Role of IL-17-producing lymphocytes in severity of multiple sclerosis upon natalizumab treatment

2016 ◽  
Vol 23 (4) ◽  
pp. 567-576 ◽  
Author(s):  
Ulrike Bühler ◽  
Vinzenz Fleischer ◽  
Felix Luessi ◽  
Ayman Rezk ◽  
Patrick Belikan ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Peripheral Blood ◽  
T Helper Cells ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Healthy Controls ◽  
T Helper ◽  
Peripheral Blood Mononuclear ◽  
Helper Cells

Objective: Natalizumab is known to prevent T-helper cells entering the central nervous system (CNS). We hypothesize that more pathogenic T-helper cells are present outside the CNS and a possible relationship to disease severity. Methods: Characterization and enrichment of human CD4+IL-17+ cells were performed ex vivo using peripheral blood mononuclear cells from natalizumab-treated relapsing-remitting multiple sclerosis (RRMS) patients ( n = 33), untreated RRMS patients ( n = 13), and healthy controls ( n = 33). Magnetic resonance imaging (MRI) scans were performed routinely for patients. Results: Lymphocytes were elevated in peripheral blood of natalizumab-treated patients compared to untreated patients and healthy controls. Whereas group comparison for CD4+IL-17+ numbers also differed, CD4+IFN-γ+ and CD4+IL-22+ counts were not increased. CD4+IL-17+ cells not only expressed but also secreted IL-17. In natalizumab-treated patients, IL-17+ cell frequency was found to correlate with T1-hypointense lesions, but was not an indicator for rebound activity after treatment discontinuation, except in one patient who experienced a fulminant rebound, and interestingly, in whom the highest IL-17+ cell levels were observed. Conclusion: Increased lymphocytes and CD4+IL-17+ cells in the blood of RRMS patients receiving natalizumab corroborate the drug’s mechanism of action, that is, blocking transmigration to CNS. Correlation between IL-17-expressing lymphocytes and T1-hypointense lesions underlines the important role of these cells in the disease pathology.

scholarly journals Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia

Blood ◽  
1991 ◽  
Vol 78 (10) ◽  
pp. 2619-2625 ◽  
Author(s):  
JW Semple ◽  
J Freedman
Keyword(s):  
Peripheral Blood ◽  
T Helper Cells ◽  
Mononuclear Cells ◽  
Interleukin 2 ◽  
Autoimmune Disorder ◽  
T Helper ◽  
Phenotypic Analysis ◽  
Activated T Cells ◽  
Peripheral Blood Mononuclear ◽  
Helper Cells

Chronic autoimmune thrombocytopenic purpura (ATP) is a common hematologic disorder in which platelet-specific autoantibodies bind to platelets and enhance their destruction by the reticuloendothelial system. While there has been considerable investigation of the humoral immune abnormalities in ATP, little work has been performed on the cellular immunoregulatory aspects of this autoimmune disorder. We describe here that patients with ATP have lymphocytes that proliferate normally when stimulated by mitogens. However, when stimulated by normal control platelets in 7-day antigen-presenting cell cultures, peripheral blood mononuclear cells (PBMC) from patients with ATP proliferate at significantly higher levels (P less than .001) and their lymphocytes secrete significantly higher amounts of interleukin-2 (IL- 2) (P less than .001) than do lymphocytes from control subjects. Depletion studies with monoclonal anti-CD8 and complement did not reduce the proliferative capacity of the responding PBMC population, indicating that CD4+ T-helper cells may be responsible for the response. Phenotypic analysis of peripheral blood lymphocyte subsets from patients with ATP showed that there was a significant reduction in CD4+Leu8+ T suppressor-inducer cells (P less than .001) and a concomitant increase in CD3+DR+ activated T cells (P less than .001) and CD19+ B cells (P less than .05). These data indicate that CD4+ T- helper cells from patients with ATP are stimulated by normal platelet antigen(s) to secrete IL-2 and may modulate the enhanced antiplatelet autoantibody response.

scholarly journals Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia

Blood ◽  
1991 ◽  
Vol 78 (10) ◽  
pp. 2619-2625 ◽  
Author(s):  
JW Semple ◽  
J Freedman
Keyword(s):  
Peripheral Blood ◽  
T Helper Cells ◽  
Mononuclear Cells ◽  
Interleukin 2 ◽  
Autoimmune Disorder ◽  
T Helper ◽  
Phenotypic Analysis ◽  
Activated T Cells ◽  
Peripheral Blood Mononuclear ◽  
Helper Cells

Abstract Chronic autoimmune thrombocytopenic purpura (ATP) is a common hematologic disorder in which platelet-specific autoantibodies bind to platelets and enhance their destruction by the reticuloendothelial system. While there has been considerable investigation of the humoral immune abnormalities in ATP, little work has been performed on the cellular immunoregulatory aspects of this autoimmune disorder. We describe here that patients with ATP have lymphocytes that proliferate normally when stimulated by mitogens. However, when stimulated by normal control platelets in 7-day antigen-presenting cell cultures, peripheral blood mononuclear cells (PBMC) from patients with ATP proliferate at significantly higher levels (P less than .001) and their lymphocytes secrete significantly higher amounts of interleukin-2 (IL- 2) (P less than .001) than do lymphocytes from control subjects. Depletion studies with monoclonal anti-CD8 and complement did not reduce the proliferative capacity of the responding PBMC population, indicating that CD4+ T-helper cells may be responsible for the response. Phenotypic analysis of peripheral blood lymphocyte subsets from patients with ATP showed that there was a significant reduction in CD4+Leu8+ T suppressor-inducer cells (P less than .001) and a concomitant increase in CD3+DR+ activated T cells (P less than .001) and CD19+ B cells (P less than .05). These data indicate that CD4+ T- helper cells from patients with ATP are stimulated by normal platelet antigen(s) to secrete IL-2 and may modulate the enhanced antiplatelet autoantibody response.

scholarly journals The Expression and Pathophysiological Role of Osteopontin in Graves' Disease

2011 ◽  
Vol 96 (11) ◽  
pp. E1866-E1870 ◽  
Author(s):  
Lingyan Xu ◽  
Xinran Ma ◽  
Yanyan Wang ◽  
Xiaoli Li ◽  
Yicheng Qi ◽  
...  
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Graves Disease ◽  
Healthy Controls ◽  
Peripheral Blood Mononuclear ◽  
Pathophysiological Role ◽  
Blood Mononuclear Cells

Abstract Context: Graves' disease (GD) is a common autoimmune disease that affects the thyroid gland. Its pathogenesis is tightly involved with aberrant proinflammatory cytokine production. Osteopontin (OPN), an extracellular matrix protein of pleiotropic properties, has recently been recognized as a potent inflammatory cytokine in several autoimmune diseases. Objective: This study sought to explore the pathophysiological role of OPN in GD by comparing OPN levels in initial GD patients and healthy controls. Methods: Seventy-six patients who met criteria for initial GD and sixty-five healthy controls were recruited. OPN and other clinical GD diagnosis parameters were measured. In addition, the coexpression of several OPN receptors as well as various nuclear factor-κB (NF-κB) downstream target genes were examined in peripheral blood mononuclear cells from human subjects. The effect of OPN on NF-κB activation was determined by in vitro assays. Results: We demonstrated for the first time that the OPN levels are enhanced in serum from GD patients. OPN levels are strongly associated with clinical serum parameters for GD diagnosis. The coexpression of selective OPN receptors and inflammatory response genes was enhanced in peripheral blood mononuclear cells from GD patients. Furthermore, serum from GD patients activated NF-κB activity in vitro, which was significantly suppressed by OPN monoclonal antibody abrogation. Conclusion: These data indicated a clinical correlation between serum OPN levels and GD. OPN could affect GD development through NF-κB activation and the subsequent changes in inflammatory milieu. OPN could serve as a novel biomarker for GD as well as a potential target for GD treatment.

scholarly journals Limited Applicability of GW9662 to Elucidate PPARγ-Mediated Fatty Acid Effects in Primary Human T-Helper Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Anke Jaudszus ◽  
Stefan Lorkowski ◽  
Michael Gruen ◽  
Alexander Roth ◽  
Gerhard Jahreis
Keyword(s):  
Fatty Acid ◽  
T Helper Cells ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Inhibitory Effect ◽  
T Helper ◽  
Peripheral Blood Mononuclear ◽  
Helper Cells ◽  
Mechanistic Investigation ◽  
Limited Applicability

Synthetic antagonists of the nuclear receptor PPARγsuch as GW9662 are widely used to elucidate receptor-mediated ligand effects. In addition and complementary to recent work, we examined whether GW9662 is suitable to serve for mechanistic investigation in T-helper cells. Human peripheral blood mononuclear cells (PBMC) were preincubated with increasing concentrations of GW9662 (0, 0.4, 2, and 10 μmol/L) 30 min before adding thec9,t11-isomer of conjugated linoleic acid (c9,t11-CLA) as representative of PPARγ-activating fatty acids with immunomodulatory properties. Corresponding cultures were incubated with GW9662 in the absence of the fatty acid. After 19 h, cells were mitogen stimulated for further 5 h. Subsequently, intracellular IL-2 was measured in CD3+CD4+lymphocytes by means of flow cytometry. 100 μmol/Lc9,t11-CLA reduced the number of T-helper cells expressing IL-2 by 68%. GW9662 failed to abrogate this fatty acid effect, likely due to the fact that the compound exerted an own inhibitory effect on IL-2 production. Moreover, GW9662 dose-dependently induced cell death in human leukocytes. These results suggest that application of GW9662 is not conducive in this experimental setting.

scholarly journals Decreased Expression of PPARγ mRNA in Patients Correlates with aGVHD after Allo-HSCT

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5776-5776
Author(s):  
Xiaojin Wu ◽  
Jubin Zhang ◽  
Shoubao Ma ◽  
Yuhan Ji ◽  
Shuangzhu Liu ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Hormone Receptors ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Ppar Gamma ◽  
Healthy Controls ◽  
Peripheral Blood Mononuclear ◽  
Hematopoietic Stem ◽  
Significant Difference

Abstract Background and objective: Peroxisome proliferator-activated receptor (PPAR)-gamma(γ) is a member of superfamily of nuclear hormone receptors and involved in the lipids metabolism, adipocyte differentiation, atherosclerosis and anti-inflammation. The role of PPARγ in acute graft versus host disease (aGVHD ) remains unclear. In this study, we aimed to investigate the role of PPARγ during aGVHD after allogenic hematopoietic stem cell transplantation (allo-HSCT ). Methods: 50 patients undering allo-HSCT and 20 healthy controls were enrolled in study. Peripheral blood (PB) of patients 30 days, 60 days, and 90 days were collected after allo-HSCT. We also collected PB samples at aGVHD onset and after aGVHD remission. Peripheral blood mononuclear cells (PBMCs) were isolated for real-time PCR to detect the mRNA expression of PPARγ, IFNγ, IL4, T-bet, GATA3, Foxp3, RORγt . Results: Expression of PPARγmRNA in healthy controls were significant lower than that in patients after allo-HSCT(P<0.05). At the onset of aGVHD, the expression of PPARγmRNA was significantly lower than that in non-GVHD and increased when remission (P<0.05). PPARγexpression in severe aGVHD (grade 3 to 4) was lower than mild aGVHD (grade 1 to 2) patients (P<0.05). Gender, age, graft type, and the kind of disease showed no significant difference in the aGVHD and non-GVHD patients. The expression of IFNγ and T-bet increased after aGVHD and were negatively correlated with PPARγmRNA expression. Conclusion: Our findings suggest that low expression of PPARγ is associated with aGVHD occurrence. PPARγ may be a useful indicator to predict aGVHD and follow-up. Disclosures No relevant conflicts of interest to declare.

scholarly journals Genetics of experimental allergic encephalomyelitis supports the role of T helper cells in multiple sclerosis pathogenesis

2011 ◽  
Vol 70 (6) ◽  
pp. 887-896 ◽  
Author(s):  
Elizabeth P. Blankenhorn ◽  
Russell Butterfield ◽  
Laure K. Case ◽  
Emma H. Wall ◽  
Roxana del Rio ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Experimental Allergic Encephalomyelitis ◽  
T Helper Cells ◽  
T Helper ◽  
Allergic Encephalomyelitis ◽  
Helper Cells ◽  
Multiple Sclerosis Pathogenesis ◽  
Experimental Allergic
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