Home LiteratureArticle Details
PMID: 20520647 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Review

B cells as therapeutic targets in SLE.

Nature reviews. Rheumatology ·Vol. 6 ·No. 6 ·2010-06-00 ·Pages 326-37

Sanz I, Lee FE

Abstract

The use of B-cell targeted therapies for the treatment of systemic lupus erythematosus (SLE) has generated great interest owing to the multiple pathogenic roles carried out by B cells in this disease. Strong support for targeting B cells is provided by genetic, immunological and clinical observations that place these cells at the center of SLE pathogenesis, as initiating, amplifying and effector cells. Interest in targeting B cells has also been fostered by the successful use of similar interventions to treat other autoimmune diseases such as rheumatoid arthritis, and by the initial promise shown by B-cell depletion to treat SLE in early studies. Although the initial high enthusiasm has been tempered by negative results from phase III trials of the B-cell-depleting agent rituximab in SLE, renewed vigor should be instilled in the field by the convergence of the latest results using agents that inhibit B-cell-activating factor (BAFF, also known as BLyS and tumor necrosis factor ligand superfamily, member 13b), further analysis of data from trials using rituximab and greatly improved understanding of B-cell biology. Combined, the available information identifies several new avenues for the therapeutic targeting of B cells in SLE.

MeSH Terms
Animals B-Lymphocytes/drug effects,immunology Biological Therapy Humans Lupus Erythematosus, Systemic/drug therapy,immunology
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Sanz Iñaki
Division of Allergy, Immunology and Rheumatology, Department of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA. ignacio_sanz@urmc.rochester.edu
Lee F Eun-Hyung
References (98)
98 references, click to expand
  1. Phenotypic and functional heterogeneity of human memory B cells.
    Semin Immunol. 2008 Feb;20(1):67-82 PMID: 18258454
  2. Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis.
    J Immunol. 2007 May 15;178(10):6092-9 PMID: 17475834
  3. The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis.
    Nat Med. 2008 Jul;14(7):748-55 PMID: 18542049
  4. B cell depletion with anti-CD79 mAbs ameliorates autoimmune disease in MRL/lpr mice.
    J Immunol. 2008 Sep 1;181(5):2961-72 PMID: 18713966
  5. How does B cell depletion therapy work, and how can it be improved?
    Ann Rheum Dis. 2005 Nov;64 Suppl 4:iv77-80 PMID: 16239394
  6. A new population of cells lacking expression of CD27 represents a notable component of the B cell memory compartment in systemic lupus erythematosus.
    J Immunol. 2007 May 15;178(10):6624-33 PMID: 17475894
  7. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial.
    Arthritis Rheum. 2010 Jan;62(1):222-33 PMID: 20039413
  8. The BLyS/BAFF family of ligands and receptors: key targets in the therapy and understanding of autoimmunity.
    Ann Rheum Dis. 2006 Nov;65 Suppl 3:iii34-6 PMID: 17038469
  9. The proteasome inhibitor bortezomib inhibits the release of NFkappaB-inducible cytokines and induces apoptosis of activated T cells from rheumatoid arthritis patients.
    Clin Exp Rheumatol. 2009 Jan-Feb;27(1):92-8 PMID: 19327235
  10. Dysregulation of germinal centres in autoimmune disease.
    Nat Rev Immunol. 2009 Dec;9(12):845-57 PMID: 19935804
  11. PI3Kgamma inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus.
    Nat Med. 2005 Sep;11(9):933-5 PMID: 16127435
  12. TLR-9 activation of marginal zone B cells in lupus mice regulates immunity through increased IL-10 production.
    J Clin Immunol. 2005 Jan;25(1):29-40 PMID: 15742155
  13. Highly sensitive B cell analysis predicts response to rituximab therapy in rheumatoid arthritis.
    Arthritis Rheum. 2008 Oct;58(10):2993-9 PMID: 18821683
  14. Impact of the BAFF/BR3 axis on B cell survival, germinal center maintenance and antibody production.
    Semin Immunol. 2006 Oct;18(5):290-6 PMID: 16931038
  15. Deficiency of type I interferon contributes to Sle2-associated component lupus phenotypes.
    Arthritis Rheum. 2005 Oct;52(10):3063-72 PMID: 16200585
  16. High-density SNP screening of the major histocompatibility complex in systemic lupus erythematosus demonstrates strong evidence for independent susceptibility regions.
    PLoS Genet. 2009 Oct;5(10):e1000696 PMID: 19851445
  17. Plasmacytoid dendritic cells control TLR7 sensitivity of naive B cells via type I IFN.
    J Immunol. 2005 Apr 1;174(7):4043-50 PMID: 15778362
  18. Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice.
    J Clin Invest. 2007 Dec;117(12):3857-67 PMID: 18060033
  19. FcgammaRIIb controls bone marrow plasma cell persistence and apoptosis.
    Nat Immunol. 2007 Apr;8(4):419-29 PMID: 17322888
  20. IL-21 and BAFF/BLyS synergize in stimulating plasma cell differentiation from a unique population of human splenic memory B cells.
    J Immunol. 2007 Mar 1;178(5):2872-82 PMID: 17312131
  21. Selective targeting of B cells with agonistic anti-CD40 is an efficacious strategy for the generation of induced regulatory T2-like B cells and for the suppression of lupus in MRL/lpr mice.
    J Immunol. 2009 Mar 15;182(6):3492-3502 PMID: 19265127
  22. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study.
    Arthritis Rheum. 2010 Feb;62(2):542-52 PMID: 20112381
  23. Competence and competition: the challenge of becoming a long-lived plasma cell.
    Nat Rev Immunol. 2006 Oct;6(10):741-50 PMID: 16977339
  24. Cutting edge: primary B lymphocytes preferentially expand allogeneic FoxP3+ CD4 T cells.
    J Immunol. 2007 Aug 15;179(4):2046-50 PMID: 17675460
  25. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma.
    N Engl J Med. 2008 Aug 28;359(9):906-17 PMID: 18753647
  26. A phase II, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of MDX-1100, a fully human anti-CXCL10 monoclonal antibody, in combination with methotrexate in patients with rheumatoid arthritis.
    Arthritis Rheum. 2012 Jun;64(6):1730-9 PMID: 22147649
  27. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus.
    Arthritis Rheum. 2009 Sep 15;61(9):1168-78 PMID: 19714604
  28. Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice.
    Nat Immunol. 2008 Feb;9(2):166-75 PMID: 18157131
  29. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression.
    J Clin Invest. 2008 Oct;118(10):3420-30 PMID: 18802481
  30. Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus.
    Arthritis Rheum. 2008 Aug;58(8):2453-9 PMID: 18668552
  31. Connective tissue diseases: The conundrum of B cell depletion in SLE.
    Nat Rev Rheumatol. 2009 Jun;5(6):304-5 PMID: 19491910
  32. FcgammaRIIB as a modulator of autoimmune disease susceptibility.
    Autoimmunity. 2007 Sep;40(6):409-17 PMID: 17729034
  33. Reciprocal generation of Th1/Th17 and T(reg) cells by B1 and B2 B cells.
    Eur J Immunol. 2007 Sep;37(9):2400-4 PMID: 17683116
  34. CD154-CD40 interactions mediate differentiation to plasma cells in healthy individuals and persons with systemic lupus erythematosus.
    Arthritis Rheum. 2002 Jun;46(6):1417-29 PMID: 12115170
  35. CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients.
    Immunity. 2010 Jan 29;32(1):129-40 PMID: 20079667
  36. TLR-activated B cells suppress T cell-mediated autoimmunity.
    J Immunol. 2008 Apr 1;180(7):4763-73 PMID: 18354200
  37. The effect of anti-CD40 ligand antibody on B cells in human systemic lupus erythematosus.
    Arthritis Rheum. 2002 Jun;46(6):1554-62 PMID: 12115186
  38. IFN-alpha amplifies human naive B cell TLR-9-mediated activation and Ig production.
    J Leukoc Biol. 2009 Aug;86(2):261-71 PMID: 19401392
  39. Immunotherapy using unconjugated CD19 monoclonal antibodies in animal models for B lymphocyte malignancies and autoimmune disease.
    Proc Natl Acad Sci U S A. 2005 Oct 18;102(42):15178-83 PMID: 16217038
  40. Development of psoriasis after B cell depletion with rituximab.
    Arthritis Rheum. 2007 Aug;56(8):2715-8 PMID: 17665440
  41. Type I IFN protects against murine lupus.
    J Immunol. 2004 Aug 1;173(3):2134-42 PMID: 15265950
  42. Not always the bad guys: B cells as regulators of autoimmune pathology.
    Nat Rev Immunol. 2008 May;8(5):391-7 PMID: 18437156
  43. Mesenteric B cells centrally inhibit CD4+ T cell colitis through interaction with regulatory T cell subsets.
    Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):2010-5 PMID: 15684084
  44. Cutting edge: anti-tumor necrosis factor therapy in rheumatoid arthritis inhibits memory B lymphocytes via effects on lymphoid germinal centers and follicular dendritic cell networks.
    J Immunol. 2008 Jan 15;180(2):688-92 PMID: 18178805
  45. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus.
    Immunity. 2006 Sep;25(3):417-28 PMID: 16973389
  46. Induction of interferon-alpha by immune complexes or liposomes containing systemic lupus erythematosus autoantigen- and Sjögren's syndrome autoantigen-associated RNA.
    Arthritis Rheum. 2006 Jun;54(6):1917-27 PMID: 16729300
  47. Genetic association of interleukin-21 polymorphisms with systemic lupus erythematosus.
    Ann Rheum Dis. 2008 Apr;67(4):458-61 PMID: 17720724
  48. Spleen tyrosine kinase: an Src family of non-receptor kinase has multiple functions and represents a valuable therapeutic target in the treatment of autoimmune and inflammatory diseases.
    Autoimmunity. 2010 Feb;43(1):48-55 PMID: 20001666
  49. B cell depletion therapy in systemic lupus erythematosus: relationships among serum B lymphocyte stimulator levels, autoantibody profile and clinical response.
    Ann Rheum Dis. 2008 Jul;67(7):1011-6 PMID: 17962238
  50. Decreased survival of B cells of HIV-viremic patients mediated by altered expression of receptors of the TNF superfamily.
    J Exp Med. 2004 Sep 6;200(5):587-99 PMID: 15353552
  51. Selective blockade of the inhibitory Fcgamma receptor (FcgammaRIIB) in human dendritic cells and monocytes induces a type I interferon response program.
    J Exp Med. 2007 Jun 11;204(6):1359-69 PMID: 17502666
  52. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells.
    Blood. 2006 Jun 15;107(12):4907-16 PMID: 16507771
  53. Chemokine receptor expression and functional effects of chemokines on B cells: implication in the pathogenesis of rheumatoid arthritis.
    Arthritis Res Ther. 2009;11(5):R149 PMID: 19804625
  54. Germinal-center organization and cellular dynamics.
    Immunity. 2007 Aug;27(2):190-202 PMID: 17723214
  55. Cytokine-producing B lymphocytes-key regulators of immunity.
    Curr Opin Immunol. 2008 Jun;20(3):332-8 PMID: 18417336
  56. A granulocyte-macrophage colony-stimulating factor and interleukin-15 fusokine induces a regulatory B cell population with immune suppressive properties.
    Nat Med. 2009 Sep;15(9):1038-45 PMID: 19668193
  57. Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating trial.
    Arthritis Rheum. 2007 Dec;56(12):4142-50 PMID: 18050206
  58. Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus.
    Arthritis Rheum. 2004 Nov;50(11):3580-90 PMID: 15529346
  59. Control of spontaneous B lymphocyte autoimmunity with adenovirus-encoded soluble TACI.
    Arthritis Rheum. 2004 Jun;50(6):1884-96 PMID: 15188365
  60. Differential effects of epratuzumab on peripheral blood B cells of patients with systemic lupus erythematosus versus normal controls.
    Ann Rheum Dis. 2008 Apr;67(4):450-7 PMID: 17673490
  61. Type I interferon receptor controls B-cell expression of nucleic acid-sensing Toll-like receptors and autoantibody production in a murine model of lupus.
    Arthritis Res Ther. 2009;11(4):R112 PMID: 19624844
  62. B-cell-depleting induction therapy and acute cellular rejection.
    N Engl J Med. 2009 Jun 18;360(25):2683-5 PMID: 19535812
  63. B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans.
    J Exp Med. 2010 Jan 18;207(1):155-71 PMID: 20048285
  64. B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab.
    Arthritis Rheum. 2004 Aug;50(8):2580-9 PMID: 15334472
  65. Activated memory B cell subsets correlate with disease activity in systemic lupus erythematosus: delineation by expression of CD27, IgD, and CD95.
    Arthritis Rheum. 2008 Jun;58(6):1762-73 PMID: 18512812
  66. Recent insights into the genetic basis of systemic lupus erythematosus.
    Genes Immun. 2009 Jul;10(5):373-9 PMID: 19440199
  67. PI3K delta and PI3K gamma: partners in crime in inflammation in rheumatoid arthritis and beyond?
    Nat Rev Immunol. 2007 Mar;7(3):191-201 PMID: 17290298
  68. BAFF: a local and systemic target in autoimmune diseases.
    Clin Exp Immunol. 2009 Nov;158(2):155-63 PMID: 19737141
  69. Effect of long-term belimumab treatment on B cells in systemic lupus erythematosus: extension of a phase II, double-blind, placebo-controlled, dose-ranging study.
    Arthritis Rheum. 2010 Jan;62(1):201-10 PMID: 20039404
  70. BAFF selectively enhances the survival of plasmablasts generated from human memory B cells.
    J Clin Invest. 2003 Jul;112(2):286-97 PMID: 12865416
  71. Mice deficient in OX40 and CD30 signals lack memory antibody responses because of deficient CD4 T cell memory.
    J Immunol. 2005 Apr 1;174(7):3891-6 PMID: 15778343
  72. CXCR4: chemokine receptor extraordinaire.
    Immunol Rev. 2000 Oct;177:175-84 PMID: 11138774
  73. Interleukin 17 acts in synergy with B cell-activating factor to influence B cell biology and the pathophysiology of systemic lupus erythematosus.
    Nat Immunol. 2009 Jul;10(7):778-85 PMID: 19483719
  74. IFN-alpha/beta enhances BCR-dependent B cell responses.
    Int Immunol. 2002 Apr;14(4):411-9 PMID: 11934877
  75. Follicular helper T cells are required for systemic autoimmunity.
    J Exp Med. 2009 Mar 16;206(3):561-76 PMID: 19221396
  76. Neutralization of interferon-alpha/beta-inducible genes and downstream effect in a phase I trial of an anti-interferon-alpha monoclonal antibody in systemic lupus erythematosus.
    Arthritis Rheum. 2009 Jun;60(6):1785-96 PMID: 19479852
  77. Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF.
    Immunity. 2004 Apr;20(4):441-53 PMID: 15084273
  78. Treatment of lupus-prone mice with a dual inhibitor of TLR7 and TLR9 leads to reduction of autoantibody production and amelioration of disease symptoms.
    Eur J Immunol. 2007 Dec;37(12):3582-6 PMID: 18034431
  79. PI3K/AKT/mTOR hypersignaling in autoimmune lymphoproliferative disease engendered by the epistatic interplay of Sle1b and FASlpr.
    Int Immunol. 2007 Apr;19(4):509-22 PMID: 17369192
  80. Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus.
    J Immunol. 2000 Nov 15;165(10):5970-9 PMID: 11067960
  81. Delayed memory B cell recovery in peripheral blood and lymphoid tissue in systemic lupus erythematosus after B cell depletion therapy.
    Arthritis Rheum. 2007 Sep;56(9):3044-56 PMID: 17763423
  82. New therapies in systemic lupus erythematosus--trials, troubles and tribulations--working towards a solution: part 2--the politically incorrect version.
    Lupus. 2009 Feb;18(2):101-3 PMID: 19151109
  83. B cells regulate autoimmunity by provision of IL-10.
    Nat Immunol. 2002 Oct;3(10):944-50 PMID: 12244307
  84. Variability in the biological response to anti-CD20 B cell depletion in systemic lupus erythaematosus.
    Ann Rheum Dis. 2008 Dec;67(12):1724-31 PMID: 18250115
  85. Selective dysregulation of the FcgammaIIB receptor on memory B cells in SLE.
    J Exp Med. 2006 Sep 4;203(9):2157-64 PMID: 16923849
  86. Translational Mini-Review Series on B Cell-Directed Therapies: The pathogenic role of B cells in autoantibody-associated autoimmune diseases--lessons from B cell-depletion therapy.
    Clin Exp Immunol. 2009 Aug;157(2):191-7 PMID: 19604258
  87. CXCL13 neutralization reduces the severity of collagen-induced arthritis.
    Arthritis Rheum. 2005 Feb;52(2):620-6 PMID: 15692971
  88. Systemic lupus erythematosus clinical trials-an interim analysis.
    Nat Rev Rheumatol. 2009 Jun;5(6):348-51 PMID: 19491915
  89. B-lymphocyte contributions to human autoimmune disease.
    Immunol Rev. 2008 Jun;223:284-99 PMID: 18613843
  90. Development of TLR inhibitors for the treatment of autoimmune diseases.
    Immunol Rev. 2008 Jun;223:271-83 PMID: 18613842
  91. Novel human transitional B cell populations revealed by B cell depletion therapy.
    J Immunol. 2009 May 15;182(10):5982-93 PMID: 19414749
  92. An orally bioavailable spleen tyrosine kinase inhibitor delays disease progression and prolongs survival in murine lupus.
    Arthritis Rheum. 2008 May;58(5):1433-44 PMID: 18438845
  93. A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses.
    Immunity. 2008 May;28(5):639-50 PMID: 18482568
  94. Lipopolysaccharide-activated B cells down-regulate Th1 immunity and prevent autoimmune diabetes in nonobese diabetic mice.
    J Immunol. 2001 Jul 15;167(2):1081-9 PMID: 11441119
  95. B cells and immunological tolerance.
    J Invest Dermatol. 2009 Feb;129(2):278-88 PMID: 19148217
  96. Novel suppressive function of transitional 2 B cells in experimental arthritis.
    J Immunol. 2007 Jun 15;178(12):7868-78 PMID: 17548625
  97. A retrospective seven-year analysis of the use of B cell depletion therapy in systemic lupus erythematosus at University College London Hospital: the first fifty patients.
    Arthritis Rheum. 2009 Apr 15;61(4):482-7 PMID: 19333973
  98. 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 Jan 18;189(2):403-12 PMID: 9892622
Article Info
Journal
Nature reviews. Rheumatology
Abbr.
Nat Rev Rheumatol
ISSN
1759-4804
DOI
10.1038/nrrheum.2010.68
Email
ignacio_sanz@urmc.rochester.edu
Published
2010-06-00
Pages
326-37
Language
English
Region
United States
NLM ID
101500080
PMCID
PMC3934759
Subset
IM
Grants
NIAID NIH HHS · U19 AI56390 · United States
NIAID NIH HHS · U19 AI056390 · United States
NIAID NIH HHS · K23 AI67501 · United States
NIAID NIH HHS · P01 AI078907 · United States
NIAID NIH HHS · K23 AI067501 · United States
NIAID NIH HHS · R01 AI049660 · United States
NIAID NIH HHS · R37 AI049660 · United States
External Links
PubMed source DOI: 10.1038/nrrheum.2010.68 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2