Intravenous immunoglobulin suppresses IL-10 production by activated B cells in vitro


A therapeutic preparation of polyclonal human IgG, i.e., intravenous immunoglobulin (IVIg), has been employed to treat several inflammatory and autoimmune disorders. B cells are supposed to be a target of IVIg, but the molecular mechanism is elusive because of the lack of a suitable experimental system. To gain an insight into the beneficial effect of IVIg on B cells, we first established an experimental setting in which IVIg modulates a murine B cell function in vitro, and then aimed at identifying the mechanistic features at the molecular level. Here we show that IVIg down-regulates IL-10 production by CpG-activated B cells in vitro. The responsible component of IVIg was identified as the F(ab’)2 portion, whose polyclonality is mandatory for the suppressive effect. IVIg, bound to the surface of activated B cells, was found to be co-localized with intracellular SHP-1 on confocal laser microscopy, suggesting that B cell-surface immunoreceptor tyrosine-based inhibitory motif-harboring receptors that recruit SHP-1 are target molecules for IVIg in our experimental setting. Overall, we postulate a scenario in which IVIg attenuates B cells by suppressing IL-10 production, a B cell growth factor, and thus down-regulates the production of pathogenic antibodies.

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Tanaka, J. , Hirano, K. , Sakamoto, Y. , Sugahara-Tobinai, A. , Endo, S. , Ito-Matsuoka, Y. , Nakano, A. , Inui, M. , Nitschke, L. and Takai, T. (2012) Intravenous immunoglobulin suppresses IL-10 production by activated B cells in vitro. Open Journal of Immunology, 2, 149-160. doi: 10.4236/oji.2012.24019.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Ballow, M. (2011) The IgG molecule as a biological immune response modifier: mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory disorders. Journal of Allergy and Clinical Immunology, 127, 315-323. doi:10.1016/j.jaci.2010.10.030
[2] Anthony, R.M., Wermeling, F. and Ravetch, J.V. (2012) Novel roles for the IgG Fc glycan. Annals of the New York Academy of Sciences, 1253, 170-180. doi:10.1111/j.1749-6632.2011.06305.x
[3] Ibá?ez, C. and Montoro-Ronsano, J.B. (2003) Intravenous immunoglobulin preparations and autoimmune disorders: Mechanisms of action. Current Pharmaceutical Biotechnology, 4, 239-247. doi:10.2174/1389201033489775
[4] Lemieux, R., Bazin, R. and Néron, S. (2005) Therapuetic intravenous immunoglobulins. Molecular Immunology, 42, 839-848.doi:10.1016/j.molimm.2004.07.046
[5] Hartung, H.P. (2008) Advances in the understanding of the mechanism of action of IVIg. Journal of Neurology, 255, 3-6. doi:10.1007/s00415-008-3002-0
[6] Néron, S., Boire, G., Dussault, N., Racine, C., de Brum-Fernandes, A.J., C?té, S. and Jacques, A. (2009) CD40-activated B cells from patients with systemic lupus erythematosus can be modulated by therapeutic immunoglobulins in vitro. Archivum Immunologiae et Therapiae Experimentalis, 57, 447-458. doi:10.1007/s00005-009-0048-3
[7] Branch, D.W., Porter, T.F., Paidas, M.J., Belfort, M.A. and Gonik, B. (2001) Obstetric uses of intravenous immunoglobulin: Successes, failures, and promises. Journal of Allergy and Clinical Immunology, 108, S133-S138. doi:10.1067/mai.2001.117821
[8] Kaveri, S.V., Dietrich, G., Hurez, V. and Kazatchkine, M.D. (1992) Intravenous immunoglobulins (IVIg) in the treatment of autoimmune diseases. Clinical and Experimental Immunology, 86, 192-198. doi:10.1111/j.1365-2249.1991.tb05794.x
[9] Ehrenstein, M.R. and Notley, C.A. (2010) The importance of natural IgM: Scavenger, protector and regulator. Nature Reviews Immunology, 10, 778-786. doi:10.1038/nri2849
[10] Griffin, D.O. and Rothstein, T.L. (2012) Human b1 cell frequency: Isolation and analysis of human b1 cells. Frontiers in Immunology, 3, 122. doi:10.3389/fimmu.2012.00122
[11] Nimmerjahn, F. and Ravetch, J.V. (2006) Fc receptors: Old friends and new family members. Immunity, 24, 19-28. doi:10.1016/j.immuni.2005.11.010
[12] Takai, T., Ono, M., Hikida, M., Ohmori, H. and Ravetch, J.V. (1996) Augmented humoral and anaphylactic responses in Fc RII-deficient mice. Nature, 379, 346-349. doi:10.1038/379346a0
[13] Jellusova, J. and Nitschke, L. (2011) Regulation of B cell functions by the sialic acid-binding receptors Siglec-G and CD22. Frontiers in Immunology, 2, 96. doi:10.3389/fimmu.2011.00096
[14] Hayami, K., Fukuta, D., Nishikawa, Y., Yamashita, Y., Inui, M., Ohyama, Y., Hikida, M., Ohmori, H. and Takai, T. (1997) Molecular cloning of a novel murine cell-surface glycoprotein homologous to killer cell inhibitory receptors. The Journal of Biological Chemistry, 272, 7320-7327. doi:10.1074/jbc.272.11.7320
[15] Kubagawa, H., Burrows, P.D. and Cooper, M.D. (1997) A novel pair of immunoglobulin-like receptors expressed by B cells and myeloid cells. Proceedings of the National Academy of Sciences of the United States of America, 94, 5261-5266. doi:10.1073/pnas.94.10.5261
[16] Ujike, A., Takeda, K., Nakamura, A., Ebihara, S., Akiyama, K. and Takai, T. (2002) Impaired dendritic cell maturation and increased TH2 responses in PIR-B-/-mice. Nature Immunology, 3, 542-548. doi:10.1038/ni801
[17] Nitschke, L., Carsetti, R., Ocker, B., K?hler, G. and Lamers, M.C. (1997) CD22 is a negative regulator of B-cell receptor signalling. Current Biology, 7, 133-143. doi:10.1016/S0960-9822(06)00057-1
[18] Parr, D., Connell, G., Kells, D. and Hofmann, T. (1976) Fb’2, a new peptic fragment of human immunoglobulin G. Biochemical Journal, 155, 31-36.
[19] Snigurowicz, J. and Powiertowska, M.R. (1980) Papain hydrolysis products in four M-IgG subclass. Archivum Immunologiae, 28, 265-273.
[20] Virella, G. and Parkhouse, R. (1971) Papain sensitivity of heavy chain sub-classes in normal human IgG and localization of antigenic determinants for the sub-classes. Immunochemistry, 8, 243-250. doi:10.1016/0019-2791(71)90478-2
[21] Kubo, T., Uchida, Y., Watanabe, Y., Abe, M., Nakamura, A., Ono, M., Akira, S. and Takai, T. (2009) Augmented TLR9-induced Btk activation in PIR-B-deficient B-1 cells provokes excessive autoantibody production and autoimmunity. The Journal of Experimental Medicine, 206, 1971-1982.doi:10.1084/jem.20082392
[22] Parnes, J.R. and Pan, C. (2000) CD72, a negative regulator of B-cell responsiveness. Immunological Reviews, 176, 75-85.doi:10.1034/j.1600-065X.2000.00608.x
[23] Li, D.H., Winslow, M.M., Cao, T.M., Chen, A.H., Davis, C.R., Mellins, E.D., Utz, P.J., Crabtree, G.R. and Parnes, J.R. (2008) Modulation of peripheral B cell tolerance by CD72 in a murine model. Arthritis and Rheumatism, 58, 3192-3204.doi:10.1002/art.23812
[24] Hoffmann, A., Kerr, S., Jellusova, J., Zhang, J., Weisel, F., Wellmann, U., Winkler, T.H., Kneitz, B., Crocker, P.R. and Nitschke, L. (2007) Siglec-G is a B1 cell-inhibitory receptor that controls expansion and calcium signaling of the B1 cell population. Nature Immunology, 8, 695-704. doi:10.1038/ni1480
[25] Ono, M., Bolland, S., Tempst, P. and Ravetch, J.V. (1996) Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor Fc RIIB. Nature, 383, 263-266.doi:10.1038/383263a0
[26] Leucht, S., Uttenreuther-Fischer, M.M., Gaedicke, G. and Fischer, P. (2001) The B cell superantigen-like interaction of intravenous immunoglobulin (IVIG) with Fab fragments of V(H) 3-23 and 3-30/3-30.5 germline gene origin cloned from a patient with Kawasaki disease is enhanced after IVIG therapy. Clinical Immunology, 99, 18-29. doi:10.1006/clim.2001.5004
[27] Proulx, D.P., Aubin, E., Lemieux, R. and Bazin, R. (2009) Spontaneous internalization of IVIg in activated B cells. Immunology Letters, 124, 18-26. doi:10.1016/j.imlet.2009.03.012
[28] Sé?té, J.F., Cornec, D., Renaudineau, Y., Youinou, P., Mageed, R.A. and Hillion, S. (2010) IVIg modulates BCR signaling through CD22 and promotes apoptosis in mature human B lymphocytes. Blood, 116, 1698-1704. doi:10.1182/blood-2009-12-261461
[29] Séité, J.F., Guerrier, T., Cornec, D., Jamin, C., Youinou, P. and Hillion, S. (2011) TLR9 responses of B cells are repressed by intravenous immunoglobulin through the recruitment of phosphatase. Journal of Autoimmunity, 37, 190-197.doi:10.1016/j.jaut.2011.05.014
[30] Saraiva, M. and O’Garra, A. (2010) The regulation of IL-10 production by immune cells. Nature Reviews Immunology, 10, 170-181.doi:10.1038/nri2711
[31] O’Garra, A., Barret, F.J., Castro, A.G., Vicari, A. and Hawrylowicz, C. (2008) Strategies for use of IL-10 or its antagonists in human disease. Immunological Reviews, 223, 114-131.doi:10.1111/j.1600-065X.2008.00635.x
[32] Kessel, A., Peri, R., Haj, T., Snir, A., Slobodin, G., Sabo, E., Rosner, I., Shoenfeld, Y. and Toubi, E. (2011) IVIg attenuates TLR-9 activation in B cells from SLE patients. Journal of Clinical Immunology, 31, 30-38. doi:10.1007/s10875-010-9469-3

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