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BAFF in SLE

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https://www.readbyqxmd.com/read/29563108/phase-iii-trial-results-with-blisibimod-a-selective-inhibitor-of-b-cell-activating-factor-in-subjects-with-systemic-lupus-erythematosus-sle-results-from-a-randomised-double-blind-placebo-controlled-trial
#1
Joan T Merrill, William R Shanahan, Morton Scheinberg, Kenneth C Kalunian, David Wofsy, Renee S Martin
BACKGROUND: Targeted inhibitors of B-cell activating factor (BAFF) have been evaluated in phase III trials in over 4000 patients with systemic lupus erythematosus (SLE). Post hoc analyses of these studies identify greater treatment effect in patients entering with higher disease activity, greater corticosteroid doses, anti double-stranded DNA (dsDNA) and low complement C3 or C4. OBJECTIVES: To evaluate the efficacy and safety of blisibimod, a BAFF inhibitor, in a population of patients with SLE enriched for high disease activity...
March 21, 2018: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/29462939/peripheral-b-cell-subset-distribution-in-primary-antiphospholipid-syndrome
#2
Lorena Alvarez, Leyre Riancho, Jime Calvo-Alén, Marcos Lopez Hoyos, Victor Martinez-Taboada
BACKGROUND: B-cell differentiation and B-cell tolerance checkpoints may be different in antiphospholipid syndrome (APS) from systemic lupus erythematosus (SLE) and can help to understand differences between them. Our aim was to define alterations of B-cell subsets in patients with primary APS (pAPS) and to compare them with SLE patients and healthy controls (HC). METHODS: Cross-sectional study including three study groups: 37 patients with pAPS, 11 SLE patients, and 21 age- and gender-matched HC...
February 16, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29447842/neutrophils-drive-type-i-interferon-production-and-autoantibodies-in-patients-with-wiskott-aldrich-syndrome
#3
Karla E Cervantes-Luevano, Nicoletta Caronni, Maria C Castiello, Elena Fontana, Giulia M Piperno, Asma Naseem, Paolo Uva, Marita Bosticardo, Genni E Marcovecchio, Luigi D Notarangelo, Maria P Cicalese, Alessandro Aiuti, Anna Villa, Federica Benvenuti
BACKGROUND: Wiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency caused by mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal dynamics in hematopoietic cells. A high proportion of patients experience autoimmunity caused by a breakdown in T- and B-cell tolerance. Moreover, excessive production of type I interferon (IFN-I) by plasmacytoid dendritic cells (pDCs) contributes to autoimmune signs; however, the factors that trigger excessive innate activation have not been defined...
February 13, 2018: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29426575/systematic-review-and-meta-analysis-of-steroid-sparing-effect-of-biologic-agents-in-randomized-placebo-controlled-phase-3-trials-for-systemic-lupus-erythematosus
#4
REVIEW
Shereen Oon, Molla Huq, Timothy Godfrey, Mandana Nikpour
OBJECTIVES: To systematically review, and conduct a meta-analysis of steroid-sparing effect in, phase 3 randomized, placebo-controlled trials of biologic therapies for systemic lupus erythematosus (SLE). METHODS: Studies were identified by searching Medline (via Pubmed), EMBASE, CINAHL and SCOPUS databases, the Cochrane library, and clinicaltrials.gov. Adult human studies published in English in the last ten years (until 18/04/2017) were included. A random-effects meta-analysis comparing a common corticosteroid-reduction endpoint in the trials of rituximab, belimumab, tabalumab and epratuzumab in SLE, was conducted...
January 6, 2018: Seminars in Arthritis and Rheumatism
https://www.readbyqxmd.com/read/29385899/insulin-like-growth-factor-1-igf1-in-systemic-lupus-erythematosus-relation-to-disease-activity-organ-damage-and-immunological-findings
#5
J Waldron, W Raymond, G Ostli-Eilertsen, J Nossent
Background Insulin growth factor-1 (IGF1) activates cell proliferation pathways and inhibits apoptosis. IGF1 is involved in tumour growth and required for T-cell independent activation of B cells. Activated B cells and autoantibody production are a hallmark of systemic lupus erythematosus (SLE). To investigate the possible role of IGF1 in SLE, we studied IGF1 across clinical characteristics, immunological biomarkers, disease activity and organ damage in SLE patients. Method In a cross-sectional study, we collected clinical characteristics, medication, disease activity (SLEDAI-2K) and organ damage (SDI) for 94 SLE patients...
January 1, 2018: Lupus
https://www.readbyqxmd.com/read/29358664/delayed-onset-of-autoreactive-antibody-production-and-m2-skewed-macrophages-contribute-to-improved-survival-of-taci-deficient-mrl-fas-lpr-mouse
#6
Lunhua Liu, Windy Rose Allman, Adam Steven Coleman, Kazuyo Takeda, Tsai-Lien Lin, Mustafa Akkoyunlu
Anti-B cell activating factor belonging to TNF-family (BAFF) antibody therapy is indicated for the treatment of patients with active systemic lupus erythematosus (SLE). We hypothesized that the BAFF receptor, transmembrane activator and calcium-modulator and cyclophilin interactor (TACI) may be responsible for the generation of antibody secreting plasma cells in SLE. To test this hypothesis, we generated TACI deficient MRL-Fas/Lpr (LPR-TACI-/-) mouse. TACI deficiency resulted in improved survival of MRL-Fas/Lpr mice and delayed production of anti-dsDNA and anti-SAM/RNP antibodies...
January 22, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29330524/nf-%C3%AE%C2%BAb-inducing-kinase-is-a-therapeutic-target-for-systemic-lupus-erythematosus
#7
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/29224674/drivers-of-the-immunopathogenesis-in-systemic-lupus-erythematosus
#8
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/28992184/immune-complexes-containing-serum-b-cell-activating-factor-and-immunoglobulin-g-correlate-with-disease-activity-in-systemic-lupus-erythematosus
#9
Justa Friebus-Kardash, Leonore Branco, Camillo Ribi, Carlo Chizzolini, Uyen Huynh-Do, Denise Dubler, Pascale Roux-Lombard, Sebastian Dolff, Andreas Kribben, Ute Eisenberger, Marten Trendelenburg
Background: B-cell activating factor belonging to the TNF family (BAFF) is important for the survival of autoreactive B-cells in systemic lupus erythematosus (SLE). However, the association between serum BAFF levels and SLE disease activity is controversial. Independently, autoantibodies targeting BAFF [immunoglobulin G (IgG) anti-BAFF] have also been described in SLE patients and were associated with increased disease activity. The aim of our study was to analyse the relationship between SLE disease manifestations and serum levels of BAFF, IgG anti-BAFF and BAFF-IgG complexes...
August 8, 2017: Nephrology, Dialysis, Transplantation
https://www.readbyqxmd.com/read/28844943/the-unknown-aspect-of-baff-inducing-il-35-production-by-a-cd5-cd1d-hi-fc%C3%AE-riib-hi-regulatory-b-cell-subset-in-lupus
#10
Yamin Zhang, Jun Li, Nuoya Zhou, Yi Zhang, Min Wu, Jian Xu, Chen Shen, Xiangjie An, Guanxin Shen, Ming Yang, Chun Zhang, Juan Tao
IL-35 is a critical immunosuppressive cytokine that plays an important role in various autoimmune diseases. The purpose of this study was to determine whether BAFF, a key pathogenic factor in systemic lupus erythematosus, also a dichotomous regulator for B-cell immune responses, has an effect on IL-35-producing regulatory B cells and their underlying mechanisms in lupus. We found that exogenous BAFF could induce IL-35 production by splenic B cells from MRL-Faslpr/lpr mice. BAFF-induced IL-35-producing B cells were mainly from the marginal zone B-cell subset and exhibited a CD5+ CD1dhi FcγRIIbhi phenotype...
December 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28745239/therapeutic-interventions-of-tissue-specific-autoimmune-onset-in-systemic-lupus-erythematosus
#11
Subhajit Dasgupta
Systemic lupus erythematosus (SLE) is a female predominant autoimmune disease. The onset of SLE has been found to affect kidney, bone, cardiovascular and central nervous system. Auto activation of B cells and T helper cells together are known to develop self-reactive immune responses in SLE. The therapy still includes corticosteroids to prevent allergic manifestations and inflammatory immune responses. Recent observations suggested that, mycophenolate mofetil and cyclophosphamide treatment in combination with corticosteroids have benefit to control disease manifestations...
July 25, 2017: Mini Reviews in Medicinal Chemistry
https://www.readbyqxmd.com/read/28683581/reduction-of-cd19-autoimmunity-marker-on-b-cells-of-paediatric-sle-patients-through-repressing-pu-1-tnf-%C3%AE-baff-axis-pathway-by-mir-155
#12
H R Aboelenein, M T Hamza, H Marzouk, R A Youness, M Rahmoon, S Salah, A I Abdelaziz
microRNA-155 (miR-155) is implicated in regulating B-cell activation and survival that is important in systemic lupus erythematosus (SLE) pathogenesis. PU.1, a target for miR-155, is a crucial regulator of B-cell development and enhances Tumour-Necrosis-factor-alpha (TNF-α) expression. TNF-α induces the expression of B-cell-activating-factor (BAFF). BAFF is reported to increase the expression of the autoimmunity marker; CD19. This study aimed to investigate the regulation of expression of PU.1 in pediatric-systemic-lupus-erythematosus (pSLE) patients by miR-155, and hence evaluate its impact on TNF-α/BAFF/CD19 signalling pathway...
July 7, 2017: Growth Factors
https://www.readbyqxmd.com/read/28659046/renal-tubular-epithelial-cell-derived-baff-expression-mediates-kidney-damage-and-correlates-with-activity-of-proliferative-lupus-nephritis-in-mouse-and-men
#13
A Schwarting, M Relle, M Meineck, B Föhr, K Triantafyllias, A Weinmann, W Roth, J Weinmann-Menke
B-cell activating factor of the tumour necrosis factor family (BAFF) is a cytokine, mainly produced by hematopoietic cells (e.g. monocytes/macrophages, dendritic cells), indispensable for B-cell maturation. The BLISS studies have demonstrated that blocking BAFF by the human monoclonal antibody belimumab is a valuable therapeutic approach in patients with clinically and serologically active systemic lupus erythematosus (SLE). However, the defined sources of BAFF, which contributes to SLE, are still unclear. Recent findings show that BAFF expression is not restricted to myeloid cells...
February 2018: Lupus
https://www.readbyqxmd.com/read/28485798/immune-complexes-induce-tnf-%C3%AE-and-baff-production-from-u937-cells-by-hmgb1-and-rage
#14
X-J Gao, Y-Y Qu, X-W Liu, M Zhu, C-Y Ma, Y-L Jiao, B Cui, Z-J Chen, Y-R Zhao
OBJECTIVE: This study investigated the effects of immune complexes (ICs) on tumor necrosis factor α (TNF-α) and B cell-activating factor (BAFF) production from U937 cells and further explored the mechanism. MATERIALS AND METHODS: U937 cells were incubated with necrosis supernatant or systemic lupus erythematosus (SLE) sera alone, or their combination. The expression of TNF-α and BAFF was determined by Real-time polymerase chain reaction and enzyme-linked immunosorbent assay...
April 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28463395/clinical-relevance-of-circulating-anti-ena-and-anti-dsdna-secreting-cells-from-sle-patients-and-their-dependence-on-stat-3-activation
#15
Raquel de la Varga Martínez, Beatriz Rodríguez-Bayona, Gustavo A Añez, Fermín Medina Varo, José J Pérez Venegas, José A Brieva, Carmen Rodríguez
Disturbances of plasma cell homeostasis and auto-antibody production are hallmarks of systemic lupus erythematosus. The aim of this study was to explore the presence of circulating anti-ENA and anti-dsDNA antibody-secreting cells, to determine their dependence on plasma cell-niche cytokines and to analyze their clinical value. The study was performed in SLE patients with serum anti-ENA and/or anti-dsDNA antibodies (n = 57). Enriched B-cell fractions and sorted antibody-secreting cells (CD19low CD38high ) were obtained from blood...
July 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28445677/overexpression-of-the-cytokine-baff-and-autoimmunity-risk
#16
Maristella Steri, Valeria Orrù, M Laura Idda, Maristella Pitzalis, Mauro Pala, Ilenia Zara, Carlo Sidore, Valeria Faà, Matteo Floris, Manila Deiana, Isadora Asunis, Eleonora Porcu, Antonella Mulas, Maria G Piras, Monia Lobina, Sandra Lai, Mara Marongiu, Valentina Serra, Michele Marongiu, Gabriella Sole, Fabio Busonero, Andrea Maschio, Roberto Cusano, Gianmauro Cuccuru, Francesca Deidda, Fausto Poddie, Gabriele Farina, Mariano Dei, Francesca Virdis, Stefania Olla, Maria A Satta, Mario Pani, Alessandro Delitala, Eleonora Cocco, Jessica Frau, Giancarlo Coghe, Lorena Lorefice, Giuseppe Fenu, Paola Ferrigno, Maria Ban, Nadia Barizzone, Maurizio Leone, Franca R Guerini, Matteo Piga, Davide Firinu, Ingrid Kockum, Izaura Lima Bomfim, Tomas Olsson, Lars Alfredsson, Ana Suarez, Patricia E Carreira, Maria J Castillo-Palma, Joseph H Marcus, Mauro Congia, Andrea Angius, Maurizio Melis, Antonio Gonzalez, Marta E Alarcón Riquelme, Berta M da Silva, Maurizio Marchini, Maria G Danieli, Stefano Del Giacco, Alessandro Mathieu, Antonello Pani, Stephen B Montgomery, Giulio Rosati, Jan Hillert, Stephen Sawcer, Sandra D'Alfonso, John A Todd, John Novembre, Gonçalo R Abecasis, Michael B Whalen, Maria G Marrosu, Alessandra Meloni, Serena Sanna, Myriam Gorospe, David Schlessinger, Edoardo Fiorillo, Magdalena Zoledziewska, Francesco Cucca
BACKGROUND: Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways...
April 27, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28405610/btk-specific-inhibition-blocks-pathogenic-plasma-cell-signatures-and-myeloid-cell-associated-damage-in-ifn%C3%AE-driven-lupus-nephritis
#17
Arna Katewa, Yugang Wang, Jason A Hackney, Tao Huang, Eric Suto, Nandhini Ramamoorthi, Cary D Austin, Meire Bremer, Jacob Zhi Chen, James J Crawford, Kevin S Currie, Peter Blomgren, Jason DeVoss, Julie A DiPaolo, Jonathan Hau, Adam Johnson, Justin Lesch, Laura E DeForge, Zhonghua Lin, Marya Liimatta, Joseph W Lubach, Sami McVay, Zora Modrusan, Allen Nguyen, Chungkee Poon, Jianyong Wang, Lichuan Liu, Wyne P Lee, Harvey Wong, Wendy B Young, Michael J Townsend, Karin Reif
Systemic lupus erythematosus (SLE) is often associated with exaggerated B cell activation promoting plasma cell generation, immune-complex deposition in the kidney, renal infiltration of myeloid cells, and glomerular nephritis. Type-I IFNs amplify these autoimmune processes and promote severe disease. Bruton's tyrosine kinase (Btk) inhibitors are considered novel therapies for SLE. We describe the characterization of a highly selective reversible Btk inhibitor, G-744. G-744 is efficacious, and superior to blocking BAFF and Syk, in ameliorating severe lupus nephritis in both spontaneous and IFNα-accelerated lupus in NZB/W_F1 mice in therapeutic regimens...
April 6, 2017: JCI Insight
https://www.readbyqxmd.com/read/28388832/associations-of-b-cell-activating-factor-baff-and-anti-baff-autoantibodies-with-disease-activity-in-multi-ethnic-asian-systemic-lupus-erythematosus-patients-in-singapore
#18
H S Howe, B Y H Thong, K O Kong, H H Chng, T Y Lian, F L Chia, K S S Tay, T C Lau, W G Law, E T Koh, B P Leung
To measure the levels of B cell-activating factor (BAFF) and endogenous anti-BAFF autoantibodies in a cohort of multi-ethnic Asian systemic lupus erythematosus (SLE) patients in Singapore, to determine their correlation with disease activity. Serum samples from 121 SLE patients and 24 age- and sex-matched healthy controls were assayed for BAFF and anti-BAFF immunoglobulin (Ig)G antibody levels by enzyme-linked immunosorbent assay (ELISA). The lowest reliable detection limit for anti-BAFF-IgG antibody levels was defined as 2 standard deviations (s...
September 2017: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/28383107/a-mouse-model-of-systemic-lupus-erythematosus-responds-better-to-soluble-taci-than-to-soluble-baffr-correlating-with-depletion-of-plasma-cells
#19
Philipp Haselmayer, Michele Vigolo, Josquin Nys, Pascal Schneider, Henry Hess
The TNF family cytokines B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) support plasma cell survival. It is known that inhibitors of BAFF only (BAFFR-Fc) or BAFF and APRIL (TACI-Fc) administered early enough in an NZB/NZW F1 mouse model of systemic lupus erythematosus (SLE) ameliorate clinical outcomes, pointing to a pathogenic role of BAFF. In the present study, TACI-Fc administrated at a later stage of disease, after onset of autoimmunity, decreased the number of bone marrow plasma cells and slowed down further formation of autoantibodies...
June 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28331294/spotlight-on-blisibimod-and-its-potential-in-the-treatment-of-systemic-lupus-erythematosus-evidence-to-date
#20
REVIEW
Aleksander Lenert, Timothy B Niewold, Petar Lenert
B cells in general and BAFF (B cell activating factor of the tumor necrosis factor [TNF] family) in particular have been primary targets of recent clinical trials in systemic lupus erythematosus (SLE). In 2011, belimumab, a monoclonal antibody against BAFF, became the first biologic agent approved for the treatment of SLE. Follow-up studies have shown excellent long-term safety and tolerability of belimumab. In this review, we critically analyze blisibimod, a novel BAFF-neutralizing agent. In contrast to belimumab that only blocks soluble BAFF trimer but not soluble 60-mer or membrane BAFF, blisibimod blocks with high affinity all three forms of BAFF...
2017: Drug Design, Development and Therapy
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