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Signalling Pathways in B Cells: Implications for Autoimmunity

  • Chapter
Current Concepts in Autoimmunity and Chronic Inflammation

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 305))

Abstract

Following investigations of the pathogenic role of autoantibodies in rheumatic diseases, preclinical and clinical studies suggest a more central role of B cells in the maintenance of the disease process beyond just being precursors of (auto)antibody-producing plasma cells. Detailed analyses have implicated a number of surface molecules and subsequent downstream signalling pathways in the regulation of the events induced by BCR engagement. In this review, we discuss the potential role of molecules involved in altered B cell longevity, especially molecules involved in apoptosis (bcl-2, bcl-x, mutations in the Fas/Fas-L pathway), as well as molecules that might alter activation thresholds of B cells (CD19, CD21, CD22, lyn, SHP, SHIP-1) in the development of autoimmunity. Although focused on intrinsic B cell abnormalities, the complexity of interactions of B cells with other immune cells also makes it possible that increased B cell activation can be induced by distortions in the interaction with other cells. Further delineation of these alterations of B cell function in autoimmune conditions will allow development of more precise B cell-directed therapies beyond drastic B cell depletion, with the potential to improve the risk-benefit ratio of the treatments of autoimmune diseases.

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References

  • Anolik JH, Barnard J, Cappione A, Pugh-Bernard AE, Felgar RE, Looney RJ, Sanz I (2004) Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus. Arthritis Rheum 50:3580–3590

    Article  PubMed  CAS  Google Scholar 

  • Benschop RJ, Cambier JC (1999) B cell development: signal transduction by antigen receptors and their surrogates. CurrOpin Immunol11:143–151

    CAS  Google Scholar 

  • Boackle SA, Holers VM, Chen XJ, Szakonyi G, Karp DR, Wakeland EK, Morel L (2001) Cr2, a candidate gene in the murine Sle1c lupus susceptibility locus, encodes a dysfunctional protein. Immunity 15:775–785

    Article  PubMed  CAS  Google Scholar 

  • Bohnhorst JO, Bjorgan MB, Thoen JE, Natvig JB, Thompson KM (2001a) Bm1-Bm5 classification of peripheral blood B cells reveals circulating germinal center founder cells in healthy individuals and disturbance in the B cell subpopulations in patients with primary Sjogren’s syndrome. J Immunol 167:3610–3618

    PubMed  CAS  Google Scholar 

  • Bohnhorst JO, Thoen JE, Natvig JB, Thompson KM (2001b) Significantly depressed percentage of CD27+(memory) B cells among peripheral blood B cells in patients with primary Sjogren’s syndrome. Scan J Immunol 54:421–427

    Article  CAS  Google Scholar 

  • Bohnhorst JO, Bjorgan MB, Thoen JE, Jonsson R, Natvig JB, Thompson KM (2002) Abnormal B cell differentiation in primary Sjogren’s syndrome results in a depressed percentage of circulating memory B cells and elevated levels of soluble CD27 that correlate with serum IgG concentration. Clin Immunol 103:79–88

    Article  PubMed  CAS  Google Scholar 

  • Bolland S, Ravetch JV (2000) Spontaneous autoimmune disease in Fc gamma RIIB-deficient mice results from strain-specific epistasis. Immunity 13:277–285

    Article  PubMed  CAS  Google Scholar 

  • Brezinschek HP, Brezinschek RI, Lipsky PE (1995a) Analysis of the heavy-chain repertoire of human peripheral B-cells using single-cell polymerase chain reaction. J Immunol 155:190–202

    PubMed  CAS  Google Scholar 

  • Brezinschek HP, Foster SJ, Brezinschek RI, Lipsky PE (1995b) The human-immunoglobulin variable heavy-chain repertoire. Arthritis Rheum 38:1007

    Google Scholar 

  • Brezinschek HP, Brezinschek RI, Foster SJ, Dörner T, Lipsky PE (1996) Analysis of the immunoglobulin repertoire of human B-1 (CD5+) B cells. Arthritis Rheum 39:102

    Google Scholar 

  • Cambridge G, Leandro MJ, Edwards JCW, Ehrenstein MR, Salden M, Webster D (2002) B lymphocyte depletion in patients with rheumatoid arthritis: serial studies of immunological parameters. Arthritis Rheum 46:S506

    Google Scholar 

  • Cambridge G, Leandro MJ, Edwards JCW, Ehrenstein MR, Salden M, Bodman-Smith M, Webster ADB (2003) Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis. Arthritis Rheum 48:2146–2154

    Article  PubMed  Google Scholar 

  • Cappione A, Anolik J, Pugh-Bernard A, Silverman G, Sanz I (2002)Human autoreactive VH4.34 B-cells are compartmentalized in the spleen marginal zone. Arthritis Rheum 46:S416

    Google Scholar 

  • Carsetti R, Kohler G, Lamers MC (1995) Transitional B-cells are the target of negative selection in the B-cell compartment. J Exp Med 181:2129–2140

    Article  PubMed  CAS  Google Scholar 

  • Chan OTM, Madaio MP, Shlomchik MJ (1999) The central and multiple roles of B cells in lupus pathogenesis. Immunol Rev 169:107–121

    Article  PubMed  CAS  Google Scholar 

  • Cornall RJ, Cyster JG, Hibbs ML, Dunn AR, Otipoby KL, Clark EA, Goodnow CC (1998) Polygenic autoimmune traits: Lyn, CD22, and SHP-1 are limiting elements of a biochemical pathway regulating BCR signaling and selection. Immunity 8:497–508

    Article  PubMed  CAS  Google Scholar 

  • Corr M, Firestein GS (2002) Commentary—innate immunity as a hired gun: but is it rheumatoid arthritis? J Exp Med 195:F33–F35

    Article  PubMed  CAS  Google Scholar 

  • Daeron M (1997) Fc receptor biology. Ann Rev Immunol 15:203–234

    Article  CAS  Google Scholar 

  • De Vita S, Zaja F, Sacco S, De Candia A, Fanin R, Ferraccioli G (2002) Efficacy of selective B cell blockade in the treatment of rheumatoid arthritis-evidence for a pathogenetic role of B cells. Arthritis Rheum 46:2029–2033

    Article  PubMed  CAS  Google Scholar 

  • Doody GM, Justement LB, Delibrias CC, Matthews RJ, Lin JJ, Thomas ML, Fearon DT (1995) A role in B-cell activation for Cd22 and the protein-tyrosine-phosphatase Shp. Science 269:242–244

    PubMed  CAS  Google Scholar 

  • Dörner T, Burmester GR (2003) The role of B cells in rheumatoid arthritis: mechanisms and therapeutic targets. Curr Opin Rheumatol 15:246–252

    Article  PubMed  Google Scholar 

  • Dörner T, Putterman C (2001) B cells, BAFF/zTNF4, TACl, and systemic lupus erythematosus. Arthritis Res 3:197–199

    Article  PubMed  Google Scholar 

  • Dörner T, Foster SJ, Farner NL, Lipsky PE (1998) Immunoglobulin kappa chain receptor editing in systemic lupus erythematosus. J Clin Invest 102:688–694

    PubMed  Google Scholar 

  • Edwards JC, Cambridge G, Leandro MJ (2000) Sustained improvement in rheumatoid arthritis following B lymphocyte depletion. Arthritis Rheum 43:S391

    Google Scholar 

  • Edwards JCW, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T (2004) Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Eng J Med 350:2572–2581

    Article  CAS  Google Scholar 

  • Firestein GS, Zvaifler NJ (2002) How important are T cells in chronic rheumatoid synovitis? II. T cell-independent mechanisms from beginning to end. Arthritis Rheum 46:298–308

    Article  PubMed  CAS  Google Scholar 

  • Fujimoto M, Bradney AP, Poe JC, Steeber DA, Tedder TF (1999) Modulation of B lymphocyte antigen receptor signal transduction by a CD19/CD22 regulatory loop. Immunity 11:191–200

    Article  PubMed  CAS  Google Scholar 

  • Gaffney PM, Kearns GM, Shark KB, Ortmann WA, Selby SA, Malmgren ML, Rohlf KE, Ockenden TC, Messner RP, King RA, Rich SS, Behrens TW (1998) A genome-wide search for susceptibility genes in human systemic lupus erythematosus sib-pair families. Proc Natl Acad Sci U S A 95:14875–14879

    Article  PubMed  CAS  Google Scholar 

  • Grimbacher B, Hutloff A, Schlesier M, Glocker E, Warnatz K, Drager R, Eibel H, Fischer B, Schaffer AA, Mages HW, Kroczek RA, Peter HH (2003) Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol 4:261–268

    Article  PubMed  CAS  Google Scholar 

  • Gross JA, Johnston J, Mudri S, Enselman R, Dillon SR, Madden K, Xu WF, Parrish-Novak J, Foster D, Lofton-Day C, Moore M, Littau A, Grossman A, Haugen H, Foley K, Blumberg H, Harrison K, Kindsvogel W, Clegg CH (2000) TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature 404:995–999

    Article  PubMed  CAS  Google Scholar 

  • Hansen A, Odendahl M, Reiter K, Jacobi A, Burmester GR, Lipsky PE, Dörner T (2002a) Disturbances in peripheral B cell subsets in patients with primary Sjogren’s syndrome with a markedly diminished peripheral CD5+/CD27+ memory population. Arthritis Rheum 46:S597

    Article  CAS  Google Scholar 

  • Hansen A, Odendahl M, Reiter K, Jacobi AM, Feist E, Scholze J, Burmester GR, Lipsky PE, Dörner T (2002b) Diminished peripheral blood memory B cells and accumulation of memory B cells in the salivary glands of patients with Sjogren’s syndrome. Arthritis Rheum 46:2160–2171

    Article  PubMed  CAS  Google Scholar 

  • Hansen A, Gosemann M, Pruss A, Reiter K, Ruzickova S, Lipsky PE, Dörner T (2004) Abnormalities in peripheral B cell memory of patients with primary Sjogren’s syndrome. Arthritis Rheum 50:1897–1908

    Article  PubMed  CAS  Google Scholar 

  • Harley JB, Moser KL, Gaffney PM, Behrens TW (1998) The genetics of human systemic lupus erythematosus. Curr Opin Immunol 10:690–696

    Article  PubMed  CAS  Google Scholar 

  • Helgason CD, Damen JE, Rosten P, Grewal R, Sorensen P, Chappel SM, Borowski A, Jirik F, Krystal G, Humphries RK (1998) Targeted disruption of SHIP leads to hemopoietic perturbations lung pathology, and a shortened life span. Genes Dev 12:1610–1620

    PubMed  CAS  Google Scholar 

  • Hirohata S, Ohshima N, Yanagida T, Aramaki K (2002) Regulation of human B cell function by sulfasalazine and its metabolites. Int Immunopharmacol 2:631–640

    Article  PubMed  CAS  Google Scholar 

  • Huang SC, Jiang RH, Glas AM, Milner ECB (1996) Non-stochastic utilization of Ig V region genes in unselected human peripheral B cells. Mol Immunol 33:553–560

    Article  PubMed  CAS  Google Scholar 

  • Hutloff A, Buchner K, Reiter K, Baelde HJ, Odendahl M, Jacobi A, Dörner T, Kroczek RA (2004) Involvement of inducible costimulator in the exaggerated memory B cell and plasma cell generation in systemic lupus erythematosus. Arthritis Rheum 50:3211–3220

    Article  PubMed  Google Scholar 

  • Inaoki M, Sato S, Weintraub BC, Goodnow CC, Tedder TF (1997) CD19-regulated signaling thresholds control peripheral tolerance and autoantibody production in B lymphocytes. J Exp Med 186:1923–1931

    Article  PubMed  CAS  Google Scholar 

  • Isenberg DA, McClure C, Farewell V, Spellerberg M, Williams W, Cambridge G, Stevenson F (1998) Correlation of 9G4 idiotope with disease activity in patients with systemic lupus erythematosus. Ann Rheum Dis 57:566–570

    Article  PubMed  CAS  Google Scholar 

  • Iwai H, Abe M, Hirose S, Tsushima F, Tezuka K, Akiba H, Yagita H, Okumura K, Kohsaka H, Miyasaka N, Azuma M (2003) Involvement of inducible costimulator-B7 homologous protein costimulatory pathway in murine lupus nephritis. J Immunol 171:2848–2854

    PubMed  CAS  Google Scholar 

  • Jacobi A, Dörner T, Hansen A, Lipsky PE (1999) Identification of enhanced mutational activity and disturbed selection mechanisms on V-H gene rearrangements in systemic lupus erythematosus (SLE). Arthritis Rheum 42:S54

    Google Scholar 

  • Jacobi AM, Odendahl M, Reiter K, Bruns A, Burmester GR, Radbruch A, Valet G, Lipsky PE, Dörner T (2003) Correlation between circulating CD27 (high) plasma cells and disease activity in patients with systemic lupus erythematosus. Arthritis Rheum 48:1332–1342

    Article  PubMed  Google Scholar 

  • Kassahn D, Kolb C, Solomon S, Bochtler P, Illges H (2002) Few human autoimmune sera detect GPI. Nat Immunol 3:411–412

    Article  PubMed  CAS  Google Scholar 

  • Kim HJ, Krenn V, Steinhauser G, Berek C (1999) Plasma cell development in synovial germinal centers in patients with rheumatoid and reactive arthritis. J Immunol 162:3053–3062

    PubMed  CAS  Google Scholar 

  • Korganow AS, Ji H, Mangialaio S, Duchatelle V, Pelanda R, Martin T, Degott C, Kikutani H, Rajewsky K, Pasquali JL, Benoist C, Mathis D (1999) From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins. Immunity 10:451–461

    Article  PubMed  CAS  Google Scholar 

  • Kouskoff V, Korganow AS, Duchatelle V, Degott C, Benoist C, Mathis D (1996) Organspecific disease provoked by systemic autoimmunity. Cell 87:811–822

    Article  PubMed  CAS  Google Scholar 

  • Kraj P, Rao SP, Glas AM, Hardy RR, Milner ECB, Silberstein LE (1997) The human heavy chain Ig V region gene repertoire is biased at all stages of B cell ontogeny, including early pre-B cells. J Immunol 158:5824–5832

    PubMed  CAS  Google Scholar 

  • Kremer JM, Westhovens R, Leon M, Di Giorgio E, Alten R, Steinfeld S, Russell A, Dougados M, Emery P, Nuamah IF, Williams GR, Becker JC, Hagerty DT, Moreland LW (2003) Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Eng J Med 349:1907–1915

    Article  CAS  Google Scholar 

  • Kyogoku C, Dijstelbloem HM, Tsuchiya N, Hatta Y, Kato H, Yamaguchi A, Fukazawa T, Jansen MD, Hashimoto H, van deWinkel JGJ, Kallenberg CGM, Tokunaga K (2002) Fc gamma receptor gene polymorphisms in Japanese patients with systemic lupus erythematosus-contribution of FCGR2B to genetic susceptibility. Arthritis Rheum 46:1242–1254

    Article  PubMed  CAS  Google Scholar 

  • Latour S, Fridman WH, Daeron M (1996) Identification, molecular cloning, biologic properties, and tissue distribution of a novel isoform of murine low-affinity IgG receptor homologous to human Fc gamma RIIB1. J Immunol 157:189–197

    PubMed  CAS  Google Scholar 

  • Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A (2002) Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416:603–607

    Article  PubMed  CAS  Google Scholar 

  • Leandro MJ, Edwards JCW, Cambridge G (2001) B lymphocyte depletion in rheumatoid arthritis. Early evidence for safety, efficacy, and dose response. Arthritis Rheum 44: S370

    Google Scholar 

  • Leandro MJ, Edwards JC, Cambridge G, Ehrenstein MR, Isenberg DA (2002a) An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum 46:2673–2677

    Article  PubMed  Google Scholar 

  • Leandro MJ, Edwards JCW, Cambridge G (2002b) Clinical outcome in 22 patients with rheumatoid arthritis treated with B lymphocyte depletion. Ann Rheum Dis 61:883–888

    Article  PubMed  CAS  Google Scholar 

  • Leandro MJ, Ehrenstein MR, Edwards JCW, Manson J, Cambridge G, Isenberg DA (2003) Treatment of refractory lupus nephritis with B lymphocyte depletion. Arthritis Rheum 48:S378

    Article  Google Scholar 

  • Lioubin MN, Algate PA, Tsai S, Carlberg K, Aebersold R, Rohrschneider LR (1996) p150(Ship), a signal transduction molecule with inositol polyphosphate-5-phosphatase activity. Genes Dev 10:1084–1095

    PubMed  CAS  Google Scholar 

  • Looney RJ, Anolik J, Sanz I (2004a) B cells as therapeutic targets for rheumatic diseases. Curr Opin Rheumatol 16:180–185

    Article  PubMed  CAS  Google Scholar 

  • Looney RJ, Anolik J, Sanz I (2004b) B lymphocytes in systemic lupus erythematosus: lessons from therapy targeting B cells. Lupus 13:381–390

    Article  PubMed  CAS  Google Scholar 

  • Maccioni M, Zeder-Lutz G, Huang HC, Ebel C, Gerber P, Hergueux J, Marchal P, Duchatelle V, Degott C, van Regenmortel M, Benoist C, Mathis D (2002) Arthritogenic monoclonal antibodies from K/BxN mice. J Exp Med 195:1071–1077

    Article  PubMed  CAS  Google Scholar 

  • Mackay F, Browning JL (2002) BAFF: a fundamental survival factor for B cells. Nature Rev Immunol 2:465–475

    Article  CAS  Google Scholar 

  • Mackay F, Mackay CR (2002) The role of BAFF in B-cell maturation, T-cell activation and autoimmunity. Trends Immunol 23:113–115

    Article  PubMed  CAS  Google Scholar 

  • Mackay F, Woodcock SA, Lawton P, Ambrose C, Baetscher M, Schneider P, Tschopp J, Browning JL (1999) Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med 190:1697–1710

    Article  PubMed  CAS  Google Scholar 

  • Malbec O, Fridman WH, Daeron M (1999) Negative regulation of hematopoietic cell activation and proliferation by Fc gamma RIIB. Curr Top Microbiol Immunol 244:13–27

    PubMed  CAS  Google Scholar 

  • Mangialaio S, Ji H, Korganow AS, Kouskoff V, Benoist C, Mathis D (1999) The arthritogenic T cell receptor and its ligand in a model of spontaneous arthritis. Arthritis Rheum 42:2517–2523

    Article  PubMed  CAS  Google Scholar 

  • Maruyama M, Lam KP, Rajewsky K (2000) Memory B-cell persistence is independent of persisting immunizing antigen. Nature 407:636–642

    Article  PubMed  CAS  Google Scholar 

  • Matsumoto I, Staub A, Benoist C, Mathis D (1999) Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme. Science 286:1732–1735

    Article  PubMed  CAS  Google Scholar 

  • Mockridge CI, Chapman CJ, Spellerberg MB, Sheth B, Fleming TP, Isenberg DA, Stevenson FK (1998) Sequence analysis of V4-34-encoded antibodies from single B cells of two patients with systemic lupus erythematosus (SLE). Clin Exp Immunol 114:129–136

    Article  PubMed  CAS  Google Scholar 

  • Nishimura H, Honjo T (2001) PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. Trends Immunol 22:265–268

    Article  PubMed  CAS  Google Scholar 

  • O’Connor BP, Raman VS, Erickson LD, Cook WJ, Weaver LK, Ahonen C, Lin LL, Mantchev GT, Bram RJ, Noelle RJ (2004) BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med 199:91–97

    Article  PubMed  CAS  Google Scholar 

  • O’Keefe TL, Williams GT, Batista FD, Neuberger MS (1999) Deficiency inCD22, a B cell-specific inhibitory receptor, is sufficient to predispose to development of high affinity autoantibodies. J Exp Med 189:1307–1313

    Article  PubMed  CAS  Google Scholar 

  • Odendahl M, Jacobi A, Hansen A, Feist E, Hiepe F, Burmester GR, Lipsky PE, Radbruch A, Dörner T (2000a) Disturbed peripheral B cell hemeostasis in SLE. Arthritis Rheum 43:S234

    Google Scholar 

  • Odendahl M, Jacobi A, Hansen A, Feist E, Hiepe F, Burmester GR, Lipsky PE, Radbruch A, Dörner T (2000b) Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J Immunol 165:5970–5979

    PubMed  CAS  Google Scholar 

  • Odendahl M, Keitzer R, Wahn U, Hiepe F, Radbruch A, Dörner T, Bunikowski R (2003) Perturbations of peripheral B lymphocyte homoeostasis in childrenwith systemic lupus erythematosus. Ann Rheum Dis 62:851–858

    Article  PubMed  CAS  Google Scholar 

  • Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T (2001) PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A 98:13866–13871

    Article  PubMed  CAS  Google Scholar 

  • Potter KN, Mockridge CI, Rahman A, Buchan S, Hamblin T, Davidson B, Isenberg DA, Stevenson FK (2002) Disturbances in peripheral blood B cell subpopulations in autoimmune patients. Lupus 11:872–877

    Article  PubMed  CAS  Google Scholar 

  • Pritchard NR, Smith KGC (2003) B cell inhibitory receptors and autoimmunity. Immunology 108:263–273

    Article  PubMed  CAS  Google Scholar 

  • Prodeus AP, Goerg S, Shen LM, Pozdnyakova OO, Chu L, Alicot EM, Goodnow CC, Carroll MC (1998) A critical role for complement in maintenance of self-tolerance. Immunity 9:721–731

    Article  PubMed  CAS  Google Scholar 

  • Pugh-Bernard AE, Silverman GJ, Cappione AJ, Villano ME, Ryan DH, Insel RA, Sanz I (2001) Regulation of inherently autoreactive VH4-34B cells in the maintenance of human B cell tolerance. J Clin Invest 108:1061–1070

    Article  PubMed  CAS  Google Scholar 

  • Rahman A, Latchman DS, Isenberg DA (1998) Immunoglobulin variable region sequences of human monoclonal anti-DNA antibodies. Semin Arthritis Rheum 28:141–154

    Article  PubMed  CAS  Google Scholar 

  • Saito E, Fujimoto M, Hasegawa M, Komura K, Hamaguchi Y, Koburagi Y, Nagaoka T, Takehara K, Tedder TF, Sato S (2002) CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse. J Clin Invest 109:1453–1462

    Article  PubMed  CAS  Google Scholar 

  • Schiemann B, Gommerman JL, Vora K, Cachero TG, Shulga-Morskaya S, Dobles M, Frew E, Scott ML (2001) An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 293:2111–2114

    Article  PubMed  CAS  Google Scholar 

  • Schubert D, Schmidt M, Zaiss D, Jungblut PR, Kamradt T (2002) Autoantibodies to GPI and creatine kinase in RA. Nature Immunol 3:411

    Article  CAS  Google Scholar 

  • Shai R, Quismorio FP, Li LL, Kwon OJ, Morrison J, Wallace DJ, Neuwelt CM, Brautbar C, Gauderman WJ, Jacob CO (1999) Genome-wide screen for systemic lupus erythematosus susceptibility genes in multiplex families. Human Mol Genet 8:639–644

    Article  CAS  Google Scholar 

  • Shlomchik MJ, Craft JE, Mamula MJ (2001) From T to B and back again: positive feedback in systemic autoimmune disease. Nature Rev Immunol 1:147–153

    Article  CAS  Google Scholar 

  • Shultz LD, Coman DR, Bailey CL, Beamer WG, Sidman CL (1984) Viable motheaten, a new allele at the motheaten locus. 1. Pathology. Am J Pathol 116:179–192

    PubMed  CAS  Google Scholar 

  • Sidman CL, Shultz LD, Hardy RR, Hayakawa K, Herzenberg LA (1986) Production of immunoglobulin isotypes by Ly-1+ B cells in viable moth-eaten and normal mice. Science 232:1423–1425

    PubMed  CAS  Google Scholar 

  • Smith KGC, Fearon DT (2000) Receptor modulators of B-cell receptor signalling—CD19/CD22. Signal transduction and the coordination of B lymphocyte development and function I. Curr Top Microbiol Immunol 245:195–212

    PubMed  CAS  Google Scholar 

  • Smith KGC, Tarlinton DM, Doody GM, Hibbs ML, Fearon DT (1998) Inhibition of the B cell by CD22: a requirement for Lyn. J Exp Med 187:807–811

    Article  PubMed  CAS  Google Scholar 

  • Strasser A, Whittingham S, Vaux DL, Bath ML, Adams JM, Cory S, Harris AW (1991) Enforced Bcl2 expression in B-lymphoid cells prolongs antibody-responses and elicits autoimmune-disease. Proc Natl Acad Sci U S A 88:8661–8665

    Article  PubMed  CAS  Google Scholar 

  • Takahashi Y, Cerasoli DM, Dal Porto JM, Shimoda M, Freund R, Fang W, Telander DG, Malvey EN, Mueller DL, Behrens TW, Kelsoe G (1999) Relaxed negative selection in germinal centers and impaired affinity maturation in bcl-x(L) transgenic mice. J Exp Med 190:399–409

    Article  PubMed  CAS  Google Scholar 

  • Tamir I, Dal Porto JM, Cambier JC (2000) Cytoplasmic protein tyrosine phosphatases SHP-1 and SHP-2: regulators of B cell signal transduction. CurrOpin Immunol 12:307–315

    CAS  Google Scholar 

  • Tedder TF (1998) Introduction: response-regulators of B lymphocyte signaling thresholds provide a context for antigen receptor signal transduction. Semin Immunol 10:259–265

    Article  PubMed  CAS  Google Scholar 

  • Tedder TF, Tuscano J, Sato S, Kehrl JH (1997) CD22, a B lymphocyte-specific adhesion molecule that regulates antigen receptor signaling. Ann Rev Immunol 15:481–504

    Article  CAS  Google Scholar 

  • Thompson JS, Bixler SA, Qian F, Vora K, Scott ML, Cachero TG, Hession C, Schneider P, Sizing ID, Mullen C, Strauch K, Zafari M, Benjamin CD, Tschopp J, Browning JL, Ambrose C (2001) BAFF-R, a newly identified TNF receptor that specifically interacts with BAFF. Science 293:2108–2111

    Article  PubMed  CAS  Google Scholar 

  • Van Vollenhoven RF, Bieber MM, Powell MJ, Gupta PK, Bhat NM, Richards KL, Albano SA, Teng NNH (1999) VH4-34 encoded antibodies in systemic lupus erythematosus: a specific diagnostic marker that correlates with clinical disease characteristics. J Rheumatol 26:1727–1733

    PubMed  Google Scholar 

  • Von Bulow GU, van Deursen JM, Bram RJ (2001) Regulation of the T-independent humoral response by TACI. Immunity 14:573–582

    Article  Google Scholar 

  • Voswinkel J, Trumper L, Carbon G, Hopf T, Pfreundschuh M, Gause A (1996) Evidence for a selected humoral immune response encoded by V(H)4 family genes in the synovial membrane of a patient with rheumatoid arthritis (RA). Clin Exp Immunol 106:5–12

    Article  PubMed  CAS  Google Scholar 

  • Wakeland EK, Liu K, Graham RR, Behrens TW (2001) Delineating the genetic basis of systemic lupus erythematosus. Immunity 15:397–408

    Article  PubMed  CAS  Google Scholar 

  • Xu SL, Lam KP (2001) B-cell maturation protein, which binds the tumor necrosis factor family members BAFF and APRIL, is dispensable for humoral immune responses. Mol Cell Biol 21:4067–4074

    Article  PubMed  CAS  Google Scholar 

  • Yan MH, Wang M, Chan B, Roose-Girma M, Erickson S, Baker T, Tumas D, Grewal IS, Dixit VM (2001) Activation and accumulation of B cells in TACI-deficient mice. Nature Immunol 2:638–643

    Article  CAS  Google Scholar 

  • Yavuz AS, Monson NL, Yavuz S, Grammer AC, Longo N, Girschick HJ, Lipsky PE (2002) Different patterns of bcl-6 and p53 gene mutations in tonsillar B cells indicate separate mutational mechanisms. Mol Immunol 39:485–493

    Article  PubMed  CAS  Google Scholar 

  • Yi AK, Tuetken R, Redford T, Waldschmidt M, Kirsch J, Krieg AM (1998) CpG motifs in bacterial DNA activate leukocytes through the pH-dependent generation of reactive oxygen species. J Immunol 160:4755–4761

    PubMed  CAS  Google Scholar 

  • Yu CCK, Tsui HW, Ngan BY, Shulman MJ, Wu GE, Tsui FWL (1996) B and T cells are not required for the viable motheaten phenotype. J Exp Med 183:371–380

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Campus Mitte, Coagulation Unit, Institute of Transfusion Medicine, Charite University Medicine Berlin, Schumannstr. 20/21, 10098, Berlin, Germany

    T. Dörner

  2. National Institutes of Health, NIAMS, Bethesda, MD, USA

    P. E. Lipsky

Authors
  1. T. Dörner
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  2. P. E. Lipsky
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Editors and Affiliations

  1. Deutsches Rheumaforschungszentrum Berlin (DRFZ), Schumannstr.21/22, 10117, Berlin, Germany

    Andreas Radbruch Ph.D.

  2. National Institute of Arthritis and Musculoskeletal and Skin Diseases, 9000 Rockville Pike, Bethesda, MD, 20892-1560, USA

    Peter E. Lipsky MD

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© 2006 Springer-Verlag Berlin Heidelberg

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Dörner, T., Lipsky, P.E. (2006). Signalling Pathways in B Cells: Implications for Autoimmunity. In: Radbruch, A., Lipsky, P.E. (eds) Current Concepts in Autoimmunity and Chronic Inflammation. Current Topics in Microbiology and Immunology, vol 305. Springer, Berlin, Heidelberg . https://doi.org/10.1007/3-540-29714-6_11

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