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01.02.2011

IVIg Attenuates TLR-9 Activation in B Cells from SLE Patients

verfasst von: Aharon Kessel, Regina Peri, Tharwat Haj, Ayelet Snir, Gleb Slobodin, Edmond Sabo, Itzhak Rosner, Yehuda Shoenfeld, Elias Toubi

Erschienen in: Journal of Clinical Immunology | Ausgabe 1/2011

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Abstract

Introduction

Toll-like receptor-9 (TLR-9) plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study was to evaluate the influence of intravenous immunoglobulin (IVIg) on CpG oligodeoxynucleotides (ODN-CpG) activated B cells from SLE patients.

Methods

Peripheral blood B cells were isolated from 16 SLE patients and 21 healthy age-matched controls. B cells were cultured with ODN-CpG 1μM alone or IVIg (10mg/ml) together with ODN-CpG. After 24-h incubation, B cells and supernatants were collected and analyzed for interleukin (IL)-10, IL-6 secretion, and TLR-9 expression.

Results

IVIg decreased the secretion of IL-10 from ODN-CpG-activated B cells isolated from both SLE patients and healthy controls (194 ± 46.2 to 103.2 ± 27.13 pg/ml, p < 0.016, 153.2 ± 19 vs 84.6 ± 7.5, p < 0.0001, respectively). Similarly, IVIg decreased the secretion of IL-6 from ODN-CpG-activated B cell isolated from both SLE patients and healthy controls (431.2 ± 83 to 307.6 ± 94.3 pg/ml, p < 0.0008, 319.5 ± 31 vs 193.3 ± 22.8, p < 0.0001, respectively). The decrement of IL-10 and IL-6 secretion was associated with a significant decrease in TLR-9 expression in memory B cells from SLE patients and healthy controls (11.47 ± 1.2 vs 13.29 ± 1.2, p = 0.005, 11 ± 0.8 vs 12.8 ± 0.98, p = 0.0016, respectively).

Conclusions

IVIg attenuates the activation of TLR-9 in B cells from SLE patients, suggesting a novel additional mechanism of IVIg mode of action in these patients.

Shlomchik MJ, Craft JE, Mamula MJ. From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol. 2001;1:147–53.CrossRefPubMed

Bernasconi NL, Onai N, Lanzavecchia A. A role for Toll-like receptors in acquired immunity: up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells. Blood. 2003;101(11):4500–4.CrossRefPubMed

Bernasconi NL, Traggiai E, Lanzavecchia A. Maintenance of serological memory by polyclonal activation of human memory B cells. Science. 2002;298:2199–202.CrossRefPubMed

Nakano S, Morimoto S, Suzuki J, et al. Role of pathogenic auto-antibody production by Toll-like receptor 9 of B cells in active systemic lupus erythematosus. Rheumatol (Oxf Print). 2008;47(2):145–9.CrossRef

Papadimitraki ED, Choulaki C, Koutala E, et al. Expansion of toll-like receptor 9-expressing B cells in active systemic lupus erythematosus: implications for the induction and maintenance of the autoimmune process. Arthritis Rheum. 2006;54(11):3601–11.CrossRefPubMed

Krieg AM, Yi AK, Matson S, et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature. 1995;374:546–9.CrossRefPubMed

Hartmann G, Krieg AM. Mechanism and function of a newly identified CpG DNA motif in human primary B cells. J Immunol. 2000;164:944–53.PubMed

Klinman DM, Yi AK, Beaucage SL, Conover J, Krieg AM. CpG motifs present in bacteria DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and interferon gamma. Proc Natl Acad Sci U S A. 1996;93:2879–83.CrossRefPubMed

Rousset F, Garcia E, Defrance T, et al. Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc Natl Acad Sci U S A. 1992;89:1890–3.CrossRefPubMed

10.

Llorente L, Zou W, Levy Y, et al. Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus. J Exp Med. 1995;181:839–44.CrossRefPubMed

11.

Linker-Israeli M, Deans RJ, Wallace DJ, et al. Elevated levels of endogenous IL-6 in systemic lupus erythematosus. A putative role in pathogenesis. J Immunol. 1991;147(1):117–23.PubMed

12.

Hirohata S, Miyamoto T. Elevated levels of interleukin-6 in cerebrospinal fluid from patients with systemic lupus erythematosus and central nervous system involvement. Arthritis Rheum. 1990;33(5):644–9.CrossRefPubMed

13.

Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med. 2001;345:747–55.CrossRefPubMed

14.

Schroeder JO, Zeuner RA, Euler HH, Loffler H. High dose intravenous immunoglobulins in systemic lupus erythematosus: clinical and serological results of a pilot study. J Rheumatol. 1996;23:71–5.PubMed

15.

Akashi K, Nagasawa K, Mayumi T, et al. Successful treatment of refractory systemic lupus erythematosus with intravenous immunoglobulins. J Rheumatol. 1990;17:375–9.PubMed

16.

Levy Y, Sherer Y, Ahmed A, et al. A study of 20 SLE patients with intravenous immunoglobulin—clinical and serologic response. Lupus. 1999;8:705–12.CrossRefPubMed

17.

Kessel A, Ammuri H, Peri R, et al. Intravenous immunoglobulin therapy affects T regulatory cells by increasing their suppressive function. J Immunol. 2007;179(8):5571–5.PubMed

18.

Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725.CrossRefPubMed

19.

Bauer S, Kirschning CJ, Häcker H, et al. Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc Natl Acad Sci U S A. 2001;98:9237–42.CrossRefPubMed

20.

Richardson B, Scheinbart L, Strahler J, et al. Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum. 1990;33:1665–73.CrossRefPubMed

21.

Shoshan Y, Shapira I, Toubi E, et al. Accelerated Fas-mediated apoptosis of monocytes and maturing macrophages from patients with systemic lupus erythematosus: relevance to in vitro impairment of interaction with iC3b-opsonized apoptotic cells. J Immunol. 2000;167(10):5963–9.

22.

Herrmann M, Voll RE, Zoller OM, et al. Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus. Arthritis Rheum. 1998;41(7):1241–50.CrossRefPubMed

23.

Emlen W, Niebur J, Kadera R. Accelerated in vitro apoptosis of lymphocytes from patients with systemic lupus erythematosus. J Immunol. 1994;152(7):3685–92.PubMed

24.

Marshak-Rothstein A. Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol. 2006;6:823–35.CrossRefPubMed

25.

Christensen SR, Shlomchik MJ. Regulation of lupus-related autoantibody production and clinical disease by Toll-like receptors. Semin Immunol. 2007;19:11–23.CrossRefPubMed

26.

Leadbetter EA, Rifkin IR, Hohlbaum AM, et al. Chromatin–IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature. 2002;416:603–7.CrossRefPubMed

27.

Lau CM, Broughton C, Tabor AS, et al. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J Exp Med. 2005;202(9):1171–7.CrossRefPubMed

28.

Hagiwara E, Gourley MF, Lee S, Klinman DK. 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. 1996;39:379–85.CrossRefPubMed

29.

Llorente L, Richaud-Patin Y, Fior R, et al. In vivo production of interleukin-10 by non-T cells in rheumatoid arthritis, Sjogren’s syndrome, and systemic lupus erythematosus: a potential mechanism of B lymphocyte hyperactivity and autoimmunity. Arthritis Rheum. 1994;37:1647–55.CrossRefPubMed

30.

Lacki JK, Samborski W, Mackiewicz SH. Interleukin-10 and interleukin-6 in lupus erythematosus and rheumatoid arthritis, correlations with acute phase proteins. Clin Rheumatol. 1997;16:275–8.CrossRefPubMed

31.

Houssiau FA, Lefebvre C, van den Berghe M, et al. Serum interleukin 10 titers in systemic lupus erythematosus reflect disease activity. Lupus. 1995;4:393–5.CrossRefPubMed

32.

Park YB, Lee SK, Kim DS, et al. Elevated interleukin-10 levels correlated with disease activity in systemic lupus erythematosus. Clin Exp Rheumatol. 1998;16:283–8.PubMed

33.

Llorente L, Richaud-Patin Y, García-Padilla C, et al. Clinical and biologic effects of anti-interleukin-10 monoclonal antibody administration in systemic lupus erythematosus. Arthritis Rheum. 2000;43(8):1790–800.CrossRefPubMed

34.

Mocellin S, Marincola F, Rossi CR, Nitti D, Lise M. The multifaceted relationship between IL-10 and adaptive immunity: putting together the pieces of a puzzle. Cytokine Growth Factor Rev. 2004;15:61–76.CrossRefPubMed

35.

Bayry J, Lacroix-Desmazes S, Carbonneil C, et al. Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin. Blood. 2003;101(2):758–65.CrossRefPubMed

36.

Nagafuchi H, Suzuki N, Mizushima Y, Sakane T. Constitutive expression of IL-6 receptors and their role in the excessive B cell function in patients with systemic lupus erythematosus. J Immunol. 1993;151:6525–34.PubMed

37.

Kitani A, Hara M, Hirose T, et al. Autostimulatory effects of IL-6 on excessive B cell differentiation in patients with SLE: analysis of IL-6 production and IL-6R expression. Clin Exp Immunol. 1992;88:75–83.CrossRefPubMed

38.

Finck BK, Chan B, Wofsy D. IL-6 promotes murine lupus in NZB/NZW F1 mice. J Clin Invest. 1994;94:585–91.CrossRefPubMed

39.

Illei GG, Shirota Y, Yarboro CH, et al. 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;62(2):542–52.CrossRefPubMed

40.

Toyoda M, Pao A, Petrosian A, Jordan SC. Pooled human gamma globulin modulates surface molecule expression and induces apoptosis in human B cells. Am J Transplant. 2003;3:156–66.CrossRefPubMed

41.

Schiff RI. Half-life and clearance of pH 6.8 and pH 4.25 immunoglobulin G intravenous preparations in patients with primary disorders of humoral immunity. Rev Infect Dis. 1986;8 suppl 4:S449–56.CrossRefPubMed

42.

Mankarious S, Lee M, Fischer S, et al. The half-lives of IgG subclasses and specific antibodies in patients with primary immunodeficiency who are receiving intravenously administered immunoglobulin. J Lab Clin Med. 1988;112:634–40.PubMed

43.

Guiducci C, Gong M, Xu Z, et al. TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus. Nature. 2010;465(7300):937–41.CrossRefPubMed

44.

Ott VL, Fong DC, Cambier JC. Fc gamma RIIB as a potential molecular target for intravenous gamma globulin therapy. J Allergy Clin Immunol. 2001;108:S95–8.CrossRefPubMed

45.

Proulx DP, Aubin E, Lemieux R, Bazin R. Spontaneous internalization of IVIg in activated B cells. Immunol Lett. 2009;124(1):18–26.CrossRefPubMed

46.

Paquin Proulx D, Aubin E, Lemieux R, Bazin R. Inhibition of B cell-mediated antigen presentation by intravenous immunoglobulins (IVIg). Clin Immunol. 2010;135(3):422–9.CrossRefPubMed

47.

Séïté JF, Cornec D, Renaudineau Y, et al. IVIg modulates BCR-signaling through CD22 and promotes apoptosis in mature human B lymphocytes. Blood. 2010;116:1698–704.CrossRefPubMed

48.

Macfarlane DE, Manzel I. Antagonism of immunostimulatory CpG-oligodeoxynucleotides by quinacrine, chloroquine, and structurally related compounds. J Immunol. 1998;160:1122–31.PubMed

Titel: IVIg Attenuates TLR-9 Activation in B Cells from SLE Patients
verfasst von: Aharon Kessel
Regina Peri
Tharwat Haj
Ayelet Snir
Gleb Slobodin
Edmond Sabo
Itzhak Rosner
Yehuda Shoenfeld
Elias Toubi
Publikationsdatum: 01.02.2011
Verlag: Springer US
Erschienen in: Journal of Clinical Immunology / Ausgabe 1/2011
Print ISSN: 0271-9142
Elektronische ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-010-9469-3

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Abstract

Introduction

Methods

Results

Conclusions

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