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https://www.readbyqxmd.com/read/29330524/nf-%C3%AE%C2%BAb-inducing-kinase-is-a-therapeutic-target-for-systemic-lupus-erythematosus
#1
Hans D Brightbill, Eric Suto, Nicole Blaquiere, Nandhini Ramamoorthi, Swathi Sujatha-Bhaskar, Emily B Gogol, Georgette M Castanedo, Benjamin T Jackson, Youngsu C Kwon, Susan Haller, Justin Lesch, Karin Bents, Christine Everett, Pawan Bir Kohli, Sandra Linge, Laura Christian, Kathy Barrett, Allan Jaochico, Leonid M Berezhkovskiy, Peter W Fan, Zora Modrusan, Kelli Veliz, Michael J Townsend, Jason DeVoss, Adam R Johnson, Robert Godemann, Wyne P Lee, Cary D Austin, Brent S McKenzie, Jason A Hackney, James J Crawford, Steven T Staben, Moulay H Alaoui Ismaili, Lawren C Wu, Nico Ghilardi
NF-κB-inducing kinase (NIK) mediates non-canonical NF-κB signaling downstream of multiple TNF family members, including BAFF, TWEAK, CD40, and OX40, which are implicated in the pathogenesis of systemic lupus erythematosus (SLE). Here, we show that experimental lupus in NZB/W F1 mice can be treated with a highly selective and potent NIK small molecule inhibitor. Both in vitro as well as in vivo, NIK inhibition recapitulates the pharmacological effects of BAFF blockade, which is clinically efficacious in SLE...
January 12, 2018: Nature Communications
https://www.readbyqxmd.com/read/29324237/dna-induction-of-mdm2-promotes-proliferation-of-human-renal-mesangial-cells-and-alters-peripheral-b-cells-subsets-in-pediatric-systemic-lupus-erythematosus
#2
Chen-Xing Zhang, Ji Chen, Li Cai, Jing Wu, Jia-Yuan Wang, Lan-Fang Cao, Wei Zhou, Tong-Xin Chen
The study is aimed to investigate the role of MDM2 in the pathogenesis of lupus nephritis (LN) in pediatric SLE (pSLE). We confirmed that MDM2 expression was increased in peripheral blood mononuclear cells (PBMCs) as well as renal specimen of SLE compared with that of controls by western blot and immunofluorescence staining. Percentage of apoptotic and necrotic CD4+T, CD8+T and B cells were detected by flow cytometry respectively and levels of plasma cell free DNA (cfDNA) were quantified in SLE and healthy controls (HC)...
January 8, 2018: Molecular Immunology
https://www.readbyqxmd.com/read/29245286/case-report-for-recurrent-and-new-onset-sle-patients-treated-by-high-dose-glucocorticoid-therapy-characteristics-of-peripheral-tcr-beta-chain-cdr3-repertoires
#3
Jiang Yu, Bin Shi, Long Ma, Chunmei Liu, Suhong Sun, Rui Ma, Yuehong Qiu, Xinsheng Yao
RATIONALE: High-dose glucocorticoid therapy has been widely applied in clinical practice in systemic lupus erythematosus (SLE)patients, but less is known about the changes of T cells, especially the T cell receptor (TCR) repertoires, during the treatment. The aim of this paper is to describe the changes of TCR that recurrent and new-onset SLE patients treated by high-dose glucocorticoid therapy. PATIENT CONCERNS: Drugs of clinical treatment of SLE mainly include glucocorticoid, immunosuppressive agents, nonsteroidal anti-inflammatory drugs and B cell targeted drugs, etc, but the clinical symptoms were in remission and recurrent of onset patients with SLE...
December 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29224674/drivers-of-the-immunopathogenesis-in-systemic-lupus-erythematosus
#4
REVIEW
Thomas Rose, Thomas Dörner
This review summarises a number of current insights into the pathogenesis of SLE. On the basis of the interaction of environmental factors within a predisposed host, a chronic autoimmune process gains function with a positive feed-forward loop between innate and adaptive immunity. A current focus of SLE pathogenesis is on the enhanced production of certain cytokines, such as type I interferons and BLyS/BAFF, suggesting continuous plasmacytoid dendritic and myeloid cell activity together with disturbances of B lineage cells (increased autoantibodies, including anti-dsDNA and plasmablasts, which correlate with SLE activity and memory B-cell abnormalities)...
June 2017: Best Practice & Research. Clinical Rheumatology
https://www.readbyqxmd.com/read/29219063/an-insight-on-the-pathogenesis-and-treatment-of-systemic-lupus-erythematosus
#5
Murtaza Ali, Chelapram K Firoz, Nasimudeen R Jabir, Mohd Rehan, Mohd Shahnawaz Khan, Shams Tabrez
BACKGROUND AND OBJECTIVE: Systemic lupus erythematosus (SLE) is a diverse autoimmune disorder, evoked in response to self-immune system that leads to immune complex depositions and organ damage. The exact mechanism of SLE pathogenesis is still unclear but certain genetic and environmental factors have been suggested in the literature that could influence its pathogenesis. The modulation in B- and T- cell responses and genetic variations could lead to abnormal lymphocyte functions and the production of antibodies against the indigenous proteins and the immune complex depositions...
December 7, 2017: Endocrine, Metabolic & Immune Disorders Drug Targets
https://www.readbyqxmd.com/read/29214034/identification-of-biomarkers-of-response-to-abatacept-in-patients-with-sle-using-deconvolution-of-whole-blood-transcriptomic-data-from-a-phase-iib-clinical-trial
#6
Somnath Bandyopadhyay, Sean E Connolly, Omar Jabado, June Ye, Sheila Kelly, Michael A Maldonado, Rene Westhovens, Peter Nash, Joan T Merrill, Robert M Townsend
Objective: To characterise patients with active SLE based on pretreatment gene expression-defined peripheral immune cell patterns and identify clusters enriched for potential responders to abatacept treatment. Methods: This post hoc analysis used baseline peripheral whole blood transcriptomic data from patients in a phase IIb trial of intravenous abatacept (~10 mg/kg/month). Cell-specific genes were used with a published deconvolution algorithm to identify immune cell proportions in patient samples, and unsupervised consensus clustering was generated...
2017: Lupus Science & Medicine
https://www.readbyqxmd.com/read/29214033/lupus-related-single-nucleotide-polymorphisms-and-risk-of-diffuse-large-b-cell-lymphoma
#7
Sasha Bernatsky, Héctor A Velásquez García, John J Spinelli, Patrick Gaffney, Karin E Smedby, Rosalind Ramsey-Goldman, Sophia S Wang, Hans-Olov Adami, Demetrius Albanes, Emanuele Angelucci, Stephen M Ansell, Yan W Asmann, Nikolaus Becker, Yolanda Benavente, Sonja I Berndt, Kimberly A Bertrand, Brenda M Birmann, Heiner Boeing, Paolo Boffetta, Paige M Bracci, Paul Brennan, Angela R Brooks-Wilson, James R Cerhan, Stephen J Chanock, Jacqueline Clavel, Lucia Conde, Karen H Cotenbader, David G Cox, Wendy Cozen, Simon Crouch, Anneclaire J De Roos, Silvia de Sanjose, Simonetta Di Lollo, W Ryan Diver, Ahmet Dogan, Lenka Foretova, Hervé Ghesquières, Graham G Giles, Bengt Glimelius, Thomas M Habermann, Corinne Haioun, Patricia Hartge, Henrik Hjalgrim, Theodore R Holford, Elizabeth A Holly, Rebecca D Jackson, Rudolph Kaaks, Eleanor Kane, Rachel S Kelly, Robert J Klein, Peter Kraft, Anne Kricker, Qing Lan, Charles Lawrence, Mark Liebow, Tracy Lightfoot, Brian K Link, Marc Maynadie, James McKay, Mads Melbye, Thierry J Molina, Alain Monnereau, Lindsay M Morton, Alexandra Nieters, Kari E North, Anne J Novak, Kenneth Offit, Mark P Purdue, Marco Rais, Jacques Riby, Eve Roman, Nathaniel Rothman, Gilles Salles, Gianluca Severi, Richard K Severson, Christine F Skibola, Susan L Slager, Alex Smith, Martyn T Smith, Melissa C Southey, Anthony Staines, Lauren R Teras, Carrie A Thompson, Hervé Tilly, Lesley F Tinker, Anne Tjonneland, Jenny Turner, Claire M Vajdic, Roel C H Vermeulen, Joseph Vijai, Paolo Vineis, Jarmo Virtamo, Zhaoming Wang, Stephanie Weinstein, Thomas E Witzig, Andrew Zelenetz, Anne Zeleniuch-Jacquotte, Yawei Zhang, Tongzhang Zheng, Mariagrazia Zucca, Ann E Clarke
Objective: Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods: GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls...
2017: Lupus Science & Medicine
https://www.readbyqxmd.com/read/29192160/a-novel-human-systemic-lupus-erythematosus-model-in-humanised-mice
#8
Merry Gunawan, Zhisheng Her, Min Liu, Sue Yee Tan, Xue Ying Chan, Wilson Wei Sheng Tan, Shubasree Dharmaraaja, Yong Fan, Chee Bing Ong, Eva Loh, Kenneth Tou En Chang, Thiam Chye Tan, Jerry Kok Yen Chan, Qingfeng Chen
Mouse models have contributed to the bulk of knowledge on Systemic Lupus Erythematosus (SLE). Nevertheless, substantial differences exist between human and mouse immune system. We aimed to establish and characterise a SLE model mediated by human immune system. Injection of pristane into immunodeficient mice reconstituted with human immune system (humanised mice) recapitulated key SLE features, including: production of human anti-nuclear autoantibodies, lupus nephritis, and pulmonary serositis. There was a reduction in the number of human lymphocytes in peripheral blood, resembling lymphopenia in SLE patients...
November 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29186654/treatment-with-allogenic-mesenchymal-stromal-cells-in-a-murine-model-of-systemic-lupus-erythematosus
#9
Chiara Tani, Sabrina Vagnani, Linda Carli, Francesca Querci, Anja A Kühl, Simone Spieckermann, Constanze Pamela Cieluch, Simone Pacini, Rita Fazzi, Marta Mosca
Objective: Pre-clinical and uncontrolled studies in patients with systemic lupus erythematosus (SLE) showed that mesenchymal stromal cells (MSCs) have a potential therapeutic role in refractory cases. The optimal therapeutic strategy in these patients remain to be elucidated. Our aim was to test the hypothesis that repeated administrations of 1×106/kg body weight of allogenic MSCs, that is a significantly lower dosage with respect to the fixed 1×106 MSC used in animal models, can be effective in improving the clinical course of a murine SLE model...
November 30, 2017: International Journal of Stem Cells
https://www.readbyqxmd.com/read/29173182/lupus-nephritis-current-treatment-paradigm-and-unmet-needs
#10
Steven P Menez, Basset El Essawy, Mohamed G Atta
BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by chronic inflammation, which can result in a multitude of systemic or organ-limited manifestations, including the skin, lungs, heart, and kidney. SLE nephritis is present in an average of 38% of patients at the time of diagnosis, and may occur as the initial presentation of disease with progression to end-stage renal disease (ESRD) in roughly 10-20% of patients. METHODS: A review of the current literature was undertaken to investigate the evolution of treatment of SLE nephritis based on randomized trials and robust observational studies...
November 22, 2017: Reviews on Recent Clinical Trials
https://www.readbyqxmd.com/read/29172398/the-evaluation-of-cellular-immune-function-in-elderly-patients-with-systemic-lupus-erythematosus
#11
Kun Men, Yu Chen, Jingwei Zhang, Dianjun Wei
Background/Aims: To evaluate cellular immune function in systemic lupus erythematosus (SLE) patients over 60 years old, the association between antinuclear antibody (ANA) titers and the ratio of CD4+ /CD8+ was analyzed in this study. The distribution of ANAs and extractable nuclear antibodies (ENAs) in a healthy elderly population was also investigated. Methods: Serum ANA titers were assayed by indirect immunofluorescence (IIF) and the CD4+ /CD8+ T-cell ratio was determined by flow cytometry in 76 SLE patients and 30 healthy control individuals...
November 29, 2017: Korean Journal of Internal Medicine
https://www.readbyqxmd.com/read/29164585/expression-and-clinical-significance-of-mir-181a-and-mir-203-in-systemic-lupus-erythematosus-patients
#12
H-S Li, Y Ning, S-B Li, P-Y Shao, S-J Chen, Q Ye, X Heng
OBJECTIVE: MiR-181a plays a critical role in modulating T cell and B cell differentiation, as well as immune response. Its abnormal expression probably participates in the pathogenesis of systemic lupus erythematosus (SLE). MiR-203 is involved in regulating Toll-like receptor and inducing immune tolerance. Abnormal expression or function of miR-203 is related to multiple auto-immune diseases but its role in SLE remains unclear. This study, thus, investigated the serum level of miR-181a and miR-203, to analyze their roles in diagnosing and evaluating SLE...
November 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/29163765/b-cells-regulate-thymic-cd8-t-cell-differentiation-in-lupus-prone-mice
#13
Chen Xing, Gaizhi Zhu, He Xiao, Ying Fang, Xiaoling Liu, Gencheng Han, Guojiang Chen, Chunmei Hou, Beifen Shen, Yan Li, Ning Ma, Renxi Wang
Previous studies have shown that under normal physiological conditions thymic B cells play a critical function in T cell negative selection. We tested the effect of thymic B cells on thymic T-cell differentiation in autoimmune diseases including systemic lupus erythematosus (SLE). We found that thymic B cells and CD8(-) CD4(+) and CD4(-)CD8(+)T cells increased, whereas CD4(+)CD8(+)T cells decreased in lupus-prone mice. Once B cells were reduced, the change was reversed. Furthermore, we found that B cells blocked thymic immature single positive (ISP) CD4(-)CD8(+)CD3(lo/-)RORγt(-) T cells progression into CD4(+)CD8(+)T cells...
October 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/29114388/epistatic-interactions-between-mutations-of-taci-tnfrsf13b-and-tcf3-result-in-a-severe-primary-immunodeficiency-disorder-and-systemic-lupus-erythematosus
#14
Rohan Ameratunga, Wikke Koopmans, See-Tarn Woon, Euphemia Leung, Klaus Lehnert, Charlotte A Slade, Jessica C Tempany, Anselm Enders, Richard Steele, Peter Browett, Philip D Hodgkin, Vanessa L Bryant
Common variable immunodeficiency disorders (CVID) are a group of primary immunodeficiencies where monogenetic causes account for only a fraction of cases. On this evidence, CVID is potentially polygenic and epistatic although there are, as yet, no examples to support this hypothesis. We have identified a non-consanguineous family, who carry the C104R (c.310T>C) mutation of the Transmembrane Activator Calcium-modulator and cyclophilin ligand Interactor (TACI, TNFRSF13B) gene. Variants in TNFRSF13B/TACI are identified in up to 10% of CVID patients, and are associated with, but not solely causative of CVID...
October 2017: Clinical & Translational Immunology
https://www.readbyqxmd.com/read/29109527/the-rna-binding-protein-la-ss-b-promotes-rig-i-mediated-type-i-and-type-iii-ifn-responses-following-sendai-viral-infection
#15
Rebecca Mahony, Lindsay Broadbent, Jacen S Maier-Moore, Ultan F Power, Caroline A Jefferies
La/SS-B (or La) is a 48 kDa RNA-binding protein and an autoantigen in autoimmune disorders such as systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). La involvement in regulating the type I interferon (IFN) response is controversial - acting through both positive and negative regulatory mechanisms; inhibiting the IFN response and enhancing viral growth, or directly inhibiting viral replication. We therefore sought to clarify how La regulates IFN production in response to viral infection. ShRNA knockdown of La in HEK 293 T cells increased Sendai virus infection efficiency, decreased IFN-β, IFN-λ1, and interferon-stimulated chemokine gene expression...
November 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29074827/-update-on-recent-progress-in-vitamin-d-research-the-effects-of-vitamin-d-in-autoinflammatory-diseases
#16
Tomoka Ao, Junichi Kikuta, Masaru Ishii
Various kinds of immune cells -including dendritic cells, macrophages, T cells and B cells- express the vitamin D receptor and 1α-hydroxylase(CYP27B1). In vitro studies have shown the anti-inflammatory effect of 1,25-dihydroxyvitamin D:the active form of vitamin D. As vitamin D deficiency spread in our society, epidemiological studies have established the association between vitamin D deficiency and incidence or progression of several inflammatory diseases, including rheumatoid arthritis(RA), systemic lupus erythematosus(SLE), and multiple sclerosis(MS)...
2017: Clinical Calcium
https://www.readbyqxmd.com/read/29073347/efficacy-and-safety-of-atacicept-in-patients-with-systemic-lupus-erythematosus-results-of-a-24-week-randomized-placebo-controlled-phase-iib-study
#17
Joan T Merrill, Daniel J Wallace, Stephen Wax, Amy Kao, Patricia A Fraser, Peter Chang, David Isenberg
OBJECTIVE: To evaluate the efficacy and safety of atacicept, an antagonist of BLyS/APRIL-mediated B cell activation, in patients with systemic lupus erythematosus (SLE). METHODS: ADDRESS II was a phase IIb, multicentre study (NCT01972568). Patients with active, autoantibody-positive SLE receiving standard therapy were randomized (1:1:1) to atacicept (75 or 150 mg) or placebo for 24 weeks. The primary endpoint was the SLE responder index (SRI)-4 at Week 24. RESULTS: The ITT population included 306 patients...
October 26, 2017: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/29069649/the-systemic-activation-of-programmed-death-1-pd-l1-axis-protects-systemic-lupus-erythematosus-model-from-nephritis
#18
Wenjun Liao, Hua Zheng, Sha Wu, Yanmei Zhang, Wei Wang, Zili Zhang, Chenfei Zhou, Hongjun Wu, Jie Min
BACKGROUND: Systemic lupus erythematosus (SLE) is characterized by abnormal activated T cells, autoreactive B cells, and massive cytokines. The CD4+ T cells determined B-cells differentiation and cytokines production. The programmed death 1 (PD-1) is the checkpoint immunoinhibitory receptor of activated T cells, and its engagement could exhaust T cells. In this study, we investigated the role of PD-1 systemic engagement with PD-L1-Ig in lupus-like nephritis in SLE mice. METHODS: The murine PD-L1-Ig was injected into SLE-prone mice...
2017: American Journal of Nephrology
https://www.readbyqxmd.com/read/29066741/peripheral-cd19hi-b-cells-exhibit-activated-phenotype-and-functionality-in-promoting-igg-and-igm-production-in-human-autoimmune-diseases
#19
Zhicui Liu, Weihong Zeng, Xiangyang Huang, Shujun Wang, Jie Zheng, Meng Pan, Ying Wang
Systemic Lupus Erythematosus (SLE) and pemphigus are two representative autoimmune diseases driven by pathogenic autoantibody systemically and organ-specifically, respectively. Given the involvement of antibody in the pathogenesis, B cells are inclined to differentiate and function in an abnormal activation model. Here we defined a unique CD19hi B cell population existing in the periphery of SLE and pemphigus patients as well as in human tonsils. CD19hi B cells could be induced in vitro after co-culturing fully activated CD4+ T cells with autologous B cells...
October 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29045964/-increased-serum-c-c-chemokine-ligand-19-levels-correlated-with-b-cell-abnormalities-in-systemic-lupus-erythematosus
#20
H J Liu, L J Shi, F L Hu, H H Yao, Z G Li, Y Jia
OBJECTIVE: To detect the levels of serum C-C chemokine ligand 19 (CCL19) in patients with systemic lupus erythematosus (SLE) and to evaluate the correlation between CCL19 expression and clinical features and laboratory parameters, trying to reveal the possible role of CCL19 in the pathogenesis of systemic lupus erythematosus. METHODS: The levels of serum CCL19 were measured by enzyme linked immunosorbent assay (ELISA) in 90 patients with SLE and 30 healthy controls...
October 18, 2017: Beijing da Xue Xue Bao. Yi Xue Ban, Journal of Peking University. Health Sciences
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