The role of B cells in lupus pathogenesis

International Journal of Biochemistry and Cell Biology

Volumn 42, Issue 4, 2010, Pages 543-550

  Nashi, Emil ^a   Wang, YingHua ^a   Diamond, Betty ^a  

^a FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH   (United States)

Author keywords

B cell; B cell receptor; Lupus; Signaling; Tolerance

Indexed keywords

AUTOANTIBODY; B LYMPHOCYTE RECEPTOR; CYTOKINE; DNA ANTIBODY; DOUBLE STRANDED DNA ANTIBODY; RITUXIMAB; SINGLE STRANDED DNA; T LYMPHOCYTE RECEPTOR; TOLL LIKE RECEPTOR;

AUTOIMMUNITY; B CELL LYMPHOMA; B LYMPHOCYTE ACTIVATION; CELL MATURATION; CELL SURVIVAL; CLINICAL TRIAL; CYTOKINE RELEASE; DISEASE PREDISPOSITION; HUMAN; IMMUNOCOMPETENT CELL; IMMUNOLOGICAL TOLERANCE; IMMUNOPATHOGENESIS; IMMUNOREGULATION; LUPUS ERYTHEMATOSUS NEPHRITIS; LYMPHOCYTE SUBPOPULATION; NONHUMAN; PROTEIN PROTEIN INTERACTION; REVIEW; RHEUMATOID ARTHRITIS; SIGNAL TRANSDUCTION; SYSTEMIC LUPUS ERYTHEMATOSUS;

ANIMALS; AUTOANTIBODIES; B-CELL ACTIVATING FACTOR; B-LYMPHOCYTE SUBSETS; B-LYMPHOCYTES; ESTROGENS; HUMANS; IMMUNE TOLERANCE; LUPUS ERYTHEMATOSUS, SYSTEMIC; RECEPTORS, ANTIGEN, B-CELL; SIGNAL TRANSDUCTION; TOLL-LIKE RECEPTORS;

EID: 77649185242     PISSN: 13572725     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.biocel.2009.10.011     Document Type: Review

References (102)

1. Anolik J.H. B cell biology and dysfunction in SLE. Bull NYU Hosp Jt Dis 65 3 (2007) 182-186
2. Arbuckle M.R., McClain M.T., Rubertone M.V., Scofield R.H., Dennis G.J., James J.A., et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 349 16 (2003) 1526-1533
3. Bossen C., and Schneider P. BAFF, APRIL and their receptors: structure, function and signaling. Semin Immunol 18 5 (2006) 263-275
4. Budhai L., Oh K., and Davidson A. An in vitro assay for detection of glomerular binding IgG autoantibodies in patients with systemic lupus erythematosus. J Clin Invest 98 7 (1996) 1585-1593
5. Buoncompagni A., Barbano G.C., Pistoia V., Fasce L., Micalizzi C., Gusmano R., et al. Childhood systemic lupus erythematosus: a review of 30 cases. Clin Exp Rheumatol 9 4 (1991) 425-430
6. Buyon J.P., Petri M.A., Kim M.Y., Kalunian K.C., Grossman J., Hahn B.H., et al. The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial. Ann Intern Med 142 12 Pt 1 (2005) 953-962
7. Bynoe M.S., Grimaldi C.M., and Diamond B. Estrogen up-regulates Bcl-2 and blocks tolerance induction of naive B cells. Proc Natl Acad Sci USA 97 6 (2000) 2703-2708
8. Cabral A.R., and Alarcon-Segovia D. Autoantibodies in systemic lupus erythematosus. Curr Opin Rheumatol 9 5 (1997) 387-392
9. Cappione III A., Anolik J.H., Pugh-Bernard A., Barnard J., Dutcher P., Silverman G., et al. Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus. J Clin Invest 115 11 (2005) 3205-3216
10. Carlsten H., Tarkowski A., Holmdahl R., and Nilsson L.A. Oestrogen is a potent disease accelerator in SLE-prone MRL lpr/lpr mice. Clin Exp Immunol 80 3 (1990) 467-473
11. Chan O.T., Hannum L.G., Haberman A.M., Madaio M.P., and Shlomchik M.J. A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus. J Exp Med 189 10 (1999) 1639-1648
12. Chong W.P., Ip W.K., Wong W.H., Lau C.S., Chan T.M., and Lau Y.L. Association of interleukin-10 promoter polymorphisms with systemic lupus erythematosus. Genes Immun 5 6 (2004) 484-492
13. Cinamon G., Zachariah M.A., Lam O.M., Foss Jr. F.W., and Cyster J.G. Follicular shuttling of marginal zone B cells facilitates antigen transport. Nat Immunol 9 1 (2008) 54-62
14. Cohen P.L., Caricchio R., Abraham V., Camenisch T.D., Jennette J.C., Roubey R.A., et al. Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J Exp Med 196 1 (2002) 135-140
15. Culton D.A., O'Conner B.P., Conway K.L., Diz R., Rutan J., Vilen B.J., et al. Early preplasma cells define a tolerance checkpoint for autoreactive B cells. J Immunol 176 2 (2006) 790-802
16. DeGiorgio L.A., Konstantinov K.N., Lee S.C., Hardin J.A., Volpe B.T., and Diamond B. A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat Med 7 11 (2001) 1189-1193
17. Diamond B., Katz J.B., Paul E., Aranow C., Lustgarten D., and Scharff M.D. The role of somatic mutation in the pathogenic anti-DNA response. Annu Rev Immunol 10 (1992) 731-757
18. Diamond B., and Scharff M.D. Somatic mutation of the T15 heavy chain gives rise to an antibody with autoantibody specificity. Proc Natl Acad Sci USA 81 18 (1984) 5841-5844
19. Edwards J.C., Szczepanski L., Szechinski J., Filipowicz-Sosnowska A., Emery P., Close D.R., et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 350 25 (2004) 2572-2581
20. Ehrenstein M.R., Katz D.R., Griffiths M.H., Papadaki L., Winkler T.H., Kalden J.R., et al. Human IgG anti-DNA antibodies deposit in kidneys and induce proteinuria in SCID mice. Kidney Int 48 3 (1995) 705-711
21. Fairhurst A.M., Hwang S.H., Wang A., Tian X.H., Boudreaux C., Zhou X.J., et al. Yaa autoimmune phenotypes are conferred by overexpression of TLR7. Eur J Immunol 38 7 (2008) 1971-1978
22. Gaynor B., Putterman C., Valadon P., Spatz L., Scharff M.D., and Diamond B. Peptide inhibition of glomerular deposition of an anti-DNA antibody. Proc Natl Acad Sci USA 94 5 (1997) 1955-1960
23. Glennie M.J., French R.R., Cragg M.S., and Taylor R.P. Mechanisms of killing by anti-CD20 monoclonal antibodies. Mol Immunol 44 16 (2007) 3823-3837
24. Grammer A.C., and Lipsky P.E. B cell abnormalities in systemic lupus erythematosus. Arthritis Res Ther 5 Suppl. 4 (2003) S22-S27
25. Grimaldi C.M., Cleary J., Dagtas A.S., Moussai D., and Diamond B. Estrogen alters thresholds for B cell apoptosis and activation. J Clin Invest 109 12 (2002) 1625-1633
26. Grimaldi C.M., Hill L., Xu X., Peeva E., and Diamond B. Hormonal modulation of B cell development and repertoire selection. Mol Immunol 42 7 (2005) 811-820
27. Grimaldi C.M., Jeganathan V., and Diamond B. Hormonal regulation of B cell development: 17 beta-estradiol impairs negative selection of high-affinity DNA-reactive B cells at more than one developmental checkpoint. J Immunol 176 5 (2006) 2703-2710
28. Grimaldi C.M., Michael D.J., and Diamond B. Cutting edge: expansion and activation of a population of autoreactive marginal zone B cells in a model of estrogen-induced lupus. J Immunol 167 4 (2001) 1886-1890
29. Han S., Zheng B., Dal Porto J., and Kelsoe G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. IV. Affinity-dependent, antigen-driven B cell apoptosis in germinal centers as a mechanism for maintaining self-tolerance. J Exp Med 182 6 (1995) 1635-1644
30. Hardin J.A., and Craft J.E. Patterns of autoimmunity to nucleoproteins in patients with systemic lupus erythematosus. Rheum Dis Clin North Am 13 1 (1987) 37-46
31. Hoffmann K.F., Cheever A.W., and Wynn T.A. IL-10 and the dangers of immune polarization: excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis. J Immunol 164 12 (2000) 6406-6416
32. Hom G., Graham R.R., Modrek B., Taylor K.E., Ortmann W., Garnier S., et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med 358 9 (2008) 900-909
33. Isenberg D.A., Ravirajan C.T., Rahman A., and Kalsi J. The role of antibodies to DNA in systemic lupus erythematosus-a review and introduction to an international workshop on DNA antibodies held in London, May 1996. Lupus 6 3 (1997) 290-304
34. Jayne D. Role of rituximab therapy in glomerulonephritis. J Am Soc Nephrol (2008) epub
35. Jegerlehner A., Maurer P., Bessa J., Hinton H.J., Kopf M., and Bachmann M.F. TLR9 signaling in B cells determines class switch recombination to IgG2a. J Immunol 178 4 (2007) 2415-2420
36. Kaliyaperumal A., Mohan C., Wu W., and Datta S.K. Nucleosomal peptide epitopes for nephritis-inducing T helper cells of murine lupus. J Exp Med 183 6 (1996) 2459-2469
37. Koncz G., Bodor C., Kovesdi D., Gati R., and Sarmay G. BCR mediated signal transduction in immature and mature B cells. Immunol Lett 82 1-2 (2002) 41-49
38. Kono H., Kyogoku C., Suzuki T., Tsuchiya N., Honda H., Yamamoto K., et al. FcgammaRIIB Ile232Thr transmembrane polymorphism associated with human systemic lupus erythematosus decreases affinity to lipid rafts and attenuates inhibitory effects on B cell receptor signaling. Hum Mol Genet 14 19 (2005) 2881-2892
39. Krieg A.M., and Vollmer J. Toll-like receptors 7, 8, and 9: linking innate immunity to autoimmunity. Immunol Rev 220 (2007) 251-269
40. Kumar K.R., Li L., Yan M., Bhaskarabhatla M., Mobley A.B., Nguyen C., et al. Regulation of B cell tolerance by the lupus susceptibility gene Ly108. Science 312 5780 (2006) 1665-1669
41. Kuo P., Bynoe M., and Diamond B. Crossreactive B cells are present during a primary but not secondary response in BALB/c mice expressing a bcl-2 transgene. Mol Immunol 36 7 (1999) 471-479
42. Lavie F., Miceli-Richard C., Ittah M., Sellam J., Gottenberg J.E., and Mariette X. Increase of B cell-activating factor of the TNF family (BAFF) after rituximab treatment: insights into a new regulating system of BAFF production. Ann Rheum Dis 66 5 (2007) 700-703
43. Linton P.J., Rudie A., and Klinman N.R. Tolerance susceptibility of newly generating memory B cells. J Immunol 146 12 (1991) 4099-4104
44. Llorente L., Richaud-Patin Y., Garcia-Padilla C., Claret E., Jakez-Ocampo J., Cardiel M.H., et al. Clinical and biologic effects of anti-interleukin-10 monoclonal antibody administration in systemic lupus erythematosus. Arthritis Rheum 43 8 (2000) 1790-1800
45. Lu L., Kaliyaperumal A., Boumpas D.T., and Datta S.K. Major peptide autoepitopes for nucleosome-specific T cells of human lupus. J Clin Invest 104 3 (1999) 345-355
46. Mackay F., Silveira P.A., and Brink R. B cells and the BAFF/APRIL axis: fast-forward on autoimmunity and signaling. Curr Opin Immunol 19 3 (2007) 327-336
47. Mackay M., Stanevsky A., Wang T., Aranow C., Li M., Koenig S., et al. Selective dysregulation of the FcgammaIIB receptor on memory B cells in SLE. J Exp Med 203 9 (2006) 2157-2164
48. Martinez Valle F., Balada E., Ordi-Ros J., and Vilardell-Tarres M. DNase 1 and systemic lupus erythematosus. Autoimmun Rev 7 5 (2008) 359-363
49. Marwick C. Monoclonal antibody to treat lymphoma. JAMA 278 8 (1997) 616-618
50. Mauri C., Gray D., Mushtaq N., and Londei M. Prevention of arthritis by interleukin 10-producing B cells. J Exp Med 197 4 (2003) 489-501
51. McGaha T.L., Sorrentino B., and Ravetch J.V. Restoration of tolerance in lupus by targeted inhibitory receptor expression. Science 307 5709 (2005) 590-593
52. Mietzner B., Tsuiji M., Scheid J., Velinzon K., Tiller T., Abraham K., et al. Autoreactive IgG memory antibodies in patients with systemic lupus erythematosus arise from nonreactive and polyreactive precursors. Proc Natl Acad Sci USA 105 28 (2008) 9727-9732
53. Min D.J., Kim S.J., Park S.H., Seo Y.I., Kang H.J., Kim W.U., et al. Anti-nucleosome antibody: significance in lupus patients lacking anti-double-stranded DNA antibody. Clin Exp Rheumatol 20 1 (2002) 13-18
54. Mizoguchi A., Mizoguchi E., Takedatsu H., Blumberg R.S., and Bhan A.K. Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity 16 2 (2002) 219-230
55. Monroe J.G., Bannish G., Fuentes-Panana E.M., King L.B., Sandel P.C., Chung J., et al. Positive and negative selection during B lymphocyte development. Immunol Res 27 2-3 (2003) 427-442
56. Monticielo O.A., Mucenic T., Xavier R.M., Brenol J.C., and Chies J.A. The role of mannose-binding lectin in systemic lupus erythematosus. Clin Rheumatol 27 4 (2008) 413-419
57. Ng K.P., Manson J.J., Rahman A., and Isenberg D.A. Association of antinucleosome antibodies with disease flare in serologically active clinically quiescent patients with systemic lupus erythematosus. Arthritis Rheum 55 6 (2006) 900-904
58. Ng Y.S., Wardemann H., Chelnis J., Cunningham-Rundles C., and Meffre E. Bruton's tyrosine kinase is essential for human B cell tolerance. J Exp Med 200 7 (2004) 927-934
59. Nossal G.J., Karvelas M., and Pulendran B. Soluble antigen profoundly reduces memory B-cell numbers even when given after challenge immunization. Proc Natl Acad Sci USA 90 7 (1993) 3088-3092
60. O'Connor B.P., Vogel L.A., Zhang W., Loo W., Shnider D., Lind E.F., et al. Imprinting the fate of antigen-reactive B cells through the affinity of the B cell receptor. J Immunol 177 11 (2006) 7723-7732
61. Okamura M., Kanayama Y., Amastu K., Negoro N., Kohda S., Takeda T., et al. Significance of enzyme linked immunosorbent assay (ELISA) for antibodies to double stranded and single stranded DNA in patients with lupus nephritis: correlation with severity of renal histology. Ann Rheum Dis 52 1 (1993) 14-20
62. Pillai S., Cariappa A., and Moran S.T. Marginal zone B cells. Annu Rev Immunol 23 (2005) 161-196
63. Pisetsky D.S. Anti-DNA and autoantibodies. Curr Opin Rheumatol 12 5 (2000) 364-368
64. Pulendran B., Kannourakis G., Nouri S., Smith K.G., and Nossal G.J. Soluble antigen can cause enhanced apoptosis of germinal-centre B cells. Nature 375 6529 (1995) 331-334
65. Putterman C., and Diamond B. Immunization with a peptide surrogate for double-stranded DNA (dsDNA) induces autoantibody production and renal immunoglobulin deposition. J Exp Med 188 1 (1998) 29-38
66. Radic M., Marion T., and Monestier M. Nucleosomes are exposed at the cell surface in apoptosis. J Immunol 172 11 (2004) 6692-6700
67. Radic M.Z., and Weigert M. Genetic and structural evidence for antigen selection of anti-DNA antibodies. Annu Rev Immunol 12 (1994) 487-520
68. Ray S.K., Putterman C., and Diamond B. Pathogenic autoantibodies are routinely generated during the response to foreign antigen: a paradigm for autoimmune disease. Proc Natl Acad Sci USA 93 5 (1996) 2019-2024
69. Rieck M., Arechiga A., Onengut-Gumuscu S., Greenbaum C., Concannon P., and Buckner J.H. Genetic variation in PTPN22 corresponds to altered function of T and B lymphocytes. J Immunol 179 7 (2007) 4704-4710
70. Roubinian J.R., Talal N., Greenspan J.S., Goodman J.R., and Siiteri P.K. Effect of castration and sex hormone treatment on survival, anti-nucleic acid antibodies, and glomerulonephritis in NZB/NZW F1 mice. J Exp Med 147 6 (1978) 1568-1583
71. Schiffer L.E., Hussain N., Wang X., Huang W., Sinha J., Ramanujam M., et al. Lowering anti-dsDNA antibodies-what's new?. Lupus 11 12 (2002) 885-894
72. Shlomchik M.J., Madaio M.P., Ni D., Trounstein M., and Huszar D. The role of B cells in lpr/lpr-induced autoimmunity. J Exp Med 180 4 (1994) 1295-1306
73. Shokat K.M., and Goodnow C.C. Antigen-induced B-cell death and elimination during germinal-centre immune responses. Nature 375 6529 (1995) 334-338
74. Shultz L.D., Rajan T.V., and Greiner D.L. Severe defects in immunity and hematopoiesis caused by SHP-1 protein-tyrosine-phosphatase deficiency. Trends Biotechnol 15 8 (1997) 302-307
75. Simon J.A., Cabiedes J., Ortiz E., Alcocer-Varela J., and Sanchez-Guerrero J. Anti-nucleosome antibodies in patients with systemic lupus erythematosus of recent onset. Potential utility as a diagnostic tool and disease activity marker. Rheumatology (Oxford) 43 2 (2004) 220-224
76. Sundar K., Jacques S., Gottlieb P., Villars R., Benito M.E., Taylor D.K., et al. Expression of the Epstein-Barr virus nuclear antigen-1 (EBNA-1) in the mouse can elicit the production of anti-dsDNA and anti-Sm antibodies. J Autoimmun 23 2 (2004) 127-140
77. ter Borg E.J., Horst G., Hummel E.J., Limburg P.C., and Kallenberg C.G. Measurement of increases in anti-double-stranded DNA antibody levels as a predictor of disease exacerbation in systemic lupus erythematosus. A long-term, prospective study. Arthritis Rheum 33 5 (1990) 634-643
78. Tiller T., Tsuiji M., Yurasov S., Velinzon K., Nussenzweig M.C., and Wardemann H. Autoreactivity in human IgG+ memory B cells. Immunity 26 2 (2007) 205-213
79. Tomer Y., Buskila D., and Shoenfeld Y. Pathogenic significance and diagnostic value of lupus autoantibodies. Int Arch Allergy Immunol 100 4 (1993) 293-306
80. Trolle S., Chachaty E., Kassis-Chikhani N., Wang C., Fattal E., Couvreur P., et al. Intranasal immunization with protein-linked phosphorylcholine protects mice against a lethal intranasal challenge with streptococcus pneumoniae. Vaccine 18 26 (2000) 2991-2998
81. Truedsson L., Bengtsson A.A., and Sturfelt G. Complement deficiencies and systemic lupus erythematosus. Autoimmunity 40 8 (2007) 560-566
82. Tsubata T., and Honjo T. B cell tolerance and autoimmunity. Rev Immunogenet 2 1 (2000) 18-25
83. Tsuiji M., Yurasov S., Velinzon K., Thomas S., Nussenzweig M.C., and Wardemann H. A checkpoint for autoreactivity in human IgM+ memory B cell development. J Exp Med 203 2 (2006) 393-400
84. Tsukumo S., and Yasutomo K. DNaseI in pathogenesis of systemic lupus erythematosus. Clin Immunol 113 1 (2004) 14-18
85. Vang T., Congia M., Macis M.D., Musumeci L., Orru V., Zavattari P., et al. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat Genet 37 12 (2005) 1317-1319
86. Vang T., Miletic A.V., Bottini N., and Mustelin T. Protein tyrosine phosphatase PTPN22 in human autoimmunity. Autoimmunity 40 6 (2007) 453-461
87. Viglianti G.A., Lau C.M., Hanley T.M., Miko B.A., Shlomchik M.J., and Marshak-Rothstein A. Activation of autoreactive B cells by CpG dsDNA. Immunity 19 6 (2003) 837-847
88. Wang C., Khalil M., Ravetch J., and Diamond B. The naive B cell repertoire predisposes to antigen-induced systemic lupus erythematosus. J Immunol 170 9 (2003) 4826-4832
89. Wang Y.H., and Diamond B. B cell receptor revision diminishes the autoreactive B cell response after antigen activation in mice. J Clin Invest 118 8 (2008) 2896-2907
90. Wardemann H., Yurasov S., Schaefer A., Young J.W., Meffre E., and Nussenzweig M.C. Predominant autoantibody production by early human B cell precursors. Science 301 5638 (2003) 1374-1377
91. Wermeling F., Chen Y., Pikkarainen T., Scheynius A., Winqvist O., Izui S., et al. Class A scavenger receptors regulate tolerance against apoptotic cells, and autoantibodies against these receptors are predictive of systemic lupus. J Exp Med 204 10 (2007) 2259-2265
92. William J., Euler C., Primarolo N., and Shlomchik M.J. B cell tolerance checkpoints that restrict pathways of antigen-driven differentiation. J Immunol 176 4 (2006) 2142-2151
93. Williams Jr. R.C., Malone C., Blood B., and Silvestris F. Anti-DNA and anti-nucleosome antibody affinity--a mirror image of lupus nephritis?. J Rheumatol 26 2 (1999) 331-346
94. Williams Jr. R.C., Malone C.C., Meyers C., Decker P., and Muller S. Detection of nucleosome particles in serum and plasma from patients with systemic lupus erythematosus using monoclonal antibody 4H7. J Rheumatol 28 1 (2001) 81-94
95. Witte T. IgM antibodies against dsDNA in SLE. Clin Rev Allergy Immunol 34 3 (2008) 345-347
96. Wolf S.D., Dittel B.N., Hardardottir F., and Janeway Jr. C.A. Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. J Exp Med 184 6 (1996) 2271-2278
97. Yanaba K., Bouaziz J.D., Matsushita T., Magro C.M., St Clair E.W., and Tedder T.F. B-lymphocyte contributions to human autoimmune disease. Immunol Rev 223 (2008) 284-299
98. Yin Z., Bahtiyar G., Zhang N., Liu L., Zhu P., Robert M.E., et al. IL-10 regulates murine lupus. J Immunol 169 4 (2002) 2148-2155
99. Yurasov S., Wardemann H., Hammersen J., Tsuiji M., Meffre E., Pascual V., et al. Defective B cell tolerance checkpoints in systemic lupus erythematosus. J Exp Med 201 5 (2005) 703-711
100. Zeng D., Lee M.K., Tung J., Brendolan A., and Strober S. Cutting edge: a role for CD1 in the pathogenesis of lupus in NZB/NZW mice. J Immunol 164 10 (2000) 5000-5004
101. Zhang J., Jacobi A.M., Mackay M., Aranow C., Wang T., Chinnasamy P., et al. Identification of DNA-reactive B cells in patients with systemic lupus erythematosus. J Immunol Methods 338 1-2 (2008) 79-84
102. Zhang J., Jacobi A.M., Wang T., and Diamond B. Pathogenic autoantibodies in systemic lupus erythematosus are derived from both self-reactive and non-self-reactive B cells. Mol Med 14 11-12 (2008) 675-681