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Immune Complex-Mediated Cytokine Production is Regulated by Classical Complement Activation both In Vivo and In Vitro

  • Johan Rönnelid*
  • Erik Åhlin
  • Bo Nilsson
  • Kristina Nilsson-Ekdahl
  • Linda Mathsson
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 632)

Abstract

Immune complexes (IC) induce a number of cellular functions, including the enhancement of cytokine production from monocytes, macrophages and plasmacytoid dendritic cells. The range and the composition of cytokines induced by IC in vitro is influenced by the availability of an intact classical complement cascade during cell culture, as we have showed in our studies on artificial IC and on cryoglobulins purified from patients with lymphoproliferative diseases. When IC purified from systemic lupus erythematosus sera were used to stimulate in vitro cytokine production, the amount of circulating IC and IC-induced cytokine levels depended both on in vivo classical complement function as well as on the occurrence of anti-SSA, but not on anti-dsDNA or any other autoantibodies. Collectively these findings illustrate that studies on IC-induced cytokine production in vitro requires stringent cell culture conditions with complete control and definition of access to an intact classical complement pathway in the cell cultures. If IC are formed in vivo, the results have to be interpreted in the context of classical complement activation in vivo as well as the occurrence of IC-associated autoantibodies at the time of serum sampling.

Keywords

Systemic Lupus Erythematosus Immune Complex Normal Human Serum Systemic Lupus Erythematosus Disease Active Systemic Lupus Erythematosus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We are indebted to professor John D. Lambris for use of Compstatin and the control peptide.

References

  1. Berger, S., Balló, H. and Stutte, H.J. (1996) Immune complex-induced interleukin-6, interleukin-10 and prostaglandin secretion by human monocytes: a network of pro- and antiinflammatory cytokines dependent on the antigen-antibody ratio. Eur. J. Immunol. 26, 1297–1301PubMedCrossRefGoogle Scholar
  2. Blom, A.B., Radstake, T.R., Holthuysen, A.E., Sloetjes, A.W., Pesman, G.J., Sweep, F.G., van de Loo, F.A., Joosten, L.A., Barrera, P., van Lent, P.L. and van den Berg, W.B. (2003) Increased expression of Fcgamma receptors II and III on macrophages of rheumatoid arthritis patients results in higher production of tumor necrosis factor alpha and matrix metalloproteinase. Arthritis Rheum. 48, 1002–1014PubMedCrossRefGoogle Scholar
  3. Braun, M.C., Lahey, E. and Kelsall, B.L. (2000) Selective suppression of IL-12 production by chemoattractants. J. Immunol. 164, 3009–3017PubMedGoogle Scholar
  4. Elshafie, A., Åhlin, E., Mathsson, L., Elghazali, G. and Rönnelid, J. (2007) Circulating immune complexes (IC) and IC-induced levels of GM-CSF are increased in Sudanese patients with acute visceral Leishmania donovani infection undergoing sodium stibogluconate treatment: implications for disease pathogenesis. J. Immunol. 178, 5383–5389PubMedGoogle Scholar
  5. Elshafie, A., Elghazali, G., Rönnelid, J. and Venge, P. (2006) Cystatin C as a marker of immune complex-associated renal impairment in a Sudanese population with visceral leishmaniasis. Am. J. Trop. Med. Hyg. 75, 864–868PubMedGoogle Scholar
  6. Gorczynski, R.M., Kilburn, D.G., Knight, R.A., Norbury, C., Parker, D.C. and Smith, J.B.(1975) Nonspecific and specific immunosuppression in tumour-bearing mice by soluble immune complexes. Nature 254, 141–143PubMedCrossRefGoogle Scholar
  7. Gu, Z.J., Costes, V., Lu, Z.Y., Zhang, X.G., Pitard, V., Moreau, J.F., Bataille, R., Wijdenes, J., Rossi, J.F. and Klein, B. (1996) Interleukin-10 is a growth factor for human myeloma cells by induction of an oncostatin M autocrine loop. Blood 88, 3972–3986PubMedGoogle Scholar
  8. Hassan, A.B., Lundberg, I.E., Isenberg, D. and Wahren-Herlenius, M. (2002) Serial analysis of Ro/SSA and La/SSB antibody levels and correlation with clinical disease activity in patients with systemic lupus erythematosus. Scand. J. Rheumatol. 31, 133–139PubMedGoogle Scholar
  9. Hawlisch, H., Belkaid, Y., Baelder, R., Hildeman, D., Gerard, C. and Kohl, J. (2005) C5a negatively regulates toll-like receptor 4-induced immune responses. Immunity 22, 415–426PubMedCrossRefGoogle Scholar
  10. Hideshima, T., Chauhan, D., Schlossman, R., Richardson, P. and Anderson, K.C.(2001) The role of tumor necrosis factor alpha in the pathophysiology of human multiple myeloma: therapeutic applications. Oncogene 20, 4519–4527PubMedCrossRefGoogle Scholar
  11. Jerry, L.M., Lewis, M.G. and Cano, P. (1976) Anergy, anti-antibodies and immune complex disease: a syndrome of disordered immune regulation in human cancer. Immunocancerology in solid tumors. M. Martin and L. Dionne.New York, Stratton, 63–79Google Scholar
  12. Kallemuchikkal, U. and Gorevic, P.D. (1999) Evaluation of cryoglobulins. Arch. Pathol. Lab. Med. 123, 119–125PubMedGoogle Scholar
  13. Kilburn, D.G., Fairhurst, M., Levy, J.G. and Whitney, R.B. (1976) Synergism between immune complexes and serum from tumor-bearing mice in the suppression of mitogen responses. J. Immunol. 117, 1612–1617PubMedGoogle Scholar
  14. Kim, K.N., Watanabe, S., Ma, Y., Thornton, S., Giannini, E.H. and Hirsch, R. (2000) Viral IL-10 and soluble TNF receptor act synergistically to inhibit collagen-induced arthritis following adenovirus-mediated gene transfer. J. Immunol. 164, 1576–1581PubMedGoogle Scholar
  15. Lacki, J.K., Samborski, W. and Mackiewicz, S.H. (1997) Interleukin-10 and interleukin-6 in lupus erythematosus and rheumatoid arthritis, correlations with acute phase proteins. Clin. Rheumatol. 16, 275–278PubMedCrossRefGoogle Scholar
  16. Lauta, V.M. (2003) A review of the cytokine network in multiple myeloma: diagnostic, prognostic, and therapeutic implications. Cancer 97, 2440–2452PubMedCrossRefGoogle Scholar
  17. Liu, T.F. and Jones, B.M. (1998a) Impaired production of IL-12 in system lupus erythematosus. II: IL-12 production in vitro is correlated negatively with serum IL-10, positively with serum IFN-gamma and negatively with disease activity in SLE. Cytokine 10, 148–153CrossRefGoogle Scholar
  18. Liu, T.F. and Jones, B.M. (1998b) Impaired production of IL-12 in systemic lupus erythematosus. I. Excessive production of IL-10 suppresses production of IL-12 by monocytes. Cytokine–10,140–147Google Scholar
  19. Liu, T.F., Jones, B.M., Wong, R.W. and Srivastava, G. (1999) Impaired production of IL-12 in systemic lupus erythematosus. III: deficient IL-12 p40 gene expression and cross-regulation of IL-12, IL-10 and IFN-gamma gene expression. Cytokine 11,805–811PubMedCrossRefGoogle Scholar
  20. Llorente, L., Richaud-Patin, Y., Wijdenes, J., Alcocer-Varela, J., Maillot, M.C., Durand-Gasselin, I., Fourrier, B.M., Galanaud, P. and Emilie, D. (1993) Spontaneous production of interleukin-10 by B lymphocytes and monocytes in systemic lupus erythematosus. Eur. Cytokine Netw. 4, 421–427PubMedGoogle Scholar
  21. Lövgren, T., Eloranta, M.L., Båve, U., Alm, G.V. and Rönnblom, L. (2004) Induction of interferon-alpha production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG. Arthritis Rheum. 50, 1861–1872PubMedCrossRefGoogle Scholar
  22. Lu,Z.Y., Zhang,X.G., Rodriguez,C.,Wijdenes,J.,Gu,Z.J.,Morel-Fournier,B.,Harousseau,J.L.BatailleR.,Rossi,J.F.,andKlein,B.(1995) Interleukin-10 is a proliferation factor but not a differentiation factor for human myeloma cells. Blood 85, 2521–2527PubMedGoogle Scholar
  23. Mathsson, L., Tejde, A., Carlson, K., Höglund, M., Nilsson, B., Nilsson-Ekdahl, K. and Rönnelid, J. (2005) Cryoglobulin-induced cytokine production via FcgRIIa: inverse effects of complement blockade on the production of TNF-a and IL-10. Implications for the growth of malignant B-cell clones. Br. J. Haematol. 129, 830–838PubMedCrossRefGoogle Scholar
  24. Mathsson, L., Lampa, J., Mullazehi, M. and Rönnelid, J. (2006) Immune complexes from rheumatoid arthritis synovial fluid induce FcgRIIa dependent and rheumatoid factor correlated production of tumour necrosis factor-alpha by peripheral blood mononuclear cells. Arthritis Res. Ther.;8:(3)R64 Mar 28, [Epub ahead of print] doi:10.1186/ar1926PubMedCrossRefGoogle Scholar
  25. Mathsson, L., Åhlin, E., Sjövall, C., Skogh, T. andRönnelid, J. (2007) Cytokine induction by circulating immune complexes and signs of in-vivo complement activation in systemic lupus erythematosus are associated with the occurrence of anti-SSA antibodies. Clin. Exp. Immunol. 147, 513–520PubMedCrossRefGoogle Scholar
  26. McInnes, I.B. and Schett, G. (2007) Cytokines in the pathogenesis of rheumatoid arthritis. Nat. Rev. Immunol. 7, 429–442PubMedCrossRefGoogle Scholar
  27. Mullazehi, M., Mathsson, L., Lampa, J. and Rönnelid, J. (2006) Surface-bound anti-type II collagen containing immune complexes induce production of TNF-a, IL-1ß and IL-8 from peripheral blood monocytes via FcgRIIa. A potential patho-physiological mechanism for humoral anti-collagen type II immunity in RA. Arthritis Rheum. 54,1759–1771PubMedCrossRefGoogle Scholar
  28. Nilsson, U.R. (2001) Deposition of C3b/iC3b leads to the concealment of antigens, immunoglobulins and bound C1q in complement-activating immune complexes. Mol. Immunol. 38, 151–160PubMedCrossRefGoogle Scholar
  29. Park, Y.B., Lee, S.K., Kim, D.S., Lee, J., Lee, C.H. and Song, C.H. (1998) Elevated interleukin-10 levels correlated with disease activity in systemic lupus erythematosus. Clin. Exp. Rheumatol. 16, 283–288PubMedGoogle Scholar
  30. Peeva, E., Fishman, A.D., Goddard, G., Wadler, S. and Barland, P. (2000) Rheumatoid arthritis exacerbation caused by exogenous interleukin-12. Arthritis Rheum. 43, 461–463PubMedCrossRefGoogle Scholar
  31. Radstake, T., van Lent, P.L.E.M., Pesman, G.J., Blom, A.B., Sweep, F.G.J., Rönnelid, J., Figdor, C.G., Adema, G.J., Barrera, P. and van den Berg, W.B. (2004) High production of proinflammatory and Th1 cytokines by dendritic cells from patients with rheumatoid arthritis, and down regulation upon Fc{gamma}R triggering. Ann. Rheum. Dis. 63, 696–702PubMedCrossRefGoogle Scholar
  32. Rönnelid, J., Tejde, A., Mathsson, L., Nilsson-Ekdahl, K. and Nilsson, B. (2003) Immune complexes from SLE sera induce IL10 production from normal peripheral blood mononuclear cells by an FcgammaRII dependent mechanism: implications for a possible vicious cycle maintaining B cell hyperactivity in SLE. Ann. Rheum. Dis. 62, 37–42PubMedCrossRefGoogle Scholar
  33. Sahu, A., Soulika, A.M., Morikis, D., Spruce, L., Moore, W.T. and Lambris, J.D. (2000) Binding kinetics, structure-activity relationship, and biotransformation of the complement inhibitor compstatin. J. Immunol. 165, 2491–2499PubMedGoogle Scholar
  34. Segal-Eiras,A. and Croce,M.V(1984) Immune complexes in human malignant tumours. A review. Allergol. Immunopathol.(Madr)12, 225–232Google Scholar
  35. Tarkowski, A., Czerkinsky, C. and Nilsson, L.A. (1985) Simultaneous induction of rheumatoid factor- and antigen-specific antibody-secreting cells during the secondary immune response in man. Clin. Exp. Immunol. 61, 379–387PubMedGoogle Scholar
  36. Tejde, A., Mathsson, L., Nilsson Ekdahl, K., Nilsson, B. and Rönnelid, J. (2004) Immune complex stimulation of peripheral blood mononuclear cells result in enhancement or suppression of IL-12 production dependent on serum factors. Role of complement activation. Clin. Exp. Immunol. 137, 521–528PubMedCrossRefGoogle Scholar
  37. Urbanska-Rys, H., Wiersbowska, A., Stepien, H. and Robak, T. (2000) Relationship between circulating interleukin-10 (IL-10) with interleukin-6 (IL-6) type cytokines (IL-6, interleukin-11 (IL-11), oncostatin M (OSM)) and soluble interleukin-6 (IL-6) receptor (sIL-6R) in patients with multiple myeloma. Eur. Cytokine Netw. 11, 443–451PubMedGoogle Scholar
  38. Weiner, S.M., Prasauskas, V., Lebrecht, D., Weber, S., Peter, H.H. and Vaith, P. (2001) Occurrence of C-reactive protein in cryoglobulins. Clin. Exp. Immunol. 125, 316–322PubMedCrossRefGoogle Scholar
  39. Wittmann, M., Zwirner, J., Larsson, V.A., Kirchhoff, K., Begemann, G., Kapp, A., Gotze, O. and Werfel, T. (1999) C5a suppresses the production of IL-12 by IFN-gamma-primed and lipopolysaccharide-challenged human monocytes. J. Immunol. 162, 6763–6769PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Johan Rönnelid*
    • 1
  • Erik Åhlin
  • Bo Nilsson
  • Kristina Nilsson-Ekdahl
  • Linda Mathsson
  1. 1.Unit of Clinical ImmunologyUppsala UniversityUppsalaSweden

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