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b cells AND SLE AND T cells

Thomas Dörner, Peter E Lipsky
New insights into the mechanisms of autoimmune diseases have been obtained not only from preclinical studies, but also from clinical trials of pan-B-cell-directed therapy. Overall, the results of these clinical trials suggest that more-specific approaches focusing on pathogenic B-cell functions, and perhaps sparing or even enhancing regulatory B-cell activity, might be attractive alternatives. Importantly, pathogenic B-cell subpopulations function within a network of cellular interactions, many of which might require additional interventions to restore immunologic balance and suppress autoimmune disease...
October 13, 2016: Nature Reviews. Rheumatology
Robert W Hoffman, Joan T Merrill, Marta M E Alarcón-Riquelme, Michelle Petri, Ernst R Dow, Eric Nantz, Laura K Nisenbaum, Krista M Schroeder, Wendy J Komocsar, Narayanan B Perumal, Matthew D Linnik, David C Airey, Yushi Liu, Guilherme V Rocha, Richard E Higgs
OBJECTIVE: Systemic lupus erythematosus (SLE) has substantial unmet medical need and its pathogenesis is incompletely understood. This study characterized baseline gene expression and pharmacodynamic (PD)-induced changes in whole blood gene expression from two phase III, 52-week (W), randomized, placebo-controlled, double-blind studies of 1,760 SLE patients treated with the B cell activating factor (BAFF)-blocking IgG4 monoclonal antibody, tabalumab. METHODS: Patient samples were obtained from ILLUMINATE-1 and -2 while control samples were from healthy donors...
October 9, 2016: Arthritis & Rheumatology
Tue Kruse Rasmussen
Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are lifelong diseases with increased mortality and chronic pains. They are both characterized by immunological imbalances causing the immune system attack and destroy the bodies own tissues (called autoimmune disease). The best treatment, we are currently able to offer these patients, cause significant side-effects and can not prevent significant loss of quality of life. At the heart of the disease mechanisms in RA and SLE are subsets of immune cells called T and B cells...
October 2016: Danish Medical Journal
J K Presto, E Z Hejazi, V P Werth
Cutaneous lupus erythematosus (CLE) is an autoimmune skin disease occurring in association with or without systemic lupus erythematosus (SLE). Although antimalarials are widely used as the first-line systemic agent, refractory cases may benefit from additional immunomodulators, immunosuppressives, and biologics. An interest in biological therapies for CLE has emerged in recent years due to novel insight into the pathogenesis of CLE. These targets include B cells, T cells, and cytokines that are involved in immune system pathways...
September 29, 2016: Lupus
Matthieu Sawaf, Hélène Dumortier, Fanny Monneaux
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by B cell hyperactivity leading to the production of autoantibodies, some of which having a deleterious effect. Reducing autoantibody production thus represents a way of controlling lupus pathogenesis, and a better understanding of the molecular and cellular factors involved in the differentiation of B cells into plasma cells could allow identifying new therapeutic targets. Follicular helper T cells (TFH) represent a distinct subset of CD4(+) T cells specialized in providing help to B cells...
2016: Journal of Immunology Research
Benoit Desnues, Amanda B Macedo, Diana Ordoñez-Rueda, Annie Roussel-Queval, Bernard Malissen, Pierre Bruhns, Marie Malissen, Lena Alexopoulou
The transcriptional repressor growth factor independence 1 (Gfi1) is important in myeloid and lymphoid differentiation. In the current study we evaluated the involvement of Gfi1 in systemic lupus erythematosus (SLE). We found that Genista mice, which carry a hypomorphic mutation in the gfi1 gene or Gfi1-deficient (Gfi1(-/-) ) mice develop signs of spontaneous lupus autoimmunity, including increased serum levels of IgM and IgG2a, autoantibodies against RNA and DNA, glomerular immunodeposits and increased frequencies of plasmablasts, germinal center (GC) B cells and age-associated B cells (ABCs)...
September 7, 2016: European Journal of Immunology
Andrea Doria, M Eric Gershwin, Carlo Selmi
The significant decrease in mortality rates worldwide, the increased proportion of patients achieving a durable remission, and the recent approval of a new drug after several decades are encouraging advances in the tangled history of systemic lupus erythematosus (SLE). However, when data are observed more closely, the research findings on disease pathogenesis and targeted treatments have been quite misleading, as illustrated by the central role of B cells but the missed endpoints in rituximab clinical trials which are burdened by the wide variability of SLE manifestations or the ethnic determinants of disease severity...
August 31, 2016: Journal of Autoimmunity
Aikaterini Thanou, Stavros Stavrakis, John W Dyer, Melissa E Munroe, Judith A James, Joan T Merrill
BACKGROUND: Decreased heart rate variability (HRV) is associated with adverse outcomes in cardiovascular diseases and has been observed in patients with systemic lupus erythematosus (SLE). We examined the relationship of HRV with SLE disease activity and selected cytokine pathways. METHODS: Fifty-three patients from the Oklahoma Lupus Cohort were evaluated at two visits each. Clinical assessments included the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), British Isles Lupus Assessment Group (BILAG) index, physician global assessment (PGA), and Safety of Estrogens in Lupus Erythematosus National Assessment-SLEDAI Flare Index...
2016: Arthritis Research & Therapy
Mikhail Olferiev, Elzbieta Jacek, Kyriakos A Kirou, Mary K Crow
To gain novel insights into the immunopathogenesis of systemic lupus erythematosus we have analyzed gene expression data from isolated CD4(+) T cells, CD8(+) T cells, CD19(+) B cells, and CD56(+) NK-cell enriched peripheral blood cell fractions from patients and healthy donors. As predicted, type I interferon-inducible gene transcripts are overexpressed in all populations. Transcripts preferentially expressed in SLE CD4(+) and CD8(+) T cells include those associated with Tregulatory and Th17 effector cell programs, respectively, but in each case additional transcripts predicted to limit differentiation of those effector cells are detected...
August 26, 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Marwa M Shakweer, Maha Behairy, Nadia G Elhefnawy, Tamer W Elsaid
BACKGROUND: Forkhead box P3 (Foxp3) functions as a master regulator in the development and function of T-regulatory (Treg) cells. Recent studies have shown that autoimmune diseases including systemic lupus erythematosus (SLE) are associated with an imbalance with the Treg cells and T helper (Th) subtypes. OBJECTIVES: To evaluate immunohistochemical expression of Foxp3 positive Treg cells in lupus nephritis (LN) and analyze its association with clinicopathologic parameters...
July 2016: Journal of Nephropathology
K C Kalunian
Clinical trials of investigational agents in systemic lupus erythematosus (SLE) have focused on targeting dysregulated B and T cells; however, recent translational research findings of the importance of the dysregulation of the innate immune system in SLE have led to clinical trials that target interferon. Three biologics that target type I interferons have been tested for their efficacy and safety in active SLE patients; these phase II trials have tested the hypothesis that down-regulation of interferon-regulated gene expression (the interferon signature) lessen the clinical burden of SLE...
September 2016: Lupus
P Nandkumar, R Furie
Drug development for the treatment of systemic lupus erythematosus (SLE) has largely focused on B-cell therapies. A greater understanding of the immunopathogenesis of SLE coupled with advanced bioengineering has allowed for clinical trials centered on other targets for SLE therapy. The authors discuss the benefits and shortcomings of focusing on T-cell-directed therapies in SLE and lupus nephritis clinical trials.
September 2016: Lupus
Jonathan M Weiss, Wei Chen, Melanie S Nyuydzefe, Alissa Trzeciak, Ryan Flynn, James R Tonra, Suzana Marusic, Bruce R Blazar, Samuel D Waksal, Alexandra Zanin-Zhorov
Rho-associated kinase 2 (ROCK2) determines the balance between human T helper 17 (TH17) cells and regulatory T (Treg) cells. We investigated its role in the generation of T follicular helper (TFH) cells, which help to generate antibody-producing B cells under normal and autoimmune conditions. Inhibiting ROCK2 in normal human T cells or peripheral blood mononuclear cells from patients with active systemic lupus erythematosus (SLE) decreased the number and function of TFH cells induced by activation ex vivo. Moreover, inhibition of ROCK2 activity decreased the abundance of the transcriptional regulator Bcl6 (B cell lymphoma 6) and increased that of Blimp1 by reducing the binding of signal transducer and activator of transcription 3 (STAT3) and increasing that of STAT5 to the promoters of the genes Bcl6 and PRDM1, respectively...
2016: Science Signaling
Sahar Mortezagholi, Zohreh Babaloo, Parisa Rahimzadeh, Mojgan Ghaedi, Hayedeh Namdari, Shirin Assar, Maryam Azimi Mohamadabadi, Eisa Salehi
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease which results in damage to various organs. Some animal studies have revealed that activation of Toll-like receptors (TLRs) is important in the pathogenesis of SLE. In the present study, the percentage of different immune cell subsets in 35 SLE patients and 38 control subjects was analyzed by flow cytometry. We also assessed the expression of TLR9 in the population of peripheral blood mononuclear cells (PBMCs) including T lymphocytes (CD4+ and CD8+), B lymphocytes (CD19+), NK cells (CD56+) and monocytes (CD14+) in SLE patients and healthy controls...
June 2016: Iranian Journal of Allergy, Asthma, and Immunology
H Tydén, C Lood, B Gullstrand, A Jönsen, F Ivars, T Leanderson, A A Bengtsson
OBJECTIVES: Systemic lupus erythematosus (SLE) is associated with elevated levels of S100A8/A9, pro-inflammatory proteins mainly secreted by activated polymorphonuclear neutrophils (PMNs). The underlying mechanisms for increased S100A8/A9 levels and their relation to the clinical phenotype have not been carefully investigated. We assessed S100A8/A9 and S100A12 levels in SLE patient sera in relation to disease activity, clinical phenotype, presence of anti-dsDNA antibodies and ability to promote phagocytosis of necrotic cells (NCs) by PMNs...
July 12, 2016: Lupus
Peter Isaac Lobo
We review how polyreactive natural IgM autoantibodies (IgM-NAA) protect the host from invading micro-organisms and host neo-antigens that are constantly being produced by oxidation mechanisms and cell apoptosis. Second, we discuss how IgM-NAA and IgM anti-leukocyte antibodies (IgM-ALA) inhibits autoimmune inflammation by anti-idiotypic mechanisms, enhancing removal of apoptotic cells, masking neo-antigens, and regulating the function of dendritic cells (DC) and effector cells. Third, we review how natural IgM prevents autoimmune disorders arising from pathogenic IgG autoantibodies, triggered by genetic mechanisms (e...
2016: Frontiers in Immunology
Ninghai Wang, Marton Keszei, Peter Halibozek, Burcu Yigit, Pablo Engel, Cox Terhorst
The nine SLAM family (Slamf) receptors are positive or negative regulators of adaptive and innate immune responses, and of several autoimmune diseases. Here we report that the transfer of Slamf6(-/-) B6 CD4(+) T cells into co-isogenic bm12 mice causes SLE-like autoimmunity with elevated levels of autoantibodies. In addition, significantly higher percentages of Tfh cells and IFN-γ-producing CD4(+) cells, as well as GC B cells were observed. Interestingly, the expression of the Slamf6-H1 isoform in Slamf6(-/-) CD4(+) T cells did not induce this lupus-like phenotype...
June 28, 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Haijing Wu, Xin Huang, Hong Qiu, Ming Zhao, Wei Liao, Shuguang Yuan, Yubing Xie, Yong Dai, Christopher Chang, Akihiko Yoshimura, Qianjin Lu
Follicular helper T cells (Tfh) have been well documented to play a critical role in autoimmunity, such as systemic lupus erythematosus (SLE), by helping B cells. In this study, high salt (sodium chloride, NaCl), under physiological conditions, was demonstrated to increase the differentiation of Tfh. A high-salt diet markedly increased lupus features in MRL/lpr mice. The mechanism is NaCl-induced DNA demethylation via the recruitment of the hydroxytransferase Ten-Eleven Translocation 2 (TET2). Gene silencing of TET2 obviously diminished NaCl-induced Tfh cell polarization in vitro...
2016: Scientific Reports
Arvind Kaul, Caroline Gordon, Mary K Crow, Zahi Touma, Murray B Urowitz, Ronald van Vollenhoven, Guillermo Ruiz-Irastorza, Graham Hughes
Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect many organs, including the skin, joints, the central nervous system and the kidneys. Women of childbearing age and certain racial groups are typically predisposed to developing the condition. Rare, inherited, single-gene complement deficiencies are strongly associated with SLE, but the disease is inherited in a polygenic manner in most patients. Genetic interactions with environmental factors, particularly UV light exposure, Epstein-Barr virus infection and hormonal factors, might initiate the disease, resulting in immune dysregulation at the level of cytokines, T cells, B cells and macrophages...
2016: Nature Reviews. Disease Primers
Helena Hiemisch Lobo Borba, Andreas Funke, Astrid Wiens, Shirley Ramos da Rosa Utiyama, Cássio Marques Perlin, Roberto Pontarolo
Systemic lupus erythematosus (SLE) is a chronic multisystemic autoimmune disease driven by genetic, hormonal, and environmental factors. Despite the advances in diagnostic and therapeutic approaches in the last decades, SLE still leads to significant morbidity and increased mortality. Although a cure for SLE is still unknown, treatment is required to control acute disease exacerbation episodes (flares), decrease the frequency and severity of subsequent lupus flares, address comorbidities, and prevent end-organ damage...
July 2016: Current Rheumatology Reports
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