Mechanisms of central tolerance for B cells

Immune tolerance hinders the potentially destructive responses of lymphocytes to host tissues. Tolerance is regulated at the stage of immature B cell development (central tolerance) by clonal deletion, involving apoptosis, and by receptor editing, which reprogrammes the specificity of B cells through secondary recombination of antibody genes. Recent mechanistic studies have begun to elucidate how these divergent mechanisms are controlled. Single-cell antibody cloning has revealed defects of B cell central tolerance in human autoimmune diseases and in several human immunodeficiency diseases caused by single gene mutations, which indicates the relevance of B cell tolerance to disease and suggests possible genetic pathways that regulate tolerance.

[1]  Vasco M. Barreto,et al.  Frequency and Characterization of Phenotypic Ig Heavy Chain Allelically Included IgM-Expressing B Cells in Mice1 , 2000, The Journal of Immunology.

[2]  P. Shastry,et al.  Efficient generation in vitro, from human peripheral blood cells, of monoclonal Epstein-Barr virus transformants producing specific antibody to a variety of antigens without prior deliberate immunization. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Jan Delabie,et al.  Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma , 2010, Nature.

[4]  M. Nussenzweig,et al.  Igβ tyrosine residues contribute to the control of B cell receptor signaling by regulating receptor internalization , 2006, The Journal of experimental medicine.

[5]  P. Schneider,et al.  Cracking the BAFF code , 2009, Nature Reviews Immunology.

[6]  Renate Kunert,et al.  Cardiolipin Polyspecific Autoreactivity in Two Broadly Neutralizing HIV-1 Antibodies , 2005, Science.

[7]  R. Hardy,et al.  Control of the B cell-intrinsic tolerance programs by ubiquitin ligases Cbl and Cbl-b. , 2007, Immunity.

[8]  David Nemazee,et al.  Receptor editing in lymphocyte development and central tolerance , 2006, Nature Reviews Immunology.

[9]  D. Nemazee,et al.  Basal B Cell Receptor-Directed Phosphatidylinositol 3-Kinase Signaling Turns Off RAGs and Promotes B Cell-Positive Selection1 , 2007, The Journal of Immunology.

[10]  H. Arakawa,et al.  Re-evaluation of the probabilities for productive rearrangements on the κ andλloci , 1996 .

[11]  M. Nussenzweig,et al.  B-cell self-tolerance in humans. , 2007, Advances in immunology.

[12]  E. Meffre,et al.  Expansion of autoreactive unresponsive CD21-/low B cells in Sjögren's syndrome-associated lymphoproliferation. , 2013, Arthritis and rheumatism.

[13]  M. Farrar,et al.  B Cell Receptor Basal Signaling Regulates Antigen-Induced Ig Light Chain Rearrangements1 , 2008, The Journal of Immunology.

[14]  M. Reth Antigen receptors on B lymphocytes. , 1992, Annual review of immunology.

[15]  J. Cyster,et al.  Competition for follicular niches excludes self-reactive cells from the recirculating B-cell repertoire , 1994, Nature.

[16]  H. Zachau,et al.  The human immunoglobulin κ locus on yeast artificial chromosomes (YACs) , 1997 .

[17]  Trey Ideker,et al.  A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates the B cell fate , 2010, Nature Immunology.

[18]  David Nemazee,et al.  A role for nuclear factor kappa B/rel transcription factors in the regulation of the recombinase activator genes. , 2005, Immunity.

[19]  J E Collins,et al.  Organization of the human immunoglobulin lambda light-chain locus on chromosome 22q11.2. , 1995, Human molecular genetics.

[20]  M. Retter,et al.  Receptor Editing Occurs Frequently during Normal B Cell Development , 1998, The Journal of experimental medicine.

[21]  X. Dai,et al.  Phospholipase Cγ2 Contributes to Light-Chain Gene Activation and Receptor Editing , 2007, Molecular and Cellular Biology.

[22]  D. Nemazee,et al.  Receptor editing in self-reactive bone marrow B cells , 1993, The Journal of experimental medicine.

[23]  E. L. Prak,et al.  Light chain editing in kappa-deficient animals: a potential mechanism of B cell tolerance , 1994, The Journal of experimental medicine.

[24]  T. Behrens,et al.  Self-reactive B lymphocytes overexpressing Bcl-xL escape negative selection and are tolerized by clonal anergy and receptor editing. , 1998, Immunity.

[25]  K. Rajewsky,et al.  Receptor editing in a transgenic mouse model: site, efficiency, and role in B cell tolerance and antibody diversification. , 1997, Immunity.

[26]  M. Wabl,et al.  Pro-B cells sense productive immunoglobulin heavy chain rearrangement irrespective of polypeptide production , 2011, Proceedings of the National Academy of Sciences.

[27]  T Pawson,et al.  Role of Syk in B-cell development and antigen-receptor signaling. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[28]  M. Neuberger,et al.  Antigen presentation by the B cell antigen receptor is driven by the alpha/beta sheath and occurs independently of its cytoplasmic tyrosines. , 1993, Cell.

[29]  P. Leder,et al.  Allelic exclusion in transgenic mice that express the membrane form of immunoglobulin mu. , 1987, Science.

[30]  D. Nemazee,et al.  Clonal deletion of autoreactive B lymphocytes in bone marrow chimeras. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[31]  K. Rajewsky,et al.  Surrogate light chain expression is required to establish immunoglobulin heavy chain allelic exclusion during early B cell development. , 1996, Immunity.

[32]  B. Haynes,et al.  HIV-1 Envelope gp41 Broadly Neutralizing Antibodies: Hurdles for Vaccine Development , 2014, PLoS pathogens.

[33]  K. Akashi,et al.  CIN85 is required for Cbl-mediated regulation of antigen receptor signaling in human B cells. , 2012, Blood.

[34]  D. Schatz,et al.  RAG1 and ATM coordinate monoallelic recombination and nuclear positioning of immunoglobulin loci , 2009, Nature Immunology.

[35]  A. Basten,et al.  Reduced life span of anergic self-reactive B cells in a double- transgenic model , 1994, The Journal of experimental medicine.

[36]  K. Hayashi,et al.  Impaired Receptor Editing in the Primary B Cell Repertoire of BASH-Deficient Mice1 , 2004, The Journal of Immunology.

[37]  T. Waldmann,et al.  Clustered arrangement of immunoglobulin lambda constant region genes in man. , 1981, Nature.

[38]  A. Notkins,et al.  Polyreactive Antibodies: Function and Quantification. , 2015, The Journal of infectious diseases.

[39]  Tetsuya Nakamura,et al.  Unexpected requirement for ZAP-70 in pre-B cell development and allelic exclusion. , 2003, Immunity.

[40]  N. Bottini,et al.  PTPN22: the archetypal non-HLA autoimmunity gene , 2014, Nature Reviews Rheumatology.

[41]  T. Yamazaki,et al.  Regulation of B-cell development by BCAP and CD19 through their binding to phosphoinositide 3-kinase. , 2008, Blood.

[42]  M. Farrar,et al.  Tonic BCR signaling represses receptor editing via Raf- and calcium-dependent signaling pathways. , 2011, Immunology letters.

[43]  M. Schlissel,et al.  NF-κB activity marks cells engaged in receptor editing , 2009, The Journal of experimental medicine.

[44]  Anthony C. Bishop,et al.  Entry of B Cell Receptor into Signaling Domains Is Inhibited in Tolerant B Cells , 2000, The Journal of experimental medicine.

[45]  D. Nemazee,et al.  Decoration of T-independent antigen with ligands for CD22 and Siglec-G can suppress immunity and induce B cell tolerance in vivo , 2010, The Journal of experimental medicine.

[46]  A. Brunet,et al.  The FoxO code , 2008, Oncogene.

[47]  The B Lymphocyte Adaptor Molecule of 32 Kilodaltons (Bam32) Regulates B Cell Antigen Receptor Internalization1 , 2004, The Journal of Immunology.

[48]  Christopher C. Goodnow,et al.  C3d of Complement as a Molecular Adjuvant: Bridging Innate and Acquired Immunity , 1996, Science.

[49]  P. Gregersen,et al.  The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans. , 2011, The Journal of clinical investigation.

[50]  H. Urlaub,et al.  The B-cell antigen receptor signals through a preformed transducer module of SLP65 and CIN85 , 2011, The EMBO journal.

[51]  K. Rajewsky,et al.  Interference with Immunoglobulin (Ig)α Immunoreceptor Tyrosine–Based Activation Motif (Itam) Phosphorylation Modulates or Blocks B Cell Development, Depending on the Availability of an Igβ Cytoplasmic Tail , 2001, The Journal of experimental medicine.

[52]  K. Rajewsky,et al.  Development of immunoglobulin λ-chain–positive B cells, but not editing of immunoglobulin κ-chain, depends on NF-κB signals , 2009, Nature Immunology.

[53]  F. Sallusto,et al.  High throughput cellular screens to interrogate the human T and B cell repertoires. , 2011, Current opinion in immunology.

[54]  J. Cambier,et al.  B lymphocyte antigen receptor signaling: initiation, amplification, and regulation , 2013, F1000prime reports.

[55]  R. Hardy,et al.  A VH11Vκ9 B Cell Antigen Receptor Drives Generation of CD5+ B Cells Both In Vivo and In Vitro1 , 2000, The Journal of Immunology.

[56]  E. L. Prak,et al.  Light chain replacement: a new model for antibody gene rearrangement , 1995, The Journal of experimental medicine.

[57]  M. Nussenzweig,et al.  Human Autoantibody Silencing by Immunoglobulin Light Chains , 2004, The Journal of experimental medicine.

[58]  A. Dinner,et al.  B Cell Antigen Receptor Signaling and Internalization Are Mutually Exclusive Events , 2006, PLoS biology.

[59]  D. Nemazee,et al.  Negative Selection by IgM Superantigen Defines a B Cell Central Tolerance Compartment and Reveals Mutations Allowing Escape , 2011, The Journal of Immunology.

[60]  George Georgiou,et al.  In-depth determination and analysis of the human paired heavy- and light-chain antibody repertoire , 2014, Nature Medicine.

[61]  M. Schlissel,et al.  Foxo1 directly regulates the transcription of recombination-activating genes during B cell development , 2008, Nature Immunology.

[62]  R. Pelanda,et al.  Receptor editing is the main mechanism of B cell tolerance toward membrane antigens , 2004, Nature Immunology.

[63]  D. Hafler,et al.  Specific peripheral B cell tolerance defects in patients with multiple sclerosis. , 2013, The Journal of clinical investigation.

[64]  E. Meffre,et al.  PTPN22 inhibition resets defective human central B cell tolerance , 2016, Science Immunology.

[65]  M. Shlomchik,et al.  TLR9 Promotes Tolerance by Restricting Survival of Anergic Anti-DNA B Cells, Yet Is Also Required for Their Activation , 2013, The Journal of Immunology.

[66]  P. Pandolfi,et al.  BCR-mediated apoptosis associated with negative selection of immature B cells is selectively dependent on Pten , 2009, Cell Research.

[67]  M. Neuberger,et al.  Antigen presentation by the B cell antigen receptor is driven by the α β sheath and occurs independently of its cytoplasmic tyrosines , 1993, Cell.

[68]  Tony Pawson,et al.  Syk tyrosine kinase required for mouse viability and B-cell development , 1995, Nature.

[69]  J. Monroe ITAM-mediated tonic signalling through pre-BCR and BCR complexes , 2006, Nature Reviews Immunology.

[70]  R. Schneider,et al.  Arginine methylation of the B cell antigen receptor promotes differentiation , 2010, The Journal of experimental medicine.

[71]  R. Pelanda,et al.  Ras activation of Erk restores impaired tonic BCR signaling and rescues immature B cell differentiation , 2010 .

[72]  M. Reth,et al.  Regulation of B-cell proliferation and differentiation by pre-B-cell receptor signalling , 2009, Nature Reviews Immunology.

[73]  S. Korsmeyer,et al.  Enforced Bcl-2 Expression Inhibits Antigen-mediated Clonal Elimination of Peripheral B Cells in an Antigen Dose–dependent Manner and Promotes Receptor Editing in Autoreactive, Immature B Cells , 1997, The Journal of experimental medicine.

[74]  Jayajit Das,et al.  Monovalent and Multivalent Ligation of the B Cell Receptor Exhibit Differential Dependence upon Syk and Src Family Kinases , 2013, Science Signaling.

[75]  D. Nemazee,et al.  Developmental Regulation of B Lymphocyte Immune Tolerance Compartmentalizes Clonal Selection from Receptor Selection , 1998, Cell.

[76]  J. Cambier,et al.  Co‐receptor and accessory regulation of B‐cell antigen receptor signal transduction , 1997, Immunological reviews.

[77]  H. Ploegh,et al.  Predominant Autoantibody Production by Early Human B Cell Precursors , 2003 .

[78]  F. Alt,et al.  Ordered rearrangement of immunoglobulin heavy chain variable region segments. , 1984, The EMBO journal.

[79]  K. Rajewsky,et al.  VH replacement in primary immunoglobulin repertoire diversification , 2015, Proceedings of the National Academy of Sciences.

[80]  M. Reth,et al.  B cell activation involves nanoscale receptor reorganizations and inside-out signaling by Syk , 2014, eLife.

[81]  U. Storb Transgenic mice with immunoglobulin genes. , 1987, Annual review of immunology.

[82]  J. Erikson,et al.  The regulation of lupus-associated autoantibodies: immunoglobulin transgenic models. , 2003, Current opinion in immunology.

[83]  M. Radic,et al.  Genetic and structural evidence for antigen selection of anti-DNA antibodies. , 1994, Annual review of immunology.

[84]  A. Feeney,et al.  Reduced receptor editing in lupus-prone MRL/lpr mice , 2007, The Journal of experimental medicine.

[85]  D. Nemazee,et al.  The scope of receptor editing and its association with autoimmunity. , 2004, Current opinion in immunology.

[86]  Shoham Shivtiel,et al.  Receptor editing in CD45‐deficient immature B cells , 2002, European journal of immunology.

[87]  A. Soley,et al.  Overexpression of Fkbp11, a feature of lupus B cells, leads to B cell tolerance breakdown and initiates plasma cell differentiation , 2015, Immunity, inflammation and disease.

[88]  C. Goodnow,et al.  Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens , 1991, Nature.

[89]  D. Baltimore,et al.  Functional immunoglobulin transgenes guide ordered B-cell differentiation in Rag-1-deficient mice. , 1994, Genes & development.

[90]  C. Goodnow,et al.  Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity , 2014, Proceedings of the National Academy of Sciences.

[91]  R. Hendriks,et al.  Cellular Maturation Defects in Bruton’s Tyrosine Kinase-Deficient Immature B Cells Are Amplified by Premature B Cell Receptor Expression and Reduced by Receptor Editing1 , 2004, The Journal of Immunology.

[92]  R. Pelanda,et al.  Activation of Ras overcomes B-cell tolerance to promote differentiation of autoreactive B cells and production of autoantibodies , 2014, Proceedings of the National Academy of Sciences.

[93]  E. L. Luning Prak,et al.  B-Cell Tolerance Defects in the B6.Aec1/2 Mouse Model of Sjögren’s Syndrome , 2012, Journal of Clinical Immunology.

[94]  M. Cooke,et al.  Elimination of self-reactive B lymphocytes proceeds in two stages: Arrested development and cell death , 1993, Cell.

[95]  R. Lu,et al.  A Role for Interferon Regulatory Factor 4 in Receptor Editing , 2008, Molecular and Cellular Biology.

[96]  H. Wardemann,et al.  Autoreactive B cell receptors mimic autonomous pre-B cell receptor signaling and induce proliferation of early B cells. , 2008, Immunity.

[97]  S. Tonegawa,et al.  Somatic generation of antibody diversity. , 1976, Nature.

[98]  E. Meffre,et al.  Rituximab does not reset defective early B cell tolerance checkpoints. , 2016, The Journal of clinical investigation.

[99]  N. Schork,et al.  Skewed Primary Igκ Repertoire and V–J Joining in C57BL/6 Mice: Implications for Recombination Accessibility and Receptor Editing , 2012, The Journal of Immunology.

[100]  D. Nemazee,et al.  Rearrangement of mouse immunoglobulin kappa deleting element recombining sequence promotes immune tolerance and lambda B cell production. , 2008, Immunity.

[101]  J. Cambier,et al.  Unique Signaling Properties of B Cell Antigen Receptor in Mature and Immature B Cells: Implications for Tolerance and Activation1 , 2001, The Journal of Immunology.

[102]  K. Kuma,et al.  The Complete Nucleotide Sequence of the Human Immunoglobulin Heavy Chain Variable Region Locus , 1998, The Journal of experimental medicine.

[103]  G. Köhler,et al.  Transitional B cells are the target of negative selection in the B cell compartment , 1995, The Journal of experimental medicine.

[104]  K. Higashi,et al.  Role of Tyrosine Phosphorylation of HS1 in B Cell Antigen Receptor-mediated Apoptosis , 1997, The Journal of experimental medicine.

[105]  K. Okkenhaug Signaling by the phosphoinositide 3-kinase family in immune cells. , 2013, Annual review of immunology.

[106]  A. Strasser,et al.  Loss of the Pro-Apoptotic BH3-only Bcl-2 Family Member Bim Inhibits BCR Stimulation–induced Apoptosis and Deletion of Autoreactive B Cells , 2003, The Journal of experimental medicine.

[107]  Kong-Peng Lam,et al.  Basal Immunoglobulin Signaling Actively Maintains Developmental Stage in Immature B Cells , 2005, PLoS biology.

[108]  M. Reth,et al.  Amplification of B cell antigen receptor signaling by a Syk/ITAM positive feedback loop. , 2002, Molecular cell.

[109]  S. Camper,et al.  Receptor editing: an approach by autoreactive B cells to escape tolerance , 1993, The Journal of experimental medicine.

[110]  N. Klinman The "clonal selection hypothesis" and current concepts of B cell tolerance. , 1996, Immunity.

[111]  J Erikson,et al.  B lymphocytes may escape tolerance by revising their antigen receptors , 1993, The Journal of experimental medicine.

[112]  Corwin M. Nycholat,et al.  Antigenic liposomes displaying CD22 ligands induce antigen-specific B cell apoptosis. , 2013, The Journal of clinical investigation.

[113]  C. Goodnow,et al.  Control systems and decision making for antibody production , 2010, Nature Immunology.

[114]  F. Grosveld,et al.  Bruton's Tyrosine Kinase Regulates the Activation of Gene Rearrangements at the λ Light Chain Locus in Precursor B Cells in the Mouse , 2001, The Journal of experimental medicine.

[115]  R. Fischel,et al.  Autoimmune NZB/NZW F1 mice utilize B cell receptor editing for generating high‐affinity anti‐dsDNA autoantibodies from low‐affinity precursors , 2003, European journal of immunology.

[116]  J. Cyster,et al.  Polygenic autoimmune traits: Lyn, CD22, and SHP-1 are limiting elements of a biochemical pathway regulating BCR signaling and selection. , 1998, Immunity.

[117]  F. Brodsky,et al.  Lipid rafts unite signaling cascades with clathrin to regulate BCR internalization. , 2002, Immunity.

[118]  K. Rajewsky,et al.  B cell deletion, anergy, and receptor editing in "knock in" mice targeted with a germline-encoded or somatically mutated anti-DNA heavy chain. , 1998, Journal of immunology.

[119]  L. Notarangelo,et al.  Activation-Induced Cytidine Deaminase Expression in Human B Cell Precursors Is Essential for Central B Cell Tolerance. , 2015, Immunity.

[120]  D. Schatz,et al.  Sin1-mTORC2 suppresses rag and il7r gene expression through Akt2 in B cells. , 2010, Molecular cell.

[121]  P. Gregersen,et al.  Checkpoints for Autoreactive B Cells in the Peripheral Blood of Lupus Patients Assessed by Flow Cytometry , 2016, Arthritis & rheumatology.

[122]  F. Alt,et al.  Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency , 2010, The Journal of experimental medicine.

[123]  J. Kearney,et al.  Lupus Susceptibility Genes May Breach Tolerance to DNA by Impairing Receptor Editing of Nuclear Antigen-Reactive B Cells1 , 2007, The Journal of Immunology.

[124]  R. Pelanda Dual immunoglobulin light chain B cells: Trojan horses of autoimmunity? , 2014, Current opinion in immunology.

[125]  B. Lim,et al.  Multiple Checkpoint Breach of B Cell Tolerance in Rasgrp1-Deficient Mice , 2013, The Journal of Immunology.

[126]  K. Rajewsky,et al.  The B-cell antigen receptor integrates adaptive and innate immune signals , 2015, Proceedings of the National Academy of Sciences.

[127]  V. Pascual,et al.  Autoreactive IgG memory antibodies in patients with systemic lupus erythematosus arise from nonreactive and polyreactive precursors , 2008, Proceedings of the National Academy of Sciences.

[128]  M. Nussenzweig,et al.  Bam32 links the B cell receptor to ERK and JNK and mediates B cell proliferation but not survival. , 2003, Immunity.

[129]  K. Rajewsky,et al.  In Vivo Ablation of Surface Immunoglobulin on Mature B Cells by Inducible Gene Targeting Results in Rapid Cell Death , 1997, Cell.

[130]  M. Gershwin,et al.  B cells in autoimmune diseases: insights from analyses of immunoglobulin variable (Ig V) gene usage. , 2007, Autoimmunity reviews.

[131]  W. Robinson,et al.  Biomarkers to guide clinical therapeutics in rheumatology? , 2016, Current opinion in rheumatology.

[132]  D. Melamed,et al.  The MAPK/ERK and PI(3)K Pathways Additively Coordinate the Transcription of Recombination-Activating Genes in B Lineage Cells , 2010, The Journal of Immunology.

[133]  Yasuhiro Imamura,et al.  BLNK Binds Active H-Ras to Promote B Cell Receptor-mediated Capping and ERK Activation* , 2009, Journal of Biological Chemistry.

[134]  D. Cantrell,et al.  The BAFF Receptor Transduces Survival Signals by Co-opting the B Cell Receptor Signaling Pathway , 2013, Immunity.

[135]  M. Schlissel,et al.  Allelic exclusion of immunoglobulin gene rearrangement and expression: why and how? , 2002, Seminars in immunology.

[136]  R. DePinho,et al.  SLP-65 regulates immunoglobulin light chain gene recombination through the PI(3)K-PKB-Foxo pathway , 2008, Nature Immunology.

[137]  J. Casanova,et al.  Defects in the CD19 complex predispose to glomerulonephritis, as well as IgG1 subclass deficiency. , 2011, The Journal of allergy and clinical immunology.

[138]  C. Cunningham-Rundles,et al.  Bruton's Tyrosine Kinase Is Essential for Human B Cell Tolerance , 2004, The Journal of experimental medicine.

[139]  F. Melchers The pre-B-cell receptor: selector of fitting immunoglobulin heavy chains for the B-cell repertoire , 2005, Nature Reviews Immunology.

[140]  S. Smith‐Gill,et al.  Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. , 2009, Journal of immunology.

[141]  T. Mak,et al.  Regulation of B-lymphocyte negative and positive selection by tyrosine phosphatase CD45 , 1996, Nature.

[142]  T. Waldmann,et al.  Clustered arrangement of immunoglobulin λ constant region genes in man , 1981, Nature.

[143]  Bernd Wollscheid,et al.  SLP-65: A New Signaling Component in B Lymphocytes which Requires Expression of the Antigen Receptor for Phosphorylation , 1998, The Journal of experimental medicine.

[144]  Franca Fraternali,et al.  Significant Differences in Physicochemical Properties of Human Immunoglobulin Kappa and Lambda CDR3 Regions , 2016, Front. Immunol..

[145]  D. Nemazee,et al.  Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes , 1989, Nature.

[146]  T. Behrens,et al.  In Vivo Assessment of the Relative Contributions of Deletion, Anergy, and Editing to B Cell Self-Tolerance1 , 2005, The Journal of Immunology.

[147]  E. L. Prak,et al.  Editing disease-associated autoantibodies. , 1997, Immunity.

[148]  E. Bertolino,et al.  A self-reinforcing regulatory network triggered by limiting IL-7 activates pre-BCR signaling and differentiation , 2012, Nature Immunology.

[149]  R. DePinho,et al.  PI3 Kinase Signals BCR-Dependent Mature B Cell Survival , 2009, Cell.

[150]  Hong Wu,et al.  Pten inactivation alters peripheral B lymphocyte fate and reconstitutes CD19 function , 2003, Nature Immunology.

[151]  D. Nemazee,et al.  Receptor editing and genetic variability in human autoreactive B cells , 2016, The Journal of experimental medicine.

[152]  A. Tarakhovsky,et al.  Essential role of Src-family protein tyrosine kinases in NF-κB activation during B cell development , 2003, Nature Immunology.

[153]  V. Pascual,et al.  Defective B cell tolerance checkpoints in systemic lupus erythematosus , 2005, The Journal of experimental medicine.

[154]  S. Akira,et al.  Contribution of Receptor Editing to the Antibody Repertoire , 2007 .

[155]  M. Reth,et al.  Induction of the antigen receptor expression on B lymphocytes results in rapid competence for signaling of SLP‐65 and Syk , 1998, The EMBO journal.

[156]  Xiaoli Li,et al.  The physiologic role of CD19 cytoplasmic tyrosines. , 2002, Immunity.

[157]  M. Reth,et al.  Oligomeric organization of the B-cell antigen receptor on resting cells , 2010, Nature.

[158]  R. Geahlen,et al.  Visualization of Syk-Antigen Receptor Interactions Using Green Fluorescent Protein: Differential Roles for Syk and Lyn in the Regulation of Receptor Capping and Internalization1 , 2001, The Journal of Immunology.

[159]  R. Hardy,et al.  Expression of anti-DNA immunoglobulin transgenes in non-autoimmune mice , 1991, Nature.

[160]  James W. Thomas,et al.  B Lymphocyte “Original Sin” in the Bone Marrow Enhances Islet Autoreactivity in Type 1 Diabetes–Prone Nonobese Diabetic Mice , 2013, The Journal of Immunology.

[161]  J. Cambier,et al.  Phosphatase regulation of immunoreceptor signaling in T cells, B cells and mast cells. , 2013, Current opinion in immunology.

[162]  R. Geha,et al.  CVID-associated TACI mutations affect autoreactive B cell selection and activation. , 2013, The Journal of clinical investigation.

[163]  M. Marks,et al.  Cis and Trans Regulatory Mechanisms Control AP2-Mediated B Cell Receptor Endocytosis via Select Tyrosine-Based Motifs , 2013, PloS one.

[164]  Anselm H. C. Horn,et al.  Responsiveness of B cells is regulated by the hinge region of IgD , 2015, Nature Immunology.

[165]  C. Xiao,et al.  Regulation of B-cell development and tolerance by different members of the miR-17∼92 family microRNAs , 2016, Nature Communications.

[166]  J. Payton,et al.  RAG-mediated DNA double-strand breaks activate a cell type–specific checkpoint to inhibit pre–B cell receptor signals , 2016, The Journal of experimental medicine.

[167]  G. Kelsoe,et al.  Activation-induced cytidine deaminase mediates central tolerance in B cells , 2011, Proceedings of the National Academy of Sciences.

[168]  M. Weigert,et al.  Autoreactive B Cells in the Marginal Zone that Express Dual Receptors , 2002, The Journal of experimental medicine.

[169]  K. Rajewsky,et al.  A Prematurely Expressed Igκ Transgene, but Not a VκJκ Gene Segment Targeted into the Igκ Locus, Can Rescue B Cell Development in λ5-Deficient Mice , 1996 .

[170]  Graham F. Brady,et al.  Regulation of basement membrane-reactive B cells in BXSB, (NZBxNZW)F1, NZB, and MRL/lpr lupus mice , 2013, Autoimmunity.

[171]  E. Meffre The establishment of early B cell tolerance in humans: lessons from primary immunodeficiency diseases , 2011, Annals of the New York Academy of Sciences.

[172]  Katherine S. Yang-Iott,et al.  The Ataxia Telangiectasia mutated kinase controls Igκ allelic exclusion by inhibiting secondary Vκ-to-Jκ rearrangements , 2013, The Journal of experimental medicine.

[173]  O. Ostrovsky,et al.  Modification of Ligand-independent B Cell Receptor Tonic Signals Activates Receptor Editing in Immature B Lymphocytes* , 2004, Journal of Biological Chemistry.

[174]  M. Reth,et al.  Molecular components of the B-cell antigen receptor complex of the IgM class , 1990, Nature.

[175]  T. Hashimshony,et al.  Regulation of immunoglobulin light-chain recombination by the transcription factor IRF-4 and the attenuation of interleukin-7 signaling. , 2008, Immunity.

[176]  J. Casanova,et al.  IRAK-4- and MyD88-dependent pathways are essential for the removal of developing autoreactive B cells in humans. , 2008, Immunity.

[177]  R. Hardy,et al.  The site and stage of anti-DNA B-cell deletion , 1995, Nature.

[178]  M. Schlissel,et al.  Changes in Locus-specific V(D)J Recombinase Activity Induced by Immunoglobulin Gene Products during B Cell Development , 1997, The Journal of experimental medicine.

[179]  C. Xiao,et al.  The microRNA miR-148a functions as a critical regulator of B cell tolerance and autoimmunity , 2015, Nature Immunology.

[180]  C. Murre,et al.  Distinct roles for E12 and E47 in B cell specification and the sequential rearrangement of immunoglobulin light chain loci , 2009, The Journal of experimental medicine.

[181]  E. Meffre,et al.  Impaired early B cell tolerance in patients with rheumatoid arthritis , 2005, The Journal of experimental medicine.

[182]  S. Shen-Orr,et al.  A c-Myc/miR17-92/Pten Axis Controls PI3K-Mediated Positive and Negative Selection in B Cell Development and Reconstitutes CD19 Deficiency. , 2016, Cell reports.

[183]  R. Moon,et al.  A disease-associated PTPN22 variant promotes systemic autoimmunity in murine models. , 2013, The Journal of clinical investigation.

[184]  C. Murre,et al.  Receptor Editing and Marginal Zone B Cell Development Are Regulated by the Helix-Loop-Helix Protein, E2A , 2004, The Journal of experimental medicine.

[185]  E. Meffre,et al.  Defective B cell tolerance in adenosine deaminase deficiency is corrected by gene therapy. , 2012, The Journal of clinical investigation.

[186]  K. Rajewsky,et al.  CIN85 drives B cell responses by linking BCR signals to the canonical NF-κB pathway , 2011, The Journal of experimental medicine.

[187]  R. Rickert New insights into pre-BCR and BCR signalling with relevance to B cell malignancies , 2013, Nature Reviews Immunology.

[188]  M. Turner,et al.  Syk Tyrosine Kinase Is Required for the Positive Selection of Immature B Cells into the Recirculating B Cell Pool , 1997, The Journal of experimental medicine.

[189]  A. Weiss,et al.  Stim1, PKCδ and RasGRP proteins set a threshold for pro-apoptotic Erk signaling during B cell development , 2011, Nature Immunology.

[190]  M. Fujimoto,et al.  CD19 regulates Src family protein tyrosine kinase activation in B lymphocytes through processive amplification. , 2000, Immunity.

[191]  M. Turner,et al.  Cutting Edge: The PI3K p110δ Is Required for Down-Regulation of RAG Expression in Immature B Cells1 , 2007, The Journal of Immunology.

[192]  H. Arakawa,et al.  Re-evaluation of the probabilities for productive arrangements on the kappa and lambda loci. , 1996, International immunology.

[193]  I. Mårtensson,et al.  VpreB1/VpreB2/λ5 Triple-Deficient Mice Show Impaired B Cell Development but Functional Allelic Exclusion of the IgH Locus1 , 2002, The Journal of Immunology.