Skip to main content
    • Aa
    • Aa

Targeting of the immune system in systemic lupus erythematosus

  • Meera Ramanujam (a1) and Anne Davidson (a1)

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.

Corresponding author
*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:
Hide All
1Wardemann H. et al. (2003) Predominant autoantibody production by early human B cell precursors. Science 301, 1374-1377
2Arbuckle M.R. et al. (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 349, 1526-1533
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, 1-69
4Theofilopoulos A.N. and Kono D.H. (1999) The genes of systemic autoimmunity. Proc Assoc Am Physicians 111, 228-240
5Lauwerys B.R. and Wakeland E.K. (2005) Genetics of lupus nephritis. Lupus 14, 2-12
6Grimaldi C.M. et al. (2002) Estrogen alters thresholds for B cell apoptosis and activation. J Clin Invest 109, 1625-1633
7Cornall R.J. and Goodnow C.C. (1998) B cell antigen receptor signalling in the balance of tolerance and immunity. Novartis Found Symp 215, 21-40
8Mahoney J.A. and Rosen A. (2005) Apoptosis and autoimmunity. Curr Opin Immunol 17, 583-588
9Navratil J.S., Liu C.C. and Ahearn J.M. (2006) Apoptosis and autoimmunity. Immunol Res 36, 3-12
10Bickerstaff M.C. et al. (1999) Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity. Nat Med 5, 694-697
11Manson J.J., Mauri C. and Ehrenstein M.R. (2005) Natural serum IgM maintains immunological homeostasis and prevents autoimmunity. Springer Semin Immunopathol 26, 425-432
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, 431-456
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, 1065-1067
14Christensen S.R. and Shlomchik M.J. (2007) Regulation of lupus-related autoantibody production and clinical disease by Toll-like receptors. Semin Immunol 19, 11-23
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, 203
16Wagner H. and Bauer S. (2006) All is not Toll: new pathways in DNA recognition. J Exp Med 203, 265-268
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, 1171-1177
18Wagner H. (2006) Endogenous TLR ligands and autoimmunity. Adv Immunol 91, 159-173
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, 2541-2550
20Akira S., Uematsu S. and Takeuchi O. (2006) Pathogen recognition and innate immunity. Cell 124, 783-801
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, 349-360
22Pandey S. and Agrawal D.K. (2006) Immunobiology of Toll-like receptors: emerging trends. Immunol Cell Biol 84, 333-341
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, 528-537
24Ronnblom L. and Alm G.V. (2003) Systemic lupus erythematosus and the type I interferon system. Arthritis Res Ther 5, 68-75
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, 2499-2506
26Pasare C. and Medzhitov R. (2003) Toll pathway-dependent blockade of CD4+ CD25+ T cell-mediated suppression by dendritic cells. Science 299, 1033-1036
27Krutzik S.R. et al. (2005) TLR activation triggers the rapid differentiation of monocytes into macrophages and dendritic cells. Nat Med 11, 653-660
28Logue E.C. et al. (2006) ICOS-induced B7 h shedding on B cells is inhibited by TLR7/8 and TLR9. J Immunol 177, 2356-2364
29Ehlers M. and Ravetch J.V. (2007) Opposing effects of Toll-like receptor stimulation induce autoimmunity or tolerance. Trends Immunol 28, 74-79
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, 487-496
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, 417-428
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, 553-561
33Wu X. and Peng S.L. (2006) Toll-like receptor 9 signaling protects against murine lupus. Arthritis Rheum 54, 336-342
34Berland R. et al. (2006) Toll-like receptor 7-dependent loss of B cell tolerance in pathogenic autoantibody knockin mice. Immunity 25, 429-440
35Pisitkun P. et al. (2006) Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science 312, 1669-1672
36Akkerman A. et al. (2004) CTLA4Ig prevents initiation but not evolution of anti-phospholipid syndrome in NZW/BXSB mice. Autoimmunity 37, 445-451
37Kanzler H. et al. (2007) Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists. Nat Med 13, 552-559
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, 651-658
39Anders H.J. and Schlondorff D. (2007) Toll-like receptors: emerging concepts in kidney disease. Curr Opin Nephrol Hypertens 16, 177-183
40Nimmerjahn F. and Ravetch J.V. (2006) Fcgamma receptors: old friends and new family members. Immunity 24, 19-28
41McGaha T.L., Sorrentino B. and Ravetch J.V. (2005) Restoration of tolerance in lupus by targeted inhibitory receptor expression. Science 307, 590-593
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, 7169-7174
43Mackay M. et al. (2006) Selective dysregulation of the FcgammaIIB receptor on memory B cells in SLE. J Exp Med 203, 2157-2164
44Su K. et al. (2007) Expression profile of FcgammaRIIb on leukocytes and its dysregulation in systemic lupus erythematosus. J Immunol 178, 3272-3280
45Bolland S. and Ravetch J.V. (2000) Spontaneous autoimmune disease in Fc(gamma)RIIB-deficient mice results from strain-specific epistasis. Immunity 13, 277-285
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, 99-106
47Harley J.B., Kelly J.A. and Kaufman K.M. (2006) Unraveling the genetics of systemic lupus erythematosus. Springer Semin Immunopathol 28, 119-130
48Karassa F.B., Trikalinos T.A. and Ioannidis J.P. (2004) The role of FcgammaRIIA and IIIA polymorphisms in autoimmune diseases. Biomed Pharmacother 58, 286-291
49Nimmerjahn F. and Ravetch J.V. (2007) The antiinflammatory activity of IgG: the intravenous IgG paradox. J Exp Med 204, 11-15
50Diamond B. et al. (1992) The role of somatic mutation in the pathogenic anti-DNA response. Annu Rev Immunol 10, 731-757
51Abbas A.K. et al. (2004) T cell tolerance and autoimmunity. Autoimmun Rev 3, 471-475
52Miyara M. and Sakaguchi S. (2007) Natural regulatory T cells: mechanisms of suppression. Trends Mol Med 13, 108-116
53Mondino A. and Mueller D.L. (2007) mTOR at the crossroads of T cell proliferation and tolerance. Semin Immunol 19, 162-172
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, 347-358
55Lohr J. et al. (2003) The inhibitory function of B7 costimulators in T cell responses to foreign and self-antigens. Nat Immunol 4, 664-669
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, 1652-1655
57Mellor A. (2005) Indoleamine 2,3 dioxygenase and regulation of T cell immunity. Biochem Biophys Res Commun 338, 20-24
58Ueda H. et al. (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506-511
59Mirenda V. et al. (2007) Physiologic and aberrant regulation of memory T-cell trafficking by the costimulatory molecule CD28. Blood 109, 2968-2977
60Davidson A. et al. (2005) Block and tackle: CTLA4Ig takes on lupus. Lupus 14, 197-203
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, 1470-1479
62Finck B.K., Linsley P.S. and Wofsy D. (1994) Treatment of murine lupus with CTLA4Ig. Science 265, 1225-1227
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, 3104-3108
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, 2046-2053
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, 489-497
66Greenwald R.J., Latchman Y.E. and Sharpe A.H. (2002) Negative co-receptors on lymphocytes. Curr Opin Immunol 14, 391-396
67Hutloff A. et al. (1999) ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397, 263-266
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, 181-193
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, 1892-1903
70McAdam A.J. et al. (2001) ICOS is critical for CD40-mediated antibody class switching. Nature 409, 102-105
71Dong C. et al. (2001) ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature 409, 97-101
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, 13-18
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, 3211-3220
74Vinuesa C.G. et al. (2005) A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435, 452-458
75Iwai H. et al. (2003) Involvement of inducible costimulator-B7 homologous protein costimulatory pathway in murine lupus nephritis. J Immunol 171, 2848-2854
76Sharpe A.H. et al. (2007) The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol 8, 239-245
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, 63-69
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, 2737-2747
79Okazaki T., Iwai Y. and Honjo T. (2002) New regulatory co-receptors: inducible co-stimulator and PD-1. Curr Opin Immunol 14, 779-782
80Prokunina L. et al. (2002) A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 32, 666-669
81Watanabe N. et al. (2003) BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nat Immunol 4, 670-679
82Sedy J.R. et al. (2005) B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat Immunol 6, 90-98
83Greenwald R.J., Freeman G.J. and Sharpe A.H. (2005) The B7 family revisited. Annu Rev Immunol 23, 515-548
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, 1505-1518
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, 2206-2213
86Choi B.K. et al. (2004) 4-1BB-dependent inhibition of immunosuppression by activated CD4+ CD25+ T cells. J Leukoc Biol 75, 785-791
87Sun Y. et al. (2002) Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease. Nat Med 8, 1405-1413
88Salomon B. and Bluestone J.A. (2001) Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu Rev Immunol 19, 225-252
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, 12135-12139
90Grewal I.S. and Flavell R.A. (1998) CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol 16, 111-135
91Vogel L.A. and Noelle R.J. (1998) CD40 and its crucial role as a member of the TNFR family. Semin Immunol 10, 435-442
92Wang X. et al. (2003) Effects of anti-CD154 treatment on B cells in murine systemic lupus erythematosus. Arthritis Rheum 48, 495-506
93Sidiropoulos P.I. and Boumpas D.T. (2004) Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients. Lupus 13, 391-397
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, 3251-3258
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, 719-727
96Huang W. et al. (2002) The effect of anti-CD40 ligand antibody on B cells in human SLE. Arthritis Rheum 46, 1554-1562
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, S282
98Mohan C. et al. (1995) Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis. J Immunol 154, 1470-1480
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, 6572
100Sutherland A.P., Mackay F. and Mackay C.R. (2006) Targeting BAFF: immunomodulation for autoimmune diseases and lymphomas. Pharmacol Ther 112, 774-786
101Ramanujam M. and Davidson A. (2004) The current status of targeting BAFF/BLyS for autoimmune diseases. Arthritis Res Ther 6, 197-202
102Mackay F. et al. (2003) BAFF AND APRIL: a tutorial on B cell survival. Annu Rev Immunol 21, 231-264
103O'Connor B.P. et al. (2004) BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med 199, 91-98
104Ingold K. et al. (2005) Identification of proteoglycans as the APRIL-specific binding partners. J Exp Med 201, 1375-1383
105Schiemann B. et al. (2001) An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 293, 2111-2114
106Ramanujam M. et al. (2006) Similarities and differences between selective and nonselective BAFF blockade in murine SLE. J Clin Invest 116, 724-734
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, 547-551
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, 2671-2680
109Groom J.R. et al. (2007) BAFF and MyD88 signals promote a lupuslike disease independent of T cells. J Exp Med 204, 1959-1971
110Lesley R. et al. (2004) Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF. Immunity 20, 441-453
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, 785-798
112Martin F. and Chan A.C. (2006) B cell immunobiology in disease: evolving concepts from the clinic. Annu Rev Immunol 24, 467-496
113Zhang J. et al. (2001) Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus. J Immunol 166, 6-10
114Cheema G.S. et al. (2001) Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum 44, 1313-1319
115Chang S.K. et al. (2006) A role for BLyS in the activation of innate immune cells. Blood 108, 2687-2694
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, 3524-3534
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,
118Grammer A.C. and Lipsky P.E. (2003) B cell abnormalities in systemic lupus erythematosus. Arthritis Res Ther 5, S22-S27
119Riley J.K. and Sliwkowski M.X. (2000) CD20: a gene in search of a function. Semin Oncol 27, 17-24
120Uchida J. et al. (2004) Mouse CD20 expression and function. Int Immunol 16, 119-129
121Clynes R.A. et al. (2000) Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med 6, 443-446
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, 1659-1669
123Gong Q. et al. (2005) Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy. J Immunol 174, 817-826
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, 4389-4399
125Lin W.Y. et al. (2007) Anti-BR3 antibodies - a new class of B cell immunotherapy combining cellular depletion and survival blockade. Blood 110, 3959-3967
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, 550-557
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, 2580-2589
128Leandro M.J. et al. (2002) An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum 46, 2673-2677
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, 423-427
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, 455-459
131Anolik J.H. et al. (2004) Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus. Arthritis Rheum 50, 3580-3590
132Leandro M.J. et al. (2006) Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis. Arthritis Rheum 54, 613-620
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, 1259-1262
134Tedder T.F. et al. (1997) CD22, a B lymphocyte-specific adhesion molecule that regulates antigen receptor signaling. Annu Rev Immunol 15, 481-504
135Crocker P.R., Paulson J.C. and Varki A. (2007) Siglecs and their roles in the immune system. Nat Rev Immunol 7, 255-266
136Otipoby K.L. et al. (1996) CD22 regulates thymus-independent responses and the lifespan of B cells. Nature 384, 634-637
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, 1307-1313
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, 5327-5334
139Dorner T. et al. (2006) Initial clinical trial of epratuzumab (humanized anti-CD22 antibody) for immunotherapy of systemic lupus erythematosus. Arthritis Res Ther 8, R74
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]
141Carnahan J. et al. (2007) Epratuzumab, a CD22-targeting recombinant humanized antibody with a different mode of action from rituximab. Mol Immunol 44, 1331-1341
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, 442-454
143Wiesendanger M. et al. (2006) Novel therapeutics for systemic lupus erythematosus. Curr Opin Rheumatol 18, 227-235
144Herrero C. et al. (2003) Reprogramming of IL-10 activity and signaling by IFN-gamma. J Immunol 171, 5034-5041
145Hu X. et al. (2007) Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways in macrophage activation. J Leukoc Biol 82, 237-243
146Liang B. et al. (2006) Anti-interleukin-6 monoclonal antibody inhibits autoimmune responses in a murine model of systemic lupus erythematosus. Immunology 119, 296-305
147Kishimoto T. (2005) Interleukin-6: from basic science to medicine – 40 years in immunology. Annu Rev Immunol 23, 1-21
148Mihara M., Nishimoto N. and Ohsugi Y. (2005) The therapy of autoimmune diseases by anti-interleukin-6 receptor antibody. Expert Opin Biol Ther 5, 683-690
149Linker-Israeli M. et al. (1991) Elevated levels of endogenous IL-6 in systemic lupus erythematosus. A putative role in pathogenesis. J Immunol 147, 117-123
150Tackey E., Lipsky P.E. and Illei G.G. (2004) Rationale for interleukin-6 blockade in systemic lupus erythematosus. Lupus 13, 339-343
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, 397-402
152Finck B.K., Chan B. and Wofsy D. (1994) Interleukin 6 promotes murine lupus in NZB/NZW F1 mice. J Clin Invest 94, 585-591
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,{6F07625D-EB8C-4B2A-9416-747B62375600}&SKey={9EABBCE4-6F21-4386-9659-6C0982180B4A}&MKey={C297FAF7-2B4C-45F5-A662-0972E559ED7D}&AKey={AA45DD66-F113-4CDD-8E62-01A05F613C0D}
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, 455-509
155Jacob C.O. and McDevitt H.O. (1988) Tumour necrosis factor-alpha in murine autoimmune ‘lupus’ nephritis. Nature 331, 356-358
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, 2038-2047
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, 305-307
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, 340-346
159Feldmann M. and Maini R.N. (2001) Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol 19, 163-196
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, 119-133
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, 1245-1250
162Tobin A.M. and Kirby B. (2005) TNF alpha inhibitors in the treatment of psoriasis and psoriatic arthritis. BioDrugs 19, 47-57
163Kollias G. (2005) TNF pathophysiology in murine models of chronic inflammation and autoimmunity. Semin Arthritis Rheum 34, 3-6
164Swale V.J. et al. (2003) Etanercept-induced systemic lupus erythematosus. Clin Exp Dermatol 28, 604-607
165Tipping P.G. and Holdsworth S.R. (2007) Cytokines in glomerulonephritis. Semin Nephrol 27, 275-285
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, 3161-3169
167Aringer M. et al. (2007) Effects of short-term infliximab therapy on autoantibodies in systemic lupus erythematosus. Arthritis Rheum 56, 274-279
168Valencia X. et al. (2007) Deficient CD4+ CD25 high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol 178, 2579-2588
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, 483-490
170Locksley R.M., Killeen N. and Lenardo M.J. (2001) The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104, 487-501
171Fu Y.X. and Chaplin D.D. (1999) Development and maturation of secondary lymphoid tissues. Annu Rev Immunol 17, 399-433
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, 427-434
173Pascual V., Farkas L. and Banchereau J. (2006) Systemic lupus erythematosus: all roads lead to type I interferons. Curr Opin Immunol 18, 676-682
174Ronnblom L. and Alm G.V. (2002) The natural interferon-alpha producing cells in systemic lupus erythematosus. Hum Immunol 63, 1181-1193
175Bennett L. et al. (2003) Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med 197, 711-723
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, 2610-2615
177Koutouzov S., Mathian A. and Dalloul A. (2006) Type-I interferons and systemic lupus erythematosus. Autoimmun Rev 5, 554-562
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, 235-246
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, 5233-5243
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, 1359-1369
181Park Y.B. et al. (1998) Elevated interleukin-10 levels correlated with disease activity in systemic lupus erythematosus. Clin Exp Rheumatol 16, 283-288
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, 379-385
183Ji J.D. et al. (2003) Inhibition of interleukin 10 signaling after Fc receptor ligation and during rheumatoid arthritis. J Exp Med 197, 1573-1583
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, 305-310
185Blenman K.R. et al. (2006) IL-10 regulation of lupus in the NZM2410 murine model. Lab Invest 86, 1136-1148
186Yin Z. et al. (2002) IL-10 regulates murine lupus. J Immunol 169, 2148-2155
187Llorente L. et al. (2000) Clinical and biologic effects of anti-interleukin-10 monoclonal antibody administration in systemic lupus erythematosus. Arthritis Rheum 43, 1790-1800
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, 798-803
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, 6-12
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, 364-371
191Singh R.R. et al. (2003) Differential contribution of IL-4 and STAT6 vs STAT4 to the development of lupus nephritis. J Immunol 170, 4818-4825
192Weaver C.T. et al. (2007) IL-17 Family Cytokines and the Expanding Diversity of Effector T Cell Lineages. Annu Rev Immunol 25, 821-852
193Clynes R., Dumitru C. and Ravetch J.V. (1998) Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis. Science 279, 1052-1054
194Bergtold A. et al. (2006) FcR-bearing myeloid cells are responsible for triggering murine lupus nephritis. J Immunol 177, 7287-7295
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, 1639-1648
196Matsumoto K. et al. (2003) Fc receptor-independent development of autoimmune glomerulonephritis in lupus-prone MRL/lpr mice. Arthritis Rheum 48, 486-494
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, 1722-1733
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, 1504-1513
199Anders H.J., Ninichuk V. and Schlondorff D. (2006) Progression of kidney disease: blocking leukocyte recruitment with chemokine receptor CCR1 antagonists. Kidney Int 69, 29-32
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 & Wilkins
201Akkerman A. et al. (2004) CTLA4Ig prevents initiation but not evolution of anti-phospholipid syndrome in NZW/BXSB mice. Autoimmunity 37, 445-451
202Theofilopoulos A.N. and Dixon F.J. (1985) Murine models of systemic lupus erythematosus. Adv Immunol 37, 269-390
203Furie R. (2006) Abetimus sodium (riquent) for the prevention of nephritic flares in patients with systemic lupus erythematosus. Rheum Dis Clin North Am 32, 149-156
204Davis J.C. Jr. et al. (1999) Recombinant human DNase I (rhDNase) in patients with lupus nephritis. Lupus 8, 68-76
205Gunnarsson I. et al. (2007) Histopathologic and clinical outcome of rituximab treatment in patients with cyclophosphamide-resistant proliferative lupus nephritis. Arthritis Rheum 56, 1263-1272
206Eisenberg R. (2006) Targeting B cells in SLE: the experience with rituximab treatment (anti-CD20). Endocr Metab Immune Disord Drug Targets 6, 345-350
207Schiffer L. et al. Activated renal macrophages are markers of disease onset and disease remission in lupus nephritis. J Immunol (in press)
208Kilmon M. et al. (2005) Low-affinity, Smith antigen-specific B cells are tolerized by dendritic cells and macrophages. J Immunol 175, 37-41
Wiesendanger M. et al. (2006) Novel therapeutics for systemic lupus erythematosus. Curr Opin Rheumatol 18, 227-235
Furie R. (2006) Abetimus sodium (riquent) for the prevention of nephritic flares in patients with systemic lupus erythematosus. Rheum Dis Clin North Am 32, 149-156
Fairhurst A.M., Wandstrat A.E. and Wakeland E.K. (2006) Systemic lupus erythematosus: multiple immunological phenotypes in a complex genetic disease. Adv Immunol 92, 1-69
Davidson A. and Aranow C. (2006) Pathogenesis and treatment of systemic lupus erythematosus nephritis. Curr Opin Rheumatol 18, 468-475
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Expert Reviews in Molecular Medicine
  • ISSN: -
  • EISSN: 1462-3994
  • URL: /core/journals/expert-reviews-in-molecular-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Full text views

Total number of HTML views: 6
Total number of PDF views: 22 *
Loading metrics...

Abstract views

Total abstract views: 255 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 21st October 2017. This data will be updated every 24 hours.