Type 17 Immune Response Facilitates Progression of Inflammation and Correlates with Cognition in Stable Schizophrenia

Dysregulation of the type 17 immune pathway has already been considered in schizophrenia and we previously measured decreased sera values of interleukin (IL)-17 in early stages. We further explored the possible correlation of IL-17 systemic levels with proinflammatory cytokines and cognitive scores and additionally analyzed the percentage of IL-17 producing lymphocytes in peripheral blood of patients with stable schizophrenia. We included 27 patients diagnosed with schizophrenia (F20), after a three-month stable depot antipsychotic therapy (risperidone or paliperidone) and 18 healthy control subjects. Positive and Negative Syndrome Scale of Schizophrenia and the Montreal-Cognitive Assessment (MoCA) were conducted. Sera concentrations of IL-17, IL-6, tumor necrosis factor alpha (TNF-α) and soluble ST2 receptor (sST2) were measured. Flow cytometry and Natural Killer (NK) and T cell analyses were done in 10 patients and 10 healthy controls. Moderate positive correlation was established between IL-17 and TNF-α (r = 0.640; p = 0.001), IL-17 and IL-6 (r = 0.514; p = 0.006), IL-17 and sST2 (r = 0.394; p = 0.042). Furthermore, a positive correlation between the serum levels of IL-17 and MoCA scores was observed, especially with visuospatial and executive functioning, as well as language functioning and delayed recall (p < 0.05). Significantly higher percentage of IL-17 producing CD56+ NK cells was measured in peripheral blood of patients with schizophrenia in remission vs. healthy individuals (p = 0.001). The percentage of CD4+ T cells and CD4+ T cells that produce IL-17 was significantly increased in patients (p = 0.001). This study revealed the involvement of innate type 17 immune response in the progression of inflammation and this could be related to cognitive functioning in stable schizophrenia.

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CD8+CD28− T cells: key cytotoxic players impacting disease pathogenesis in chronic HBV infection

Clinical Science ◽

10.1042/cs20190369 ◽

2019 ◽

Vol 133 (17) ◽

pp. 1917-1934

Author(s):

Madhuparna Nandi ◽

Sourina Pal ◽

Sumantra Ghosh ◽

Bidhan Chandra Chakraborty ◽

Debangana Dey ◽

...

Keyword(s):

T Cells ◽

Chronic Hepatitis ◽

T Cell ◽

Hepatitis B ◽

Chronic Hepatitis B ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Hepatitis B E Antigen ◽

Tnf Α ◽

Ifn Γ

Abstract During chronic hepatitis B (CHB), CD8+ T cells down-regulate CD28, the primary co-stimulation molecule for T-cell activation. Diverse functional attributes of CD8+CD28− T cells are suggested in various disease contexts. The present study aimed to characterize CD8+CD28− T cells in different phases of chronic Hepatitis B virus (HBV) infection (CHI)- Immune-tolerance (IT), Hepatitis B e-antigen-positive CHB (EP-CHB), Inactive carriers (IC) and Hepatitis B e-antigen-negative CHB (EN-CHB), to appraise their contribution in HBV-related disease pathophysiology. Flow cytometry analysis of T cells in peripheral blood of study subjects revealed enhanced CD8+CD28− T-cell accumulation in EP-/EN-CHB, compared with IT/IC and they expanded equivalently in HBV-specific and non-specific CD8+ T-cell compartments. Profound increase in CD8+CD28− T cells expressing perforin/granzyme-B/CD57/IFN-γ/TNF-α and markers of terminal differentiation were observed exclusively in EP-/EN-CHB. Further, activation with anti-NKG2D resulted in heightened IFN-γ/TNF-α production selectively from CD8+CD28− T cells, suggesting NKG2D-mediated alternative co-stimulation. CD8+CD28− T cells sorted from CHB patients induced enhanced apoptosis of peripheral blood mononuclear cells (PBMC), including CD4+ T cells. However, NKG2D-ligand (major histocompatibility complex class I chain-related molecule A/B (MICA/B)) was preferentially expressed by HBV-specific CD4+ T cells of CHB patients, making these cells a potential target to NKG2D-dependent CD8+CD28− T-cell killing. Both CD28+ and CD28− T cells in CHB expressed CXCR3 at similar levels and thus capable of homing to the liver. A positive correlation was seen between CD8+CD28− T-cell frequency and serum-alanine transaminase (ALT) levels and CHB-derived CD8+CD28− T cells caused pronounced cell death in HBV-transfected Huh7 cells. Immunofluorescence staining identified greater intrahepatic incidence of CD8+CD28− T cells but decline in CD4+ T cells in CHB than IC. Collectively, CD8+CD28− T cells demonstrated differential distribution and phenotypic/functional skewing in different CHI phases and contribute to disease progression by Perforin-Granzyme- or IFN-γ-TNF-α-mediated cytotoxicity while restraining antiviral immunity through NKG2D-dependent HBV-specific CD4+ T-cell depletion.

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Anti-Leukemia Immune Responses in CML Patients Treated with Imatinib Mesylate.

Blood ◽

10.1182/blood.v106.11.1108.1108 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1108-1108

Author(s):

Christiane I.-U. Chen ◽

Holden T. Maecker ◽

Wesley H. Neal ◽

Rhoda Falkow ◽

Peter P. Lee

Keyword(s):

Immune Response ◽

T Cells ◽

Immune Responses ◽

Cd4 T Cells ◽

Post Treatment ◽

Leukemia Cells ◽

Tnf Α ◽

Ifn Γ ◽

Cytogenetic Remission ◽

Pre Treatment

Abstract Imatinib mesylate, a selective inhibitor of the bcr/abl tyrosine kinase, has revolutionized the treatment of patients with chronic myelogenous leukemia (CML). Most CML patients in chronic phase achieve hematologic remission with imatinib, while some achieve cytogenetic remission. As imatinib is an oral agent with few side effects, it has rapidly become the first-line therapy for most CML patients. However, this therapy does not represent a cure, as patients who discontinue the drug invariably relapse. Furthermore, imatinib resistance is beginning to emerge in some patients. Hence, the need to find alternate, potentially curative, therapies for CML remains. To date, the only curative treatment for CML is allogeneic bone marrow or stem cell transplantation (ABMT). A major mechanism of the curative potential of ABMT is immunological, as evidenced by the poor clinical outcome with T cell-depleted ABMT, and the efficacy of donor lymphocyte infusions (DLI) upon relapse. We hypothesized that an effective anti-leukemia immune response may emerge in patients entering remission on imatinib which may contribute to its clinical effectiveness. If so, strategies to further enhance this anti-leukemia immune response may lead to a potential cure. To determine if CML patients in remission on imatinib develop anti-leukemia immune responses, blood and bone marrow samples from patients before and after treatment were collected and analyzed. Pre-treatment samples were utilized as sources of autologous leukemic cells to detect anti-leukemia immune responses in post-treatment samples in IFN-g ELISPOT assays. Pre-treatment samples alone, post-treatment samples alone, and when available, serial post-treatment samples mixed together served as controls. In 9 of 14 patients investigated, IFN-g release was detected in pre- and post-treatment samples together with a median response of 22 spots above background (range 10 – 56 dots, p<0.01), whereas serial post-treatment samples together in 8 patients yielded results similar to background (median 5, range 5 – 20). In 6 of these patients in hematologic (or cytogenetic) remission, sufficient cells were available to allow additional analyses via intracellular staining for IFN-g, TNF-a, and IL-2 in autologous leukemia stimulated T cells (CD4 and CD8) and NK cells. In 4 of 6 patients, leukemia-reactive T cells were detected, most prominently in CD4+ T cells expressing TNF-a (1.4 – 37%), followed by IL-2 (0.3 – 12%) and IFN-g (0.1 – 4.6%). NK cells did not show significant expression of these cytokines upon stimulation with autologous leukemia cells. In pre-treatment and post-treatment samples alone, IL-2, TNF-a, and IFN-g expression was not detectable (0 – 0.5%). These results suggest that a significant portion of CML patients in remission with imatinib develop an anti-leukemia immune response, most notably in CD4+ T cells. Mechanisms by which imatinib treatment leads to anti-leukemia immune responses, and the molecular targets to which these cells are directed, will be further investigated. This knowledge will be useful in the development of immunotherapy strategies against CML as well as other leukemias, and raises the hope that immunotherapy may be combined with imatinib to eradicate residual leukemia cells for a durable cure of the disease. intracellular cytokine staining CD4+ T Cells CD8+ T Cells IL-2 IFN- γ TNF- α IL-2 IFN- γ TNF- α pt 1 0.3 0 0.8 0.1 0.1 0.5 pt 1 0.3 0.1 1.4 0.1 0.1 0.4 pt 2 2.6 0.8 10.3 2.2 2.1 6.1 pt 3 21 2 37 2.3 0.7 1.7 pt 4 12 4.6 19 6.3 1.8 5.8

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Intracellular production of IL-2, IL-4, IFN-γ, and TNF-α by peripheral blood CD3+ and CD4+ T cells in children with atopic dermatitis

European Journal of Pediatrics ◽

10.1007/s00431-006-0319-5 ◽

2006 ◽

Vol 166 (8) ◽

pp. 789-795 ◽

Cited By ~ 16

Author(s):

Edyta Machura ◽

Bogdan Mazur ◽

Jarosław Kwiecień ◽

Krystyna Karczewska

Keyword(s):

T Cells ◽

Atopic Dermatitis ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Tnf Α ◽

Ifn Γ

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Anti-Myeloma Effects Induced by Myeloma Idiotype Pulsed Dendritic Cells In Vitro.

Blood ◽

10.1182/blood.v106.11.5131.5131 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5131-5131

Author(s):

Mei Zhang ◽

Xiaoran Yin ◽

Yunya Luo ◽

Xiu Lin ◽

Pengcheng He ◽

...

Keyword(s):

Multiple Myeloma ◽

Immune Response ◽

T Cells ◽

Dendritic Cells ◽

T Lymphocytes ◽

Cytotoxic T Lymphocytes ◽

Peripheral Blood ◽

Gm Csf ◽

Tnf Α

Abstract As the most potent antigen-presenting cells, Dendritic cells (DCs), capable of inducing immune responses from naive T cells, are operative tools for tumor immunotherapy. Derived DCs are extremely effective in capturing and presentation of antigens to T cells and play a key role in the induction of cytotoxic T lymphocytes (CTLs). In vitro culture system containing the combination of GM-CSF, IL-4 and TNF-α cytokine can affect CD14 + progenitor cells from mononuclear cells (MNCs) of peripheral blood (PB) developing into functional DCs, which have enough quantities for application in vitro researches and clinical practices. Multiple myeloma cells(MM)are able to secrete a great quantity of immunoglobulin (Ig) expressing idiotypic antigen called idiotype (Id) in its mutational hotspot. This kind of idiotypic structure regions also expressing on the surface of MM cells are high specific autologous tumor associated antigen (TAA). The combination use of DCs and tumor specific antigen can improve the immunogenicity of MM cells and stimulate specific anti-tumor immunological response effectively, so by using this new kind of DC tumor vaccine, following high dose chemical therapy, the tiny residual pathological changes might be cleared totally in the future. To investigate the specific antitumor immune response induced by Id-pulsed dendritic cells(DCs) in vitro. DCs were generated from peripheral blood monocytes of the multiple myeloma(MM) patients using GM-CSF, IL-4, and TNF-α. pulsed with idiotype protein at the immature stage, DCs could activate T cells to become tumor specific cytotoxic T lymphocytes (CTLs). The morphologic characteristics of those cells were observed with light and electron microscopes. The phenotypic figures were analyzed with FACS analysis. Methy-thiazoly-Tetrazolium (MTT) assay was employed to evaluate the effect of proliferation of autologous T cells and the inhibition rate of CTL on MM cells. DCs precursors in peripheral blood could be induced to typical mature DCs in medium containing GM-CSF, IL-4 and TNF-α. Mature DCs with Id could operatively increase proliferation of the autologous T cells and active naive T cells to become tumor specialized CTLs. Any doses of CTLs had significant inhibition or killing ability on autologous MM cells. These results suggest in suitable cytokine environment, the precursors in peripheral blood of MM patients could be induced to functional DCs, and vaccination with Id-pulsed DCs could induce active antitumor immune response. Multiple cycles of immunization using DC as APC in vitro can be beneficial in generating antigen- specific T cells from normal PBMC, and Id an auto-specific tumor antigen, can be got with ammonium sulfate four-step precipitated method, By digestion of pepsin and affinity chromatography so as to stimulate MM specific immunological responce, and Id-pulsed mature DCs from MM patients can stimulate not only the proliferation of autologous T cells, but also the specific CTL immune response against autologous MM cells. In addition, in vitro immunization may provide an alternative approach to in vivo immunization of MM. We believe that DCs vaccine can bring the breakthrough of therapy to MM in the near future.

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Decreased Expression of T-Cell Costimulatory Molecule CD28 on CD4 and CD8 T Cells of Mexican Patients with Pulmonary Tuberculosis

Tuberculosis Research and Treatment ◽

10.1155/2010/517547 ◽

2010 ◽

Vol 2010 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

German Bernal-Fernandez ◽

Patricia Espinosa-Cueto ◽

Rosario Leyva-Meza ◽

Nathalie Mancilla ◽

Raul Mancilla

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Pulmonary Tuberculosis ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Costimulatory Molecule ◽

Cell Phenotype ◽

Mexican Patients

Patients with tuberculosis frequently develop anergy, a state of T-cell hyporesponsiveness in which defective T-cell costimulation could be a factor. To know if the expression of T-cell costimulatory molecules was altered in tuberculosis, we analyzed the peripheral blood T-cell phenotype of 23 Mexican patients with pulmonary tuberculosis. There was severe CD4 (P<.001) and CD8 (P<.01) lymphopenia and upregulation of costimulatory molecule CD30 on CD4 and CD8 T cells (P<.05); this increase was higher in relapsing tuberculosis. The main finding was severe downregulation of the major costimulatory molecule CD28 on both CD8 and CD4 T cells (P<.001). Depletion of the CD4/CD28 subset, a hitherto undescribed finding, is relevant because CD4 T cells constitute the main arm of the cell-mediated antimycobacterial immune response.

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Correlation between circulating blood and microenvironment T lymphocytes in diffuse large B-cell lymphomas

Journal of Clinical Pathology ◽

10.1136/jclinpath-2020-207048 ◽

2021 ◽

pp. jclinpath-2020-207048

Author(s):

Filomena Emanuela Laddaga ◽

Giuseppe Ingravallo ◽

Anna Mestice ◽

Roberto Tamma ◽

Tommasina Perrone ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

B Cell ◽

Peripheral Blood ◽

B Cell Lymphoma ◽

Absolute Lymphocyte Count ◽

Response To Therapy ◽

Cd4 Cells ◽

Positive Correlation ◽

Large B Cell

AimsDiffuse large B-cell lymphoma (DLBCL) is characterised by marked clinical and biological heterogeneity, attributable to the tumour cells and their microenvironment.MethodsIn this study, we investigated circulating subsets of blood lymphocytes and monocytes and their relationship with T cells in the tumour microenvironment (TME) in chemoresistant and chemosensitive patients with DLBCL.ResultsThe study showed that (1) absolute lymphocyte count (ALC) and CD3+ and CD4+ cells were reduced in chemoresistant patients compared with chemosensitive patients; (2) lymphocyte:monocyte ratio (LMR) showed a positive correlation with peripheral blood CD3+ and CD4+ cells; (3) ALC, LMR, peripheral blood CD3+ and CD4+ cells showed a positive correlation with T cells in the TME.ConclusionsOverall, these data suggest that DLBCL with high TME T cells display a pre-existing antitumour immune response. In the rituximab-containing regimen, TME T cells are stimulated further to participate in the immune response against lymphoma cells. In contrast, DLBCL lymphomas with low T-cell infiltration reflect the absence of a pre-existing antitumour immunity and have a lower likelihood of obtaining an optimal response to therapy.

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Expression of Toll-Like Receptor 4, Tumor Necrosis Factor-Alpha, Matrix Metalloproteinase-9 and Effects of Benazepril in Patients with Acute Coronary Syndromes

Clinical Medicine Insights Cardiology ◽

10.4137/cmc.s5659 ◽

2010 ◽

Vol 4 ◽

pp. CMC.S5659 ◽

Cited By ~ 7

Author(s):

Ping Xie ◽

Yun-Shan Cao ◽

Peng Su ◽

Yu-Hong Li ◽

Zhi-Ling Gao ◽

...

Keyword(s):

Treatment Group ◽

Peripheral Blood ◽

Serum Levels ◽

Control Group ◽

Blood Monocytes ◽

Necrosis Factor Alpha ◽

Peripheral Blood Monocytes ◽

Regular Treatment ◽

Tnf Α ◽

Coronary Syndromes

Objectives The study aims to explore the relationship between expressions of toll-like receptor 4 (TLR4) on peripheral blood monocytes, serum tumor necrosis factor-alpha (TNF-α) and matrix metalloproteinase-9 (MMP-9) in patients with acute coronary syndromes(ACS), and to investigate the possible mechanisms of Benazepril stabilizing atherosclerosis plaques. Methods 70 patients selected were randomly divided into Benazepril treatment group (35 patients) and regular treatment group (35 patients). Meanwhile, Stable angina pectoris (SAP) group of 32 patients and control group of 22 patients were also set up. With the help of flow-cytometry, expressions of TLR4 on peripheral blood monocytes of the four groups were analyzed and compared to show differences, correlations and changes of the above mentioned indicators. The concentration of TNF-α and MMP-9 in serum were measured by enzyme linked immunosorbent assay (ELISA). Results (1) Expressions of TLR4, levels of TNF-α and MMP-9 were increased and the rate was rising from the control group, to SAP group and then to ACS group. All these indicators in ACS group are significantly higher than those in other groups ( P < 0.05). (ACS versus SAP, control; all ( P < 0.05). (2) Multi-linear regression analysis indicates that there was a positive correlation between the expression level of TLR4 and serum levels of TNF-α and MMP-9 in patients with ACS ( P < 0.01). (3) There is no significant differences between the expression level of TLR4 and serum levels of TNF-α and MMP-9 in Benazepril treatment group and regular treatment group before treatment ( P > 0.05) while they all fell after treatment ( P < 0.05). In addition, all the indicators decreased more greatly than the regular treatment group. Conclusions TLR4 on peripheral blood monocytes and serum TNF-α and MMP-9 in patients with coronary arteriosclerosis disease may be effective markers of the vulnerable plaque. Benazepril can inhibit over-expression of TLR4 and reduce serum levels of TNF-α and MMP-9, thus stabilize the vulnerable plaques and improve the condition of the patients with ACS.

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