total leukocytes and mast cell count in bronchoalveolar lavage fluid (BALF) and number of IL-17-expressing CD4(+) cells (Th17 cells) in the lung tissue using flow cytometry. Results: Typical histopathological changes of asthma were confirmed in the asthmatic model group. These changes included intensive inflammatory cell infiltration around the airways and patchy airway occlusion by hyperviscous mucus. The number of total leukocytes and mast cells in BALF were significantly increased in the asthmatic mice when compared with the control group (P<0.05). Mice in the asthmatic model group had significantly higher percentage of Th17 cells in lung tissues when compared with the control group (2.90% vs 0.76%, P<0.05). In contrast, in the asthmatic mice treated with hUC-MSCs, the inflammatory cell infiltration was significantly reduced compared with asthmatic mice, as observed by significantly lower leukocytes and mast cells in BALF (P<0.05) and significant reduction in the percentage of Th17 cells in the lung of OVA-challenged mice following hUC-MSCs treatment (percentage of Th17 cells: 0.24% vs 2.90%, P<0.05). The expression of mRNA for IL-6 and TGF-β was significantly suppressed in the hUC-MSCs treatment group (0.23 vs 2.30 and 0.56 vs 6.60, both P<0.01). No asthmatic pathological changes in both normal and hUC-MSCs control groups were observed. Conclusions: hUC-MSCs significantly inhibit the airway inflammation in OVA-induced asthmatic mice. This inhibition is associated with the suppression of Th17 cells and the down-regulation of inflammatory factors such as IL-6 and TGF-β in the lungs.

Effect of IRAK-M on Airway Inflammation Induced by Cigarette Smoking.

Background IRAK-M, negatively regulating Toll-like receptor, is shown the dual properties in the varied disease contexts. We studied the effect of IRAK-M deficiency on cigarette smoking- (CS-) induced airway inflammation under acute or subacute conditions in a mouse model. Methods A number of cellular and molecular techniques were used to detect the differences between IRAK-M knockout (KO) and wild type (WT) mice exposed to 3-day or 7-week CS. Results Airway inflammation was comparable between IRAK-M KO and WT mice under 3-day CS exposure. Upon short-term CS exposure and lipopolysaccharide (LPS) inhalation, IRAK-M KO mice demonstrated worse airway inflammation, significantly higher percentage of Th17 cells and concentrations of proinflammatory cytokines in the lungs, and significantly elevated expression of costimulatory molecules CD40 and CD86 by lung dendritic cells (DCs) or macrophages. Conversely, 7-week CS exposed IRAK-M KO mice demonstrated significantly attenuated airway inflammation, significantly lower concentrations of proinflammatory cytokines in the lungs, significantly increased percentage of Tregs, and lower expression of CD11b and CD86 by lung DCs or macrophages. Conclusions IRAK-M plays distinctive effect on CS-induced airway inflammation, and influences Treg/Th17 balance and expression of costimulatory molecules by DCs and macrophages, depending on duration and intensity of stimulus.

Changes in peripheral blood 25 - hydroxyvitamin D3, Th17 cells, and CD4+ regulatory T cells and their clinical significance in patients with primary biliary cirrhosis

Objective: To investigate the changes in peripheral blood 25-hydroxyvitamin D3[25-(OH)D3], CD4+regulatory T (Treg) cells, and Th17 cells in patients with primary biliary cirrhosis (PBC) and their mechanism of action in PBC. Methods: A total of 22 patients with PBC were enrolled and the male/female ratio was 1:21, with a mean age of 61±12 years. There were 7 healthy volunteers matched for age in the normal control group. Electrochemiluminescence immunoassay was used to measure the peripheral blood 25-(OH)D3level in the PBC group and normal control group, and flow cytometry was used to analyze the changes in Th17 cells and CD4+Treg cells. The t-test, rank sum test, Pearson correlation analysis, or Spearman's rank correlation analysis was used for statistical analysis according to the type of the data. Results: The PBC group had a significantly lower serum 25-(OH)D3level than the normal control group (9.49±3.65 vs 27.35±2.35 ng/ml,P< 0.01). Compared with the normal control group, the PBC group had a significantly higher percentage of Th17 cells (2.05%±1.17% vs 0.99%±0.12%,P< 0.01) and a significantly lower percentage of CD4+Treg cells (2.54%±1.14% vs 3.78%±0.51%,P< 0.05); there was a significant difference in Th17/Treg ratio between the PBC group and the normal control group (1.00±0.63 vs 0.26±0.02,P< 0.01). In the PBC group, peripheral blood 25-(OH)D3 was not correlated with Th17 cells or Th17/Treg ratio (r= -0.062 and -0.328,P> 0.05), while it was positively correlated with the percentage of CD4+Treg cells (r= 0.468,P< 0.05). Conclusion: Patients with PBC have significant reductions in peripheral blood 25-(OH)D3and percentage of CD4+Treg cells, a significant increase in the percentage of Th17 cells, and immune unbalance of Th17 cells and CD4+Treg cells. 25-(OH)D3can upregulate the percentage of CD4+Treg cells and thus affect the development and progression of PBC, and exogenous vitamin D may improve immune function in PBC patients.

Increased Frequency of Th17 Cells in Children With Mycoplasma pneumoniae Pneumonia.

Mycoplasma pneumoniae (M. pneumoniae, MP) is recognized globally as a significant cause of primary atypical pneumonia in humans, particularly in children. Overzealous host immune responses are viewed as key mediators of the pathogenesis of M. pneumoniae infection. Although Th17 cells have been identified as key modulators in the clearance of pathogens and induction of autoimmunity caused by excessive immune responses, little is known about the role of Th17 cells in patients with M. pneumoniae infection. The percentages of T cells, CD4+ T cells and Th17 cells in children with M. pneumoniae infection were measured by flow cytometry. We documented an increased frequency of Th17 cells in children with M. pneumoniae infection. Furthermore, we found a significantly higher percentage of Th17 cells in M. pneumoniae-infected children with extrapulmonary manifestations, compared with children without extrapulmonary manifestations. In addition, patients who experienced a short course of Mycoplasma pneumoniae pneumonia (MPP) showed an increase in the percentage of Th17 cells. Our findings suggest that Th17 cells may be involved in the clearance of M. pneumoniae during an acute infection. Excessive Th17 cell responses may also contribute to the immuno-pathological damage observed during persistent infection.

Elevated levels of Th17 cells in children with central obesity

Background. It is believed that the recently discovered interleukin 17-producing Th17 cells play a role in the pathogenesis of chronic inflammation in the course of obesity and diabetes. Objectives. The purpose of our study was to complete data on this subject in children. Methods. We assessed Th17 cell levels in the peripheral blood of children diagnosed with central obesity (n = 14) and compared the results with data obtained in patients with newly diagnosed (n = 11) and long-term type 1 diabetes mellitus (n = 18), and in a control group as well (n = 24). Results. (i) Children with central obesity were characterized by higher percentages of Th17 cells as compared to children from the control group; (ii) in the peripheral blood of patients with long-term type 1 diabetes the Th17 cell counts were higher compared to the control group; (iii) total plasma cholesterol concentration correlated positively with Th17/Treg cells ratio; and (iv) among patients with long-term diabetes, disease duration correlated positively with Th17 cell count and Th17/Th1 cell ratio. Conclusion. The results of our study indicate that Th17 cells may be involved in chronic inflammation accompanying obesity and type 1 diabetes mellitus in children.

Abstract 65: T cell Differentiation in Human Kawasaki Disease and a Murine Model of Coronary Arteritis

The role of T cell differentiation in the immunopathogenesis of Kawasaki disease (KD) remains unclear. The aim of this study is to elucidate the role of T cell subsets in coronary artery lesion (CAL) of KD. Peripheral blood was obtained in 10 patients with acute KD before and 1 week after intravenous gamma-immunoglobulin (IVIG) treatment and in 20 patients with past history of KD for more than 5~20 years. Meanwhile, induction of coronary arteritis was performed on wild type BALB/c mice by Lactobacillus casei cell wall extract (LCWE). Human peripheral blood leukocytes were analyzed by using flow cytometric analysis and murine hearts were examined for immunofluorescence study and for RNA expression levels. Results: Compared to the febrile controls, KD patients prior to IVIG treatment had increased percentage of CD3 + /CD4 + /interferon-γ + (T helper 1, Th1) cells and CD3 + /CD4 + /interleukin-17A + (Th17) cells (mean ± SD, 1.36% ± 1.39% and 0.51% ± 0.25%, respectively) among Th cells (CD3 + /CD4 + ). Both increases declined after IVIG treatment (0.71% ± 0.74% and 0.33% ± 0.18%) despite no statistically difference by Mann-Whitney test. None of these 10 acute KD patients developed CAL after IVIG treatment. However, patients with previous KD and definite CALs (n= 11) seemed to have higher percentage of Th17 cells (0.50% ± .025% versus 0.35% ± 0.23%) but similar level of Th1 cells (0.93% ± 0.51% versus 1.05% ± 0.64%) when compared to those without CAL (n= 9). Murine cardiac tissues displayed the presence of Th1 (double-stained with CD3 and T-bet) and Th17 cells (double-stained with CD3 and RORγt) during days 7 and 14 after LCWE treatment but not in PBS-treated mice. Compatible with these, cardiac mRNA levels showed both increased levels of IFN-γ and IL17A mRNA in LCWE-treated mice. Conclusions: Our initial data suggests that specific T cell differentiation into Th1 and Th17 cells occurred in both human KD and mice stimulated with LCWE. IVIG treatment was associated with the recovery of such T cell differentiation. However, the clinical application to predict IVIG responsiveness and future CAL development by such increase in the peripheral Th17 remains unclear. Further studies to elucidate the detailed immune regulation of these T subsets on CAL are warrant by using this LCWE murine model.

Involvement Of S100 Proteins and Hsp90 In The Pathogenesis Of Graft-Versus-Host Disease After Allogeneic Hematopoetic Cell Transplantation

Graft-versus-host disease (GvHD) is one of the major live threatening complications of allogeneic hematopoietic cell transplantation (HCT). The pathophysiology of GvHD is complex and not fully understood yet. However, it has been shown that Th17 cells play an important role in the pathogenesis of acute and chronic GvHD. Therefore, the development of Th17 cells in patients with GvHD was further investigated in the present study. The influence of monocytes and their activation with proinflammatory S100 proteins and 90 kDa heat shock protein (Hsp90) on the induction of Th17 cells was examined. Furthermore, the suitability of S100 proteins as diagnostic markers for intestinal GvHD was analyzed.In the present study, it could be demonstrated that monocytes from patients with acute and chronic skin or intestinal GvHD grade I-IV (n=13) induced significant higher percentages of Th17 cells compared to monocytes from healthy donors (n=32) or patients without GvHD at several timepoints after HCT (n=21) (p<0.001). It is known that faecal S100A12 is a potential non-invasive marker for inflammatory bowel disease. Therefore, the concentration of S100A12 in the stool of patients with and without intestinal GvHD was determined. The obtained results showed that the concentration of S100A12 was significantly increased in the stool of patients with intestinal GvHD (n=7) compared to patients without GvHD (n=16) (p<0.05). Furthermore, S100A9 and S100A12 could be detected immunohistochemically in intestinal tissue from patients with intestinal GvHD indicating that S100 proteins of the calgranulin subfamily could be potential diagnostic markers for intestinal GvHD. Additionally, the effect of S100A8, S100A9 and the heterodimer S100A8/9 on the induction of Th17 cells was investigated. Monocytes from healthy donors stimulated with these S100 proteins induced significant higher percentages of Th17 cells compared to unstimulated monocytes (n=7) (p<0.05). Furthermore, the influence of the 90 kDa heat shock protein (Hsp90) in monocytes on the induction of Th17 cells was examined. Therefore, Hsp90 was inhibited by the geldanamycin analog 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) in monocytes from patients with GvHD and the effect on the induction of Th17 cells was analyzed. It could be shown that inhibition of Hsp90 resulted in a significant decrease in the percentage of induced Th17 cells (n=3) (p<0.001). Further results indicated that stimulation of monocytes with S100A8, S100A9 and S100A8/9 induces an elevation in Hsp90 expression levels.In conclusion, our findings suggest that monocytes may play a major role in the pathogenesis of GvHD by triggering the induction of Th17 cells. Monocyte-induced Th17 cell development could further be enhanced by stimulation of monocytes with purified S100 proteins. The chaperone Hsp90 could be an important regulator in monocyte-induced development of Th17 cells and therefore be a therapeutic target for GvHD. Furthermore, S100 proteins might be novel diagnostic markers in intestinal tissue and potential non-invasive markers in the stool for intestinal GvHD. Disclosures:No relevant conflicts of interest to declare.

T-Helper 17 Cells Are Associated With Pathology in Human Schistosomiasis

Schistosome infections are often clinically silent, but some individuals develop severe pathological reactions. In several disease processes, T-helper 17 (Th17) cells have been linked to tissue injuries, while regulatory T cells (Tregs) are thought to downmodulate inflammatory reactions. We assessed whether bladder pathology in human Schistosoma haematobium infection is related to the balance of Th17 cells and Tregs. We used a murine model of Schistosoma mansoni infection to further investigate whether the peripheral profiles reflected ongoing events in tissues. We characterized T-helper cell subsets in the peripheral blood of children residing in a S. haematobium-endemic area and in the peripheral blood, spleen, and hepatic granulomas of S. mansoni-infected high-pathology CBA mice and low-pathology C57BL/6 mice. S. haematobium-infected children with bladder pathology had a significantly higher percentage of Th17 cells than those without pathology. Moreover, the Th17/Treg ratios were significantly higher in infected children with pathology, compared with infected children without pathology. Percentages of interleukin 17-producing cells were significantly higher in spleen and granulomas of CBA mice, compared with C57BL/6 mice. This difference was also reflected in the peripheral blood. This is the first study to indicate that Th17 cells may be involved in the pathogenesis of human schistosomiasis.

Characterization of recent thymic emigrants (RTEs), transitional B and Th17 cells in multiple sclerosis (MS)

The finding that APECED syndrome is due to a failure in negative thymic selection has suggested that central tolerance could play a role also in polygenic autoimmunity and that autoimmune patients should have an increase in RTEs. The aim of this work was to assess the frequency of RTEs, transitional B cells and Th17 lymphocytes in MS. PBLs from 55 MS patients [20 relapsing-remitting (RR) with disease modifying drugs (DMD), 20 RRMS without DMD, 10 progressive MS and 5 RRMS patients on relapse] and 32 healthy controls were analysed by FACS for RTEs, naive and memory T cells as well as Th17 cells and transitional B cells. No differences in the percentage of RTEs (CD45RA+CD31+PTK7+) (3.30±2.94 vs 3.05±1.54, 0.933) or B transitional cells (CD19+CD24hiCD38hiCD27-) (8.67±3.62 vs 8.59±3.8, p=0.45) were found between controls and MS. A significant decrease in the percentage of CD4 effector memory (CD45RA-CCR7-CD27+) (23.13±8.76 vs 20.8±6.1, p=0.043), as well as an increase in Th17 cells (6.9±3.2 vs5.49±2.33, p=0.007) was observed in MS vs controls. There were no differences in lymphocyte populations among the clinical forms of MS. RRMS under treatment had similar results to RRMS without DMD. Patients on relapse did show an increased proportion of CD4 effector memory cells, Th17 cells and RTEs and patients with higher EDSS had a higher percentage of Th17 cells (OR 2.3,p=0.045). The results of this preliminary study do not favour a failure in central tolerance in MS but confirm involvement of Th17 cells which are associated with a higher degree of disability.

GPCR Versus Cytokine Receptor: Is One As Good As the Other?

Th17 cells are a distinct lineage of CD4 + T helper (Th) cells that produce the cytokines IL-17 (interleukin-17) and IL-22 and are important in fighting infection but are also involved in mediating autoimmune disorders. The generation of Th17 cells is dependent on IL-6 and transforming growth factor-β (TGF-β), together with either IL-1 or tumor necrosis factor-α. It is unclear whether IL-23 is necessary for Th17 cell development. Liao et al . examined the effect of sphingosine 1-phosphate (S1P) on the generation of Th17 cells. S1P, acting through its G protein-coupled receptor S1P 1 , is known to affect the trafficking and proliferation of T cells. This group has previously shown that stimulation of transgenic CD4 + T cells expressing increased amounts of S1P 1 results in the production of more Th17 cells than does stimulation of control cells. In the current study, the authors demonstrated that the addition of S1P to cultures of mouse splenic CD4 + T cells (maintained in the absence of IL-23) that were activated by stimulation of the T cell antigen receptor in the presence of IL-6, IL-1, and TGF-β resulted in the production of more IL-17 protein and a higher percentage of Th17 cells than in cultures that lacked S1P. A selective agonist of S1P 1 , SEW2871, had the same effect. Separate activation cultures containing optimal concentrations of either S1P or IL-23 produced similar numbers of Th17 cells. S1P treatment suppressed the production of interferon-γ and IL-4, the signature cytokines of Th1 and Th2 cells, respectively. The effect of S1P on the generation of Th17 cells was blocked by inhibitors of phosphoinositide 3-kinase and nuclear factor κB. Finally, the immunosuppressive agent FTY720, which can down-regulate S1P 1 , inhibited S1P-mediated generation of Th17 cells. These results show that S1P can substitute for IL-23 in the development of Th17 cells and suggest that part of the immunosuppressive effect of FTY720 may be due to the inhibition of Th17 cell development. J.-J. Liao, M.-C. Huang, E. J. Goetzl, Cutting edge: Alternative signaling of Th17 cell development by sphingosine 1-phosphate. J. Immunol. 178 , 5425-5428 (2007). [PubMed]