DOCSLIB.ORG

Interferons, B Cells and Neutrophils: Innate and Adaptive Allies in Systemic Lupus Erythematosus

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Interferons, B Cells and Neutrophils: Innate and Adaptive Allies in Systemic Lupus Erythematosus www.symbiosisonline.org Symbiosis www.symbiosisonlinepublishing.com Review Article Journal of Rheumatology and Arthritic Diseases Open Access Interferons, B Cells and Neutrophils: Innate and Adaptive Allies in Systemic Lupus Erythematosus Alaa A A Mohamed 1*, Tamer A Gheita2 1Rheumatology, Rehabilitation and Physical Medicine department, Faculty of Medicine, Assiut University, Assiut, Egypt 2Rheumatology Department, Faculty of Medicine, Cairo University, Cairo, Egypt Received: March 01, 2018; Accepted: March 15, 2018; Published: April 07, 2018 *Corresponding author: Alaa Mohamed, MD, PhD, Assiut University Hospital, Assiut, 71515, Egypt. Tel: +201018554227; E-mail: a.a.a.mohamed@ aun.edu.eg Granulocyte Colony Stimulating Factor; GM-CSF: Granulocyte Abstract PAD4: Systemic lupus erythematosus (SLE) is clinically and Deiminase-IV; ACPA: immunologically heterogeneous with variable organ involvement, Siglec-1:Macrophage Colony Stimulating Factor; PeptidylUNGAL: ArginineUrinary severity and therapeutic responses. B cells are known as mediators Anti-Citrullinated Peptide Antibodies; of disease manifestations. Therefore, disease control is targeted Sialic Acid-binding Ig-like Lectin-1; by inhibiting proliferation and inducing apoptosis of B cells via NeutrophilIntroduction Gelatinase-Associated Lipocalin. conventional cytotoxic drugs or newly developing biologics. However, the outcome of therapy is sometimes heterogeneous which further Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease characterized by involvement of all organs functions such as interferons (IFNs) cytokines and the innate cells, in the body. The clinical features of the disease are heterogeneous attracts to understand other immune mechanisms influencing B cell neutrophils. Successful management of SLE requires an understanding and run in a remitting-relapsing course with variable prognosis of how these factors interact, taking into consideration the patients’ variations in these factors which might confer heterogeneity in disease outcome. In this review, it will be focused on the existing data wide range of autoantibodies targeting particularly the nuclear [1]. SLE is characterized by the important role of B cells and the neutrophils in disease pathogenesis and the clinical impact in disease whether by standard cytotoxic drugs or by B-cell depletion assessmentin literature andon the their mutual potential influence blocking. between interferons, B cells and therapyantigens as and biologics. mediating However, the disease the heterogeneity [1, 2]. B cells among are targetedpatients Keywords: Systemic Lupus Erythematosus; B Cells; Neutrophils; in the clinical effects suggests the presence of underlying factors contributing to the development of B cells and their aberrant Cytokines and Inflammatory Mediators; Autoantigens and mechanisms such as plasmacytoid dendritic cells (pDCs), Toll- Autoantibodies Abbreviations likebehaviour receptors [3, (TLRs),4]. Research interferons has focused (IFNs), onneutrophils the role ofand innate gene SLE: Systemic Lupus Erythematosus; pDCs: Plasmacytoid Dendritic Cells ; TLRs: Toll-Like Receptors; IFNs: Interferons; mutationsIFNs are in thea biginitiation family and composed perpetuation of type-I of the diseasethat includes [5-7]. BAFF: APRIL: Ligand; PBMCs: PB: Plasma blast; PCs:B-Cell Plasma Activating Cells; Factor; CSR: Class ASwitch Proliferation-Induced Recombination; importantly IFN-α/β and type-II that includes IFN-γ [8]. IFN- Ig: Immunoglobulins;Peripheral BM: Blood Mononuclear Cells;IL: Interleukin; defenselike molecules mechanism have alsoagainst been viral described and bacterial as type-III infection. IFN, (IFN-λ1, They BCR: B Cell Receptor; mAb: SHM: areλ2, andsecreted λ3) [9].IFNs in response play ato physiologically activation of pathogenimportant recognition role in the AICDA: Bone Marrow; Deaminase; TNF-α: Monoclonal Antibodies;MyD88: mimicked antiviral response is appreciated in SLE in which IFNs DifferentiationSomatic Hyper PrimaryMutation; Response 88;Activation-Induced IFNAR: Cytidine receptors on the antigen presenting cells [10].A persistent Receptor; WT: WildTumor Type; NecrosisTH: T Helper; Factor-α IFNR: ; IFN Receptors; Myeloid Ab: ODN: Oligo Deoxy Nucleotides; NK: Interferon Natural Killer;Alpha drive autoimmune reactions [11]. IFNs expression and signature, NETs: Neutrophil Extracellular Traps; MZ: TACI: mainly type-I and -II, have been confirmed in SLE and also linked Antibody; haveto disease grasped activity attention in some as studies newly [12-14]. discovered IFN blocking partners therapies in SLE Ligand Interactor; LDGs: Low-Density Granulocytes; Marginal Zone; G-CSF: have demonstrated evidence of efficacy [15]. Of note, neutrophils Transmembrane Activator and Calcium Modulator and Cyclophilin pathogenesis via synthesizing IFNs and other pro-inflammatory Symbiosis Group *Corresponding author email: [email protected] Interferons, B Cells and Neutrophils: Innate and Adaptive Allies in Systemic Lu- Copyright: pus Erythematosus © 2018 Mohamed AAA, et al. IFNs also enhance the production of immunoglobulin’s. In review sheds the light on the interplay between IFNs, B cells mice models, it was shown that TLR ligand that result in type-I andcytokines neutrophils and enhancing for better autoantibodies elucidation ofproduction the comprehensive [16]. This IFN production cause T cell-independent antibody response. This interaction between them. response was associated with high titers of all IgG subclasses Interferons Enhance B cell Development and response is preserved with type-I IFN priming indicating that Immune Repertory type-I[29, 30]. IFN Moreover, induces long-term it was noticed antibody that production the secondary and memoryimmune Interferons protect B cells at various stages of development. One mechanism is through inducing the secretion of growth function [30]. On the other hand, lack of type-I IFN was associated atwith the absenceend of culture of IgG’s where in aspDCs-depleted virus-triggered human pDCs inducedPBMCs Bafter cell donorsfactors, orB-cell patients activating treated withfactor IFNs (BAFF) showed and that A uponproliferation- exposure culturing with live influenza virus despite the presence of B cells induced ligand (APRIL). In vitro and in vivo studies on healthy differentiationInterferons into Improve PCs[31]. Proficiency of Autoimmune to IFNs, BAFF and APRIL are up regulated in peripheral blood B Cells mononuclear cells (PBMCs), granulocytes and other cell types [17- IFNs not only affect the development of B cells but also affect stage20]. In in BAFF the transgenicperipheral micedevelopment; model, excess they BAFF mature acts and as acolonize rescuer to auto-reactive B cells that are normally deleted at the late T2 threshold of stimulation of B cell receptor (BCR) and induces the at the marginal zone are found to be rescued and repopulate on B cell functions as summarized in Table 1. Type-I IFN lowers the the splenic follicles. Also, auto-reactive B cells normally deleted the antigen presenting capacity of B cells as shown in splenic expression of MHC-II, CD69, CD86 and CD25, thus potentiating inexcess the class BAFF switch [21].BAFF recombination also enhances (CSR) plasma of immunoglobulin’s blast (PB) survival (Ig) the concentration and duration needed by anti-µ monoclonal and differentiation to plasma cells (PCs) [22]. BAFF/APRIL assist and BM B cells of the murine models. Additionally, it reduces the growth factors co-receptor, heparan sulphate, on murine from C (µ) to C (γ) and /or C (α)[18]. IFN type-I also up regulates antibodies (mAb) to produce maximum BCR internalization role in B cell immune response since its removal abrogates probably via enhancing calcium influx following BCR stimulation splenic B cells. Heparan sulphate is thought to play a significant [32]. (Table 1) The influence of type-I IFNs encompasses the TLRs of antibodyNoticeably, production the effect in response of IFNs to also APRIL involves [23]. stages of B cell ‘naive B cells increases the antigen presenting capacity. This B cells. CpG-mediated TLR-9 activation of healthy donors development in bone marrow (BM). In SLE BM, transitional B results in IgM secretion with CSR and somatic hyper mutation cells, particularly T2, are shown to be significantly higher in IFN- the(SHM), differentiation via activation-induced of CpG-activated cytidine naïve deaminase B cells into (AICDA) memory up high SLE BM as compared to IFN-low SLE BM and healthy controls, regulation, and ultimately IgG production [33]. It also induces which could be attributed to the high expression of BAFF induced by IFN-α in BM[24, 25].Furthermore, the memory fraction in BM cells and increases the production of IL-1β, IL-10, IL-6 and tumor showed significant reduction in the un switched memory CD27/ necrosis factor-α (TNF-α) and myeloid differentiation primary Ig D+ and expansion of the switched CD27/IgD- memory B cells response 88 (MyD88) expression with further enhancement of In this context, pristane treated interferon alpha receptor within SLE a high-IFNparallel response BM. This in was the linked memory to more B cells autoantibodies in the peripheral and CpG function [34]. chemokine expression in the high-IFN BM and was associated complexes compared with pristane-treated wild type (WT) with (IFNAR) 2 -/- mice failed to produce IgG antibodies against immune bloodContrarily, [24]. IFN type-I showed a selective inhibition of interleukin (IL)-7 dependent growths and proliferation of pre-B cell lines
Load more

Recommended publications
  • BAFF-Neutralizing Interaction of Belimumab Related to Its Therapeutic Efficacy for Treating Systemic Lupus Erythematosus
    ARTICLE DOI: 10.1038/s41467-018-03620-2 OPEN BAFF-neutralizing interaction of belimumab related to its therapeutic efficacy for treating systemic lupus erythematosus Woori Shin1, Hyun Tae Lee1, Heejin Lim1, Sang Hyung Lee1, Ji Young Son1, Jee Un Lee1, Ki-Young Yoo1, Seong Eon Ryu2, Jaejun Rhie1, Ju Yeon Lee1 & Yong-Seok Heo1 1234567890():,; BAFF, a member of the TNF superfamily, has been recognized as a good target for auto- immune diseases. Belimumab, an anti-BAFF monoclonal antibody, was approved by the FDA for use in treating systemic lupus erythematosus. However, the molecular basis of BAFF neutralization by belimumab remains unclear. Here our crystal structure of the BAFF–belimumab Fab complex shows the precise epitope and the BAFF-neutralizing mechanism of belimumab, and demonstrates that the therapeutic activity of belimumab involves not only antagonizing the BAFF–receptor interaction, but also disrupting the for- mation of the more active BAFF 60-mer to favor the induction of the less active BAFF trimer through interaction with the flap region of BAFF. In addition, the belimumab HCDR3 loop mimics the DxL(V/L) motif of BAFF receptors, thereby binding to BAFF in a similar manner as endogenous BAFF receptors. Our data thus provides insights for the design of new drugs targeting BAFF for the treatment of autoimmune diseases. 1 Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea. 2 Department of Bio Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea. These authors contributed equally: Woori Shin, Hyun Tae Lee, Heejin Lim, Sang Hyung Lee.
    [Show full text]
  • Correlation of Cytokine Level with the Severity of Severe Fever With
    Liu et al. Virology Journal (2017) 14:6 DOI 10.1186/s12985-016-0677-1 RESEARCH Open Access Correlation of cytokine level with the severity of severe fever with thrombocytopenia syndrome Miao-Miao Liu1, Xiao-Ying Lei1, Hao Yu2, Jian-zhi Zhang3 and Xue-jie Yu1,4* Abstract Background: Severe fever with thrombocytopenia syndrome (SFTS) was an emerging hemorrhagic fever that was caused by a tick-borne bunyavirus, SFTSV. Although SFTSV nonstructural protein can inhibit type I interferon (IFN-I) production Ex Vivo and IFN-I played key role in resistance SFTSV infection in animal model, the role of IFN-I in patients is not investigated. Methods: We have assayed the concentration of IFN-α, a subtype of IFN-I as well as other cytokines in the sera of SFTS patients and the healthy population with CBA (Cytometric bead array) assay. Results: The results showed that IFN-α, tumor necrosis factor (TNF-α), granulocyte colony-stimulating factor (G-CSF), interferon-γ (IFN-γ), macrophage inflammatory protein (MIP-1α), interleukin-6 (IL-6), IL-10, interferon-inducible protein (IP-10), monocyte chemoattractant protein (MCP-1) were significantly higher in SFTS patients than in healthy persons (p < 0.05); the concentrations of IFN-α, IFN-γ, G-CSF, MIP-1α, IL-6, and IP-10 were significant higher in severe SFTS patients than in mild SFTS patients (p < 0.05). Conclusion: The concentration of IFN-α as well as other cytokines (IFN-γ, G-CSF, MIP-1α, IL-6, and IP-10) is correlated with the severity of SFTS, suggesting that type I interferon may not be significant in resistance SFTSV infection in humans and it may play an import role in cytokine storm.
    [Show full text]
  • Primary Sjogren Syndrome: Focus on Innate Immune Cells and Inflammation
    Review Primary Sjogren Syndrome: Focus on Innate Immune Cells and Inflammation Chiara Rizzo 1, Giulia Grasso 1, Giulia Maria Destro Castaniti 1, Francesco Ciccia 2 and Giuliana Guggino 1,* 1 Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Rheumatology Section, University of Palermo, Piazza delle Cliniche 2, 90110 Palermo, Italy; [email protected] (C.R.); [email protected] (G.G.); [email protected] (G.M.D.C.) 2 Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio 7, 80138 Naples, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-091-6552260 Received: 30 April 2020; Accepted: 29 May 2020; Published: 3 June 2020 Abstract: Primary Sjogren Syndrome (pSS) is a complex, multifactorial rheumatic disease that mainly targets salivary and lacrimal glands, inducing epithelitis. The cause behind the autoimmunity outbreak in pSS is still elusive; however, it seems related to an aberrant reaction to exogenous triggers such as viruses, combined with individual genetic pre-disposition. For a long time, autoantibodies were considered as the hallmarks of this disease; however, more recently the complex interplay between innate and adaptive immunity as well as the consequent inflammatory process have emerged as the main mechanisms of pSS pathogenesis. The present review will focus on innate cells and on the principal mechanisms of inflammation connected. In the first part, an overview of innate cells involved in pSS pathogenesis is provided, stressing in particular the role of Innate Lymphoid Cells (ILCs). Subsequently we have highlighted the main inflammatory pathways, including intra- and extra-cellular players.
    [Show full text]
  • Interactions Between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Auto-Immune Diseases
    Type 1 interferons and the Th17 response in TB 1 http://hdl.handle.net/1765/106444 Interactions between type 1 interferons and the Th17 response in tuberculosis: Lessons learned from auto-immune diseases Bas C. Mourik1, Erik Lubberts2, Jurriaan E.M. de Steenwinkel1, Tom H.M. Ottenhoff3, Pieter J.M. Leenen4* 1Dept.Interactions of Medical Microbiology & between Infectious Diseases, Erasmus type MC, Rotterdam,1 interferons the Netherlands 2Dept.and of Rheumatology, the Th17 Erasmus MC, response Rotterdam, the Netherlands in tuberculosis: 3Dept.2 of Immunology, Erasmus MC, Rotterdam, the Netherlands Lessons learned from auto-immune 4Dept. of Infectious Diseases, LUMC, Leiden, the Netherlands Publisheddiseases in Frontiers in Immunology 2017 Apr 5;8:294. doi: 10.3389/fimmu.2017.00294. eCollection 2017 Bas C. Mourik1, Erik Lubberts2, Jurriaan E.M. de Steenwinkel1, Tom H.M. Ottenhoff3, Pieter J.M. Leenen4* 1Dept. of Medical Microbiology & Infectious Diseases, Erasmus MC, Rotterdam, the Netherlands 2Dept. of Rheumatology, Erasmus MC, Rotterdam, the Netherlands 3Dept. of Immunology, Erasmus MC, Rotterdam, the Netherlands 4Dept. of Infectious Diseases, LUMC, Leiden, the Netherlands Published in Frontiers in Immunology 2017 Apr 5;8:294. doi: 10.3389/fimmu.2017.00294. eCollection 2017 2 Erasmus Medical Center Rotterdam ABSTRACT The classical paradigm of TB immunity, with a central protective role for Th1 responses and IFN-γ-stimulated cellular responses, has been challenged by unsatisfactory results of vaccine strategies aimed at enhancing Th1 immunity. Moreover, preclinical TB models have shown that increasing IFN-γ responses in the lungs is more damaging to the host than to the pathogen. Type 1 interferon signaling and altered Th17 responses have also been associated with active TB, but their functional roles in TB pathogenesis remain to be established.
    [Show full text]
  • Interferon Type I Responses in Primary and Secondary Infections
    Immunology and Cell Biology (2008) 86, 239–245 & 2008 Australasian Society for Immunology Inc. All rights reserved 0818-9641/08 $30.00 www.nature.com/icb REVIEW Interferon type I responses in primary and secondary infections Mohammed Alsharifi, Arno Mu¨llbacher and Matthias Regner The mammalian host responds to a microbial infection with a rapid innate immune reaction that is dominated by type I interferon (IFN-I) release. Most cells of vertebrates can respond to microbial attack with IFN-I production, but the cell type responsible for most of the systemic IFN-I release is thought to be plasmacytoid dendritic cells (pDCs). Besides its anti- microbial and especially anti-viral properties IFN-I also exerts a regulatory role on many facets of the sequential adaptive immune response. One of these is being the recently described partial, systemic activation of the vast majority of B and T lymphocytes in mice, irrespective of antigen reactivity. The biological significance of this partial activation of lymphocytes is at present speculative. Secondary infections occurring within a short time span of a primary infection fail to elicit a similar lymphocyte activation response due to a refractory period in systemic IFN-I production. This period of exhaustion in IFN-I responses is associated with an increased susceptibility of the host to secondary infections. The latter correlates with well- established clinical observations of heightened susceptibility of patients to secondary microbial infections after viral episodes. Immunology and Cell Biology (2008) 86, 239–245; doi:10.1038/sj.icb.7100159; published online 8 January 2008 Keywords: type I interferon; immunoregulation; viral infections Control of viral infections by the vertebrate host involves both the fibroblast (b) and immune (g).2,3 The currently accepted classification innate and the adaptive immune response.
    [Show full text]
  • Study Protocol
    PROTOCOL SYNOPSIS A Multicentre, Randomised, Double-blind, Placebo-controlled, Phase 3 Study Evaluating the Efficacy and Safety of Two Doses of Anifrolumab in Adult Subjects with Active Systemic Lupus Erythematosus International Coordinating Investigator Study site(s) and number of subjects planned Approximately 450 subjects are planned at approximately 173 sites. Study period Phase of development Estimated date of first subject enrolled Q2 2015 3 Estimated date of last subject completed Q2 2018 Study design This is a Phase 3, multicentre, multinational, randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of an intravenous treatment regimen of anifrolumab (150 mg or 300 mg) versus placebo in subjects with moderately to severely active, autoantibody-positive systemic lupus erythematosus (SLE) while receiving standard of care (SOC) treatment. The study will be performed in adult subjects aged 18 to 70 years of age. Approximately 450 subjects receiving SOC treatment will be randomised in a 1:2:2 ratio to receive a fixed intravenous dose of 150 mg anifrolumab, 300 mg anifrolumab, or placebo every 4 weeks (Q4W) for a total of 13 doses (Week 0 to Week 48), with the primary endpoint evaluated at the Week 52 visit. Investigational product will be administered as an intravenous (IV) infusion via an infusion pump over a minimum of 30 minutes, Q4W. Subjects must be taking either 1 or any combination of the following: oral corticosteroids (OCS), antimalarial, and/or immunosuppressants. Randomisation will be stratified using the following factors: SLE Disease Activity Index 2000 (SLEDAI-2K) score at screening (<10 points versus ≥10 points); Week 0 (Day 1) OCS dose 2(125) Revised Clinical Study Protocol Drug Substance Anifrolumab (MEDI-546) Study Code D3461C00005 Edition Number 5 Date 18 May 2016 (<10 mg/day versus ≥10 mg/day prednisone or equivalent); and results of a type 1 interferon (IFN) test (high versus low).
    [Show full text]
  • Rheumatology and CTD
    Section 16 Section Editor: G Narsimulu Rheumatology and CTD 206. Refractory Rheumatoid Arthritis 214. Treatment of SLE beyond Steroids Rohini Handa Rathindra Nath Sarkar, Rudrajit Paul 207. Difficulties in Rheumatoid Arthritis 215. Gout Is the Only Enemy That I Do Not Rajan Kumar Wish to Have at My Feet Anjana Pandey, Ajay Maurya, PK Maheshwari 208. Monoarthritis—A Clinical Dilemma to Internists Arup Kumar Kundu, Abhishek Kundu 216. Liver Dysfunction and NAFLD in RA: 209. Oral Targeted Treatments in RA—Update 2021 Is MTX Really a Culprit? Ramakrishna Rao Uppuluri, Sripurna Deepti Challa Kartik Nikhil Balankhe, Rishabh Ramu Nayak, Pulin Kumar Gupta 210. Biosimilars: Bane or Boon for India 217. Sexual Dysfunction in Rheumatic Diseases Durga Prasanna Misra, Pallavi Patro, Vikas Agarwal Vinod Ravindran 211. An Approach to Vasculitis 218. Interpretation of Common Investigations Packiamary Jerome in Rheumatology 212. How to Manage DMARDs Failure in RA? Renu Saigal, Amit Kansal, Vikram Raj Jain N Subramanian 213. IgG4-related Disease Harpreet Singh, Somdatta Giri, Anju Arya MU-206 (Sec-16).indd 1321 29-01-2021 15:25:29 MU-206 (Sec-16).indd 1322 29-01-2021 15:25:30 CHAPTER 206 Refractory Rheumatoid Arthritis Rohini Handa Abstract A sizeable number of patients with rheumatoid arthritis (RA) are unable to attain low disease activity or remission despite treatment. These difficult to treat (D2T) patients are labeled as refractory RA. The troika of D2T RA, as outlined by the European League against Rheumatism, comprises of treatment failure history, presence of active/symptomatic disease, and clinical perception. The approach to refractory RA is evolving.
    [Show full text]
  • Antagonist Antibodies Against Various Forms of BAFF: Trimer, 60-Mer, and Membrane-Bound S
    Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2016/07/19/jpet.116.236075.DC1 1521-0103/359/1/37–44$25.00 http://dx.doi.org/10.1124/jpet.116.236075 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 359:37–44, October 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics Unexpected Potency Differences between B-Cell–Activating Factor (BAFF) Antagonist Antibodies against Various Forms of BAFF: Trimer, 60-Mer, and Membrane-Bound s Amy M. Nicoletti, Cynthia Hess Kenny, Ashraf M. Khalil, Qi Pan, Kerry L. M. Ralph, Julie Ritchie, Sathyadevi Venkataramani, David H. Presky, Scott M. DeWire, and Scott R. Brodeur Immune Modulation and Biotherapeutics Discovery, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut Received June 20, 2016; accepted July 18, 2016 Downloaded from ABSTRACT Therapeutic agents antagonizing B-cell–activating factor/B- human B-cell proliferation assay and in nuclear factor kB reporter lymphocyte stimulator (BAFF/BLyS) are currently in clinical assay systems in Chinese hamster ovary cells expressing BAFF development for autoimmune diseases; belimumab is the first receptors and transmembrane activator and calcium-modulator Food and Drug Administration–approved drug in more than and cyclophilin ligand interactor (TACI). In contrast to the mouse jpet.aspetjournals.org 50 years for the treatment of lupus. As a member of the tumor system, we find that BAFF trimer activates the human TACI necrosis factor superfamily, BAFF promotes B-cell survival and receptor. Further, we profiled the activities of two clinically ad- homeostasis and is overexpressed in patients with systemic vanced BAFF antagonist antibodies, belimumab and tabalumab.
    [Show full text]
  • 1 the BAFF/APRIL System in SLE Pathogenesis. Fabien B Vincent1
    . Fabien B Vincent1, Eric F Morand2, Pascal Schneider3 and Fabienne Mackay1 1 Department of Immunology, Monash University, Central Clinical School, Alfred Medical Research and Education Precinct (AMREP), 89 Commercial Road, Melbourne, Victoria 3004, Australia 2 Monash University Centre for Inflammatory Diseases, Southern Clinical School, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria, 3168, Australia 3 Department of Biochemistry, University of Lausanne, Boveresses 155, 1066 Epalinges, Switzerland Abstract Systemic lupus erythematosus (SLE) is characterized by multisystem immune-mediated injury in the setting of autoimmunity to nuclear antigens. The clinical heterogeneity of SLE, the absence of universally agreed clinical trial end points, and the paucity of validated therapeutic targets have, historically, contributed to a lack of novel treatments for SLE. However, in 2011, a therapeutic monoclonal antibody that neutralizes the cytokine TNF ligand superfamily member 13B (also known as B-cell-activating factor of the TNF family [BAFF]), belimumab, became the first targeted therapy for SLE to have efficacy in a randomized clinical trial. Because of its specificity, the efficacy of belimumab provides an opportunity to increase understanding of SLE pathophysiology. Although belimumab depletes B cells, this effect is not as powerful as that of other B-cell-directed therapies that have not been proven efficacious in randomized clinical trials. In this article, therefore, we review results suggesting that neutralizing BAFF can have effects on the immune system other than depletion of B cells. We also identify aspects of the BAFF system for which data in relation to SLE are still missing, and we suggest studies to investigate the pathogenesis of SLE and ways to refine anti-BAFF therapies.
    [Show full text]
  • Multiple Regulatory Regions on the 5' Side of the Mouse Ea Gene
    Proc. Nad. Acad. Sci. USA Vol. 85, pp. 3075-3079, May 1988 Immunology Multiple regulatory regions on the 5' side of the mouse Ea gene (major histocompatibility genes/y-interferon/y-interferon response region) DIMITRIS THANOS*, GEORGE MAVROTHALASSITIS*, AND JOSEPH PAPAMATHEAKIS*t *Institute of Molecular Biology and Biotechnology, Research Center of Crete, P.O. Box 1527, and tDepartment of Biology, University of Crete, 711 10 Heraklion, Crete, Greece Communicated by Fotis C. Kafatos, December 10, 1987 ABSTRACT The function of the 5'-flanking region of the motifs in the 5'-flanking region of all major histocompatibil- mouse major histocompatibility complex gene E4 has been ity complex class II genes (15, 16). We provide evidence that studied by deletion analysis with the chloramphenicol acetyl- the CS are elements necessary for the inducibility by IFN-y. transferase gene as a transient expression marker in various cell lines. This analysis reveals the presence of several control regions on the 5' side of the gene. Sequences between base pair MATERIALS AND METHODS (bp) -873 and bp -353 have a negative function in human Plasmid Constructions. The following vectors were used and mouse fibroblasts but not in the mouse macrophage line for cloning Ea and E1n gene fragments. pL51CAT was derived WEHI-3. Additional positive and negative elements have been from pSV2CAT (17) by replacing the 350-base-pair (bp) Acc mapped between bp - 353 and bp - 38. A V-interferon I-Sph I fragment by a pUC19 polylinker. pLSVOCAT was response region has been also identified within that sequence. derived from pL51CAT by elimination of the 150-bp Sma I The 5' and 3' boundaries of the -interferon response region (polylinker)-HindIII fragment.
    [Show full text]
  • The Future of B-Cell Activating Factor Antagonists in the Treatment of Systemic Lupus Erythematosus
    pISSN: 2093-940X, eISSN: 2233-4718 Journal of Rheumatic Diseases Vol. 24, No. 2, April, 2017 https://doi.org/10.4078/jrd.2017.24.2.65 Review Article The Future of B-cell Activating Factor Antagonists in the Treatment of Systemic Lupus Erythematosus William Stohl Division of Rheumatology, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA To review B-cell activating factor (BAFF)-antagonist therapy in systemic lupus erythematosus (SLE), literature was searched us- ing the search words and phrases, “BAFF”, “B lymphocyte stimulator (BLyS)”, “a proliferation-inducing ligand (APRIL)”, “B-cell maturation antigen (BCMA)”, “transmembrane activator and calcium-modulating and cyclophilin ligand interactor (TACI)”, “BLyS receptor 3 (BR3)”, “belimumab”, “atacicept”, “blisibimod”, “tabalumab”, and “lupus clinical trial”. In addition, papers from the author’s personal library were searched. BAFF-antagonist therapy in SLE has a checkered past, with four late-stage clin- ical trials meeting their primary endpoints and four failing to do so. Additional late-stage clinical trials are enrolling subjects to address some of the remaining unresolved questions, and novel approaches are proposed to improve results. The BAFF-centric pathway is a proven therapeutic target in SLE. As the only pathway in the past 50+ years to have yielded an United States Food and Drug Administration-approved drug for SLE, it occupies a unique place in the armamentarium of the practicing rheumatologist. The challenges facing clinicians and investigators are how to better tweak the BAFF-centric pathway and im- prove on the successes realized. (J Rheum Dis 2017;24:65-73) Key Words.
    [Show full text]
  • Therapeutics Advisory Group
    Therapeutics Advisory Group CCG and NHS Trusts in Norfolk and Waveney Index of TAG recommendations Generic name Indication BNFclass Trafficlight IQoro euromuscular training Hiatus hernia - improving symptoms No BNF entry - device Double Red Not recommended for device routine use / Not commissioned (L-) Carnitine Carnitine Deficiency 9.8.1 Drugs used in Red Hospital / Specialist metabolic disorders only (Para-)aminosalicylic acid Tuberculosis 5.1.9 Antituberculosis Double Red Not recommended for drugs - routine use / Not Antimycobacterials commissioned 5-fluorouracil + salicyclic acid Hyperkeratotic actinic keratosis 13.8.1 Photodamage Double-GreenSuitable for GPs to topical solution initiate and prescribe 5-fluorouracil 5% w/w cream Non-hypertrophic actinic keratosis 13.8.1 Photodamage Double-GreenSuitable for GPs to initiate and prescribe Abacavir HIV infection in combination with other 5.3.1 HIV Infection Red Hospital / Specialist antiretroviral drugs only Abacavir + dolutegravir + HIV infection in combination with other 5.3.1 HIV Infection Red Hospital / Specialist lamivudine antiretroviral drugs only Abacavir and lamivudine HIV infection in combination with other 5.3.1 HIV Infection Red Hospital / Specialist antiretroviral drugs only Abaloparatide Male and juvenile osteoporosis 6.6.1 Calcitonin and Double Red Not recommended for Calcitonin and routine use / Not parathyroid hormone commissioned Abatacept Rheumatoid arthritis - 1st line biologic 10.1.3 Drugs that suppress Red Hospital / Specialist after failure of non-biologic DMARDs
    [Show full text]