B-cell selection and the development of autoantibodies

Arthritis Research and Therapy

Volumn 14, Issue SUPPL. 4, 2012, Pages

  Giltiay, Natalia V ^a   Chappell, Craig P ^a   Clark, Edward A ^a,b  

^a UNIVERSITY OF WASHINGTON   (United States)

^b UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIVATION INDUCED CYTIDINE DEAMINASE; AUTOANTIBODY; AUTOANTIGEN; B LYMPHOCYTE RECEPTOR; BRUTON TYROSINE KINASE; CD40 LIGAND; FOSTAMATINIB; HYDROXYCHLOROQUINE; IBRUTINIB; IDELALISIB; INTERFERON; INTERLEUKIN 1 RECEPTOR ASSOCIATED KINASE 4; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; MYELOID DIFFERENTIATION FACTOR 88; NON RECEPTOR PROTEIN TYROSINE PHOSPHATASE 22; PROTEIN KINASE SYK INHIBITOR; TOLL LIKE RECEPTOR; TOLL LIKE RECEPTOR 7; TOLL LIKE RECEPTOR 9;

ANTIBODY RESPONSE; AUTOIMMUNE DISEASE; AUTOIMMUNE THYROIDITIS; B LYMPHOCYTE; BONE MARROW; CD4+ T LYMPHOCYTE; CELL LINEAGE; CPG ISLAND; DRUG EFFICACY; FOLLICULAR DENDRITIC CELL; GENE FUNCTION; GENETIC POLYMORPHISM; GENETIC RECOMBINATION; GERMINAL CENTER; HUMAN; HUMORAL IMMUNITY; IMMUNOLOGICAL TOLERANCE; IMMUNOTHERAPY; INSULIN DEPENDENT DIABETES MELLITUS; LYMPHOCYTE DEPLETION; LYMPHOID TISSUE; NONHUMAN; REVIEW; RHEUMATOID ARTHRITIS; SIGNAL TRANSDUCTION; SOMATIC MUTATION; SYSTEMIC LUPUS ERYTHEMATOSUS; ANIMAL; AUTOIMMUNITY; GENE REARRANGEMENT; IMMUNOLOGY;

ANIMALS; AUTOANTIBODIES; AUTOANTIGENS; AUTOIMMUNITY; B-LYMPHOCYTES; GERMINAL CENTER; HUMANS; IMMUNOGLOBULIN CLASS SWITCHING;

MLCS; MLOWN;

EID: 84868361493     PISSN: 14786354     EISSN: 14786362     Source Type: Journal    
DOI: 10.1186/ar3918     Document Type: Review

References (119)

1. Edwards JC, Cambridge G. Prospects for B-cell-targeted therapy in autoimmune disease. Rheumatology (Oxford) 2005, 44:151-156.
2. Nakken B, Munthe LA, Konttinen YT, Sandberg AK, Szekanecz Z, Alex P, Szodoray P. B-cells and their targeting in rheumatoid arthritis - current concepts and future perspectives. Autoimmun Rev 2011, 11:28-34. 10.1016/j.autrev.2011.06.010, 21777703.
3. Yildirim-Toruner C, Diamond B. Current and novel therapeutics in the treatment of systemic lupus erythematosus. J Allergy Clin Immunol 2011, 127:303-312. quiz 313-4, 10.1016/j.jaci.2010.12.1087, 3053574, 21281862.
4. Kuraoka M, Kelsoe G. A novel role for activation-induced cytidine deaminase: central B-cell tolerance. Cell Cycle 2011, 10:3423-3424. 10.4161/cc.10.20.17693, 22067654.
5. Meffre E. The establishment of early B cell tolerance in humans: lessons from primary immunodeficiency diseases. Ann N Y Acad Sci 2011, 1246:1-10. 10.1111/j.1749-6632.2011.06347.x, 22236425.
6. Pillai S, Mattoo H, Cariappa A. B cells and autoimmunity. Curr Opin Immunol 2011, 23:721-731. 10.1016/j.coi.2011.10.007, 22119110.
7. Stavnezer J. Complex regulation and function of activation-induced cytidine deaminase. Trends Immunol 2011, 32:194-201. 10.1016/j.it.2011.03.003, 3090464, 21493144.
8. Suryani S, Fulcher DA, Santner-Nanan B, Nanan R, Wong M, Shaw PJ, Gibson J, Williams A, Tangye SG. Differential expression of CD21 identifies developmentally and functionally distinct subsets of human transitional B cells. Blood 2010, 115:519-529. 10.1182/blood-2009-07-234799, 19965666.
9. Meffre E, Wardemann H. B-cell tolerance checkpoints in health and autoimmunity. Curr Opin Immunol 2008, 20:632-638. 10.1016/j.coi.2008.09.001, 18848883.
10. Isnardi I, Ng YS, Menard L, Meyers G, Saadoun D, Srdanovic I, Samuels J, Berman J, Buckner JH, Cunningham-Rundles C, Meffre E. Complement receptor 2/CD21- human naive B cells contain mostly autoreactive unresponsive clones. Blood 2010, 115:5026-5036. 10.1182/blood-2009-09-243071, 3373152, 20231422.
11. Yurasov S, Wardemann H, Hammersen J, Tsuiji M, Meffre E, Pascual V, Nussenzweig MC. Defective B cell tolerance checkpoints in systemic lupus erythematosus. J Exp Med 2005, 201:703-711. 10.1084/jem.20042251, 2212839, 15738055.
12. Vossenkamper A, Lutalo PM, Spencer J. Translational mini-review series on B cell subsets in disease. Transitional B cells in systemic lupus erythematosus and Sjogren's syndrome: clinical implications and effects of B cell-targeted therapies. Clin Exp Immunol 2012, 167:7-14. 10.1111/j.1365-2249.2011.04460.x, 22132879.
13. Menard L, Saadoun D, Isnardi I, Ng YS, Meyers G, Massad C, Price C, Abraham C, Motaghedi R, Buckner JH, Gregersen PK, Meffre E. The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans. J Clin Invest 2011, 121:3635-3644. 10.1172/JCI45790, 3163953, 21804190.
14. Rhee I, Veillette A. Protein tyrosine phosphatases in lymphocyte activation and autoimmunity. Nat Immunol 2012, 13:439-447. 10.1038/ni.2246, 22513334.
15. Arechiga AF, Habib T, He Y, Zhang X, Zhang ZY, Funk A, Buckner JH. Cutting edge: the PTPN22 allelic variant associated with autoimmunity impairs B cell signaling. J Immunol 2009, 182:3343-3347. 10.4049/jimmunol.0713370, 2797545, 19265110.
16. Zhang J, Zahir N, Jiang Q, Miliotis H, Heyraud S, Meng X, Dong B, Xie G, Qiu F, Hao Z, McCulloch CA, Keystone EC, Peterson AC, Siminovitch KA. The autoimmune disease-associated PTPN22 variant promotes calpain-mediated Lyp/Pep degradation associated with lymphocyte and dendritic cell hyperresponsiveness. Nat Genet 2011, 43:902-907. 10.1038/ng.904, 21841778.
17. Horwood NJ, Urbaniak AM, Danks L. Tec family kinases in inflammation and disease. Int Rev Immunol 2012, 31:87-103. 10.3109/08830185.2012.670334, 22449071.
18. Fukui R, Saitoh S, Kanno A, Onji M, Shibata T, Ito A, Onji M, Matsumoto M, Akira S, Yoshida N, Miyake K. Unc93B1 restricts systemic lethal inflammation by orchestrating Toll-like receptor 7 and 9 trafficking. Immunity 2011, 35:69-81. 10.1016/j.immuni.2011.05.010, 21683627.
19. Itoh H, Tatematsu M, Watanabe A, Iwano K, Funami K, Seya T, Matsumoto M. UNC93B1 physically associates with human TLR8 and regulates TLR8-mediated signaling. PLoS One 2011, 6:e28500. 10.1371/journal.pone.0028500, 3229609, 22164301.
20. Kil LP, de Bruijn MJ, van Nimwegen M, Corneth OB, van Hamburg JP, Dingjan GM, Thaiss F, Rimmelzwaan GF, Elewaut D, Delsing D, van Loo PF, Hendriks RW. Btk levels set the threshold for B-cell activation and negative selection of autoreactive B cells in mice. Blood 2011, 119:3744-3756.
21. Mackay F, Silveira PA, Brink R. B cells and the BAFF/APRIL axis: fast-forward on autoimmunity and signaling. Curr Opin Immunol 2007, 19:327-336. 10.1016/j.coi.2007.04.008, 17433868.
22. Liu Z, Davidson A. BAFF and selection of autoreactive B cells. Trends Immunol 2011, 32:388-394. 10.1016/j.it.2011.06.004, 3151317, 21752714.
23. Groom JR, Fletcher CA, Walters SN, Grey ST, Watt SV, Sweet MJ, Smyth MJ, Mackay CR, Mackay F. BAFF and MyD88 signals promote a lupuslike disease independent of T cells. J Exp Med 2007, 204:1959-1971. 10.1084/jem.20062567, 2118661, 17664289.
24. Bombardieri M, Kam NW, Brentano F, Choi K, Filer A, Kyburz D, McInnes IB, Gay S, Buckley C, Pitzalis C. A BAFF/APRIL-dependent TLR3-stimulated pathway enhances the capacity of rheumatoid synovial fibroblasts to induce AID expression and Ig class-switching in B cells. Ann Rheum Dis 2011, 70:1857-1865. 10.1136/ard.2011.150219, 21798884.
25. Acosta-Rodriguez EV, Craxton A, Hendricks DW, Merino MC, Montes CL, Clark EA, Gruppi A. BAFF and LPS cooperate to induce B cells to become susceptible to CD95/Fas-mediated cell death. Eur J Immunol 2007, 37:990-1000. 10.1002/eji.200636698, 17357108.
26. Chappell CP, Jacob J. Germinal-center-derived B-cell memory. Adv Exp Med Biol 2007, 590:139-148. 10.1007/978-0-387-34814-8_10, 17191383.
27. Goodnow CC, Vinuesa CG, Randall KL, Mackay F, Brink R. Control systems and decision making for antibody production. Nat Immunol 2010, 11:681-688.
28. Tiller T, Kofer J, Kreschel C, Busse CE, Riebel S, Wickert S, Oden F, Mertes MM, Ehlers M, Wardemann H. Development of self-reactive germinal center B cells and plasma cells in autoimmune FcγRIIB-deficient mice. J Exp Med 2010, 207:2767-2778. 10.1084/jem.20100171, 2989760, 21078890.
29. Guo W, Smith D, Aviszus K, Detanico T, Heiser RA, Wysocki LJ. Somatic hypermutation as a generator of antinuclear antibodies in a murine model of systemic autoimmunity. J Exp Med 2010, 207:2225-2237. 10.1084/jem.20092712, 2947070, 20805563.
30. Mietzner B, Tsuiji M, Scheid J, Velinzon K, Tiller T, Abraham K, Gonzalez JB, Pascual V, Stichweh D, Wardemann H, Nussenzweig MC. Autoreactive IgG memory antibodies in patients with systemic lupus erythematosus arise from nonreactive and polyreactive precursors. Proc Natl Acad Sci USA 2008, 105:9727-9732. 10.1073/pnas.0803644105, 2474524, 18621685.
31. Tiller T, Tsuiji M, Yurasov S, Velinzon K, Nussenzweig MC, Wardemann H. Autoreactivity in human IgG+ memory B cells. Immunity 2007, 26:205-213. 10.1016/j.immuni.2007.01.009, 1839941, 17306569.
32. Linterman MA, Rigby RJ, Wong RK, Yu D, Brink R, Cannons JL, Schwartzberg PL, Cook MC, Walters GD, Vinuesa CG. Follicular helper T cells are required for systemic autoimmunity. J Exp Med 2009, 206:561-576. 10.1084/jem.20081886, 2699132, 19221396.
33. Vuyyuru R, Mohan C, Manser T, Rahman ZS. The lupus susceptibility locus Sle1 breaches peripheral B cell tolerance at the antibody-forming cell and germinal center checkpoints. J Immunol 2009, 183:5716-5727. 10.4049/jimmunol.0804215, 2879885, 19828626.
34. Scheid JF, Mouquet H, Kofer J, Yurasov S, Nussenzweig MC, Wardemann H. Differential regulation of self-reactivity discriminates between IgG+ human circulating memory B cells and bone marrow plasma cells. Proc Natl Acad Sci USA 2011, 108:18044-18048. 10.1073/pnas.1113395108, 3207704, 22025722.
35. Chappell CP, Jacob J. Identification of memory B cells using a novel transgenic mouse model. J Immunol 2006, 176:4706-4715.
36. Blink EJ, Light A, Kallies A, Nutt SL, Hodgkin PD, Tarlinton DM. Early appearance of germinal center-derived memory B cells and plasma cells in blood after primary immunization. J Exp Med 2005, 201:545-554. 10.1084/jem.20042060, 2213050, 15710653.
37. Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, Harley JB. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 2003, 349:1526-1533. 10.1056/NEJMoa021933, 14561795.
38. Townsend MJ, Monroe JG, Chan AC. B-cell targeted therapies in human autoimmune diseases: an updated perspective. Immunol Rev 2010, 237:264-283. 10.1111/j.1600-065X.2010.00945.x, 20727041.
39. Mao C, Jiang L, Melo-Jorge M, Puthenveetil M, Zhang X, Carroll MC, Imanishi-Kari T. T cell-independent somatic hypermutation in murine B cells with an immature phenotype. Immunity 2004, 20:133-144. 10.1016/S1074-7613(04)00019-6, 14975236.
40. Han JH, Akira S, Calame K, Beutler B, Selsing E, Imanishi-Kari T. Class switch recombination and somatic hypermutation in early mouse B cells are mediated by B cell and Toll-like receptors. Immunity 2007, 27:64-75. 10.1016/j.immuni.2007.05.018, 2082107, 17658280.
41. Ueda Y, Liao D, Yang K, Patel A, Kelsoe G. T-independent activation-induced cytidine deaminase expression, class-switch recombination, and antibody production by immature/transitional 1 B cells. J Immunol 2007, 178:3593-3601. 1955467, 17339456.
42. Aranburu A, Ceccarelli S, Giorda E, Lasorella R, Ballatore G, Carsetti R. TLR ligation triggers somatic hypermutation in transitional B cells inducing the generation of IgM memory B cells. J Immunol 2010, 185:7293-7301. 10.4049/jimmunol.1002722, 21078901.
43. Guo P, Hirano M, Herrin BR, Li J, Yu C, Sadlonova A, Cooper MD. Dual nature of the adaptive immune system in lampreys. Nature 2009, 459:796-801. 10.1038/nature08068, 2714547, 19474790.
44. Meyers G, Ng YS, Bannock JM, Lavoie A, Walter JE, Notarangelo LD, Kilic SS, Aksu G, Debre M, Rieux-Laucat F, Conley ME, Cunningham-Rundles C, Durandy A, Meffre E. Activation-induced cytidine deaminase (AID) is required for B-cell tolerance in humans. Proc Natl Acad Sci USA 2011, 108:11554-11559. 10.1073/pnas.1102600108, 3136251, 21700883.
45. Kuraoka M, Holl TM, Liao D, Womble M, Cain DW, Reynolds AE, Kelsoe G. Activation-induced cytidine deaminase mediates central tolerance in B cells. Proc Natl Acad Sci USA 2011, 108:11560-11565. 10.1073/pnas.1102571108, 3136303, 21700885.
46. William J, Euler C, Christensen S, Shlomchik MJ. Evolution of autoantibody responses via somatic hypermutation outside of germinal centers. Science 2002, 297:2066-2070. 10.1126/science.1073924, 12242446.
47. Sweet RA, Ols ML, Cullen JL, Milam AV, Yagita H, Shlomchik MJ. Facultative role for T cells in extrafollicular Toll-like receptor-dependent autoreactive B-cell responses in vivo. Proc Natl Acad Sci USA 2011, 108:7932-7937. 10.1073/pnas.1018571108, 3093527, 21518858.
48. He B, Qiao X, Cerutti A. CpG DNA induces IgG class switch DNA recombination by activating human B cells through an innate pathway that requires TLR9 and cooperates with IL-10. J Immunol 2004, 173:4479-4491.
49. Litinskiy MB, Nardelli B, Hilbert DM, He B, Schaffer A, Casali P, Cerutti A. DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat Immunol 2002, 3:822-829.
50. He B, Santamaria R, Xu W, Cols M, Chen K, Puga I, Shan M, Xiong H, Bussel JB, Chiu A, Puel A, Reichenbach J, Marodi L, Doffinger R, Vasconcelos J, Issekutz A, Krause J, Davies G, Li X, Grimbacher B, Plebani A, Meffre E, Picard C, Cunningham-Rundles C, Casanova JL, Cerutti A. The transmembrane activator TACI triggers immunoglobulin class switching by activating B cells through the adaptor MyD88. Nat Immunol 2010, 11:836-845. 10.1038/ni.1914, 3047500, 20676093.
51. Ngo VN, Korner H, Gunn MD, Schmidt KN, Riminton DS, Cooper MD, Browning JL, Sedgwick JD, Cyster JG. Lymphotoxin alpha/beta and tumor necrosis factor are required for stromal cell expression of homing chemokines in B and T cell areas of the spleen. J Exp Med 1999, 189:403-412. 10.1084/jem.189.2.403, 2192983, 9892622.
52. Hamaguchi Y, Uchida J, Cain DW, Venturi GM, Poe JC, Haas KM, Tedder TF. The peritoneal cavity provides a protective niche for B1 and conventional B lymphocytes during anti-CD20 immunotherapy in mice. J Immunol 2005, 174:4389-4399.
53. Astorri E, Bombardieri M, Gabba S, Peakman M, Pozzilli P, Pitzalis C. Evolution of ectopic lymphoid neogenesis and in situ autoantibody production in autoimmune nonobese diabetic mice: cellular and molecular characterization of tertiary lymphoid structures in pancreatic islets. J Immunol 2010, 185:3359-3368. 10.4049/jimmunol.1001836, 20713891.
54. Humby F, Bombardieri M, Manzo A, Kelly S, Blades MC, Kirkham B, Spencer J, Pitzalis C. Ectopic lymphoid structures support ongoing production of class-switched autoantibodies in rheumatoid synovium. PLoS Med 2009, 6:e1. 2628399, 19166263.
55. Victora GD, Nussenzweig MC. Germinal centers. Annu Rev Immunol 2012, 30:429-457. 10.1146/annurev-immunol-020711-075032, 22224772.
56. Dudziak D, Kamphorst AO, Heidkamp GF, Buchholz VR, Trumpfheller C, Yamazaki S, Cheong C, Liu K, Lee HW, Park CG, Steinman RM, Nussenzweig MC. Differential antigen processing by dendritic cell subsets in vivo. Science 2007, 315:107-111. 10.1126/science.1136080, 17204652.
57. Sancho D, Joffre OP, Keller AM, Rogers NC, Martinez D, Hernanz-Falcon P, Rosewell I, Reis e Sousa C. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 2009, 458:899-903. 10.1038/nature07750, 2671489, 19219027.
58. Gaipl US, Voll RE, Sheriff A, Franz S, Kalden JR, Herrmann M. Impaired clearance of dying cells in systemic lupus erythematosus. Autoimmun Rev 2005, 4:189-194. 10.1016/j.autrev.2004.10.007, 15893710.
59. Jego G, Pascual V, Palucka AK, Banchereau J. Dendritic cells control B cell growth and differentiation. Curr Dir Autoimmun 2005, 8:124-139.
60. Tangye SG. Plasmacytoid DCs induce gutsy plasma cells. Immunity 2011, 34:144-146. 10.1016/j.immuni.2011.02.009, 21349426.
61. Bergtold A, Desai DD, Gavhane A, Clynes R. Cell surface recycling of internalized antigen permits dendritic cell priming of B cells. Immunity 2005, 23:503-514. 10.1016/j.immuni.2005.09.013, 16286018.
62. Qi H, Egen JG, Huang AY, Germain RN. Extrafollicular activation of lymph node B cells by antigen-bearing dendritic cells. Science 2006, 312:1672-1676. 10.1126/science.1125703, 16778060.
63. Teichmann LL, Ols ML, Kashgarian M, Reizis B, Kaplan DH, Shlomchik MJ. Dendritic cells in lupus are not required for activation of T and B cells but promote their expansion, resulting in tissue damage. Immunity 2010, 33:967-978. 10.1016/j.immuni.2010.11.025, 3010763, 21167752.
64. Chappell CP, Draves KE, Giltiay NV, Clark EA. Extrafollicular B cell activation by marginal zone dendritic cells drives T cell-dependent antibody responses. J Exp Med 2012,
65. Green NM, Marshak-Rothstein A. Toll-like receptor driven B cell activation in the induction of systemic autoimmunity. Semin Immunol 2011, 23:106-112. 10.1016/j.smim.2011.01.016, 3070769, 21306913.
66. Lau CM, Broughton C, Tabor AS, Akira S, Flavell RA, Mamula MJ, Christensen SR, Shlomchik MJ, Viglianti GA, Rifkin IR, Marshak-Rothstein A. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J Exp Med 2005, 202:1171-1177. 10.1084/jem.20050630, 2213226, 16260486.
67. Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 2002, 416:603-607. 10.1038/416603a, 11948342.
68. Viglianti GA, Lau CM, Hanley TM, Miko BA, Shlomchik MJ, Marshak-Rothstein A. Activation of autoreactive B cells by CpG dsDNA. Immunity 2003, 19:837-847. 10.1016/S1074-7613(03)00323-6, 14670301.
69. Bijl M, Reefman E, Horst G, Limburg PC, Kallenberg CG. Reduced uptake of apoptotic cells by macrophages in systemic lupus erythematosus: correlates with decreased serum levels of complement. Ann Rheum Dis 2006, 65:57-63. 10.1136/ard.2005.035733, 1797975, 15919679.
70. Ren Y, Tang J, Mok MY, Chan AW, Wu A, Lau CS. Increased apoptotic neutrophils and macrophages and impaired macrophage phagocytic clearance of apoptotic neutrophils in systemic lupus erythematosus. Arthritis Rheum 2003, 48:2888-2897. 10.1002/art.11237, 14558095.
71. Uccellini MB, Busconi L, Green NM, Busto P, Christensen SR, Shlomchik MJ, Marshak-Rothstein A, Viglianti GA. Autoreactive B cells discriminate CpG-rich and CpG-poor DNA and this response is modulated by IFN-alpha. J Immunol 2008, 181:5875-5884. 2584609, 18941176.
72. Ballestar E. Epigenetic alterations in autoimmune rheumatic diseases. Nat Rev Rheumatol 2011, 7:263-271. 10.1038/nrrheum.2011.16, 21343899.
73. Diebold SS. Recognition of viral single-stranded RNA by Toll-like receptors. Adv Drug Deliv Rev 2008, 60:813-823. 10.1016/j.addr.2007.11.004, 18241955.
74. Cyster JG. B cell follicles and antigen encounters of the third kind. Nat Immunol 2010, 11:989-996. 10.1038/ni.1946, 20959804.
75. Hakkim A, Furnrohr BG, Amann K, Laube B, Abed UA, Brinkmann V, Herrmann M, Voll RE, Zychlinsky A. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci USA 2010, 107:9813-9818. 10.1073/pnas.0909927107, 2906830, 20439745.
76. Puga I, Cols M, Barra CM, He B, Cassis L, Gentile M, Comerma L, Chorny A, Shan M, Xu W, G Knowles DM, Tam W, Chiu A, Bussel JB, Serrano S, Lorente JA, Bellosillo B, Lloreta J, Juanpere N, Alameda F, Baro T, de Heredia CD, Toran N, Catala A, Torrebadell M, Fortuny C, Cusi V, Carreras C, Diaz GA, et al. B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nat Immunol 2012, 13:170-180.
77. Giltiay NV. TLR7 overexpression drives autoantigen-mediated expansion of transitional and follicular B cells independently of type I IFN signals [abstract]. Arthritis Rheum 2011, 63(Suppl 10):2548.
78. Latz E, Schoenemeyer A, Visintin A, Fitzgerald KA, Monks BG, Knetter CF, Lien E, Nilsen NJ, Espevik T, Golenbock DT. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat Immunol 2004, 5:190-198.
79. Chaturvedi A, Dorward D, Pierce SK. The B cell receptor governs the subcellular location of Toll-like receptor 9 leading to hyperresponses to DNA-containing antigens. Immunity 2008, 28:799-809. 10.1016/j.immuni.2008.03.019, 2601674, 18513998.
80. Saitoh S, Miyake K. Regulatory molecules required for nucleotide-sensing Toll-like receptors. Immunol Rev 2009, 227:32-43. 10.1111/j.1600-065X.2008.00729.x, 19120473.
81. Christensen SR, Shupe J, Nickerson K, Kashgarian M, Flavell RA, Shlomchik MJ. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 2006, 25:417-428. 10.1016/j.immuni.2006.07.013, 16973389.
82. Pisitkun P, Deane JA, Difilippantonio MJ, Tarasenko T, Satterthwaite AB, Bolland S. Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science 2006, 312:1669-1672. 10.1126/science.1124978, 16709748.
83. Deane JA, Pisitkun P, Barrett RS, Feigenbaum L, Town T, Ward JM, Flavell RA, Bolland S. Control of toll-like receptor 7 expression is essential to restrict autoimmunity and dendritic cell proliferation. Immunity 2007, 27:801-810. 10.1016/j.immuni.2007.09.009, 2706502, 17997333.
84. Christensen SR, Kashgarian M, Alexopoulou L, Flavell RA, Akira S, Shlomchik MJ. Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus. J Exp Med 2005, 202:321-331. 10.1084/jem.20050338, 2212997, 16027240.
85. Santiago-Raber ML, Dunand-Sauthier I, Wu T, Li QZ, Uematsu S, Akira S, Reith W, Mohan C, Kotzin BL, Izui S. Critical role of TLR7 in the acceleration of systemic lupus erythematosus in TLR9-deficient mice. J Autoimmun 2010, 34:339-348. 10.1016/j.jaut.2009.11.001, 19944565.
86. Demaria O, Pagni PP, Traub S, de Gassart A, Branzk N, Murphy AJ, Valenzuela DM, Yancopoulos GD, Flavell RA, Alexopoulou L. TLR8 deficiency leads to autoimmunity in mice. J Clin Invest 2010, 120:3651-3662. 2947223, 20811154.
87. Kawasaki A, Furukawa H, Kondo Y, Ito S, Hayashi T, Kusaoi M, Matsumoto I, Tohma S, Takasaki Y, Hashimoto H, Sumida T, Tsuchiya N. TLR7 single-nucleotide polymorphisms in the 3' untranslated region and intron 2 independently contribute to systemic lupus erythematosus in Japanese women: a case-control association study. Arthritis Res Ther 2011, 13:R41. 10.1186/ar3277, 3132023, 21396113.
88. Shen N, Fu Q, Deng Y, Qian X, Zhao J, Kaufman KM, Wu YL, Yu CY, Tang Y, Chen JY, Yang W, Wong M, Kawasaki A, Tsuchiya N, Sumida T, Kawaguchi Y, Howe HS, Mok MY, Bang SY, Liu FL, Chang DM, Takasaki Y, Hashimoto H, Harley JB, Guthridge JM, Grossman JM, Cantor RM, Song YW, Bae SC, Chen S, et al. Sex-specific association of X-linked Toll-like receptor 7 (TLR7) with male systemic lupus erythematosus. Proc Natl Acad Sci USA 2010, 107:15838-15843. 10.1073/pnas.1001337107, 2936646, 20733074.
89. Tao K, Fujii M, Tsukumo S, Maekawa Y, Kishihara K, Kimoto Y, Horiuchi T, Hisaeda H, Akira S, Kagami S, Yasutomo K. Genetic variations of Toll-like receptor 9 predispose to systemic lupus erythematosus in Japanese population. Ann Rheum Dis 2007, 66:905-909. 10.1136/ard.2006.065961, 1955115, 17344245.
90. Friedman RM, Preble O, Black R, Harrell S. Interferon production in patients with systemic lupus erythematosus. Arthritis Rheum 1982, 25:802-803. 10.1002/art.1780250717, 6179523.
91. Hooks JJ, Jordan GW, Cupps T, Moutsopoulos HM, Fauci AS, Notkins AL. Multiple interferons in the circulation of patients with systemic lupus erythematosus and vasculitis. Arthritis Rheum 1982, 25:396-400. 10.1002/art.1780250406, 6176247.
92. Preble OT, Black RJ, Friedman RM, Klippel JH, Vilcek J. Systemic lupus erythematosus: presence in human serum of an unusual acid-labile leukocyte interferon. Science 1982, 216:429-431. 10.1126/science.6176024, 6176024.
93. Elkon KB, Stone VV. Type I interferon and systemic lupus erythematosus. J Interferon Cytokine Res 2011, 31:803-812. 10.1089/jir.2011.0045, 21859344.
94. Ronnblom L. The type I interferon system in the etiopathogenesis of autoimmune diseases. Ups J Med Sci 2011, 116:227-237. 10.3109/03009734.2011.624649, 3207297, 22066971.
95. Pascual V, Farkas L, Banchereau J. Systemic lupus erythematosus: all roads lead to type I interferons. Curr Opin Immunol 2006, 18:676-682. 10.1016/j.coi.2006.09.014, 17011763.
96. Swanson CL, Wilson TJ, Strauch P, Colonna M, Pelanda R, Torres RM. Type I IFN enhances follicular B cell contribution to the T cell-independent antibody response. J Exp Med 2010, 207:1485-1500. 10.1084/jem.20092695, 2901065, 20566717.
97. Green NM, Laws A, Kiefer K, Busconi L, Kim YM, Brinkmann MM, Trail EH, Yasuda K, Christensen SR, Shlomchik MJ, Vogel S, Connor JH, Ploegh H, Eilat D, Rifkin IR, van Seventer JM, Marshak-Rothstein A. Murine B cell response to TLR7 ligands depends on an IFN-beta feedback loop. J Immunol 2009, 183:1569-1576. 10.4049/jimmunol.0803899, 2929820, 19587008.
98. Thibault DL, Chu AD, Graham KL, Balboni I, Lee LY, Kohlmoos C, Landrigan A, Higgins JP, Tibshirani R, Utz PJ. IRF9 and STAT1 are required for IgG autoantibody production and B cell expression of TLR7 in mice. J Clin Invest 2008, 118:1417-1426. 10.1172/JCI30065, 2267033, 18340381.
99. Bekeredjian-Ding IB, Wagner M, Hornung V, Giese T, Schnurr M, Endres S, Hartmann G. Plasmacytoid dendritic cells control TLR7 sensitivity of naive B cells via type I IFN. J Immunol 2005, 174:4043-4050.
100. Rosado MM, Diamanti AP, Capolunghi F, Carsetti R. B cell modulation strategies in autoimmunity: the SLE example. Curr Pharm Des 2011, 17:3155-3165. 10.2174/138161211798157612, 21864265.
101. Marian V, Anolik JH. Treatment targets in systemic lupus erythematosus: biology and clinical perspective. Arthritis Res Therapy 2012, 14(Suppl 4):S3..
102. Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood 2012, 120:1175-1184. 10.1182/blood-2012-02-362624, 22715122.
103. Scott DL. Role of spleen tyrosine kinase inhibitors in the management of rheumatoid arthritis. Drugs 2011, 71:1121-1132. 10.2165/11591480-000000000-00000, 21711059.
104. Bahjat FR, Pine PR, Reitsma A, Cassafer G, Baluom M, Grillo S, Chang B, Zhao FF, Payan DG, Grossbard EB, Daikh DI. An orally bioavailable spleen tyrosine kinase inhibitor delays disease progression and prolongs survival in murine lupus. Arthritis Rheum 2008, 58:1433-1444. 10.1002/art.23428, 18438845.
105. Deng GM, Liu L, Bahjat FR, Pine PR, Tsokos GC. Suppression of skin and kidney disease by inhibition of spleen tyrosine kinase in lupus-prone mice. Arthritis Rheum 2010, 62:2086-2092. 2902591, 20222110.
106. Colonna L, Catalano G, Chew C, D'Agati V, Thomas JW, Wong FS, Schmitz J, Masuda ES, Reizis B, Tarakhovsky A, Clynes R. Therapeutic targeting of Syk in autoimmune diabetes. J Immunol 2010, 185:1532-1543. 10.4049/jimmunol.1000983, 2981095, 20601600.
107. Barr PM, Wei C, Roger J, Schaefer-Cutillo J, Kelly JL, Rosenberg AF, Jung J, Sanz I, Friedberg JW. Syk inhibition with fostamatinib leads to transitional B lymphocyte depletion. Clin Immunol 2012, 142:237-242. 10.1016/j.clim.2011.12.012, 22284392.
108. Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B, Li S, Pan Z, Thamm DH, Miller RA, Buggy JJ. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci USA 2010, 107:13075-13080. 10.1073/pnas.1004594107, 2919935, 20615965.
109. Chang BY, Huang MM, Francesco M, Chen J, Sokolove J, Magadala P, Robinson WH, Buggy JJ. The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells. Arthritis Res Ther 2011, 13:R115. 10.1186/ar3400, 3239353, 21752263.
110. Durand CA, Hartvigsen K, Fogelstrand L, Kim S, Iritani S, Vanhaesebroeck B, Witztum JL, Puri KD, Gold MR. Phosphoinositide 3-kinase p110 delta regulates natural antibody production, marginal zone and B-1 B cell function, and autoantibody responses. J Immunol 2009, 183:5673-5684. 10.4049/jimmunol.0900432, 19843950.
111. Bartok B, Boyle DL, Liu Y, Ren P, Ball ST, Bugbee WD, Rommel C, Firestein GS. PI3 kinase delta is a key regulator of synoviocyte function in rheumatoid arthritis. Am J Pathol 2012, 180:1906-1916. 10.1016/j.ajpath.2012.01.030, 22433439.
112. Dil N, Marshall AJ. Role of phosphoinositide 3-kinase p110 delta in TLR4-and TLR9-mediated B cell cytokine production and differentiation. Mol Immunol 2009, 46:1970-1978. 10.1016/j.molimm.2009.03.010, 19362372.
113. Hennessy EJ, Parker AE, O'Neill LA. Targeting Toll-like receptors: emerging therapeutics?. Nat Rev Drug Discov 2010, 9:293-307. 10.1038/nrd3203, 20380038.
114. Katz SJ, Russell AS. Re-evaluation of antimalarials in treating rheumatic diseases: re-appreciation and insights into new mechanisms of action. Curr Opin Rheumatol 2011, 23:278-281. 10.1097/BOR.0b013e32834456bf, 21448012.
115. Lee SJ, Silverman E, Bargman JM. The role of antimalarial agents in the treatment of SLE and lupus nephritis. Nat Rev Nephrol 2011, 7:718-729. 10.1038/nrneph.2011.150, 22009248.
116. Goldman FD, Gilman AL, Hollenback C, Kato RM, Premack BA, Rawlings DJ. Hydroxychloroquine inhibits calcium signals in T cells: a new mechanism to explain its immunomodulatory properties. Blood 2000, 95:3460-3466.
117. Sacre K, Criswell LA, McCune JM. Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus. Arthritis Res Ther 2012, 14:R155. 10.1186/ar3895, 3446541, 22734582.
118. Yu SL, Chan PK, Wong CK, Szeto CC, Ho SC, So K, Yu MM, Yim SF, Cheung TH, Wong MC, Cheung JL, Yeung AC, Li EK, Tam LS. Antagonist-mediated down-regulation of toll-like receptors increases the prevalence of human papillomavirus infection in systemic lupus erythematosus. Arthritis Res Ther 2012, 14:R80. 10.1186/ar3803, 3446454, 22513098.
119. Clark EA, Ledbetter JA. How does B cell depletion therapy work, and how can it be improved?. Ann Rheum Dis 2005, 64(Suppl 4):iv77-iv80. 1766898, 16239394.