DOCSLIB.ORG

T Cell Reactivity + Autoantibodies and CD4 Therapy Is Mediated By

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
T Cell Reactivity + Autoantibodies and CD4 Therapy Is Mediated By Suppression of Proteoglycan-Induced Arthritis by Anti-CD20 B Cell Depletion Therapy Is Mediated by Reduction in Autoantibodies and CD4 + T Cell Reactivity This information is current as of September 27, 2021. Keith Hamel, Paul Doodes, Yanxia Cao, Yumei Wang, Jeffrey Martinson, Robert Dunn, Marilyn R. Kehry, Balint Farkas and Alison Finnegan J Immunol 2008; 180:4994-5003; ; doi: 10.4049/jimmunol.180.7.4994 Downloaded from http://www.jimmunol.org/content/180/7/4994 References This article cites 48 articles, 20 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/180/7/4994.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 27, 2021 • Fast Publication! 4 weeks from acceptance to publication *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 © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Suppression of Proteoglycan-Induced Arthritis by Anti-CD20 B Cell Depletion Therapy Is Mediated by Reduction in Autoantibodies and CD4؉ T Cell Reactivity1 Keith Hamel,* Paul Doodes,* Yanxia Cao,† Yumei Wang,† Jeffrey Martinson,* Robert Dunn,§ Marilyn R. Kehry,§ Balint Farkas,‡ and Alison Finnegan2*† B cells have been implicated in the pathogenesis of rheumatoid arthritis (RA) since the discovery of RA as an autoimmune disease. There is renewed interest in B cells in RA based on the clinical efficacy of B cell depletion therapy in RA patients. Although, reduced titers of rheumatoid factor and anti-cyclic citrullinated peptide Abs are recorded, the mechanisms that convey clinical improvement are incompletely understood. In the proteoglycan-induced arthritis (PGIA) mouse model of RA, we reported that Ag-specific B cells have two important functions in the development of arthritis. PG-specific B cells are Downloaded from required as autoantibody-producing cells as well as Ag-specific APCs. Herein we report on the effects of anti-CD20 mAb B cell depletion therapy in PGIA. Mice were sensitized to PG and treated with anti-CD20 Ab at a time when PG-specific autoantibodies and T cell activation were evident but before acute arthritis. In mice treated with anti-CD20 mAb, devel- opment of arthritis was significantly reduced in comparison to control mAb-treated mice. B cell depletion reduced the PG-specific autoantibody response. Furthermore, there was a significant reduction in the PG-specific CD4؉ T cell recall ؉ response as well as significantly fewer PG-specific CD4 T cells producing IFN-␥ and IL-17, but not IL-4. The reduction in http://www.jimmunol.org/ PG-specific T cells was confirmed by the inability of CD4؉ T cells from B cell-depleted mice to adoptively transfer disease into SCID mice. Overall, B cell depletion during PGIA significantly reduced disease and inhibited both autoreactive B cell and T cell function. The Journal of Immunology, 2008, 180: 4994–5003. heumatoid arthritis (RA)3 is a chronic and degenerative CD20 is only expressed after the pro-B cell stage and is not autoimmune disease that affects the synovial joints (1). expressed on plasma cells (9). Although autoantibodies are re- R Inflammation leads to cartilage degradation and bone duced in most RA patients treated with anti-CD20, autoanti- erosion, resulting in debilitating pain, joint deformity, and immo- body reduction does not always correlate with efficacy, suggest- by guest on September 27, 2021 bility (2, 3). Although the precise factors that initiate disease have ing that loss of other B cell functions may contribute to not been identified, several cell types have been implicated as me- suppression of RA (8, 10–12). diators of disease, including neutrophils, macrophages, B cells, Several autoimmune diseases, including systemic lupus ery- and T cells (4). The identification of rheumatoid factor (RF) in thematosus (SLE) and RA, are characterized by the presence of RA as an autoantibody provided the first key indicator that RA autoantibodies (13). In RA, the presence of RF and anti-cyclic is an autoimmune disease (5). However, because RF is not al- citrullinated peptide autoantibodies in the serum are an early ways associated with RA and because RF could be produced in predictor of disease in 50% of RA patients by an average of 7.5 diseases other than RA, interest in B cells waned (6). Recently, years (14). Autoantibodies bind to target epitopes, forming im- the importance of B cells in RA has been resurrected based on mune complexes that activate complement components and Fc the clinical efficacy of B cell depletion therapy (rituximab) in receptor-bearing cells that contribute to RA pathogenesis (15, RA patients (7, 8). Rituximab is a chimeric anti-human CD20 16). In several murine models of RA, autoantibodies are patho- mAb that selectively depletes immature and mature B cells, as genic, particularly the K/BxN and collagen-induced arthritis (CIA) models where disease is initiated by transfer of autoan- *Department of Immunology and Microbiology, †Department of Internal Medicine, tibodies to GPI and collagen respectively (17–20). Unlike these Section of Rheumatology, and ‡Department of Orthopedic Surgery, Rush University models, in proteoglycan (PG)-induced arthritis (PGIA), autoan- Medical Center, Chicago, IL 60612; and §Biogen Idec, San Diego, CA 92122 tibodies are required for initiation of disease but are insufficient Received for publication December 11, 2007. Accepted for publication January 21, 2008. to transfer arthritis (19, 21, 22). In addition to producing Abs, there are several functions of B The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance cells that could contribute to autoimmunity (11). B cells are with 18 U.S.C. Section 1734 solely to indicate this fact. highly competent APCs and present Ag 103-104-fold more ef- 1 This research was supported by National Institutes of Health Grant AR47657 ficiently than do macrophages or dendritic cells (23). Costimu- (to A.F.). latory molecules CD80 and CD86 are up-regulated on activated 2 Address correspondence and reprint requests to Dr. Alison Finnegan, Department of Medicine, Section of Rheumatology, Rush University Medical Center, 1735 West B cells, permitting T–B cell interaction. B cells also express Harrison Avenue, Chicago, IL 60612. E-mail address: [email protected] proinflammatory cytokines that may contribute to inflammation 3 Abbreviations used in this paper: RA, rheumatoid arthritis; CIA, collagen-induced (24–26). PGIA is dependent on Ag-specific B cells, and auto- arthritis; PG, proteoglycan; PGIA, proteoglycan-induced arthritis; RF, rheumatoid reactive T cells are not sufficiently activated to induce arthritis factor; SLE, systemic lupus erythematosus. unless PG is presented by B cells (19). Selective deletion of Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 costimulatory molecules CD80 and CD86 on PG-specific B www.jimmunol.org The Journal of Immunology 4995 cells is essential for autoreactive T cell activation and the de- anti-CD20 mAb were dissected, fixed in formalin, decalcified, and embed- velopment of arthritis (27). The requirement for primed auto- ded in paraffin. The tissue sections were stained with H&E. reactive B and T cells to sustain PGIA suggests a need for Abs, anti-CD20 mAb treatment, and B cell depletion reciprocal interactions that maintain chronic autoreactivity (28). Several studies in animal models of autoimmune disease have In experiments to assess the kinetics of B cell depletion, naive cells from spleen, popliteal lymph nodes, bone marrow, and peritoneal cavity (PE) shed some light on the role of B cell depletion in autoimmunity lavages were collected at days 1, 3, 7, 14, and 21 following i.v. injection (29). In CIA, depletion of B cells with an Ab specific for mouse of 250 ␮g of anti-mouse CD20 mAb (18B12, IgG2a) (31) or control Ab CD20 administered before initiation of CIA delays the onset of anti-human CD20 mAb (2B8), an engineered IgG2a derivative of the 2B8 disease; however, B cell depletion was not therapeutic after IgG1 mouse parent of rituximab that has no cross-reactivity with mouse CD20. 18B12 anti-mouse CD20 was generated by immunization of collagen immunization (30). Recently, anti-CD20 mAb con- Ϫ Ϫ CD20 / mice with CD20-transfected cell lines and CD20-peptide-key- ferred resistance in a murine model of lupus when treatment hole limpet hemocyanin conjugate (36). The 18B12 IgG2a variant was began at an early age and was continued for several weeks (31). generated by cloning and expression of 18B12 variable domain with the The ability of anti-CD20 therapy to ameliorate or delay disease IgG2a constant region in CHO cells. Mouse B cell subsets were charac- in these models may be due to the timing of treatment. Deple- terized by flow cytometry after staining with Abs: anti-IgD FITC, anti- CD21 PE, anti-B220 PerCp, anti-IgM APC, anti-IgM PerCp-Cy5.5, anti- tion of B cells in both models was before any clinical signs of CD5 PE, anti-CD38 FITC, anti-B220 PE, anti-B220 FITC, anti-CD43 PE, Ϫ/Ϫ disease and may mimic the disease course of B cell mice, (BD Biosciences), and anti-CD23 APC (Abcam). Profiling of B cell de- thus suggesting that B cells are important in initiation of auto- pletion in PG-immunized mice was performed at days 7 and 21 after anti- immunity (32, 33).
Load more

Recommended publications
  • Distribution and Clinical Significance of Heparan Sulfate Proteoglycans in Ovarian Cancer
    5178 Vol. 10, 5178–5186, August 1, 2004 Clinical Cancer Research Distribution and Clinical Significance of Heparan Sulfate Proteoglycans in Ovarian Cancer E. June Davies,1 Fiona H. Blackhall,1 decan-1 and glypican-1 were poor prognostic factors for Jonathan H. Shanks,2 Guido David,3 survival in univariate analysis. Alan T. McGown,4 Ric Swindell,5 Conclusion: We report for the first time distinct pat- 6 7 terns of expression of cell surface and extracellular matrix Richard J. Slade, Pierre Martin-Hirsch, heparan sulfate proteoglycans in normal ovary compared 1 1 John T. Gallagher, and Gordon C. Jayson with ovarian tumors. These data reinforce the role of the 1Cancer Research UK and University of Manchester Department of tumor stroma in ovarian adenocarcinoma and suggest that Medical Oncology, Paterson Institute for Cancer Research, stromal induction of syndecan-1 contributes to the patho- Manchester, England; 2Department of Histopathology, Christie Hospital NHS Trust, Manchester, England; 3Department of Medicine, genesis of this malignancy. University of Leuven, Leuven, Belgium.; 4Cancer Research UK Department of Experimental Pharmacology, Paterson Institute for Cancer Research, Manchester, England; 5Department of Medical INTRODUCTION Statistics, Christie Hospital NHS Trust, Manchester, England; The heparan sulfate proteoglycans (HSPGs) play diverse 6Department of Obstetrics and Gynaecology, Hope Hospital, Salford, Manchester, England; 7Department of Gynaecological Oncology, St. roles in tumor biology by mediating adhesion and migration
    [Show full text]
  • Three Is a Crowd
    TREPAR 1600 No. of Pages 12 Review Three Rosetting[403_TD$IF] in Plasmodium falciparum Xue Yan Yam,1,3 Makhtar Niang,2,3 Kripa Gopal Madnani,1,3 and Peter R. Preiser1,* The intracellular malaria parasites extensively modify host erythrocytes to allow Trends nutrient uptake, ensure homeostasis, and evade the host’s immune response. Rosetting, the binding of uninfected To achieve this, the parasite exports several proteins to the erythrocyte surface. RBCs to a parasite-infected RBC In Plasmodium falciparum, the parasite responsible for the most severe form of (iRBC), has been directly linked to human malaria, three major variant surface antigen families – PfEMP1, STE- the severity of clinical disease. VOR, and RIFIN – have been implicated in contributing to immune evasion, Three parasite protein families, parasite sequestration, and parasite-mediated rosetting of uninfected eryth- PfEMP1, STEVOR, and RIFIN, mediate rosetting in Plasmodium falciparum. rocytes. Sequestration and rosetting have been linked to parasite-mediated pathology, making the variant surface antigens of P. falciparum major virulence Sequential timing of surface expres- factors. Here we review our current understanding of rosetting mechanism, sion of PfEMP1, RIFIN, and STEVOR fi on iRBC suggests that the parasite has recent ndings of STEVOR, RIFIN-mediated rosetting, and their implication on developed three different rosette for- the severity and pathology of the disease. mation mechanisms, implicating a cri- tical function for parasite survival. Plasmodium Variant Surface Antigens of Parasites: A Role in Rosetting PfEMP1 mediates rosetting through Plasmodium parasites have a complex life cycle involving a mosquito vector and a mammalian CR1, heparan sulfate, and blood group host.
    [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]
  • Aggrecan (A1960)
    Aggrecan from bovine articular cartilage Catalog Number A1960 Storage Temperature –20 °C Product Description References Aggrecan is the major structural proteoglycan found in 1. Hardingham, T.E., and Muir, H., Biochim. Biophys. the extracellular matrix of cartilage. It has a molecular Acta, 279, 401-405 (1972). mass >2,500 kDa. The core protein (210–250 kDa) has 2. Hedlund, H., et al., Association of the aggrecan 100–150 glycosaminoglycan (GAG) chains attached to keratan sulfate-rich region with collagen in bovine it. The majority of the GAG chains are chondroitin/ articular cartilage. J. Biol. Chem., 274, 5777-5781 dermatan sulfate with the remainder being keratan (1999). sulfate. This structural molecule produces a rigid, 3. Cao, L., and Yang, B.B., Chondrocyte apoptosis reversibly deformable gel that resists compression. It induced by aggrecan G1 domain as a result of combines with hyaluronic acid to form very large decreased cell adhesion. Exp. Cell Res., 246, 527- macromolecular complexes. Addition of small amounts 537 (1999). (0.1–2% w/w) of hyaluronic acid to a solution of 4. Bolton, M.C., et al., Age-related changes in the aggrecan (2 mg/ml) results in the formation of a synthesis of link protein and aggrecan in human complex with an increased hydrodynamic volume and articular cartilage: implications for aggregate in a significant increase (30–40%) in the relative stability. Biochem. J., 337, 77-82 (1999). viscosity of the solution. 5. Arner, E.C., et al., Generation and Characterization of Aggrecanase. A soluble, cartilage-derived Aggrecan is a critical component for cartilage structure aggrecan-degrading activity.
    [Show full text]
  • Mucins: the Old, the New and the Promising Factors in Hepatobiliary Carcinogenesis
    International Journal of Molecular Sciences Review Mucins: the Old, the New and the Promising Factors in Hepatobiliary Carcinogenesis Aldona Kasprzak 1,* and Agnieszka Adamek 2 1 Department of Histology and Embryology, Poznan University of Medical Sciences, Swiecicki Street 6, 60-781 Pozna´n,Poland 2 Department of Infectious Diseases, Hepatology and Acquired Immunodeficiencies, University of Medical Sciences, Szwajcarska Street 3, 61-285 Pozna´n,Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-61-8546441; Fax: +48-61-8546440 Received: 25 February 2019; Accepted: 10 March 2019; Published: 14 March 2019 Abstract: Mucins are large O-glycoproteins with high carbohydrate content and marked diversity in both the apoprotein and the oligosaccharide moieties. All three mucin types, trans-membrane (e.g., MUC1, MUC4, MUC16), secreted (gel-forming) (e.g., MUC2, MUC5AC, MUC6) and soluble (non-gel-forming) (e.g., MUC7, MUC8, MUC9, MUC20), are critical in maintaining cellular functions, particularly those of epithelial surfaces. Their aberrant expression and/or altered subcellular localization is a factor of tumour growth and apoptosis induced by oxidative stress and several anti-cancer agents. Abnormal expression of mucins was observed in human carcinomas that arise in various gastrointestinal organs. It was widely believed that hepatocellular carcinoma (HCC) does not produce mucins, whereas cholangiocarcinoma (CC) or combined HCC-CC may produce these glycoproteins. However, a growing number of reports shows that mucins can be produced by HCC cells that do not exhibit or are yet to undergo, morphological differentiation to biliary phenotypes. Evaluation of mucin expression levels in precursors and early lesions of CC, as well as other types of primary liver cancer (PLC), conducted in in vitro and in vivo models, allowed to discover the mechanisms of their action, as well as their participation in the most important signalling pathways of liver cystogenesis and carcinogenesis.
    [Show full text]
  • MUC16 (CA125): Tumor Biomarker to Cancer Therapy, a Work in Progress
    Felder et al. Molecular Cancer 2014, 13:129 http://www.molecular-cancer.com/content/13/1/129 REVIEW Open Access MUC16 (CA125): tumor biomarker to cancer therapy, a work in progress Mildred Felder1†, Arvinder Kapur1†, Jesus Gonzalez-Bosquet2, Sachi Horibata1, Joseph Heintz3, Ralph Albrecht3, Lucas Fass1, Justanjyot Kaur1, Kevin Hu4, Hadi Shojaei1, Rebecca J Whelan4* and Manish S Patankar1* Abstract Over three decades have passed since the first report on the expression of CA125 by ovarian tumors. Since that time our understanding of ovarian cancer biology has changed significantly to the point that these tumors are now classified based on molecular phenotype and not purely on histological attributes. However, CA125 continues to be, with the recent exception of HE4, the only clinically reliable diagnostic marker for ovarian cancer. Many large-scale clinical trials have been conducted or are underway to determine potential use of serum CA125 levels as a screening modality or to distinguish between benign and malignant pelvic masses. CA125 is a peptide epitope of a3–5 million Da mucin, MUC16. Here we provide an in-depth review of the literature to highlight the importance of CA125 as a prognostic and diagnostic marker for ovarian cancer. We focus on the increasing body of literature describing the biological role of MUC16 in the progression and metastasis of ovarian tumors. Finally, we consider previous and on-going efforts to develop therapeutic approaches to eradicate ovarian tumors by targeting MUC16. Even though CA125 is a crucial marker for ovarian cancer, the exact structural definition of this antigen continues to be elusive. The importance of MUC16/CA125 in the diagnosis, progression and therapy of ovarian cancer warrants the need for in-depth research on the biochemistry and biology of this mucin.
    [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]
  • The Brain Chondroitin Sulfate Proteoglycan Brevican Associates with Astrocytes Ensheathing Cerebellar Glomeruli and Inhibits Neurite Outgrowth from Granule Neurons
    The Journal of Neuroscience, October 15, 1997, 17(20):7784–7795 The Brain Chondroitin Sulfate Proteoglycan Brevican Associates with Astrocytes Ensheathing Cerebellar Glomeruli and Inhibits Neurite Outgrowth from Granule Neurons Hidekazu Yamada, Barbara Fredette, Kenya Shitara, Kazuki Hagihara, Ryu Miura, Barbara Ranscht, William B. Stallcup, and Yu Yamaguchi The Burnham Institute, La Jolla, California 92037 Brevican is a nervous system-specific chondroitin sulfate surface of these cells. Binding assays with exogenously proteoglycan that belongs to the aggrecan family and is one added brevican revealed that primary astrocytes and several of the most abundant chondroitin sulfate proteoglycans in immortalized neural cell lines have cell surface binding sites adult brain. To gain insights into the role of brevican in brain for brevican core protein. These cell surface brevican binding development, we investigated its spatiotemporal expression, sites recognize the C-terminal portion of the core protein and cell surface binding, and effects on neurite outgrowth, using are independent of cell surface hyaluronan. These results rat cerebellar cortex as a model system. Immunoreactivity of indicate that brevican is synthesized by astrocytes and re- brevican occurs predominantly in the protoplasmic islet in tained on their surface by an interaction involving its core the internal granular layer after the third postnatal week. protein. Purified brevican inhibits neurite outgrowth from Immunoelectron microscopy revealed that brevican is local- cerebellar granule neurons in vitro, an activity that requires ized in close association with the surface of astrocytes that chondroitin sulfate chains. We suggest that brevican pre- form neuroglial sheaths of cerebellar glomeruli where incom- sented on the surface of neuroglial sheaths may be control- ing mossy fibers interact with dendrites and axons from ling the infiltration of axons and dendrites into maturing resident neurons.
    [Show full text]
  • Syndecan - Regulation and Function of Its Glycosaminoglycan Chains
    Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 884 Syndecan - Regulation and Function of its Glycosaminoglycan Chains ANNA S. ERIKSSON ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 ISBN 978-91-554-8637-2 UPPSALA urn:nbn:se:uu:diva-197691 2013 Dissertation presented at Uppsala University to be publicly examined in A1:107a, BMC, Husargatan 3, Uppsala, Friday, May 17, 2013 at 13:15 for the degree of Doctor of Philosophy (Faculty of Medicine). The examination will be conducted in English. Abstract Eriksson, A. S. 2013. Syndecan - Regulation and Function of its Glycosaminoglycan Chains. Acta Universitatis Upsaliensis. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 884. 54 pp. Uppsala. ISBN 978-91-554-8637-2. The cell surface is an active area where extracellular molecules meet their receptors and affect the cellular fate by inducing for example cell proliferation and adhesion. Syndecans and integrins are two transmembrane molecules that have been suggested to fine-tune these activities, possibly in cooperation. Syndecans are proteoglycans, i.e. proteins with specific types of carbohydrate chains attached. These chains are glycosaminoglycans and either heparan sulfate (HS) or chondroitin sulfate (CS). Syndecans are known to influence cell adhesion and signaling. Integrins in turn, are important adhesion molecules that connect the extracellular matrix with the cytoskeleton, and hence can regulate cell motility. In an attempt to study how the two types of glycosaminoglycans attached to syndecan-1 can interact with integrins, a cell based model system was used and functional motility assays were performed. The results showed that HS, but not CS, on the cell surface was capable of regulating integrin-mediated cell motility.
    [Show full text]
  • Sulfated Glycoaminoglycans and Proteoglycan Syndecan-4 Are Involved in Membrane Fixation of LL-37 and Its Pro-Migratory Effect I
    Sulfated Glycoaminoglycans and Proteoglycan Syndecan-4 Are Involved in Membrane Fixation of LL-37 and Its Pro-Migratory Effect in Breast Cancer Cells Chahrazed Habes, Günther Weber, Caroline Goupille To cite this version: Chahrazed Habes, Günther Weber, Caroline Goupille. Sulfated Glycoaminoglycans and Proteoglycan Syndecan-4 Are Involved in Membrane Fixation of LL-37 and Its Pro-Migratory Effect in Breast Cancer Cells. Biomolecules, MDPI, 2019, 9 (9), pp.481. 10.3390/biom9090481. hal-02958728 HAL Id: hal-02958728 https://hal.archives-ouvertes.fr/hal-02958728 Submitted on 6 Oct 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. biomolecules Article Sulfated Glycoaminoglycans and Proteoglycan Syndecan-4 Are Involved in Membrane Fixation of LL-37 and Its Pro-Migratory Effect in Breast Cancer Cells Chahrazed Habes 1, Günther Weber 1,* and Caroline Goupille 1,2 1 INSERM, Université de Tours, UMR 1069 Nutrition, Growth and Cancer, 37032 Tours, France; [email protected] (C.H.); [email protected] (C.G.) 2 CHRU de Tours, Hôpital Bretonneau, 37032 Tours, France * Correspondence: [email protected]; Tel.: +33-247-366-294 Received: 27 July 2019; Accepted: 10 September 2019; Published: 12 September 2019 Abstract: Initially characterized by its antimicrobial activities, LL-37 has also been shown to significantly contribute to tumor development.
    [Show full text]
  • Fibroblasts from the Human Skin Dermo-Hypodermal Junction Are
    cells Article Fibroblasts from the Human Skin Dermo-Hypodermal Junction are Distinct from Dermal Papillary and Reticular Fibroblasts and from Mesenchymal Stem Cells and Exhibit a Specific Molecular Profile Related to Extracellular Matrix Organization and Modeling Valérie Haydont 1,*, Véronique Neiveyans 1, Philippe Perez 1, Élodie Busson 2, 2 1, 3,4,5,6, , Jean-Jacques Lataillade , Daniel Asselineau y and Nicolas O. Fortunel y * 1 Advanced Research, L’Oréal Research and Innovation, 93600 Aulnay-sous-Bois, France; [email protected] (V.N.); [email protected] (P.P.); [email protected] (D.A.) 2 Department of Medical and Surgical Assistance to the Armed Forces, French Forces Biomedical Research Institute (IRBA), 91223 CEDEX Brétigny sur Orge, France; [email protected] (É.B.); [email protected] (J.-J.L.) 3 Laboratoire de Génomique et Radiobiologie de la Kératinopoïèse, Institut de Biologie François Jacob, CEA/DRF/IRCM, 91000 Evry, France 4 INSERM U967, 92260 Fontenay-aux-Roses, France 5 Université Paris-Diderot, 75013 Paris 7, France 6 Université Paris-Saclay, 78140 Paris 11, France * Correspondence: [email protected] (V.H.); [email protected] (N.O.F.); Tel.: +33-1-48-68-96-00 (V.H.); +33-1-60-87-34-92 or +33-1-60-87-34-98 (N.O.F.) These authors contributed equally to the work. y Received: 15 December 2019; Accepted: 24 January 2020; Published: 5 February 2020 Abstract: Human skin dermis contains fibroblast subpopulations in which characterization is crucial due to their roles in extracellular matrix (ECM) biology.
    [Show full text]
  • B Cell–Specific Expression of Inducible Costimulator Ligand Is Necessary for the Induction of Arthritis in Mice
    ARTHRITIS & RHEUMATOLOGY Vol. 66, No. 1, January 2014, pp 60–67 DOI 10.1002/art.38207 © 2014, American College of Rheumatology B Cell–Specific Expression of Inducible Costimulator Ligand Is Necessary for the Induction of Arthritis in Mice Keith M. Hamel,1 Yanxia Cao,2 Susan A. Olalekan,2 and Alison Finnegan2 Objective. Inducible costimulator (ICOS)–ICOSL actions may be an effective strategy for the treatment of interactions are necessary for activation of Teff cells rheumatoid arthritis. and follicular helper T (Tfh) cells. ICOSL is expressed on B cells, macrophages, and dendritic cells and can be In rheumatoid arthritis (RA), autoreactive T cells induced on nonhematopoietic cells. The aim of this are implicated in the disease process, based on genetic study was to determine whether expression of ICOSL on linkage between disease susceptibility and HLA alleles B cells is necessary for the development of proteoglycan and evidence derived from experimental models of (PG)–induced arthritis (PGIA). arthritis (1). T cell activation requires T cell receptor Methods. PGIA was initiated by immunizing wild- ligation in addition to secondary and tertiary signals type and ICOSL-deficient (ICOSL؊/؊) or B cell–specific provided by costimulator molecules and cytokines. The ICOSL؊/؊ chimeric BALB/c mice with human PG in interaction between CD28 on T cells and CD80/CD86 adjuvant. The onset and severity of arthritis were mon- on antigen-presenting cells (APCs) is the most promi- itored over time. CD4؉ T cell proliferation and CD4؉ nent of these costimulatory interactions (2). Successful T cell cytokine production were measured in vitro after therapeutic intervention with the CD28 costimulatory the cells were restimulated with PG.
    [Show full text]