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B Cell Activation and Escape of Tolerance Checkpoints: Recent Insights from Studying Autoreactive B Cells
cells Review B Cell Activation and Escape of Tolerance Checkpoints: Recent Insights from Studying Autoreactive B Cells Carlo G. Bonasia 1 , Wayel H. Abdulahad 1,2 , Abraham Rutgers 1, Peter Heeringa 2 and Nicolaas A. Bos 1,* 1 Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, 9713 Groningen, GZ, The Netherlands; [email protected] (C.G.B.); [email protected] (W.H.A.); [email protected] (A.R.) 2 Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9713 Groningen, GZ, The Netherlands; [email protected] * Correspondence: [email protected] Abstract: Autoreactive B cells are key drivers of pathogenic processes in autoimmune diseases by the production of autoantibodies, secretion of cytokines, and presentation of autoantigens to T cells. However, the mechanisms that underlie the development of autoreactive B cells are not well understood. Here, we review recent studies leveraging novel techniques to identify and characterize (auto)antigen-specific B cells. The insights gained from such studies pertaining to the mechanisms involved in the escape of tolerance checkpoints and the activation of autoreactive B cells are discussed. Citation: Bonasia, C.G.; Abdulahad, W.H.; Rutgers, A.; Heeringa, P.; Bos, In addition, we briefly highlight potential therapeutic strategies to target and eliminate autoreactive N.A. B Cell Activation and Escape of B cells in autoimmune diseases. Tolerance Checkpoints: Recent Insights from Studying Autoreactive Keywords: autoimmune diseases; B cells; autoreactive B cells; tolerance B Cells. Cells 2021, 10, 1190. https:// doi.org/10.3390/cells10051190 Academic Editor: Juan Pablo de 1. -
Overview of B-Cell Maturation, Activation, Differentiation
Overview of B-Cell Maturation, Activation, Differentiation B-Cell Development Begins in the Bone Marrow and Is Completed in the Periphery Antigen-Independent (Maturation) 1) Pro-B stages B-cell markers 2) Pre B-stages H- an L- chain loci rearrangements surrogate light chain 3) Naïve B-cell functional BCR . B cells are generated in the bone marrow. Takes 1-2 weeks to develop from hematopoietic stem (HSC) cells to mature B cells. Sequence of expression of cell surface receptor and adhesion molecules which allows for differentiation of B cells, proliferation at various stages, and movement within the bone marrow microenvironment. HSC passes through progressively more delimited progenitor-cell stages until it reaches the pro-B cell stage. Pre-B cell is irreversibly committed to the B-cell lineage and the recombination of the immunoglobulin genes expressed on the cell surface Immature B cell (transitional B cell) leaves the bone marrow to complete its maturation in the spleen through further differentiation. Immune system must create a repertoire of receptors capable of recognizing a large array of antigens while at the Source: Internet same time eliminating self-reactive B cells. B-Cell Activation and Differentiation • Exposure to antigen or various polyclonal mitogens activates resting B cells and stimulates their proliferation. • Activated B cells lose expression of sIgD and CD21 and acquire expression of activation antigens. Growth factor receptors, structures involved in cell-cell interaction, molecules that play a role in the localization and binding of activated B cells Two major types: T cell dependent (TD) T cell independent (TI) B-Cell Activation by Thymus-Independent and Dependent Antigens Source: Kuby T cell dependent: Involves protein antigens and CD4+ helper T cells. -
B-Cell Reconstitution Recapitulates B-Cell Lymphopoiesis Following Haploidentical BM Transplantation and Post-Transplant CY
Bone Marrow Transplantation (2015) 50, 317–319 © 2015 Macmillan Publishers Limited All rights reserved 0268-3369/15 www.nature.com/bmt LETTER TO THE EDITOR B-cell reconstitution recapitulates B-cell lymphopoiesis following haploidentical BM transplantation and post-transplant CY Bone Marrow Transplantation (2015) 50, 317–319; doi:10.1038/ From week 9, the proportion of transitional B cells progressively bmt.2014.266; published online 24 November 2014 decreased (not shown), whereas that of mature B cells increased (Figure 1d). To further evaluate the differentiation of mature cells, we included markers of naivety (IgM and IgD) and memory (IgG) in The treatment of many hematological diseases benefits from our polychromatic panel. At week 9, when a sufficient proportion myeloablative or non-myeloablative conditioning regimens of cells were available for the analysis, B cells were mostly naive followed by SCT or BMT. HLA-matched donors are preferred but and remained so for 26 weeks after haploBMT (Figure 1d). Despite not always available. Instead, haploidentical donors can be rapidly low, the proportion of memory B cells reached levels similar to identified. Unmanipulated haploidentical BMT (haploBMT) with that of marrow donors (Supplementary Figure 1D). non-myeloablative conditioning and post-transplant Cy has been To further investigate the steps of B-cell maturation, we developed to provide a universal source of BM donors.1 Cy, analyzed CD5, a regulator of B-cell activation, and CD21, a which depletes proliferating/allogeneic cells, prevents GVHD.1 component of the B-cell coreceptor complex, on transitional B Importantly, the infection-related mortality was remarkably low, cells. These surface markers characterize different stages of 5,6 5,6 suggesting effective immune reconstitution.1,2 However, a transitional B-cell development. -
Human B Cell Isolation Product Selection Diagram
Human B Cell Isolation Product Selection Explore the infographic below to find the correct human B cell isolation product for your application. 1. Your Starting Sample Whole Peripheral Blood/Buffy Coat PBMCs/Leukapheresis Pack 2. Cell Separation Platform Immunodensity Cell Separation Immunomagnetic Cell Separation Immunomagnetic Cell Separation 3. Product Line RosetteSep™ EasySep™ EasySep™ Sequential Selection Negative Selection Negative Selection Positive Selection Negative Selection Positive Selection 4. Selection Method (Positive + Negative) iRosetteSep™ HLA iEasySep™ Direct HLA i, iiEasySep™ HLA iEasySep™ HLA B Cell viEasySep™ Human CD19 EasySep™ Human IgG+ B Cell Enrichment Cocktail B Cell Isolation Kit Chimerism Whole Blood Enrichment Kit Positive Selection Kit II Memory B Cell Isolation (15064HLA)1, 2, 3 (89684) / EasySep™ Direct B Cell Positive Selection (19054HLA)1, 2 (17854)1, 2 Kit (17868)1 (optional), 2' HLA Crossmatch B Cell Kit (17886)1, 2 Isolation Kit (19684 - 1, 2 RosetteSep™ Human available in the US only) iiiEasySep™ Human B Cell viEasySep™ Release EasySep™ Human Memory 5. Cell Isolation Kits B Cell Enrichment Cocktail i, iiEasySep™ HLA Enrichment Kit Human CD19 Positive B Cell Isolation Kit 1, 2, 3 1, 2 1, 2 1 (optional), 2 Catalog #s shown in ( ) (15024) Chimerism Whole Blood (19054) Selection Kit (17754) (17864) EasySep™ Direct Human CD19 Positive Selection B-CLL Cell Isolation Kit Kit (17874)1, 2 1, 2, 3, 4 *RosetteSep™ Human (19664) iiiEasySep™ Human B Cell EasySep™ Human CD138 Multiple Myeloma Cell Isolation Kit -
Somatic Hypermutation Targeting to Intrinsic Hotspots of Immunoglobulin
Leukemia (2001) 15, 1772–1778 2001 Nature Publishing Group All rights reserved 0887-6924/01 $15.00 www.nature.com/leu Somatic hypermutation targeting to intrinsic hotspots of immunoglobulin genes in follicular lymphoma and multiple myeloma C Belessi1, K Stamatopoulos2, N Stavroyianni2, K Zoi2, T Papadaki3 and C Kosmas4 1Hematology Laboratory, General Hospital of Nikea, Piraeus; 2First Department of Medicine, Athens University School of Medicine, Laikon General Hospital, Athens; 3Hemopathology Unit, Evangelismos Hospital, Athens; and 4Department of Medicine, Helena Venizelou Hospital, Athens, Greece In this study, we analyzed the targeting of the somatic hyper- of the secondary lymphoid organs where contact with and mutation (SHM) mechanism at specific hotspot sequence 3 selection by antigen takes place. The molecular hallmark of motifs in the VH and V genes of 10 follicular lymphoma (FL) cases and the V and V genes of 11 - and six -light chain this phase is the introduction of mutations within rearranged expressing multiple myeloma (MM) cases. These sequences IgV genes, at a rate much higher than usual, a phenomenon were analyzed for targeting of specific motifs, ie certain highly described as somatic hypermutation.4 mutable trinucleotides (3-NTPs), the tetranucleotide (4-NTP) Antigen selection in B cell ontogeny is evidenced by non- RGYW and its complementary, WRCY (where R = purine, random distribution of somatic mutations in lg HC and LC V = = Y pyrimidine and W A or T). Comparisons were carried out genes, a feature providing useful information concerning the between mutation frequencies in RGYW vs WRCY and the inci- 5 dence of mutations in complementarity determining region ontogenetic assignment of B cell neoplastic disorders. -
Human Naive B Cells Cells by Cpg Oligodeoxynucleotide-Primed T+
Presentation of Soluble Antigens to CD8+ T Cells by CpG Oligodeoxynucleotide-Primed Human Naive B Cells This information is current as Wei Jiang, Michael M. Lederman, Clifford V. Harding and of September 27, 2021. Scott F. Sieg J Immunol 2011; 186:2080-2086; Prepublished online 14 January 2011; doi: 10.4049/jimmunol.1001869 http://www.jimmunol.org/content/186/4/2080 Downloaded from References This article cites 36 articles, 21 of which you can access for free at: http://www.jimmunol.org/content/186/4/2080.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 27, 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 © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Presentation of Soluble Antigens to CD8+ T Cells by CpG Oligodeoxynucleotide-Primed Human Naive B Cells Wei Jiang,*,† Michael M. Lederman,*,† Clifford V. Harding,†,‡ and Scott F. Sieg*,† Naive B lymphocytes are generally thought to be poor APCs, and there is limited knowledge of their role in activation of CD8+ T cells. -
Plasma Cells: Finding New Light at the End of B Cell Development Kathryn L
© 2001 Nature Publishing Group http://immunol.nature.com REVIEW Plasma cells: finding new light at the end of B cell development Kathryn L. Calame Plasma cells are cellular factories devoted entire- Upon plasma cell differentiation, there is a marked increase in ly to the manufacture and export of a single prod- steady-state amounts of Ig heavy and light chain mRNA and, when 2 uct: soluble immunoglobulin (Ig). As the final required for IgM and IgA secretion, J chain mRNA . Whether the increase in Ig mRNA is due to increased transcription, increased mediators of a humoral response, plasma cells mRNA stability or, as seems likely, both mechanisms, remains con- play a critical role in adaptive immunity.Although troversial2. There is also an increase in secreted versus membrane intense effort has been devoted to studying the forms of heavy chain mRNA, as determined by differential use of poly(A) sites that may involve the availability of one component of regulation and requirements for early B cell the polyadenylation machinery, cleavage-stimulation factor Cst-643. development, little information has been avail- To accommodate translation and secretion of the abundant Ig able on plasma cells. However, more recent mRNAs, plasma cells have an increased cytoplasmic to nuclear ratio work—including studies on genetically altered and prominent amounts of rough endoplasmic reticulum and secreto- ry vacuoles. mice and data from microarray analyses—has Numerous B cell–specific surface proteins are down-regulated begun to identify the regulatory cascades that upon plasma cell differentiation, including major histocompatibility initiate and maintain the plasma cell phenotype. complex (MHC) class II, B220, CD19, CD21 and CD22. -
Somatic Hypermutation of T Cell Receptor a Chain Contributes To
RESEARCH ARTICLE Somatic hypermutation of T cell receptor a chain contributes to selection in nurse shark thymus Jeannine A Ott1, Caitlin D Castro2, Thaddeus C Deiss1, Yuko Ohta2, Martin F Flajnik2, Michael F Criscitiello1,3* 1Comparative Immunogenetics Laboratory, Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, Texas, United States; 2Department of Microbiology and Immunology, University of Maryland at Baltimore, Baltimore, United States; 3Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M Health Science Center, Texas A&M University, Texas, United States Abstract Since the discovery of the T cell receptor (TcR), immunologists have assigned somatic hypermutation (SHM) as a mechanism employed solely by B cells to diversify their antigen receptors. Remarkably, we found SHM acting in the thymus on a chain locus of shark TcR. SHM in developing shark T cells likely is catalyzed by activation-induced cytidine deaminase (AID) and results in both point and tandem mutations that accumulate non-conservative amino acid replacements within complementarity-determining regions (CDRs). Mutation frequency at TcRa was as high as that seen at B cell receptor loci (BcR) in sharks and mammals, and the mechanism of SHM shares unique characteristics first detected at shark BcR loci. Additionally, fluorescence in situ hybridization showed the strongest AID expression in thymic corticomedullary junction and medulla. We suggest that TcRa utilizes SHM to broaden diversification of the primary ab T cell repertoire in sharks, the first reported use in vertebrates. DOI: https://doi.org/10.7554/eLife.28477.001 *For correspondence: [email protected] Competing interests: The Introduction authors declare that no competing interests exist. -
Allergic Rhinitis Patients of Switch Recombination in the Nasal Mucosa Local Somatic Hypermutation and Class
Local Somatic Hypermutation and Class Switch Recombination in the Nasal Mucosa of Allergic Rhinitis Patients This information is current as Heather A. Coker, Stephen R. Durham and Hannah J. Gould of September 23, 2021. J Immunol 2003; 171:5602-5610; ; doi: 10.4049/jimmunol.171.10.5602 http://www.jimmunol.org/content/171/10/5602 Downloaded from References This article cites 33 articles, 7 of which you can access for free at: http://www.jimmunol.org/content/171/10/5602.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • 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 *average by guest on September 23, 2021 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 © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Local Somatic Hypermutation and Class Switch Recombination in the Nasal Mucosa of Allergic Rhinitis Patients Heather A. Coker,1* Stephen R. Durham,† and Hannah J. Gould2* Immunoglobulin E is produced by nasal B cells in response to allergen. -
B-Helper Neutrophils in Regional Lymph Nodes Correlate with Improved Prognosis in Patients with Head and Neck Cancer
cancers Article B-Helper Neutrophils in Regional Lymph Nodes Correlate with Improved Prognosis in Patients with Head and Neck Cancer Ekaterina Pylaeva 1,† , Irem Ozel 1,† , Anthony Squire 2, Ilona Spyra 1, Charlotte Wallner 1, Magdalena Korek 1, Georg Korschunow 1, Maksim Domnich 1 , Elena Siakaeva 1, Moritz Goetz 3, Agnes Bankfalvi 3, Stephan Lang 1,4, Benjamin Kansy 1,4,*,‡ and Jadwiga Jablonska 1,4,*,‡ 1 Department of Otorhinolaryngology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany; [email protected] (E.P.); [email protected] (I.O.); [email protected] (I.S.); [email protected] (C.W.); [email protected] (M.K.); [email protected] (G.K.); [email protected] (M.D.); [email protected] (E.S.); [email protected] (S.L.) 2 Institute of Experimental Immunology and Imaging, University Hospital Essen, University Duisburg-Essen, 45141 Essen, Germany; [email protected] 3 Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; [email protected] (M.G.); [email protected] (A.B.) 4 German Cancer Consortium (DKTK) Partner Site Düsseldorf/Essen, 45147 Essen, Germany * Correspondence: [email protected] (B.K.); [email protected] (J.J.) † These authors contributed equally. ‡ These authors contributed equally. Simple Summary: Neutrophils exhibit multiple functions during cancer progression and are believed Citation: Pylaeva, E.; Ozel, I.; Squire, to regulate adaptive immune responses to cancer. In addition to their interactions with T cells in A.; Spyra, I.; Wallner, C.; Korek, M.; this context, these cells are also believed to interact with B cells. -
B Cell Responses: Plasmablasts Walk the Line
RESEARCH HIGHLIGHTS B CELL RESPONSES Plasmablasts walk the line During an adaptive immune patterns in lymph nodes. Following molecule intercellular adhesion response, long-lived antibody- immunization with specific antigen, molecule 1 (ICAM1) in plasmablast producing plasma cells are generated YFP+ cells mainly aggregated in migration. Both YFP+ and naive in T cell-dependent germinal centres. the medulla of the lymph node but B cells migrated on ICAM1-coated Plasma cells subsequently localize to could also be found in the B and glass surfaces, but only naive B cells the lymph node medullary chords, T cell zones and at the border of required Gαi-signalling for this move- but their migration to these sites has germinal centres. By contrast, naive ment. In addition, naive B cells and never been directly observed. A study B cells were predominantly localized plasma blasts had different migratory in Immunity has now reported in B cell follicles. behaviour on the ICAM1-coated sur- unique migratory behaviour for their When the migratory patterns faces; naive B cells showed frequent precursors, plasmablasts; these cells of the different populations were detachment and reattachment to the traverse the lymph node in a linear observed in situ using time-lapse substrate, but YFP+ cells migrated in manner and, surprisingly, do not two-photon intravital microscopy, a steady, amoeboid manner. + require Gαi-coupled receptor YFP cells in the medullary chords Interestingly, in assays carried signalling to migrate. were found to be mainly stationary, out in vivo and in vitro, the authors The transcriptional repressor but YFP+ cells in the follicles were reported an inverse correlation B lymphocyte-induced maturation highly motile. -
A Natural Killer Cell-Centric Approach Toward New Therapeutics For
A natural killer cell-centric approach toward new therapeutics for autoimmune disease A dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Ph.D.) in the Immunology Graduate Training Program of the College of Medicine 2019 By Seth D. Reighard B.S., University of Pittsburgh, 2010 Thesis Advisor: Stephen N. Waggoner, Ph.D. Dissertation Committee Chair: William M. Ridgway, M.D. 1 Abstract The debilitating autoimmune disease systemic lupus erythematosus (SLE) is the 5th leading cause of death for African American and Hispanic women between 15 and 24 years of age. Current therapeutics for SLE are blunt weapons that broadly suppress a patient’s immune system, and only one new treatment option has been approved in over 50 years. Standard treatments for SLE potentially lack efficacy because they do not specifically target the immune dysfunction underlying disease. SLE is characterized by the abnormal production of self-targeting autoantibodies that cause widespread organ damage. SLE autoantibodies are generated by rampant germinal center (GC) reactions: immune processes wherein memory B cells and antibody secreting cells (ASC) arise from naïve B lymphocytes following clonal expansion, somatic hypermutation, affinity maturation, and antibody class switching while receiving critical help from follicular helper T (TFH) cells. We hypothesize that inhibition of TFH and GC responses in SLE may be accomplished by harnessing the therapeutic potential of the natural killer (NK) cell. Though classically implicated in anti-tumor and antiviral immunity, NK cells also suppress activated TFH, resulting in reduced GC reactions and decreased antibodies.