DOCSLIB.ORG

Antagonist Antibodies Against Various Forms of BAFF: Trimer, 60-Mer, and Membrane-Bound S

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read 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. lupus erythematosus and other autoimmune diseases. BAFF Unexpectedly, we revealed differences in inhibitory potencies exists in three recognized forms: membrane-bound and two against the various BAFF forms, in particular that belimumab secreted, soluble forms of either trimeric or 60-mer oligomeric does not potently inhibit BAFF 60-mer. Through this increased states. To date, most in vitro pharmacology studies of BAFF understanding of the activity of BAFF antagonists against at ASPET Journals on September 26, 2021 neglect one or more of these forms. Here, we report a different forms of BAFF, we hope to influence the discovery of comprehensive in vitro cell-based analysis of BAFF in assay BAFF antagonist antibodies with distinct therapeutic mecha- systems that measure all forms of BAFF-mediated activation. We nisms for improvement in the treatment of lupus or other related demonstrate the effects of these BAFF forms in both a primary autoimmune pathologies. Introduction factor (TNF) SF13B provided clinical benefit in SLE, resulting in Food and Drug Administration (FDA) approval of the selective Systemic lupus erythematosus (SLE) is a chronic multisys- BAFF antagonist, belimumab (Benlysta) (Furie et al., 2011; Liu tem autoimmune disease characterized by the generation of and Davidson, 2011; Navarra et al., 2011). autoantibodies directed against a variety of self-antigens BAFF is a highly conserved member of the TNF superfamily (Tsokos, 2011). These autoantibodies form pathogenic im- of cytokines, primarily expressed by innate immune cells mune complexes that deposit into organs, ultimately inducing including monocytes, macrophages, dendritic cells, and other inflammation and tissue damage (Cancro et al., 2009; Sang nonhematopoetic cells (Shu et al., 1999; Tribouley et al., 1999; et al., 2014). Many of the current therapeutic options for the Nardelli et al., 2001). Early reports on BAFF function in- treatment of SLE include antimalarial agents, nonsteroidal anti-inflammatory drugs, glucocorticoids, and immunosup- dicated a potential critical role for determining B-cell fate and pressive drugs, which all seek to reduce the autoimmune the establishment of tolerance (Moore et al., 1999). The inflammatory process but also can result in general immuno- physiologic activity of BAFF is reportedly mediated by suppression and toxicity (Tsokos, 2011). Opportunities for new signaling via three receptors: B-cell activating factor receptor therapies exist among patients with the most severe disease (BAFFR), transmembrane activator and calcium-modulator as well as for steroid-sparing treatments. In recent years, and cyclophilin ligand interactor (TACI), and, in some reports, inhibition of the cytokine B-cell–activating factor [BAFF, also B-cell maturation antigen (BCMA). These three receptors are known as B-lymphocyte stimulator (BLyS)], tumor necrosis primarily expressed on B cells at different developmental stages (Gross et al., 2000; Marsters et al., 2000; Wu et al., dx.doi.org/10.1124/jpet.116.236075. 2000; Thompson et al., 2001; Yan et al., 2001; Karpusas s This article has supplemental material available at jpet.aspetjournals.org. et al., 2002; Liu et al., 2003; Bossen and Schneider, 2006). In ABBREVIATIONS: BAFF, B-cell–activating factor; BAFFR, B-cell–activating factor receptor; BCMA, B-cell maturation antigen; belim-comp, belimumab-comparator; BLyS, B-lymphocyte stimulator; CHO, Chinese hamster ovary; FDA, Food and Drug Administration; NF, nuclear factor; SLE, systemic lupus erythematosus; tabal-comp, tabalumab-comparator; TACI, transmembrane activator and calcium-modulator and cyclophilin ligand interactor; TEV, tobacco etch virus; TNF, tumor necrosis factor. 37 38 Nicoletti et al. humans, BAFFR is widely expressed by all B cells, with the distinct oligomeric states remain unclear, and in vitro phar- exception of bone marrow plasma cells, and BAFF-BAFFR macology assays often neglect one of these forms. interactions have been proven critical to maintenance of We sought to characterize and compare the activities of primary B cells (Oren et al., 2002; Ng et al., 2004). BAFFR membrane-bound and secreted, soluble BAFF forms with selectively recruits TNF receptor–associated factor 3, leading trimer and 60-mer oligomeric states in a set of in vitro, cell- to downstream signaling cascades that can modulate B-cell based assay systems. Further,weprofiletwomonoclonal survival and differentiation, including activation of the nu- antibodies generated based on the published sequences of clear factor kB (NFkB) pathway (Mukhopadhyay et al., 1999; belimumab and tabalumab for their inhibitory capacity Claudio et al., 2002; Hatada et al., 2003; Bossen and against these various BAFF forms. Interestingly, we find Schneider, 2006; Mackay and Schneider, 2009). Transgenic significantly differing potencies at inhibiting the various mice that overexpress BAFF display phenotypic characteris- membrane and soluble forms of BAFF. Results reported here tics that closely mimic those observed in SLE and Sjögren’s provide insight on the biologic activity of membrane-bound syndrome, including increased numbers of anti-DNA anti- and soluble, secreted BAFF as well as the pharmacologic bodies, B-cell expansion, proteinuria, and glomerulonephritis mechanisms of BAFF antagonists. A better pharmacologic (Mackay et al., 1999; Yan et al., 2001; Groom et al., 2002). In understanding of the inhibitory capability of BAFF antago- humans, serum levels of BAFF are significantly elevated in nists against all forms of BAFF has the potential to impact patients with SLE, Sjögren’s syndrome, and rheumatoid the therapeutic success of these antibodies in the treatment arthritis compared with healthy controls (Cheema et al., of lupus and related pathologies. Downloaded from 2001; Mariette et al., 2003; Tan et al., 2003). In humans, BAFF exists in both a membrane-bound form (of 285 amino acids) and two soluble forms (Moore et al., 1999; Materials and Methods Schneider et al., 1999; Thompson et al., 2001). Soluble BAFF Antibodies. Amino acid sequence for the belimumab-comparator exists predominantly as a trimer or 60-mer (Liu et al., (belim-comp) antibody was derived from patent US20110293610 2002; Cachero et al., 2006); however, the oligomeric state of (Ruben et al., 2011). Belim-comp was produced on a human IgG1 jpet.aspetjournals.org soluble BAFF in vivo has been the subject of debate. Both wild-type framework with a l light chain to conform to the FDA- soluble and membrane-bound forms of BAFF are biologically approved molecule (Baker et al., 2003). Belimumab was also pur- active (Schneider et al., 1999; Liu et al., 2002; Liu et al., chased as the marketed product (GlaxoSmithKline, London, UK) and 2003; Zhukovsky et al., 2004), and data from transgenic mice showed identical inhibitory potency to the inhouse produced material indicate a role for soluble BAFF in homeostasis; membrane- in the Chinese hamster ovary (CHO)-BAFFR assay (data not shown). Amino acid sequence for the tabalumab-comparator (tabal-comp) bound BAFF plays an accessory role (Bossen et al., 2011). antibody was derived from World Health Organization INN publi- at ASPET Journals on September 26, 2021 Binding affinities of BAFF for BAFFR, TACI, and BCMA have cation vol. 25 (WHO, 2011). Tabal-comp was produced on a human been previously described (Wu et al., 2000; Yu et al., 2000; IgG4-Pro (S228P) framework with a k light chain to conform to the Bossen and Schneider, 2006), although the subsequent down- clinical-stage molecule (Manetta et al., 2014). Each antibody was stream signaling properties of the various BAFF forms have cloned in pTT5-Neo, expressed in CHO-E cells, and purified by not been well studied. The clinical consequences of blocking
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]
  • CD40L TNF-Related Factors BAFF, APRIL, and Lymphocytic Leukemia
    Published May 16, 2012, doi:10.4049/jimmunol.1102066 The Journal of Immunology Stromal Endothelial Cells Establish a Bidirectional Crosstalk with Chronic Lymphocytic Leukemia Cells through the TNF-Related Factors BAFF, APRIL, and CD40L Montserrat Cols,* Carolina M. Barra,† Bing He,* Irene Puga,† Weifeng Xu,* April Chiu,‡ Wayne Tam,x Daniel M. Knowles,x Stacey R. Dillon,{ John P. Leonard,‖ Richard R. Furman,‖ Kang Chen,* and Andrea Cerutti*,†,# Chronic lymphocytic leukemia (CLL) is a clonal B cell disorder of unknown origin. Accessory signals from the microenvironment are critical for the survival, expansion, and progression of malignant B cells. We found that the CLL stroma included microvascular endothelial cells (MVECs) expressing BAFF and APRIL, two TNF family members related to the T cell-associated B cell-stimulating molecule CD40L. Constitutive release of soluble BAFF and APRIL increased upon engagement of CD40 on MVECs by CD40L aberrantly expressed on CLL cells. In addition to enhancing MVEC expression of CD40, leukemic CD40L induced cleavases that elicited intracellular processing of pro-BAFF and pro-APRIL proteins in MVECs. The resulting soluble BAFF and APRIL proteins delivered survival, activation, Ig gene remodeling, and differentiation signals by stimulating CLL cells through TACI, BAFF-R, and BCMA receptors. BAFF and APRIL further amplified CLL cell survival by upregulating the expression of leukemic CD40L. Inhibition of TACI, BCMA, and BAFF-R expression on CLL cells; abrogation of CD40 expression in MVECs; or suppression of BAFF and APRIL cleavases in MVECs reduced the survival and diversification of malignant B cells. These data indicate that BAFF, APRIL, and CD40L form a CLL-enhancing bidirectional signaling network linking neoplastic B cells with the microvascular stroma.
    [Show full text]
  • Tabalumab for Systemic Lupus Erythematosus
    Horizon Scanning Centre May 2014 Tabalumab for systemic lupus erythematosus SUMMARY NIHR HSC ID: 5581 Tabalumab (LY-2127399) is intended to be used as second line therapy for the treatment of systemic lupus erythematosus (SLE). If licensed, it would offer an additional treatment option for patients who have active moderate to severe SLE despite treatment with glucocorticoids, anti-malarials, and/or immunosuppressants; a group who currently have few effective therapies This briefing is available. Tabalumab is a human anti-B-cell activating factor (BAFF or B based on lymphocyte stimulator [BLyS]) monoclonal antibody. It is administered information subcutaneously, in contrast to the only existing licensed BAFF antagonist, which is administered via IV infusion. available at the time of research and a The annual incidence of SLE in the UK is between 3 and 4 cases per limited literature 100,000 population, which equates to approximately 1,600 and 2,100 new search. It is not cases in England per year. The estimated prevalence of SLE is 25-28 per intended to be a 100,000 population, commensurate with around 15,000 people in England definitive statement with the disease. SLE is associated with considerable morbidity and on the safety, mortality, with 10-year survival rates ranging from 70% to 92%. Around 40– efficacy or 70% of SLE patients develop renal involvement which confers a worse effectiveness of the prognosis for survival; and approximately 10% of patients with lupus nephritis health technology develop end-stage renal failure requiring dialysis or transplantation. covered and should Neuropsychiatric involvement occurs in 27% of people with SLE, and SLE is not be used for also characterised by haematological features and cardiovascular commercial complications.
    [Show full text]
  • RANKL As a Novel EMT Marker 858 Cell Research (2008) 18:858-870
    npg RANKL as a novel EMT marker 858 Cell Research (2008) 18:858-870. npg © 2008 IBCB, SIBS, CAS All rights reserved 1001-0602/08 $ 30.00 ORIGINAL ARTICLE www.nature.com/cr Receptor activator of NF-κB Ligand (RANKL) expression is associated with epithelial to mesenchymal transition in human prostate cancer cells Valerie A Odero-Marah1, Ruoxiang Wang1, Gina Chu1, Majd Zayzafoon2, Jianchun Xu1, Chunmeng Shi1, Fray F Marshall1, Haiyen E Zhau1, Leland WK Chung1 1Molecular Urology and Therapeutics Program, Department of Urology and Winship Cancer Institute, Emory University School of Medicine, 1365B Clifton Road, NE, Atlanta, GA 30322, USA; 2Department of Pathology, University of Alabamn, Birmingham, AL 35294, USA Epithelial-mesenchymal transition (EMT) in cancer describes the phenotypic and behavioral changes of cancer cells from indolent to virulent forms with increased migratory, invasive and metastatic potential. EMT can be induced by soluble proteins like transforming growth factor β1 (TGFβ1) and transcription factors including Snail and Slug. We uti- lized the ARCaPE/ARCaPM prostate cancer progression model and LNCaP clones stably overexpressing Snail to identify novel markers associated with EMT. Compared to ARCaPE cells, the highly tumorigenic mesenchymal ARCaPM and ARCaPM1 variant cells displayed a higher incidence of bone metastasis after intracardiac administration in SCID mice. ARCaPM and ARCaPM1 expressed mesenchymal stromal markers of vimentin and N-cadherin in addition to elevated levels of Receptor Activator of NF-κB Ligand (RANKL). We observed that both epidermal growth factor (EGF) plus TGFβ1 treatment and Snail overexpression induced EMT in ARCaPE and LNCaP cells, and EMT was associated with increased expression of RANKL protein.
    [Show full text]
  • CD137 Microbead Kit CD137 Microbead + Cells
    CD137 MicroBead Kit human Order no. 130-093-476 Contents 1.2 Background information 1. Description The activation-induced antigen CD137 (4-1BB) is a 30 kDa glycoprotein of the tumor necrosis factor (TNF) receptor 1.1 Principle of the MACS® Separation + + superfamily. It is mainly expressed on activated CD4 and CD8 1.2 Background information T cells, activated B cells, and natural killer cells, but can also be 1.3 Applications found on resting monocytes and dendritic cells. As a costimulatory molecule, CD137 is involved in the activation 1.4 Reagent and instrument requirements and survival of CD4, CD8, and NK cells. Its engagement enhances 2. Protocol expansion of T cells and activates them to secrete cytokines. CD137 has been described to be a suitable marker for antigen- 2.1 Sample preparation specific activation of human CD8+ T cells, as CD137 is not expressed 2.2 Magnetic labeling on resting CD8+ T cells and its expression is reliably induced after 2.3 Magnetic separation 24 hours of stimulation.¹,² 3. Example of a separation using the CD137 MicroBead Kit 1.3 Applications 4. References ● Enrichment of CD137+ T cells for phenotypical and functional 5. Appendix characterization. ● Enrichment of activated antigen-specific T cells after antigen- Warnings specific stimulation. Reagents contain sodium azide. Under acidic conditions sodium 1.4 Reagent and instrument requirements azide yields hydrazoic acid, which is extremely toxic. Azide ● compounds should be diluted with running water before discarding. Buffer: Prepare a solution containing phosphate-buffered These precautions are recommended to avoid deposits in plumbing saline (PBS), pH 7.2, 0.5% bovine serum albumin (BSA), where explosive conditions may develop.
    [Show full text]
  • Dimerization of Ltβr by Ltα1β2 Is Necessary and Sufficient for Signal
    Dimerization of LTβRbyLTα1β2 is necessary and sufficient for signal transduction Jawahar Sudhamsua,1, JianPing Yina,1, Eugene Y. Chiangb, Melissa A. Starovasnika, Jane L. Groganb,2, and Sarah G. Hymowitza,2 Departments of aStructural Biology and bImmunology, Genentech, Inc., South San Francisco, CA 94080 Edited by K. Christopher Garcia, Stanford University, Stanford, CA, and approved October 24, 2013 (received for review June 6, 2013) Homotrimeric TNF superfamily ligands signal by inducing trimers survival in a xenogeneic human T-cell–dependent mouse model of of their cognate receptors. As a biologically active heterotrimer, graft-versus-host disease (GVHD) (11). Lymphotoxin(LT)α1β2 is unique in the TNF superfamily. How the TNFRSF members are typically activated by TNFSF-induced three unique potential receptor-binding interfaces in LTα1β2 trig- trimerization or higher order oligomerization, resulting in initiation ger signaling via LTβ Receptor (LTβR) resulting in lymphoid organ- of intracellular signaling processes including the canonical and ogenesis and propagation of inflammatory signals is poorly noncanonical NF-κB pathways (2, 3). Ligand–receptor interactions α β understood. Here we show that LT 1 2 possesses two binding induce higher order assemblies formed between adaptor motifs in sites for LTβR with distinct affinities and that dimerization of LTβR the cytoplasmic regions of the receptors such as death domains or α β fi by LT 1 2 is necessary and suf cient for signal transduction. The TRAF-binding motifs and downstream signaling components such α β β crystal structure of a complex formed by LT 1 2,LT R, and the fab as Fas-associated protein with death domain (FADD), TNFR1- fragment of an antibody that blocks LTβR activation reveals the associated protein with death domain (TRADD), and TNFR-as- lower affinity receptor-binding site.
    [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]
  • The Unexpected Role of Lymphotoxin Β Receptor Signaling
    Oncogene (2010) 29, 5006–5018 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 www.nature.com/onc REVIEW The unexpected role of lymphotoxin b receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development MJ Wolf1, GM Seleznik1, N Zeller1,3 and M Heikenwalder1,2 1Department of Pathology, Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland and 2Institute of Virology, Technische Universita¨tMu¨nchen/Helmholtz Zentrum Mu¨nchen, Munich, Germany The cytokines lymphotoxin (LT) a, b and their receptor genesis. Consequently, the inflammatory microenviron- (LTbR) belong to the tumor necrosis factor (TNF) super- ment was added as the seventh hallmark of cancer family, whose founder—TNFa—was initially discovered (Hanahan and Weinberg, 2000; Colotta et al., 2009). due to its tumor necrotizing activity. LTbR signaling This was ultimately the result of more than 100 years of serves pleiotropic functions including the control of research—indeed—the first observation that tumors lymphoid organ development, support of efficient immune often arise at sites of inflammation was initially reported responses against pathogens due to maintenance of intact in the nineteenth century by Virchow (Balkwill and lymphoid structures, induction of tertiary lymphoid organs, Mantovani, 2001). Today, understanding the underlying liver regeneration or control of lipid homeostasis. Signal- mechanisms of why immune cells can be pro- or anti- ing through LTbR comprises the noncanonical/canonical carcinogenic in different types of tumors and which nuclear factor-jB (NF-jB) pathways thus inducing cellular and molecular inflammatory mediators (for chemokine, cytokine or adhesion molecule expression, cell example, macrophages, lymphocytes, chemokines or proliferation and cell survival.
    [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]
  • Cells Promote Survival and Differentiation of B Up-Regulated In
    Expression of the Adaptor Protein Hematopoietic Src Homology 2 is Up-Regulated in Response to Stimuli That Promote Survival and Differentiation of B This information is current as Cells of September 28, 2021. Brantley R. Herrin and Louis B. Justement J Immunol 2006; 176:4163-4172; ; doi: 10.4049/jimmunol.176.7.4163 http://www.jimmunol.org/content/176/7/4163 Downloaded from References This article cites 48 articles, 23 of which you can access for free at: http://www.jimmunol.org/content/176/7/4163.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 28, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Expression of the Adaptor Protein Hematopoietic Src Homology 2 is Up-Regulated in Response to Stimuli That Promote Survival and Differentiation of B Cells Brantley R. Herrin and Louis B. Justement1 Analysis of hematopoietic Src homology 2 (HSH2) protein expression in mouse immune cells demonstrated that it is expressed at low levels in resting B cells but not T cells or macrophages.
    [Show full text]
  • Circadian Phase-Specific Degradation of the F-Box Protein ZTL Is Mediated by the Proteasome
    Circadian phase-specific degradation of the F-box protein ZTL is mediated by the proteasome Woe-Yeon Kim*, Ruishuang Geng*, and David E. Somers† Department of Plant Biology͞Plant Biotechnology Center, Ohio State University, Columbus, OH 43210 Edited by Maarten J. Chrispeels, University of California at San Diego, La Jolla, CA, and approved February 3, 2003 (received for review November 14, 2002) Critical to the maintenance of circadian rhythmicity is the cyclic Materials and Methods expression of at least some components of the central oscillator. Plant and Cell Culture Growth and Maintenance. Arabidopsis High-amplitude cycling of mRNA and protein abundance, protein suspension-cultured cells were grown in 50 ml of Gamborg B5 ͞ phosphorylation and nuclear cytoplasmic shuttling have all been medium (Sigma) supplemented with 1.1 mg͞liter 2,4-D and 0.5 implicated in the maintenance of circadian period. Here we use a g͞liter MES at 22°C under continuous fluorescent white light (60 newly characterized Arabidopsis suspension cell culture to estab- ␮mol mϪ2⅐sϪ1). Cells were subcultured every 7 days at a 10-fold lish that the rhythmic changes in the levels of the clock-associated dilution with fresh medium. For circadian studies, 15 ml of F-box protein, ZTL, are posttranscriptionally controlled through 8-day-old cultures were diluted to 50 ml with fresh medium, different circadian phase-specific degradation rates. This proteol- grown in constant light for 1 day, then shifted to 12͞12 h ysis is proteasome dependent, implicating ZTL itself as substrate light͞dark cycles for 2 or 3 days before onset of treatments. for ubiquitination.
    [Show full text]
  • TACI:Fc Scavenging B Cell Activating Factor (BAFF) Alleviates Ovalbumin-Induced Bronchial Asthma in Mice
    EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 39, No. 3, 343-352, June 2007 TACI:Fc scavenging B cell activating factor (BAFF) alleviates ovalbumin-induced bronchial asthma in mice 1,2,3 2 Eun-Yi Moon and Sook-Kyung Ryu the percentage of non-lymphoid cells and no changes were detected in lymphoid cell population. 1 Department of Bioscience and Biotechnology Hypodiploid cell formation in BALF was decreased Sejong University by OVA-challenge but it was recovered by TACI:Fc Seoul 143-747, Korea treatment. Collectively, data suggest that asthmatic 2 Laboratory of Human Genomics symptom could be alleviated by scavenging BAFF Korea Research Institute of Bioscience and Biotechnology (KRIBB) and then BAFF could be a novel target for the Daejeon 305-806, Korea develpoment of anti-asthmatic agents. 3 Corresponding author: Tel, 82-2-3408-3768; Fax, 82-2-466-8768; E-mail, [email protected] Keywords: asthma; B-cell activating factor; ovalbu- and [email protected] min; transmembrane activator and CAML interactor protein Accepted 28 March 2007 Introduction Abbreviations: BAFF, B cell activating factor belonging to TNF- family; BALF, bronchoalveolar lavage fluid; OVA, ovalbumin; PAS, Mature B cell generation and maintenance are regu- periodic acid-Schiff; Prx, peroxiredoxin; TACI, transmembrane lated by B-cell activating factor (BAFF). BAFF is pro- activator and calcium modulator and cyclophilin ligand interactor duced by macrophages or dendritic cells upon stim- ulation with LPS or IFN- . BAFF belongs to the TNF family. Its biological role is mediated by the specific Abstract receptors, B-cell maturation antigen (BCMA), trans- membrane activator and calcium modulator and cy- Asthma was induced by the sensitization and chal- clophilin ligand interactor (TACI) and BAFF receptor, lenge with ovalbumin (OVA) in mice.
    [Show full text]