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B-cell tolerance checkpoints in health and autoimmunity
Eric Meffre1 and Hed...
Human B cell tolerance checkpoints Meffre and Wardemann 633

Figure 1                                                  ...
634 Autoimmunity

Figure 2

Patients with autoimmunity show increased frequency of autoreactive clones in the naıve ...
Human B cell tolerance checkpoints Meffre and Wardemann 635

including ANAs [18]. Thus, CD40/CD40L interactions        ...
636 Autoimmunity

cells. The alteration of these factors in immunodeficient                  11. Yurasov S, Wardemann H,...
Human B cell tolerance checkpoints Meffre and Wardemann 637

26. Leslie D, Lipsky P, Notkins AL: Autoantibodies as pred...
638 Autoimmunity

58. Casali P, Burastero SE, Nakamura M, Inghirami G, Notkins AL:   60. Kasaian MT, Ikematsu H, Casali...
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B-cell tolerance checkpoints in health and autoimmunity


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B-cell tolerance checkpoints in health and autoimmunity

  1. 1. Available online at www.sciencedirect.com B-cell tolerance checkpoints in health and autoimmunity Eric Meffre1 and Hedda Wardemann2 The enormous diversity of the antibody repertoire is generated ensured by several B-cell tolerance checkpoints at which by two mechanisms: recombination of immunoglobulin (Ig) developing autoreactive B cells are counterselected. gene variable (V), diversity (D), and joining (J) gene segments Although transgenic mice carrying prerearranged self- during the early stages of B-cell development in the bone reactive Ig genes were instrumental in understanding marrow and somatic hypermutation (SHM) of functional Ig the mechanisms that regulate developing selfreactive B genes from antigen-activated B cells within secondary cells, these models did not allow estimates on the fre- lymphoid organs. Diversity by V(D)J recombination and SHM quency at which selfreactive BCRs are generated by not only provides protective humoral immunity but also V(D)J recombination in normal mice or healthy humans generates potentially harmful clones expressing with a quasi-unlimited Ig gene repertoire [2–7]. In the last autoantibodies. Under normal circumstances, several five years, insight in the contribution of autoreactive B mechanisms regulate the removal of autoreactive B cells and cells to the normal human B cell repertoire and their defects in central and peripheral B cell tolerance checkpoints regulation at selftolerance checkpoints came from the are associated with the development of autoimmunity in analysis of monoclonal antibodies cloned from single humans. purified B cells at different stages during their develop- Addresses ment [8,9,10,11,12,13–15,16,17,18,19]. 1 Hospital for Special Surgery, Weill Medical College of Cornell University, New York, NY 10021, USA 2 Selection of the naıve B cell repertoire ¨ ´ Max-Planck-Institute for Infection Biology, Chariteplatz 1, 10117 Berlin, ¨ The naıve B cell repertoire is devoid of SHMs and its Germany BCR diversity relies entirely on random Ig V(D)J gene Corresponding author: Meffre, Eric (meffree@hss.edu) and Wardemann, recombination in developing B-cell precursors. Early Hedda (wardemann@mpiib-berlin.mpg.de) immature B cells are the first precursors in the BM that express functionally rearranged Ig gene transcripts but lack detectable surface IgMs (Figure 1). In healthy Current Opinion in Immunology 2008, 20:632–638 donors, we found that more than 75% of the recombinant This review comes from a themed issue on antibodies cloned from single early immature B cells were Autoimmunity autoreactive that is polyreactive with several individual Edited by Ciriaco Piccirillo and Roberta Pelanda antigens that included insulin, DNA, and lipopolysac- Available online 25th October 2008 charide (LPS) and/or reactive against the human larynx carcinoma HEp-2 cell line (Figure 1) [8]. In addition, 0952-7915/$ – see front matter many early immature B cells expressed antinuclear anti- # 2008 Elsevier Ltd. All rights reserved. bodies (ANAs) typically associated with autoimmunity DOI 10.1016/j.coi.2008.09.001 [8]. Thus, random V(D)J recombination generates large numbers of potentially harmful B cells expressing auto- reactive BCRs. However, many autoreactive B cells in- cluding those expressing ANAs were removed from the Introduction nascent repertoire at a first central tolerance checkpoint A prerequisite for the generation of effective humoral before the surface IgM-positive immature B cell stage immune responses is the diversity and specificity of the [8]. antibody repertoire. Diversity of the nascent B cell pool in the bone marrow (BM) is generated by the random Three known selftolerance mechanisms regulate devel- recombination of immunoglobulin (Ig) variable (V), oping autoreactive B cells in the BM [2–7]. Strong BCR diversity (D), and joining (J) gene segments at the heavy signals induce deletion by apoptosis whereas intermedi- (H) and light (L) chain locus. In addition, antibody ate signals promote secondary recombination events pre- specificity of antigen-challenged B cells in the periphery dominantly at the IgL chain locus thus giving the cell the is further improved by random somatic hypermutations chance to edit its BCR and decrease its selfreactivity. (SHM) on IgH and IgL genes and subsequent selection of Alternatively, selfreactive B cells can become anergic or B-cell clones expressing Igs with increased affinity for the ignorant, a status of antigen unresponsiveness, which stimulating antigen. Because V(D)J recombination and allows the cells to leave the BM [3,4,20]. Estimates on SHM are random mechanisms, the resulting Ig repertoire the relative contribution of deletion, editing, and anergy cannot be predicted and includes the generation of B-cell in mice and humans suggest that 20–50% of all peripheral receptors (BCRs) that can recognize the body’s own ¨ naıve B cells have undergone receptor editing by IgL selfantigens [1]. Attempts to thwart autoimmunity are chain replacement whereas deletion and anergy play only Current Opinion in Immunology 2008, 20:632–638 www.sciencedirect.com
  2. 2. Human B cell tolerance checkpoints Meffre and Wardemann 633 Figure 1 cells lacking surface Ig because of high levels of self- reactivity and that the majority of these cells are actively undergoing receptor editing [25]. Only about 10% of early immature B cell antibodies were refractory to silencing of selfreactivity by in vitro IgL chain exchange suggesting that they may be lost from the repertoire by deletion [25]. Despite the efficient removal of large numbers of auto- reactive B cells in the BM, some selfreactive clones escape central tolerance and migrate in the periphery as transitional/new emigrant B cells (Figure 1) [8]. The decreased frequency of autoreactive clones in mature ¨ naıve B cells as compared to new emigrant B cells revealed a second B cell tolerance checkpoint in the periphery which likely results from the removal of auto- reactive new emigrant B cells that recognize peripheral antigens not expressed in the BM (Figure 1) [8]. Thus under normal circumstances, two early tolerance check- points regulate developing autoreactive human B cells: the first one at the immature B cell stage in the BM and the second one at the transition from new emigrant to ¨ mature naıve B cells in the periphery. Defective early B cell tolerance checkpoints in SLE and RA Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are autoimmune diseases characterized by high serum IgG autoantibody titers [26]. Hence, B- cell tolerance is broken and ultimately results in the production of antibody-secreting plasma cells in these patients. However, active nontreated SLE and RA patients already showed elevated frequencies of auto- ¨ reactive B cells in the naıve B cell compartments suggesting an early break of B-cell tolerance even before ¨ antigen-mediated activation of naıve B cells and their differentiation into antibody-secreting cells (Figure 2a) [11,12]. Indeed, SLE and RA patients showed high frequencies of autoreactivity in new emigrant and mature ¨ naıve B cells indicative of defective central B cell toler- B-cell tolerance checkpoints in healthy humans. Single early immature B ance checkpoints (Figure 2a) [11,12]. SLE patients in cells and immature B cells from bone marrow and new emigrant and clinical remission continued to show higher numbers of mature naıve B cells from peripheral blood of healthy humans were ¨ ¨ mature naıve B cells, albeit at lower frequency than in isolated by FACS based on the expression of the indicated surface markers. IgH and IgL chain genes from single purified B cells were patients with active disease [14]. Thus, the treatment is cloned and the monoclonal antibodies were expressed in vitro [61]. (a) not effective in restoring defective early B cell tolerance The frequency of HEp-2 reactive antibodies was determined by HEp-2 checkpoints in SLE. cell ELISA and indirect immunofluorescence on HEp-2 cells. (b) The frequency of polyreactive antibodies was determined by ELISA with What pathways and mechanisms may result in defective ssDNA, dsDNA, insulin, and lipopolysaccharide as antigens. Polyreactive antibodies recognized at least two structurally diverse central B cell tolerance checkpoints? BCR signaling in antigens and often all four. Filled circles indicate the frequency of HEp-2 immature B cells plays an essential role in sensing self- reactive and polyreactive antibodies in B cells from individual donors. antigen bound to autoreactive BCRs and defects in BCR Horizontal lines indicate mean values of reactivity for all donors. The signaling such as in patients with X-linked agammaglo- central and peripheral B cell tolerance checkpoints are indicated. bulinemia may result in a failure to properly control receptor editing and to counterselect developing auto- a minor role in silencing of selfreactive B cells [21– reactive B cells [10,27]. 23,24]. In vitro IgL chain replacement experiments of human early immature B cell antibodies suggest that the Little is known about BCR-signaling defects in RA B early immature B cell compartment may be enriched in cells, but abnormal BCR signaling has been reported in www.sciencedirect.com Current Opinion in Immunology 2008, 20:632–638
  3. 3. 634 Autoimmunity Figure 2 Patients with autoimmunity show increased frequency of autoreactive clones in the naıve but not IgG+ memory B cell compartments. The frequency of ¨ HEp-reactive and polyreactive antibodies in peripheral blood new emigrant and mature naıve B cells (a) and IgG+ memory B cells (b) of healthy donors ¨ and patients with SLE and RA were determined as described in Figure 1. Increased frequencies of HEp-2 reactivity and polyreactivity were found in naıve B cell populations of patients with SLE and RA but not in IgG+ memory B cells of SLE patients as compared to healthy controls. ¨ SLE B cells that also suffer from defective B cell toler- amino acid-long CDR3 Igk chains mostly requires the ance [11,28]. More recently, the R620W missense poly- addition of nontemplate nucleotides to V–J junctions by morphism in the protein tyrosine phosphatase PTPN22 the terminal deoxynucleotidyl transferase (TdT). Since gene has been shown to segregate with T1D, RA, and TdT expression is downregulated by pre-BCR expression SLE patients [29–32]. This R620W amino acid replace- at the pre-B cell stage, abnormal pre-BCR signaling may ment in PTPN22 affects its interaction with Csk tyrosine fail to downregulate TdT expression and may result in kinase and alters TCR and potentially BCR signaling the generation of 11 amino acid-long CDR3 Igk chains [29,33]. found in these RA patients [39,40]. In conclusion, altera- tions in BCR signaling may affect the mechanisms that A clue supporting defective BCR signaling in RA patients regulate developing autoreactive B cells at the central B came from the analysis of new emigrant Igk gene reper- cell tolerance checkpoint in patients with autoimmunity toires which displayed in about half of RA patients ¨ and may explain differences in the naıve Igk repertoires features associated with abnormal secondary recombina- observed in RA and SLE patients. tion regulation that mediates receptor editing [12]. Indeed, these RA patients showed reduced or increased Regulation of the peripheral B cell tolerance downstream Jk combined to upstream Vk usage reflecting checkpoint a lack or an excess of secondary recombination events, Transgenic mouse models have suggested that CD4+ T respectively [12]. Similarly to RA, both an increase and cells may play an important role in the elimination of decrease in secondary recombination have been reported peripheral autoreactive B cells through MHC class II/T in SLE and suggest that defects in receptor editing can be cell receptor; CD40/CD40L and Fas/FasL interactions a common feature shared by different rheumatic diseases [41,42]. By studying CD40L-deficient and MHC class [14,34–36]. II-deficient (bare lymphocyte syndrome, BLS) patients, we found that antibody reactivity from CD40L-deficient About half of the analyzed RA patients did not show any and MHC class II-deficient new emigrant B cells was significant evidence of defective secondary recombina- similar to those from healthy donors, suggesting that tion but instead displayed new emigrant B cells that CD40/CD40L interactions and antigen presentation do expressed unusually long Igk chains that contained 11 not regulate central B cell tolerance. In contrast, mature or more amino acids in their complementarity determin- ¨ naıve B cells from CD40L-deficient and BLS patients ing regions 3 (CDR3s) [12,37,38]. The production of 11 expressed a high proportion of autoreactive antibodies Current Opinion in Immunology 2008, 20:632–638 www.sciencedirect.com
  4. 4. Human B cell tolerance checkpoints Meffre and Wardemann 635 including ANAs [18]. Thus, CD40/CD40L interactions IgG serum autoantibodies present in healthy individuals. and antigen presentation are essential for the establish- However, it is important to note that selfreactive IgG ¨ ment of peripheral naıve B cell tolerance. The decreased antibodies per se are not associated with autoimmunity numbers of Treg cells in CD40L-deficient and BLS and in fact could play an important role in autoantigen patients suggest that these cells may be involved in clearance to prevent autoimmunity [49]. Furthermore, regulating peripheral human B cell tolerance through polyreactive IgG antibodies may also be important in the MHC class II/TCR and CD40/CD40L interactions early phase of infection as suggested by the fact that [18]. Treg cells in RA patients although at normal hyper-IgM patients lacking IgG antibodies are highly frequencies in their blood are not functional and fail to susceptible to bacterial infection if not treated with secrete TGFb and IL-10 suggesting that abnormal Treg polyclonal IgG [50,51]. Serum levels of polyreactivity cells may be responsible for the accumulation of auto- have been attributed to natural IgM antibodies, but the ¨ reactive mature naıve B cells in these patients [43,44]. comparison of purified IgG and IgM molecules showed that this was due to the high avidity of multimeric IgMs. In addition, we found that serum BAFF levels were In fact, monomeric IgG purified from normal serum significantly increased threefold to fourfold in CD40L- showed higher levels of autoreactivity than monomeric deficient and BLS patients [18]. BAFF is a serum cyto- IgM molecules [15,16,52]. ¨ kine that promotes transitional and mature naıve B cell survival. Elevated BAFF concentration inhibits the coun- B-cell ablative therapy with anti-CD20 antibody, which terselection of autoreactive new emigrant/transitional B ¨ efficiently depletes naıve and memory B cells but not cells [45,46]. Hence, the elevated serum BAFF con- long-lived plasma cells, is effective in patients with SLE centration in CD40L-deficient and BLS patients likely and RA suggesting that IgG+ memory B cells may play an contributes to the accumulation of autoreactive mature important role in autoimmunity [53,54]. The analysis of ¨ naıve B cells in the blood of these patients. Elevated monoclonal antibodies cloned from single circulating BAFF levels have been reported in SLE patients with IgG+ memory B cells of untreated, active SLE patients active disease [47,48] and may contribute to the increase showed frequencies of autoreactive IgG+ memory B cells in selfreactivity at the transition between new emigrant similar to those of healthy donor controls (Figure 2b) [19]. ¨ and mature naıve B cells observed in patients with SLE However, a high frequency of SLE autoantigen-specific [11]. and highly extractable nuclear antigen reactive IgG+ memory B cells (15%) was observed in one individual Autoreactivity and tolerance in memory B with serum autoantibodies of the same specificity [19]. cells in health and autoimmunity The unmutated germline counterparts of the IgG mem- ¨ T-cell-dependent antigen-mediated activation of naıve B ory B cell autoantibodies were either nonautoreactive or cells induces Ig gene somatic mutations and class switch- displayed low levels of selfreactivity and polyreactivity ing in germinal centers followed by differentiation into [19]. Thus, it remains unclear if the increased frequencies antibody-secreting cells and memory B cells. Somatic ¨ of autoreactive naıve B cells in patients with SLE and RA mutations are random Ig gene modifications and may predispose to the development of the disease. However, not be beneficial in most cases but antigen-experienced specific autoantibodies with high levels of autoreactivity B cells that leave the GC under physiological circum- can be enriched in the IgG+ memory B cell compartment stances are selected for high reactivity and specificity to and somatic mutations play an important role in generat- foreign antigens. Surprisingly, we found that circulating ing highly specific IgG+ memory B cell autoantibodies in IgG+ memory B cells in healthy donors were significantly SLE [19,55,56]. ¨ enriched in autoreactive clones compared to naıve B cells from which they arose (Figure 2b) [16]. Since most Conclusion germline counterparts of these IgG+ memory B cells It has long been known that low levels of serum auto- did not express autoreactive antibodies, the increase in antibodies are present under normal circumstances and selfreactivity in IgG+ memory B cells is therefore the studies on hybridomas and EBV transformed B cell clones result of somatic mutations [16]. It is unclear whether B demonstrated that autoreactive B cells are expressed by cells developing autoreactive antibodies through the ¨ naıve and antigen-experienced B cells in mice and SHM process are regulated at a yet undefined tolerance humans [57–60]. The analysis of antibodies cloned from checkpoint within the germinal center, but the increased single human B cells at different stages of development levels of autoreactivity in the circulating IgG+ memory B determined for the first time the frequency at which cell pool may represent a by-product of affinity matu- V(D)J recombination generates selfreactivity that is coun- ration for strong reactivity to foreign antigen. terselected at the central and peripheral B cell tolerance checkpoints presumably to avoid autoimmunity. B-cell Memory B cells do not secrete antibodies but they can be intrinsic factors such as alterations in BCR signaling as readily activated to differentiate into plasma cells well as cellular and soluble B cell extrinsic factors play an suggesting that they may contribute to the low level of important role in regulating developing autoreactive B www.sciencedirect.com Current Opinion in Immunology 2008, 20:632–638
  5. 5. 636 Autoimmunity cells. The alteration of these factors in immunodeficient 11. Yurasov S, Wardemann H, Hammersen J, Tsuiji M, Meffre E, Pascual V, Nussenzweig MC: Defective B cell tolerance patients lead to increased numbers of autoreactive naıve¨ checkpoints in systemic lupus erythematosus. J Exp Med ¨ B cells at frequencies similar to what is observed in naıve 2005, 201:703-711. This report demonstrates that developing autoreactive naıve B cells fail to ¨ B cells from autoimmune SLE and RA patients. Whether be properly removed in SLE patients and accumulate in their blood. ¨ polyreactive naıve B cells may have a selective advantage 12. Samuels J, Ng Y-S, Coupillaud C, Paget D, Meffre E: Impaired to develop into high affinity autoreactive IgG+ memory B early B cell tolerance in patients with rheumatoid arthritis. cell antibodies through the accumulation of somatic J Exp Med 2005, 201:1659-1667. Similarly to the previous reference, RA patients fail to counterselect mutations and affinity maturation remains to be deter- ¨ developing autoreactive naıve B cells, which are enriched in the mature mined, but IgG+ memory B cells expressing high affinity naıve B cell compartment of these patients, thereby potentially favoring ¨ the development of autoimmunity. autoantibodies can develop in SLE from selfreactive and polyreactive precursors. The frequency at which plasma ´ 13. Herve M, Xu K, Ng Y-S, Wardemann H, Albesiano E, Messmer BT, Chiorazzi N, Meffre E: Unmutated and mutated chronic cells secrete serum autoantibodies in patients with auto- lymphocytic leukemias derive from self-reactive B cell immunity has not been determined, but understanding precursors despite expressing different antibody reactivity. J Clin Invest 2005, 115:1636-1643. where, when, and to what extent B-cell tolerance is broken in patients with autoimmunity may help to design 14. Yurasov S, Tiller T, Tsuiji M, Velinzon K, Pascual V, Wardemann H, Nussenzweig MC: Persistent expression of autoantibodies in more specific and sustained therapies. SLE patients in remission. J Exp Med 2006, 203:2255-2261. 15. Tsuiji M, Yurasov S, Velinzon K, Thomas S, Nussenzweig MC, Acknowledgements Wardemann H: A checkpoint for autoreactivity in human IgM+ This work is supported by National Institutes of Health grants P01 memory B cell development. J Exp Med 2006, 203:393-400. AI061093 and R01 AI071087 to EM and by the German Research 16. Tiller T, Tsuiji M, Yurasov S, Velinzon K, Nussenzweig MC, Foundation (DFG WA-2590) to HW. Wardemann H: Autoreactivity in human IgG+ memory B cells. Immunity 2007, 26:205-213. References and recommended reading This report reveals that the amount of autoreactivity is increased in IgG+ isotype switched B cells compared to IgM+ mature naıve B cells from the ¨ Papers of particular interest, published within the period of review, same healthy donors. Since the IgG+ autoreactive clones were shown to have been highlighted as: have arisen from nonautoreactive B cells, the autoreactivity of IgG mutated antibodies is likely a by-product of SHM. of special interest of outstanding interest 17. Koelsch K, Zheng NY, Zhang Q, Duty A, Helms C, Mathias MD, Jared M, Smith K, Capra JD, Wilson PC: Mature B cells class 1. Rajewsky K: Clonal selection and learning in the antibody switched to IgD are autoreactive in healthy individuals. J Clin system. Nature 1996, 381:751-758. Invest 2007, 117:1558-1565. 2. Nemazee DA, Burki K: Clonal deletion of B lymphocytes in a ´ 18. Herve M, Isnardi I, Ng YS, Bussel JB, Ochs HD, Cunningham- transgenic mouse bearing anti-MHC class I antibody genes. Rundles C, Meffre E: CD40 ligand and MHC class II expression Nature 1989, 337:562-566. are essential for human peripheral B cell tolerance. J Exp Med 2007, 204:1583-1593. 3. Goodnow CC, Crosbie J, Adelstein S, Lavoie TB, Smith-Gill SJ, This report suggests that extrinsic B cell factors such as Treg cells and Brink RA, Pritchard-Briscoe H, Wotherspoon JS, Loblay RH, serum BAFF levels play an important role in controlling the removal of Raphael K et al.: Altered immunoglobulin expression and peripheral autoreactive B cells in humans. functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 1988, 334:676-682. 19. Mietzner B, Tsuiji M, Scheid J, Velinzon K, Tiller T, Abraham K, Gonzalez JB, Pascual V, Stichweh D, Wardemann H et al.: 4. Erikson J, Radic MZ, Camper SA, Hardy RR, Carmack C, Autoreactive IgG memory antibodies in patients with systemic Weigert M: Expression of anti-DNA immunoglobulin lupus erythematosus arise from nonreactive and polyreactive transgenes in non-autoimmune mice. Nature 1991, precursors. Proc Natl Acad Sci U S A 2008, 105:9727-9732. 349:331-334. 20. Hannum LG, Ni D, Haberman AM, Weigert MG, Shlomchik MJ: A 5. Tiegs SL, Russell DM, Nemazee D: Receptor editing in self- disease-related rheumatoid factor autoantibody is not reactive bone marrow B cells. J Exp Med 1993, 177:1009-1020. tolerized in a normal mouse: implications for the origins of autoantibodies in autoimmune disease. J Exp Med 1996, 6. Radic MZ, Erickson J, Litwin S, Weigert M: B lymphocytes may 184:1269-1278. escape tolerance by revising their antigen receptors. J Exp Med 1993, 177:1165-1173. 21. Retter MW, Nemazee D: Receptor editing occurs frequently during normal B cell development. J Exp Med 1998, 7. Gay D, Saunders T, Camper S, Weigert M: Receptor editing: an 188:1231-1238. approach by autoreactive B cells to escape tolerance. J Exp Med 1993, 177:999-1008. 22. Casellas R, Shih TA, Kleinewietfeld M, Rakonjac J, Nemazee D, Rajewsky K, Nussenzweig MC: Contribution of receptor editing 8. Wardemann H, Yurasov S, Schaefer A, Young JW, Meffre E, to the antibody repertoire. Science 2001, 291:1541-1544. Nussenzweig MC: Predominant autoantibody production by early human B cell precursors. Science 2003, 301:1374-1377. 23. Oberdoerffer P, Novobrantseva TI, Rajewsky K: Expression of a By testing the reactivity of recombinant antibodies express by single B targeted {lambda}1 light chain gene is developmentally cells at different stages of human B cell development, the authors regulated and independent of Ig{kappa} rearrangements. assessed the amount of autoreactivity generated by random V(D)J J Exp Med 2003, 197:1165-1172. recombination and identified a central and a peripheral B cell tolerance checkpoint at which autoreactive B cells are counterselected. 24. Halverson R, Torres RM, Pelanda R: Receptor editing is the main mechanism of B cell tolerance toward membrane antigens. 9. Meffre E, Schaefer A, Wardemann H, Wilson P, Davis E, Nat Immunol 2004, 6:645-650. Nussenzweig MC: Surrogate light chain expressing human The elegant experiments of this report demonstrate that receptor editing peripheral B cells produce self-reactive antibodies. J Exp Med can silence most developing autoreactive B cells thereby rescuing them 2004, 199:145-150. from being deleted by apoptosis. 10. Ng Y-S, Wardemann H, Chelnis J, Cunningham-Rundles C, 25. Wardemann H, Hammersen J, Nussenzweig MC: Human Meffre E: Bruton’s tyrosine kinase (Btk) is essential for human autoantibody silencing by immunoglobulin light chains. B cell tolerance. J Exp Med 2004, 200:927-934. J Exp Med 2004, 200:191-199. Current Opinion in Immunology 2008, 20:632–638 www.sciencedirect.com
  6. 6. Human B cell tolerance checkpoints Meffre and Wardemann 637 26. Leslie D, Lipsky P, Notkins AL: Autoantibodies as predictors of and Fas (CD95)-ligands modulated by the B cell antigen disease. J Clin Invest 2001, 108:1417-1422. receptor. Cell 1996, 87:319-329. 27. Grimaldi CM, Hicks R, Diamond B: B cell selection and 43. Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, susceptibility to autoimmunity. J Immunol 2005, 174:1775-1781. Isenberg DA, Mauri C: Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha 28. Liossis SN, Kovacs B, Dennis G, Kammer GM, Tsokos GC: B cells therapy. J Exp Med 2004, 200:277-285. from patients with systemic lupus erythematosus display abnormal antigen receptor-mediated early signal 44. Nadkarni S, Mauri C, Ehrenstein MR: Anti-TNF-alpha therapy transduction events. J Clin Invest 1996, 98:2549-2557. induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta. J Exp Med 2007, 29. Begovich AB, Carlton VEH, Honigberg LA, Schrodi SJ, 204:33-39. Chokkalingam AP, Alexander HC, Ardlie KG, Huang Q, Smith AM, Spoerke JM et al.: A missense single-nucleotide polymorphism 45. Lesley R, Xu Y, Kalled SL, Hess DM, Schwab SR, Shu H-B, in a gene encoding a protein tyrosine phosphatase (PTPN22) is Cyster JG: Reduced competitiveness of autoantigen-engaged associated with rheumatoid arthritis. Am J Hum Genet 2004, B cells due to increased dependence on BAFF. Immunity 2004, 75:330-337. 20:441-453. This report demonstrated that elevated serum BAFF levels rescued 30. Kyogoku C, Langfeld CD, Ortmann WA, Lee A, Selby S, autoantigen-engaged B cells from rapid competitive elimination by indu- Carlton VEH, Chang M, Ramos P, Baechler EC, Batliwalla FM et al.: cing prosurvival factors that inhibited their programmed cell death. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum 46. Thien M, Phan TG, Gardam S, Amesbury M, Basten A, Mackay F, Genet 2004, 75:504-507. Brink R: Excess BAFF rescues self-reactive B cells from peripheral deletion and allows them to enter forbidden 31. Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, follicular and marginal zone niches. Immunity 2004, 20:785-798. Rostamkhani M, MacMurray J, Meloni GF, Lucarelli P, These authors showed that the survival of autoreactive anti-HEL trans- Pellecchia M et al.: A functional variant of lymphoid tyrosine genic B cells was more sensitive to BAFF than nonautoreactive B cells. phosphatase is associated with type 1 diabetes. Nat Genet 2004, 36:337-338. 47. Groom J, Kalled SL, Cutler AH, Olson C, Woodcock SA, Schneider P, Tschopp J, Cachero TG, Batten M, Wheway J et al.: 32. Michou L, Lasbleiz S, Rat AC, Migliorini P, Balsa A, Westhovens R, Association of BAFF/BLys overexpression and altered B cell Barrera P, Alves H, Pierlot C, Glikmans E et al.: Linkage proof for differentiation with Sjogren’s syndrome. J Clin Invest 2002, PTPN22, a rheumatoid arthritis susceptibility gene and a 109:59-68. human autoimmunity gene. Proc Natl Acad Sci U S A 2007, 104:1649-1654. 48. Mariette X, Roux S, Zhang J, Bengoufa D, Lavie F, Zhou T, Kimberly R: The level of BLyS (BAFF) correlates with the titre of 33. Rieck M, Arechiga A, Onengut-Gumuscu S, Greenbaum C, autoantibodies in human Sjogren’s syndrome. Ann Rheum Dis Concannon P, Buckner JH: Genetic variation in PTPN22 2003, 62:168-171. corresponds to altered function of T and B lymphocytes. J Immunol 2007, 179:4704-4710. 49. Kim SJ, Gershov D, Ma X, Brot N, Elkon KB: I-PLA(2) activation during apoptosis promotes the exposure of membrane 34. Bensimon C, Chastagner P, Zouali M: Human lupus anti-DNA lysophosphatidylcholine leading to binding by natural autoantibodies undergo essentially primary V kappa gene immunoglobulin M antibodies and complement activation. rearrangements. EMBO J 1994, 13:2951-2962. J Exp Med 2002, 196:655-665. 35. Suzuki N, Harada T, Mihara S, Sakane T: Characterization of a 50. Quartier P, Bustamante J, Sanal O, Plebani A, Debre M, Deville A, germline Vk gene encoding cationic anti-DNA antibody and Litzman J, Levy J, Fermand JP, Lane P et al.: Clinical, role of receptor editing for development of the autoantibody in immunologic and genetic analysis of 29 patients with patients with systemic lupus erythematosus. J Clin Invest 1996, autosomal recessive hyper-IgM syndrome due to activation- 98:1843-1850. induced cytidine deaminase deficiency. Clin Immunol 2004, 110:22-29. 36. Dorner T, Foster SJ, Farner NL, Lipsky PE: Immunoglobulin kappa chain receptor editing in systemic lupus 51. Alachkar H, Taubenheim N, Haeney MR, Durandy A, Arkwright PD: erythematosus. J Clin Invest 1998, 102:688-694. Memory switched B cell percentage and not serum immunoglobulin concentration is associated with clinical 37. Victor KD, Randen I, Thompson K, Forre O, Natvig JB, Fu SM, complications in children and adults with specific antibody Capra JD: Rheumatoid factors isolated from patients with deficiency and common variable immunodeficiency. Clin autoimmune disorders are derived from germline genes Immunol 2006, 120:310-318. distinct from those encoding the Wa, Po, and Bla cross- reactive idiotypes. J Clin Invest 1991, 87:1603-1613. 52. Martin F, Oliver AM, Kearney JF: Marginal zone and B1 B cells unite in the early response against T-independent blood- 38. Bridges SL Jr, Lee SK, Johnson ML, Lavelle JC, Fowler PG, borne particulate antigens. Immunity 2001, 14:617-629. Koopman WJ, Schroeder HW Jr: Somatic mutation and CDR3 lengths of immunoglobulin kappa light chains expressed in 53. Leandro MJ, Cambridge G, Edwards JC, Ehrenstein MR, patients with rheumatoid arthritis and in normal individuals. Isenberg DA: B-cell depletion in the treatment of patients with J Clin Invest 1995, 96:831-841. systemic lupus erythematosus: a longitudinal analysis of 24 patients. Rheumatology (Oxford) 2005, 44:1542-1545. 39. Wasserman R, Li YS, Hardy RR: Down-regulation of terminal deoxynucleotidyl transferase by Ig heavy chain in B lineage 54. Edwards JCW, Szczepanski L, Szechinski J, Filipowicz- cells. J Immunol 1997, 158:1133-1138. Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T: Efficacy of B cell-targeted therapy with Rituximab in patients with 40. Ghia P, ten Boekel E, Sanz E, de la Hera A, Rolink A, Melchers F: rheumatoid arthritis. N Engl J Med 2004, 350:2572-2581. Ordering of human bone marrow B lymphocyte precursors by single-cell polymerase chain reaction analyses of the 55. Manheimer-Lory A, Katz JB, Pillinger M, Ghossein C, Smith A, rearrangement status of the immunoglobulin H and L chain Diamond B: Molecular characteristics of antibodies gene loci. J Exp Med 1996, 184:2217-2229. bearing an anti-DNA-associated idiotype. J Exp Med 1991, 174:1639-1652. 41. Rathmell JC, Cooke MP, Ho WY, Grein J, Townsend SE, Davis MM, Goodnow CC: CD95 (Fas)-dependent elimination of 56. Wellmann U, Letz M, Herrmann M, Angermuller S, Kalden JR, self-reactive B cells upon interaction with CD4+ T cells. Nature Winkler TH: The evolution of human anti-double-stranded DNA 1995, 376:181-184. autoantibodies. Proc Natl Acad Sci U S A 2005, 102:9258-9263. These authors first demonstrated using transgenic mouse models that CD4+T cells were involved in the counterselection of autoreactive B cells. 57. Souroujon M, White-Scharf ME, Andreschwartz J, Gefter ML, Schwartz RS: Preferential autoantibody reactivity of the 42. Rathmell JC, Townsend SE, Xu JC, Flavell RA, Goodnow CC: preimmune B cell repertoire in normal mice. J Immunol 1988, Expansion or elimination of B cells in vivo: dual roles for CD40- 140:4173-4179. www.sciencedirect.com Current Opinion in Immunology 2008, 20:632–638
  7. 7. 638 Autoimmunity 58. Casali P, Burastero SE, Nakamura M, Inghirami G, Notkins AL: 60. Kasaian MT, Ikematsu H, Casali P: Identification and analysis of Human lymphocytes making rheumatoid factor and antibody a novel human surface CD5-B lymphocyte subset producing to ssDNA belong to Leu-1+ B-cell subset. Science 1987, natural antibodies. J Immunol 1992, 148:2690-2702. 236:77-81. 61. Tiller T, Meffre E, Yurasov S, Tsuiji M, Nussenzweig MC, 59. Hardy RR, Hayakawa K, Shimizu M, Yamasaki K, Kishimoto T: Wardemann H: Efficient generation of monoclonal antibodies Rheumatoid factor secretion from human Leu-1+ B cells. from single human B cells by single cell RT-PCR and expression Science 1987, 236:81-83. vector cloning. J Immunol Methods 2008, 329:112-124. Current Opinion in Immunology 2008, 20:632–638 www.sciencedirect.com