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CD20+ B Cells (cd20+ + b_cell)
Selected AbstractsDifferential regulation of SOCS-1 signalling in B and T lymphocytes by hepatitis C virus core proteinIMMUNOLOGY, Issue 2 2008Zhi Qiang Yao Summary Hepatitis C virus (HCV) infection is characterized by a strong propensity toward chronicity, autoimmune phenomena and lymphomagenesis, supporting a role for lymphocyte dysregulation during persistent viral infection. We have shown that HCV core protein inhibits T-cell functions through interaction with a complement receptor, gC1qR. Here, we further report that B cells also express gC1qR that can be bound by HCV core protein. Importantly, using flow cytometry, we demonstrated differential regulation of B and T lymphocytes by the HCV core,gC1qR interaction, with down-regulation of CD69 activation in T cells but up-regulation of CD69 activation and cell proliferation in B cells. HCV core treatment led to decreased interferon-, production in CD8+ T cells but to increased immunoglobulin M and immunoglobulin G production as well as cell surface expression of costimulatory and chemokine receptors, including CD86 (B7-2), CD154 (CD40L) and CD195 (CCR5), in CD20+ B cells. Finally, we showed down-regulation of suppressor of cytokine signalling-1 (SOCS-1) using real-time reverse transcription,polymerase chain reaction, accompanied by up-regulation of signal transducer and activator of transcription-1 (STAT1) phosphorylation in B cells in response to HCV core protein, with the opposite pattern observed in HCV core-treated T cells. This study demonstrates differential regulation of B and T lymphocytes by HCV core and supports a mechanism by which lymphocyte dysregulation occurs in the course of persistent HCV infection. [source] Rituximab in patients with primary progressive multiple sclerosis: Results of a randomized double-blind placebo-controlled multicenter trial,ANNALS OF NEUROLOGY, Issue 4 2009Kathleen Hawker MD Objective Rituximab, a monoclonal antibody selectively depleting CD20+ B cells, has demonstrated efficacy in reducing disease activity in relapsing-remitting multiple sclerosis (MS). We evaluated rituximab in adults with primary progressive MS (PPMS) through 96 weeks and safety through 122 weeks. Methods Using 2:1 randomization, 439 PPMS patients received two 1,000mg intravenous rituximab or placebo infusions every 24 weeks, through 96 weeks (4 courses). The primary endpoint was time to confirmed disease progression (CDP), a prespecified increase in Expanded Disability Status Scale sustained for 12 weeks. Secondary endpoints were change from baseline to week 96 in T2 lesion volume and total brain volume on magnetic resonance imaging scans. Results Differences in time to CDP between rituximab and placebo did not reach significance (96-week rates: 38.5% placebo, 30.2% rituximab; p = 0.14). From baseline to week 96, rituximab patients had less (p < 0.001) increase in T2 lesion volume; brain volume change was similar (p = 0.62) to placebo. Subgroup analysis showed time to CDP was delayed in rituximab-treated patients aged <51 years (hazard ratio [HR] = 0.52; p = 0.010), those with gadolinium-enhancing lesions (HR = 0.41; p = 0.007), and those aged <51 years with gadolinium-enhancing lesions (HR = 0.33; p = 0.009) compared with placebo. Adverse events were comparable between groups; 16.1% of rituximab and 13.6% of placebo patients reported serious events. Serious infections occurred in 4.5% of rituximab and <1.0% of placebo patients. Infusion-related events, predominantly mild to moderate, were more common with rituximab during the first course, and decreased to rates comparable to placebo on successive courses. Interpretation Although time to CDP between groups was not significant, overall subgroup analyses suggest selective B-cell depletion may affect disease progression in younger patients, particularly those with inflammatory lesions. Ann Neurol 2009;66:460,471 [source] Cellular characterization of the gouty tophus: A quantitative analysisARTHRITIS & RHEUMATISM, Issue 5 2010Nicola Dalbeth Objective To characterize the cellular architecture of the tophus and to determine the presence of cytokines implicated in the initiation and resolution of gouty inflammation. Methods Sixteen fixed, paraffin-embedded, uninfected tophus samples were surgically obtained from 12 patients with microscopically proven gout and were analyzed by quantitative immunohistochemistry. The number of cells present in the corona and fibrovascular zones of the tophus was analyzed by Genmod mixed models analysis. Results Numerous CD68+ mononucleated and multinucleated cells were present within the corona zone. Mast cells were identified in all tophus samples and at similar densities throughout the corona and fibrovascular zones. In contrast, neutrophils were rarely observed. Plasma cells were present in very high numbers within the corona zone. The overall number of CD20+ B cells was much lower. However, in 6 of 12 patients (50%), at least 1 B cell aggregate was present in the fibrovascular zone. Large numbers of cells expressing interleukin-1, (IL-1,) were observed in the corona zone. Transforming growth factor ,1 (TGF,1),expressing mononucleated cells were also identified. The number of CD68+ cells correlated with the number of cells expressing IL-1, (r = 0.691, P = 0.009) and the number expressing TGF,1 (r = 0.518, P = 0.04). Conclusion The tophus represents a complex and organized chronic inflammatory tissue response to monosodium urate monohydrate crystals involving both innate and adaptive immune cells. The coexpression of IL-1, and TGF,1 suggests that both proinflammatory and antiinflammatory factors present within the tophus contribute to a cycle of chronic inflammation, attempted resolution, and tissue remodeling. [source] Light up-regulated on B lymphocytes and monocytes in rheumatoid arthritis mediates cellular adhesion and metalloproteinase production by synoviocytesARTHRITIS & RHEUMATISM, Issue 4 2007Young Mo Kang Objective To study the expression of LIGHT (tumor necrosis factor superfamily 14) and herpesvirus entry mediator (HVEM; tumor necrosis factor receptor superfamily 14) in rheumatoid arthritis (RA) and to determine the regulatory role of LIGHT on the effector functions of fibroblast-like synoviocytes (FLS). Methods The expression of LIGHT and HVEM was assessed by immunohistochemical staining of synovial tissue and by flow cytometric analysis of mononuclear cells. The presence of HVEM and lymphotoxin , receptor was measured by reverse transcriptase,polymerase chain reaction and by flow cytometry. The regulation of effector molecules, including matrix metalloproteinases (MMPs) and adhesion molecules, was evaluated. The adhesiveness of FLS was determined by adhesion assay. Results HVEM was detected in most cell types within rheumatoid synovial tissue, while only a few cells were positive for LIGHT. In RA patients, LIGHT expression was significantly up-regulated only in CD20+ B cells and monocytes, whereas the mean fluorescence intensity of HVEM was down-regulated in mononuclear cells. The stimulation of FLS with LIGHT resulted in the production of MMPs and the expression of adhesion molecules, which were efficiently inhibited by dexamethasone. LIGHT-mediated up-regulation of MMPs and intercellular adhesion molecule 1 was blocked by inhibitors of NF-,B and JNK, whereas up-regulation of vascular cell adhesion molecule 1 was blocked by inhibitors of phosphatidylinositol 3-kinase, as well as NF-,B. Conclusion These data suggest that binding of LIGHT with its receptors may play a role in the progression of inflammation within rheumatoid synovium, especially by mediating the interactions between infiltrating inflammatory cells and stromal cells. These findings thus emphasize the relevance of LIGHT as a potential therapeutic target in RA. [source] Rituximab for rheumatoid arthritis refractory to anti,tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeksARTHRITIS & RHEUMATISM, Issue 9 2006Stanley B. Cohen Objective To determine the efficacy and safety of treatment with rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to anti,tumor necrosis factor (anti-TNF) therapies and to explore the pharmacokinetics and pharmacodynamics of rituximab in this population. Methods We evaluated primary efficacy and safety at 24 weeks in patients enrolled in the Randomized Evaluation of Long-Term Efficacy of Rituximab in RA (REFLEX) Trial, a 2-year, multicenter, randomized, double-blind, placebo-controlled, phase III study of rituximab therapy. Patients with active RA and an inadequate response to 1 or more anti-TNF agents were randomized to receive intravenous rituximab (1 course, consisting of 2 infusions of 1,000 mg each) or placebo, both with background MTX. The primary efficacy end point was a response on the American College of Rheumatology 20% improvement criteria (ACR20) at 24 weeks. Secondary end points were responses on the ACR50 and ACR70 improvement criteria, the Disease Activity Score in 28 joints, and the European League against Rheumatism (EULAR) response criteria at 24 weeks. Additional end points included scores on the Functional Assessment of Chronic Illness Therapy,Fatigue (FACIT-F), Health Assessment Questionnaire (HAQ) Disability Index (DI), and Short Form 36 (SF-36) instruments, as well as Genant-modified Sharp radiographic scores at 24 weeks. Results Patients assigned to placebo (n = 209) and rituximab (n = 311) had active, longstanding RA. At week 24, significantly more (P < 0.0001) rituximab-treated patients than placebo-treated patients demonstrated ACR20 (51% versus 18%), ACR50 (27% versus 5%), and ACR70 (12% versus 1%) responses and moderate-to-good EULAR responses (65% versus 22%). All ACR response parameters were significantly improved in rituximab-treated patients, who also had clinically meaningful improvements in fatigue, disability, and health-related quality of life (demonstrated by FACIT-F, HAQ DI, and SF-36 scores, respectively) and showed a trend toward less progression in radiographic end points. Rituximab depleted peripheral CD20+ B cells, but the mean immunoglobulin levels (IgG, IgM, and IgA) remained within normal ranges. Most adverse events occurred with the first rituximab infusion and were of mild-to-moderate severity. The rate of serious infections was 5.2 per 100 patient-years in the rituximab group and 3.7 per 100 patient-years in the placebo group. Conclusion At 24 weeks, a single course of rituximab with concomitant MTX therapy provided significant and clinically meaningful improvements in disease activity in patients with active, longstanding RA who had an inadequate response to 1 or more anti-TNF therapies. [source] Rituximab for severe myasthenia gravis , experience from five patientsACTA NEUROLOGICA SCANDINAVICA, Issue 4 2010C. Lindberg Lindberg C, Bokarewa M. Rituximab for severe myasthenia gravis , experience from five patients. Acta Neurol Scand: 2010: 122: 225,228. © 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard. Background,,, Rituximab (RTX), a monoclonal antibody directed against CD20+ B cells, is used in the treatment of several autoimmune disorders including severe generalized myasthenia gravis (MG). Aims of the study,,, To describe the experience with RTX in five MG patients treated at our Neuromuscular Centre. Methods,,, Effect of RTX treatment was monitored by quantitative MG score (QMG score), forced vital capacity (FVC) and records of clinical parameters. Three patients had thymoma. Duration of MG prior to the first course of RTX was 3, 7, 26, 26 and 38 years. Results,,, We found favourable response to RTX treatment in all five patients. QMG score was markedly lower after RTX and in the three patients with respiratory muscle affection the FVC was increased. A good relief of bulbar, respiratory or extremity MG weakness was thus also found in the three patients who had long-standing severe MG. Repeated RTX treatment was needed in four patients. Conclusions,,, We conclude that RTX is effective in recent onset MG as well as in long-standing cases. As thymoma is prevalent in patients with severe MG, further studies are needed to evaluate the risk of thymoma recurrence following RTX treatment. [source] | ||||||||||