Targeting of the immune system in systemic lupus erythematosus

Meera Ramanujam; Anne Davidson

doi:10.1017/S1462399408000562

Targeting of the immune system in systemic lupus erythematosus

Published online by Cambridge University Press: 21 January 2008

Meera Ramanujam and

Anne Davidson

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Meera Ramanujam: Affiliation:
Feinstein Institute for Medical Research, NS-LIJHS, Manhasset, NY 11030, USA.
Anne Davidson*: Affiliation:
Feinstein Institute for Medical Research, NS-LIJHS, Manhasset, NY 11030, USA.
*: *Corresponding author: Anne Davidson, Feinstein Institute for Medical Research, NS-LIJHS, Autoimmune Laboratory, 350 Community Drive, Manhasset, NY 11030, USA. Tel: +1 516 562 3840; Fax: +1 516 562 2953; E-mail: [email protected]

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Abstract

Systemic lupus erythematosus (SLE) is a complex immune disorder in which loss of tolerance to nucleic acid antigens and other crossreactive antigens is associated with the development of pathogenic autoantibodies that damage target organs, including the skin, joints, brain and kidney. New drugs based on modulation of the immune system are currently being developed for the treatment of SLE. Many of these new therapies do not globally suppress the immune system but target specific activation pathways relevant to SLE pathogenesis. Immune modulation in SLE is complicated by differences in the immune defects between patients and at different disease stages. Since both deficiency and hyperactivity of the immune system can give rise to SLE, the ultimate goal for SLE therapy is to restore homeostasis without affecting protective immune responses to pathogens. Here we review recent immunological advances that have enhanced our understanding of SLE pathogenesis and discuss how they may lead to the development of new treatment regimens.

Type: Review Article
Information: Expert Reviews in Molecular Medicine , Volume 10 , October 2008 , e2

DOI: https://doi.org/10.1017/S1462399408000562 [Opens in a new window]
Copyright: Copyright © Cambridge University Press 2008

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References

1Wardemann, H. et al. (2003) Predominant autoantibody production by early human B cell precursors. Science 301, 1374-1377CrossRef Google Scholar PubMed

2Arbuckle, M.R. et al. (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 349, 1526-1533CrossRef Google Scholar PubMed

3Fairhurst, A.M., Wandstrat, A.E. and Wakeland, E.K. (2006) Systemic lupus erythematosus: multiple immunological phenotypes in a complex genetic disease. Adv Immunol 92, 1-69CrossRef Google Scholar

4Theofilopoulos, A.N. and Kono, D.H. (1999) The genes of systemic autoimmunity. Proc Assoc Am Physicians 111, 228-240CrossRef Google Scholar PubMed

5Lauwerys, B.R. and Wakeland, E.K. (2005) Genetics of lupus nephritis. Lupus 14, 2-12CrossRef Google Scholar PubMed

6Grimaldi, C.M. et al. (2002) Estrogen alters thresholds for B cell apoptosis and activation. J Clin Invest 109, 1625-1633CrossRef Google Scholar PubMed

7Cornall, R.J. and Goodnow, C.C. (1998) B cell antigen receptor signalling in the balance of tolerance and immunity. Novartis Found Symp 215, 21-40Google Scholar PubMed

8Mahoney, J.A. and Rosen, A. (2005) Apoptosis and autoimmunity. Curr Opin Immunol 17, 583-588CrossRef Google Scholar PubMed

9Navratil, J.S., Liu, C.C. and Ahearn, J.M. (2006) Apoptosis and autoimmunity. Immunol Res 36, 3-12CrossRef Google Scholar PubMed

10Bickerstaff, M.C. et al. (1999) Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity. Nat Med 5, 694-697CrossRef Google Scholar PubMed

11Manson, J.J., Mauri, C. and Ehrenstein, M.R. (2005) Natural serum IgM maintains immunological homeostasis and prevents autoimmunity. Springer Semin Immunopathol 26, 425-432CrossRef Google Scholar PubMed

12Manderson, A.P., Botto, M. and Walport, M.J. (2004) The role of complement in the development of systemic lupus erythematosus. Annu Rev Immunol 22, 431-456CrossRef Google Scholar PubMed

13Lee-Kirsch, M.A. et al. (2007) Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet 39, 1065-1067CrossRef Google Scholar

14Christensen, S.R. and Shlomchik, M.J. (2007) Regulation of lupus-related autoantibody production and clinical disease by Toll-like receptors. Semin Immunol 19, 11-23CrossRef Google Scholar PubMed

15Lenert, P.S. (2006) Targeting Toll-like receptor signaling in plasmacytoid dendritic cells and autoreactive B cells as a therapy for lupus. Arthritis Res Ther 8, 203CrossRef Google Scholar PubMed

16Wagner, H. and Bauer, S. (2006) All is not Toll: new pathways in DNA recognition. J Exp Med 203, 265-268CrossRef Google Scholar PubMed

17Lau, C.M. et al. (2005) RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J Exp Med 202, 1171-1177CrossRef Google Scholar PubMed

18Wagner, H. (2006) Endogenous TLR ligands and autoimmunity. Adv Immunol 91, 159-173CrossRef Google Scholar PubMed

19Rutz, M. et al. (2004) Toll-like receptor 9 binds single-stranded CpG-DNA in a sequence- and pH-dependent manner. Eur J Immunol 34, 2541-2550CrossRef Google Scholar

20Akira, S., Uematsu, S. and Takeuchi, O. (2006) Pathogen recognition and innate immunity. Cell 124, 783-801CrossRef Google Scholar PubMed

21Honda, K., Takaoka, A. and Taniguchi, T. (2006) Type I interferon [corrected] gene induction by the interferon regulatory factor family of transcription factors. Immunity 25, 349-360CrossRef Google Scholar PubMed

22Pandey, S. and Agrawal, D.K. (2006) Immunobiology of Toll-like receptors: emerging trends. Immunol Cell Biol 84, 333-341CrossRef Google Scholar PubMed

23Sigurdsson, S. et al. (2005) Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet 76, 528-537CrossRef Google Scholar PubMed

24Ronnblom, L. and Alm, G.V. (2003) Systemic lupus erythematosus and the type I interferon system. Arthritis Res Ther 5, 68-75CrossRef Google Scholar PubMed

25Mathian, A. et al. (2005) IFN-alpha induces early lethal lupus in preautoimmune (New Zealand Black x New Zealand White) F1 but not in BALB/c mice. J Immunol 174, 2499-2506CrossRef Google Scholar

26Pasare, C. and Medzhitov, R. (2003) Toll pathway-dependent blockade of CD4+ CD25+ T cell-mediated suppression by dendritic cells. Science 299, 1033-1036CrossRef Google Scholar PubMed

27Krutzik, S.R. et al. (2005) TLR activation triggers the rapid differentiation of monocytes into macrophages and dendritic cells. Nat Med 11, 653-660CrossRef Google Scholar PubMed

28Logue, E.C. et al. (2006) ICOS-induced B7 h shedding on B cells is inhibited by TLR7/8 and TLR9. J Immunol 177, 2356-2364CrossRef Google Scholar

29Ehlers, M. and Ravetch, J.V. (2007) Opposing effects of Toll-like receptor stimulation induce autoimmunity or tolerance. Trends Immunol 28, 74-79CrossRef Google Scholar PubMed

30Tian, J. et al. (2007) Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol 8, 487-496CrossRef Google Scholar PubMed

31Christensen, S.R. et al. (2006) Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 25, 417-428CrossRef Google Scholar

32Ehlers, M. et al. (2006) TLR9/MyD88 signaling is required for class switching to pathogenic IgG2a and 2b autoantibodies in SLE. J Exp Med 203, 553-561CrossRef Google Scholar PubMed

33Wu, X. and Peng, S.L. (2006) Toll-like receptor 9 signaling protects against murine lupus. Arthritis Rheum 54, 336-342CrossRef Google Scholar PubMed

34Berland, R. et al. (2006) Toll-like receptor 7-dependent loss of B cell tolerance in pathogenic autoantibody knockin mice. Immunity 25, 429-440CrossRef Google Scholar PubMed

35Pisitkun, P. et al. (2006) Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science 312, 1669-1672CrossRef Google Scholar PubMed

36Akkerman, A. et al. (2004) CTLA4Ig prevents initiation but not evolution of anti-phospholipid syndrome in NZW/BXSB mice. Autoimmunity 37, 445-451CrossRef Google Scholar

37Kanzler, H. et al. (2007) Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists. Nat Med 13, 552-559CrossRef Google Scholar PubMed

38Dong, L. et al. (2005) Suppressive oligodeoxynucleotides delay the onset of glomerulonephritis and prolong survival in lupus-prone NZB x NZW mice. Arthritis Rheum 52, 651-658CrossRef Google Scholar PubMed

39Anders, H.J. and Schlondorff, D. (2007) Toll-like receptors: emerging concepts in kidney disease. Curr Opin Nephrol Hypertens 16, 177-183CrossRef Google Scholar PubMed

40Nimmerjahn, F. and Ravetch, J.V. (2006) Fcgamma receptors: old friends and new family members. Immunity 24, 19-28CrossRef Google Scholar PubMed

41McGaha, T.L., Sorrentino, B. and Ravetch, J.V. (2005) Restoration of tolerance in lupus by targeted inhibitory receptor expression. Science 307, 590-593CrossRef Google Scholar PubMed

42Clatworthy, M.R. et al. (2007) Systemic lupus erythematosus-associated defects in the inhibitory receptor FcgammaRIIb reduce susceptibility to malaria. Proc Natl Acad Sci U S A 104, 7169-7174CrossRef Google Scholar PubMed

43Mackay, M. et al. (2006) Selective dysregulation of the FcgammaIIB receptor on memory B cells in SLE. J Exp Med 203, 2157-2164CrossRef Google Scholar PubMed

44Su, K. et al. (2007) Expression profile of FcgammaRIIb on leukocytes and its dysregulation in systemic lupus erythematosus. J Immunol 178, 3272-3280CrossRef Google Scholar PubMed

45Bolland, S. and Ravetch, J.V. (2000) Spontaneous autoimmune disease in Fc(gamma)RIIB-deficient mice results from strain-specific epistasis. Immunity 13, 277-285CrossRef Google Scholar PubMed

46Fukuyama, H., Nimmerjahn, F. and Ravetch, J.V. (2005) The inhibitory Fcgamma receptor modulates autoimmunity by limiting the accumulation of immunoglobulin G+ anti-DNA plasma cells. Nat Immunol 6, 99-106CrossRef Google Scholar PubMed

47Harley, J.B., Kelly, J.A. and Kaufman, K.M. (2006) Unraveling the genetics of systemic lupus erythematosus. Springer Semin Immunopathol 28, 119-130CrossRef Google Scholar PubMed

48Karassa, F.B., Trikalinos, T.A. and Ioannidis, J.P. (2004) The role of FcgammaRIIA and IIIA polymorphisms in autoimmune diseases. Biomed Pharmacother 58, 286-291CrossRef Google Scholar PubMed

49Nimmerjahn, F. and Ravetch, J.V. (2007) The antiinflammatory activity of IgG: the intravenous IgG paradox. J Exp Med 204, 11-15CrossRef Google Scholar PubMed

50Diamond, B. et al. (1992) The role of somatic mutation in the pathogenic anti-DNA response. Annu Rev Immunol 10, 731-757CrossRef Google Scholar PubMed

51Abbas, A.K. et al. (2004) T cell tolerance and autoimmunity. Autoimmun Rev 3, 471-475CrossRef Google Scholar PubMed

52Miyara, M. and Sakaguchi, S. (2007) Natural regulatory T cells: mechanisms of suppression. Trends Mol Med 13, 108-116CrossRef Google Scholar PubMed

53Mondino, A. and Mueller, D.L. (2007) mTOR at the crossroads of T cell proliferation and tolerance. Semin Immunol 19, 162-172CrossRef Google Scholar PubMed

54Vincenti, F. and Luggen, M. (2007) T cell costimulation: a rational target in the therapeutic armamentarium for autoimmune diseases and transplantation. Annu Rev Med 58, 347-358CrossRef Google Scholar PubMed

55Lohr, J. et al. (2003) The inhibitory function of B7 costimulators in T cell responses to foreign and self-antigens. Nat Immunol 4, 664-669CrossRef Google Scholar

56Mellor, A.L. et al. (2003) Cutting edge: induced indoleamine 2,3 dioxygenase expression in dendritic cell subsets suppresses T cell clonal expansion. J Immunol 171, 1652-1655CrossRef Google Scholar PubMed

57Mellor, A. (2005) Indoleamine 2,3 dioxygenase and regulation of T cell immunity. Biochem Biophys Res Commun 338, 20-24CrossRef Google Scholar PubMed

58Ueda, H. et al. (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506-511CrossRef Google Scholar PubMed

59Mirenda, V. et al. (2007) Physiologic and aberrant regulation of memory T-cell trafficking by the costimulatory molecule CD28. Blood 109, 2968-2977CrossRef Google Scholar PubMed

60Davidson, A. et al. (2005) Block and tackle: CTLA4Ig takes on lupus. Lupus 14, 197-203CrossRef Google Scholar PubMed

61Moreland, L.W. et al. (2002) Costimulatory blockade in patients with rheumatoid arthritis: a pilot, dose-finding, double-blind, placebo-controlled clinical trial evaluating CTLA-4Ig and LEA29Y eighty-five days after the first infusion. Arthritis Rheum 46, 1470-1479CrossRef Google Scholar PubMed

62Finck, B.K., Linsley, P.S. and Wofsy, D. (1994) Treatment of murine lupus with CTLA4Ig. Science 265, 1225-1227CrossRef Google Scholar PubMed

63Daikh, D.I. et al. (1997) Long-term inhibition of murine lupus by brief simultaneous blockade of the B7/CD28 and CD40/gp39 costimulation pathways. J Immunol 159, 3104-3108CrossRef Google Scholar PubMed

64Wang, X. et al. (2002) Mechanism of action of combined short-term CTLA4Ig and anti-CD40 ligand in murine systemic lupus erythematosus. J Immunol 168, 2046-2053CrossRef Google Scholar PubMed

65Schiffer, L. et al. (2003) Short term administration of costimulatory blockade and cyclophosphamide induces remission of systemic lupus erythematosus nephritis in NZB/W F1 mice by a mechanism downstream of renal immune complex deposition. J Immunol 171, 489-497CrossRef Google Scholar PubMed

66Greenwald, R.J., Latchman, Y.E. and Sharpe, A.H. (2002) Negative co-receptors on lymphocytes. Curr Opin Immunol 14, 391-396CrossRef Google Scholar PubMed

67Hutloff, A. et al. (1999) ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397, 263-266CrossRef Google Scholar PubMed

68Lohning, M. et al. (2003) Expression of ICOS in vivo defines CD4+ effector T cells with high inflammatory potential and a strong bias for secretion of interleukin 10. J Exp Med 197, 181-193CrossRef Google Scholar

69Rasheed, A.U. et al. (2006) Follicular B helper T cell activity is confined to CXCR5(hi)ICOS(hi) CD4 T cells and is independent of CD57 expression. Eur J Immunol 36, 1892-1903CrossRef Google Scholar PubMed

70McAdam, A.J. et al. (2001) ICOS is critical for CD40-mediated antibody class switching. Nature 409, 102-105CrossRef Google Scholar PubMed

71Dong, C. et al. (2001) ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature 409, 97-101CrossRef Google Scholar PubMed

72Shilling, R.A., Bandukwala, H.S. and Sperling, A.I. (2006) Regulation of T:B cell interactions by the inducible costimulator molecule: does ICOS “induce” disease? Clin Immunol 121, 13-18CrossRef Google Scholar PubMed

73Hutloff, A. et al. (2004) Involvement of inducible costimulator in the exaggerated memory B cell and plasma cell generation in systemic lupus erythematosus. Arthritis Rheum 50, 3211-3220CrossRef Google Scholar PubMed

74Vinuesa, C.G. et al. (2005) A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435, 452-458CrossRef Google Scholar PubMed

75Iwai, H. et al. (2003) Involvement of inducible costimulator-B7 homologous protein costimulatory pathway in murine lupus nephritis. J Immunol 171, 2848-2854CrossRef Google Scholar PubMed

76Sharpe, A.H. et al. (2007) The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol 8, 239-245CrossRef Google Scholar PubMed

77Ansari, M.J. et al. (2003) The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med 198, 63-69CrossRef Google Scholar PubMed

78Fife, B.T. et al. (2006) Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway. J Exp Med 203, 2737-2747CrossRef Google Scholar PubMed

79Okazaki, T., Iwai, Y. and Honjo, T. (2002) New regulatory co-receptors: inducible co-stimulator and PD-1. Curr Opin Immunol 14, 779-782CrossRef Google Scholar PubMed

80Prokunina, L. et al. (2002) A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 32, 666-669CrossRef Google Scholar PubMed

81Watanabe, N. et al. (2003) BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nat Immunol 4, 670-679CrossRef Google Scholar PubMed

82Sedy, J.R. et al. (2005) B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat Immunol 6, 90-98CrossRef Google Scholar

83Greenwald, R.J., Freeman, G.J. and Sharpe, A.H. (2005) The B7 family revisited. Annu Rev Immunol 23, 515-548CrossRef Google Scholar PubMed

84Foell, J. et al. (2003) CD137 costimulatory T cell receptor engagement reverses acute disease in lupus-prone NZB x NZW F1 mice. J Clin Invest 111, 1505-1518CrossRef Google Scholar PubMed

85Kim, J. et al. (2005) Stimulation with 4-1BB (CD137) inhibits chronic graft-versus-host disease by inducing activation-induced cell death of donor CD4+ T cells. Blood 105, 2206-2213CrossRef Google Scholar PubMed

86Choi, B.K. et al. (2004) 4-1BB-dependent inhibition of immunosuppression by activated CD4+ CD25+ T cells. J Leukoc Biol 75, 785-791CrossRef Google Scholar PubMed

87Sun, Y. et al. (2002) Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease. Nat Med 8, 1405-1413CrossRef Google Scholar PubMed

88Salomon, B. and Bluestone, J.A. (2001) Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu Rev Immunol 19, 225-252CrossRef Google Scholar PubMed

89Castigli, E. et al. (1994) CD40-deficient mice generated by recombination-activating gene-2-deficient blastocyst complementation. Proc Natl Acad Sci U S A 91, 12135-12139CrossRef Google Scholar PubMed

90Grewal, I.S. and Flavell, R.A. (1998) CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol 16, 111-135CrossRef Google Scholar PubMed

91Vogel, L.A. and Noelle, R.J. (1998) CD40 and its crucial role as a member of the TNFR family. Semin Immunol 10, 435-442CrossRef Google Scholar PubMed

92Wang, X. et al. (2003) Effects of anti-CD154 treatment on B cells in murine systemic lupus erythematosus. Arthritis Rheum 48, 495-506CrossRef Google Scholar

93Sidiropoulos, P.I. and Boumpas, D.T. (2004) Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients. Lupus 13, 391-397CrossRef Google Scholar PubMed

94Kalunian, K.C. et al. (2002) Treatment of systemic lupus erythematosus by inhibition of T cell costimulation with anti-CD154: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 46, 3251-3258CrossRef Google Scholar PubMed

95Boumpas, D.T. et al. (2003) A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum 48, 719-727CrossRef Google Scholar

96Huang, W. et al. (2002) The effect of anti-CD40 ligand antibody on B cells in human SLE. Arthritis Rheum 46, 1554-1562CrossRef Google Scholar

97Grammer, A.C. et al. (2001) Normalization of peripheral B cells following treatment of active SLE patients with humanized anti-CD154 MAb (5c8, BG9588) (Abstract). Arthritis Rheum 44, S282Google Scholar

98Mohan, C. et al. (1995) Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis. J Immunol 154, 1470-1480CrossRef Google Scholar PubMed

99Drachman, J.G. et al. (2005) A humanized anti-CD40 monoclonal antibody (SGN-40) demonstrates antitumor activity in non-Hodgkin's lymphoma: initiation of a Phase I clinical trial. J Clin Oncol 23, 6572CrossRef Google Scholar

100Sutherland, A.P., Mackay, F. and Mackay, C.R. (2006) Targeting BAFF: immunomodulation for autoimmune diseases and lymphomas. Pharmacol Ther 112, 774-786CrossRef Google Scholar PubMed

101Ramanujam, M. and Davidson, A. (2004) The current status of targeting BAFF/BLyS for autoimmune diseases. Arthritis Res Ther 6, 197-202CrossRef Google Scholar PubMed

102Mackay, F. et al. (2003) BAFF AND APRIL: a tutorial on B cell survival. Annu Rev Immunol 21, 231-264CrossRef Google Scholar

103O'Connor, B.P. et al. (2004) BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med 199, 91-98CrossRef Google Scholar PubMed

104Ingold, K. et al. (2005) Identification of proteoglycans as the APRIL-specific binding partners. J Exp Med 201, 1375-1383CrossRef Google Scholar PubMed

105Schiemann, B. et al. (2001) An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 293, 2111-2114CrossRef Google Scholar PubMed

106Ramanujam, M. et al. (2006) Similarities and differences between selective and nonselective BAFF blockade in murine SLE. J Clin Invest 116, 724-734CrossRef Google Scholar PubMed

107Vora, K.A. et al. (2003) Cutting edge: germinal centers formed in the absence of B cell-activating factor belonging to the TNF family exhibit impaired maturation and function. J Immunol 171, 547-551CrossRef Google Scholar

108Jacob, C.O. et al. (2006) Paucity of clinical disease despite serological autoimmunity and kidney pathology in lupus-prone New Zealand mixed 2328 mice deficient in BAFF. J Immunol 177, 2671-2680CrossRef Google Scholar PubMed

109Groom, J.R. et al. (2007) BAFF and MyD88 signals promote a lupuslike disease independent of T cells. J Exp Med 204, 1959-1971CrossRef Google Scholar PubMed

110Lesley, R. et al. (2004) Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF. Immunity 20, 441-453CrossRef Google Scholar PubMed

111Thien, M. et al. (2004) Excess BAFF rescues self-reactive B cells from peripheral deletion and allows them to enter forbidden follicular and marginal zone niches. Immunity 20, 785-798CrossRef Google Scholar PubMed

112Martin, F. and Chan, A.C. (2006) B cell immunobiology in disease: evolving concepts from the clinic. Annu Rev Immunol 24, 467-496CrossRef Google Scholar PubMed

113Zhang, J. et al. (2001) Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus. J Immunol 166, 6-10CrossRef Google Scholar

114Cheema, G.S. et al. (2001) Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum 44, 1313-13193.0.CO;2-S>CrossRef Google Scholar PubMed

115Chang, S.K. et al. (2006) A role for BLyS in the activation of innate immune cells. Blood 108, 2687-2694CrossRef Google Scholar PubMed

116Ramanujam, M. et al. (2004) Mechanism of action of transmembrane activator and calcium modulator ligand interactor-Ig in murine systemic lupus erythematosus. J Immunol 173, 3524-3534CrossRef Google Scholar PubMed

117Ginzler, E. et al. (2007) Novel combined response endpoint shows that belimumab (fully human monoclonal antibody to B-lymphocyte stimulator [BLyS]) improves or stabilizes SLE disease activity in a phase 2 trial. Presented at EULAR 2007 Meeting (13–16 June 2007; Barcelona, Spain), Abstract OP0018, http://abstract.mci-group.com/cgi-bin/mc/printabs.pl?APP=EULAR2007SCIE-abstract&TEMPLATE=&keyf=0267&showHide=show&client=Google Scholar

118Grammer, A.C. and Lipsky, P.E. (2003) B cell abnormalities in systemic lupus erythematosus. Arthritis Res Ther 5, S22-S27CrossRef Google Scholar PubMed

119Riley, J.K. and Sliwkowski, M.X. (2000) CD20: a gene in search of a function. Semin Oncol 27, 17-24Google Scholar PubMed

120Uchida, J. et al. (2004) Mouse CD20 expression and function. Int Immunol 16, 119-129CrossRef Google Scholar PubMed

121Clynes, R.A. et al. (2000) Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med 6, 443-446CrossRef Google Scholar

122Uchida, J. et al. (2004) The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy. J Exp Med 199, 1659-1669CrossRef Google Scholar PubMed

123Gong, Q. et al. (2005) Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy. J Immunol 174, 817-826CrossRef Google Scholar PubMed

124Hamaguchi, Y. et al. (2005) The peritoneal cavity provides a protective niche for B1 and conventional B lymphocytes during anti-CD20 immunotherapy in mice. J Immunol 174, 4389-4399CrossRef Google Scholar PubMed

125Lin, W.Y. et al. (2007) Anti-BR3 antibodies - a new class of B cell immunotherapy combining cellular depletion and survival blockade. Blood 110, 3959-3967CrossRef Google Scholar PubMed

126Sfikakis, P.P., Boletis, J.N. and Tsokos, G.C. (2005) Rituximab anti-B-cell therapy in systemic lupus erythematosus: pointing to the future. Curr Opin Rheumatol 17, 550-557CrossRef Google Scholar PubMed

127Looney, R.J. et al. (2004) B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab. Arthritis Rheum 50, 2580-2589CrossRef Google Scholar PubMed

128Leandro, M.J. et al. (2002) An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum 46, 2673-2677CrossRef Google Scholar PubMed

129van Vollenhoven, R.F. et al. (2004) Biopsy-verified response of severe lupus nephritis to treatment with rituximab (anti-CD20 monoclonal antibody) plus cyclophosphamide after biopsy-documented failure to respond to cyclophosphamide alone. Scand J Rheumatol 33, 423-427CrossRef Google Scholar PubMed

130Anolik, J.H. et al. (2003) The relationship of FcgammaRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus. Arthritis Rheum 48, 455-459CrossRef Google Scholar PubMed

131Anolik, J.H. et al. (2004) Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus. Arthritis Rheum 50, 3580-3590CrossRef Google Scholar PubMed

132Leandro, M.J. et al. (2006) Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis. Arthritis Rheum 54, 613-620CrossRef Google Scholar

133Ng, K.P. et al. (2007) B cell depletion therapy in systemic lupus erythematosus: long-term follow-up and predictors of response. Ann Rheum Dis 66, 1259-1262CrossRef Google Scholar PubMed

134Tedder, T.F. et al. (1997) CD22, a B lymphocyte-specific adhesion molecule that regulates antigen receptor signaling. Annu Rev Immunol 15, 481-504CrossRef Google Scholar

135Crocker, P.R., Paulson, J.C. and Varki, A. (2007) Siglecs and their roles in the immune system. Nat Rev Immunol 7, 255-266CrossRef Google Scholar PubMed

136Otipoby, K.L. et al. (1996) CD22 regulates thymus-independent responses and the lifespan of B cells. Nature 384, 634-637CrossRef Google Scholar PubMed

137O'Keefe, T.L. et al. (1999) Deficiency in CD22, a B cell-specific inhibitory receptor, is sufficient to predispose to development of high affinity autoantibodies. J Exp Med 189, 1307-1313CrossRef Google Scholar

138Leonard, J.P. et al. (2004) Epratuzumab, a humanized anti-CD22 antibody, in aggressive non-Hodgkin's lymphoma: phase I/II clinical trial results. Clin Cancer Res 10, 5327-5334CrossRef Google Scholar PubMed

139Dorner, T. et al. (2006) Initial clinical trial of epratuzumab (humanized anti-CD22 antibody) for immunotherapy of systemic lupus erythematosus. Arthritis Res Ther 8, R74CrossRef Google Scholar PubMed

140Jacobi, A.M. et al. (2007) Differential effects of epratuzumab on peripheral blood B cells of SLE patients versus normal controls. Ann Rheum Dis [doi:10.1136/ard.2007.075762]Google Scholar

141Carnahan, J. et al. (2007) Epratuzumab, a CD22-targeting recombinant humanized antibody with a different mode of action from rituximab. Mol Immunol 44, 1331-1341CrossRef Google Scholar PubMed

142Alarcon-Segovia, D. et al. (2003) LJP 394 for the prevention of renal flare in patients with systemic lupus erythematosus: results from a randomized, double-blind, placebo-controlled study. Arthritis Rheum 48, 442-454CrossRef Google Scholar PubMed

143Wiesendanger, M. et al. (2006) Novel therapeutics for systemic lupus erythematosus. Curr Opin Rheumatol 18, 227-235CrossRef Google Scholar PubMed

144Herrero, C. et al. (2003) Reprogramming of IL-10 activity and signaling by IFN-gamma. J Immunol 171, 5034-5041CrossRef Google Scholar PubMed

145Hu, X. et al. (2007) Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways in macrophage activation. J Leukoc Biol 82, 237-243CrossRef Google Scholar PubMed

146Liang, B. et al. (2006) Anti-interleukin-6 monoclonal antibody inhibits autoimmune responses in a murine model of systemic lupus erythematosus. Immunology 119, 296-305CrossRef Google Scholar

147Kishimoto, T. (2005) Interleukin-6: from basic science to medicine – 40 years in immunology. Annu Rev Immunol 23, 1-21CrossRef Google Scholar PubMed

148Mihara, M., Nishimoto, N. and Ohsugi, Y. (2005) The therapy of autoimmune diseases by anti-interleukin-6 receptor antibody. Expert Opin Biol Ther 5, 683-690CrossRef Google Scholar PubMed

149Linker-Israeli, M. et al. (1991) Elevated levels of endogenous IL-6 in systemic lupus erythematosus. A putative role in pathogenesis. J Immunol 147, 117-123CrossRef Google Scholar PubMed

150Tackey, E., Lipsky, P.E. and Illei, G.G. (2004) Rationale for interleukin-6 blockade in systemic lupus erythematosus. Lupus 13, 339-343CrossRef Google Scholar PubMed

151Mihara, M. et al. (1998) IL-6 receptor blockage inhibits the onset of autoimmune kidney disease in NZB/W F1 mice. Clin Exp Immunol 112, 397-402CrossRef Google Scholar PubMed

152Finck, B.K., Chan, B. and Wofsy, D. (1994) Interleukin 6 promotes murine lupus in NZB/NZW F1 mice. J Clin Invest 94, 585-591CrossRef Google Scholar PubMed

153Illei, G.G. et al. (2006) Tocilizumab (humanized anti IL-6 receptor monoclonal antibody) in patients with systemic lupus erythematosus (SLE): safety, tolerability and preliminary efficacy. Presented at American College of Rheumatology Meeting, (10–15 November 2006; Washington DC, USA). Abstract no. 500, http://www.abstractsonline.com/viewer/viewAbstractPrintFriendly.asp?CKey={6F07625D-EB8C-4B2A-9416-747B62375600}&SKey={9EABBCE4-6F21-4386-9659-6C0982180B4A}&MKey={C297FAF7-2B4C-45F5-A662-0972E559ED7D}&AKey={AA45DD66-F113-4CDD-8E62-01A05F613C0D}Google Scholar

154Hill, C.M. and Lunec, J. (1996) The TNF-ligand and receptor superfamilies: controllers of immunity and the Trojan horses of autoimmune disease? Mol Aspects Med. 17, 455-509CrossRef Google Scholar PubMed

155Jacob, C.O. and McDevitt, H.O. (1988) Tumour necrosis factor-alpha in murine autoimmune ‘lupus’ nephritis. Nature 331, 356-358CrossRef Google Scholar PubMed

156Kontoyiannis, D. and Kollias, G. (2000) Accelerated autoimmunity and lupus nephritis in NZB mice with an engineered heterozygous deficiency in tumor necrosis factor. Eur J Immunol 30, 2038-20473.0.CO;2-K>CrossRef Google Scholar PubMed

157Mountz, J.D. (2001) Re: collagen-induced arthritis in TNF receptor-1-deficient mice: TNF receptor-2 can modulate arthritis in the absence of TNF receptor 1. Clin Immunol 99, 305-307CrossRef Google Scholar PubMed

158Romas, E., Gillespie, M.T. and Martin, T.J. (2002) Involvement of receptor activator of NFkappaB ligand and tumor necrosis factor-alpha in bone destruction in rheumatoid arthritis. Bone 30, 340-346CrossRef Google Scholar PubMed

159Feldmann, M. and Maini, R.N. (2001) Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol 19, 163-196CrossRef Google Scholar PubMed

160Sandborn, W.J. and Hanauer, S.B. (1999) Antitumor necrosis factor therapy for inflammatory bowel disease: a review of agents, pharmacology, clinical results, and safety. Inflamm Bowel Dis 5, 119-133CrossRef Google Scholar PubMed

161Feldmann, M. and Maini, R.N. (2003) Lasker Clinical Medical Research Award. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat Med 9, 1245-1250CrossRef Google Scholar PubMed

162Tobin, A.M. and Kirby, B. (2005) TNF alpha inhibitors in the treatment of psoriasis and psoriatic arthritis. BioDrugs 19, 47-57CrossRef Google Scholar PubMed

163Kollias, G. (2005) TNF pathophysiology in murine models of chronic inflammation and autoimmunity. Semin Arthritis Rheum 34, 3-6CrossRef Google Scholar

164Swale, V.J. et al. (2003) Etanercept-induced systemic lupus erythematosus. Clin Exp Dermatol 28, 604-607CrossRef Google Scholar PubMed

165Tipping, P.G. and Holdsworth, S.R. (2007) Cytokines in glomerulonephritis. Semin Nephrol 27, 275-285CrossRef Google Scholar PubMed

166Aringer, M. et al. (2004) Safety and efficacy of tumor necrosis factor alpha blockade in systemic lupus erythematosus: an open-label study. Arthritis Rheum 50, 3161-3169CrossRef Google Scholar PubMed

167Aringer, M. et al. (2007) Effects of short-term infliximab therapy on autoantibodies in systemic lupus erythematosus. Arthritis Rheum 56, 274-279CrossRef Google Scholar

168Valencia, X. et al. (2007) Deficient CD4+ CD25 high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol 178, 2579-2588CrossRef Google Scholar

169Chan, F.K. and Lenardo, M.J. (2002) Tumor Necrosis Factor Family Ligands and Receptors in the Immune System: Targets for Future Pharmaceuticals. Drug News Perspect 15, 483-490CrossRef Google Scholar PubMed

170Locksley, R.M., Killeen, N. and Lenardo, M.J. (2001) The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104, 487-501CrossRef Google Scholar PubMed

171Fu, Y.X. and Chaplin, D.D. (1999) Development and maturation of secondary lymphoid tissues. Annu Rev Immunol 17, 399-433CrossRef Google Scholar PubMed

172Kassiotis, G. and Kollias, G. (2001) Uncoupling the proinflammatory from the immunosuppressive properties of tumor necrosis factor (TNF) at the p55 TNF receptor level: implications for pathogenesis and therapy of autoimmune demyelination. J Exp Med 193, 427-434CrossRef Google Scholar PubMed

173Pascual, V., Farkas, L. and Banchereau, J. (2006) Systemic lupus erythematosus: all roads lead to type I interferons. Curr Opin Immunol 18, 676-682CrossRef Google Scholar PubMed

174Ronnblom, L. and Alm, G.V. (2002) The natural interferon-alpha producing cells in systemic lupus erythematosus. Hum Immunol 63, 1181-1193CrossRef Google Scholar PubMed

175Bennett, L. et al. (2003) Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med 197, 711-723CrossRef Google Scholar PubMed

176Baechler, E.C. et al. (2003) Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A 100, 2610-2615CrossRef Google Scholar PubMed

177Koutouzov, S., Mathian, A. and Dalloul, A. (2006) Type-I interferons and systemic lupus erythematosus. Autoimmun Rev 5, 554-562CrossRef Google Scholar PubMed

178Meyers, J.A. et al. (2006) Blockade of TLR9 agonist-induced type I interferons promotes inflammatory cytokine IFN-gamma and IL-17 secretion by activated human PBMC. Cytokine 35, 235-246CrossRef Google Scholar PubMed

179Nagai, T. et al. (2003) Timing of IFN-beta exposure during human dendritic cell maturation and naive Th cell stimulation has contrasting effects on Th1 subset generation: a role for IFN-beta-mediated regulation of IL-12 family cytokines and IL-18 in naive Th cell differentiation. J Immunol 171, 5233-5243CrossRef Google Scholar PubMed

180Dhodapkar, K.M. et al. (2007) Selective blockade of the inhibitory Fc gamma receptor (Fc gamma RIIB) in human dendritic cells and monocytes induces a type I interferon response program. J Exp Med 204, 1359-1369CrossRef Google Scholar

181Park, Y.B. et al. (1998) Elevated interleukin-10 levels correlated with disease activity in systemic lupus erythematosus. Clin Exp Rheumatol 16, 283-288Google Scholar PubMed

182Hagiwara, E. et al. (1996) Disease severity in patients with systemic lupus erythematosus correlates with an increased ratio of interleukin-10: interferon-gamma-secreting cells in the peripheral blood. Arthritis Rheum 39, 379-385CrossRef Google Scholar PubMed

183Ji, J.D. et al. (2003) Inhibition of interleukin 10 signaling after Fc receptor ligation and during rheumatoid arthritis. J Exp Med 197, 1573-1583CrossRef Google Scholar PubMed

184Ishida, H. et al. (1994) Continuous administration of anti-interleukin 10 antibodies delays onset of autoimmunity in NZB/W F1 mice. J Exp Med 179, 305-310CrossRef Google Scholar PubMed

185Blenman, K.R. et al. (2006) IL-10 regulation of lupus in the NZM2410 murine model. Lab Invest 86, 1136-1148CrossRef Google Scholar PubMed

186Yin, Z. et al. (2002) IL-10 regulates murine lupus. J Immunol 169, 2148-2155CrossRef Google Scholar PubMed

187Llorente, L. et al. (2000) Clinical and biologic effects of anti-interleukin-10 monoclonal antibody administration in systemic lupus erythematosus. Arthritis Rheum 43, 1790-18003.0.CO;2-2>CrossRef Google Scholar PubMed

188Jacob, C.O., van der Meide, P.H. and McDevitt, H.O. (1987) In vivo treatment of (NZB X NZW)F1 lupus-like nephritis with monoclonal antibody to gamma interferon. J Exp Med 166, 798-803CrossRef Google Scholar PubMed

189Ozmen, L. et al. (1995) Experimental therapy of systemic lupus erythematosus: the treatment of NZB/W mice with mouse soluble interferon-gamma receptor inhibits the onset of glomerulonephritis. Eur J Immunol 25, 6-12CrossRef Google Scholar PubMed

190Balomenos, D., Rumold, R. and Theofilopoulos, A.N. (1998) Interferon-gamma is required for lupus-like disease and lymphoaccumulation in MRL-lpr mice. J Clin Invest 101, 364-371CrossRef Google Scholar PubMed

191Singh, R.R. et al. (2003) Differential contribution of IL-4 and STAT6 vs STAT4 to the development of lupus nephritis. J Immunol 170, 4818-4825CrossRef Google Scholar

192Weaver, C.T. et al. (2007) IL-17 Family Cytokines and the Expanding Diversity of Effector T Cell Lineages. Annu Rev Immunol 25, 821-852CrossRef Google Scholar PubMed

193Clynes, R., Dumitru, C. and Ravetch, J.V. (1998) Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis. Science 279, 1052-1054CrossRef Google Scholar PubMed

194Bergtold, A. et al. (2006) FcR-bearing myeloid cells are responsible for triggering murine lupus nephritis. J Immunol 177, 7287-7295CrossRef Google Scholar PubMed

195Chan, O.T. et al. (1999) 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, 1639-1648CrossRef Google Scholar PubMed

196Matsumoto, K. et al. (2003) Fc receptor-independent development of autoimmune glomerulonephritis in lupus-prone MRL/lpr mice. Arthritis Rheum 48, 486-494CrossRef Google Scholar PubMed

197Peterson, K.S. et al. (2004) Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli. J Clin Invest 113, 1722-1733CrossRef Google Scholar PubMed

198Anders, H.J. et al. (2004) Late onset of treatment with a chemokine receptor CCR1 antagonist prevents progression of lupus nephritis in MRL-Fas(lpr) mice. J Am Soc Nephrol 15, 1504-1513CrossRef Google Scholar PubMed

199Anders, H.J., Ninichuk, V. and Schlondorff, D. (2006) Progression of kidney disease: blocking leukocyte recruitment with chemokine receptor CCR1 antagonists. Kidney Int 69, 29-32CrossRef Google Scholar PubMed

200Hahn, B.H. (1997) An overview of the pathogenesis of systemic lupus erythematosus. In Dubois's Lupus Erythematosus (5th edn) (Wallace, D.J. and Hahn, B.H., eds), pp 69-76, Williams & WilkinsGoogle Scholar

201Akkerman, A. et al. (2004) CTLA4Ig prevents initiation but not evolution of anti-phospholipid syndrome in NZW/BXSB mice. Autoimmunity 37, 445-451CrossRef Google Scholar

202Theofilopoulos, A.N. and Dixon, F.J. (1985) Murine models of systemic lupus erythematosus. Adv Immunol 37, 269-390CrossRef Google Scholar PubMed

203Furie, R. (2006) Abetimus sodium (riquent) for the prevention of nephritic flares in patients with systemic lupus erythematosus. Rheum Dis Clin North Am 32, 149-156CrossRef Google Scholar PubMed

204Davis, J.C. Jr. et al. (1999) Recombinant human DNase I (rhDNase) in patients with lupus nephritis. Lupus 8, 68-76CrossRef Google Scholar PubMed

205Gunnarsson, I. et al. (2007) Histopathologic and clinical outcome of rituximab treatment in patients with cyclophosphamide-resistant proliferative lupus nephritis. Arthritis Rheum 56, 1263-1272CrossRef Google Scholar PubMed

206Eisenberg, R. (2006) Targeting B cells in SLE: the experience with rituximab treatment (anti-CD20). Endocr Metab Immune Disord Drug Targets 6, 345-350CrossRef Google Scholar PubMed

207Schiffer, L. et al. Activated renal macrophages are markers of disease onset and disease remission in lupus nephritis. J Immunol (in press)Google Scholar

208Kilmon, M. et al. (2005) Low-affinity, Smith antigen-specific B cells are tolerized by dendritic cells and macrophages. J Immunol 175, 37-41CrossRef Google Scholar PubMed

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Targeting of the immune system in systemic lupus erythematosus

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Targeting of the immune system in systemic lupus erythematosus

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