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Immunoglobulin-free light chains elicit immediate hypersensitivity-like responses

Nature Medicine volume 8, pages 694–701 (2002)Cite this article

Abstract

Immunoglobulin (Ig)-free light chains IgLC are present in serum and their production is augmented under pathological conditions such as multiple sclerosis, rheumatoid arthritis and neurological disorders. Until now, no (patho)physiological function has been ascribed to circulating Ig light chains. Here we show that IgLCs can confer mast cell–dependent hypersensitivity in mice. Antigenic stimulation results in plasma extravasation, cutaneous swelling and mast-cell degranulation. We show that IgLCs have a crucial role in development of contact sensitivity, which could be completely prevented by a novel IgLC antagonist. Although IgE and IgG1 are central to the induction of immediate hypersensitivity reactions, our results show that IgLCs have similar activity. IgLCs may therefore be a novel factor in the humoral immune response to antigen exposure. Our findings open new avenues in investigating the pathogenesis of autoimmune diseases and their treatments.

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Figure 1: IgLC transfers hapten sensitivity.
Figure 2: Antigen-specificity of sensitization with IgLC.
Figure 3: Mast-cell dependency of hapten-induced ear swelling in IgLC-sensitized mice.
Figure 4: Binding of Ig free light chain to mast cells.
Figure 5: Antigen-specific IgLC is produced after contact sensitization with low molecular weight compounds.
Figure 6: F991 prevents hapten–induced ear swelling in passively and actively sensitized mice.

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References

  1. Corry, D.B. & Kheradmand, F. Induction and regulation of the IgE response. Nature 402, B18–23 (1999).

    Article  CAS  Google Scholar 

  2. Oettgen, H.C. et al. Active anaphylaxis in IgE-deficient mice. Nature 370, 367–370 (1994).

    Article  CAS  Google Scholar 

  3. Miyajima, I. et al. Systemic anaphylaxis in the mouse can be mediated largely through IgG1 and Fc γRIII. Assessment of the cardiopulmonary changes, mast cell degranulation, and death associated with active or IgE- or IgG1-dependent passive anaphylaxis. J. Clin. Invest. 99, 901–914 (1997).

    Article  CAS  Google Scholar 

  4. Van Loveren, H. et al. Immune serum from mice contact-sensitized with picryl chloride contains an antigen-specific T cell factor that transfers immediate cutaneous reactivity. Eur. J. Immunol. 16, 1203–1208 (1986).

    Article  CAS  Google Scholar 

  5. Hopper, J.E. & Papagiannes, E. Evidence by radioimmunoassay that mitogen-activated human blood mononuclear cells secrete significant amounts of light chain Ig unassociated with heavy chain. Cell. Immunol. 101, 122–131 (1986).

    Article  CAS  Google Scholar 

  6. Shapiro, A.L., Scharff, M.D., Maizel, J.V. & Uhr, J.W. Synthesis of excess light chains of γ globulin by rabbit lymph node cells. Nature 211, 243–245 (1966).

    Article  CAS  Google Scholar 

  7. Skvortsov, V.T. & Gurvich, A.E. Relative rates of synthesis of immunoglobulins and light chains in rabbit spleen cells during secondary response. Nature 218, 377–378 (1968).

    Article  CAS  Google Scholar 

  8. Hannam-Harris, A.C. & Smith, J.L. Free immunoglobulin light chain synthesis by human foetal liver and cord blood lymphocytes. Immunology 43, 417–423 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Waldmann, T.A., Strober, W. & Mogielnicki, R.P. The renal handling of low molecular weight proteins. II. Disorders of serum protein catabolism in patients with tubular proteinuria, the nephrotic syndrome, or uremia. J. Clin. Invest. 51, 2162–2174 (1972).

    Article  CAS  Google Scholar 

  10. Yoo, T.J., Roholt, O.A. & Pressman, D. Specific binding activity of isolated light chains of antibodies. Science 157, 707–709 (1967).

    Article  CAS  Google Scholar 

  11. Masat, L., Wabl, M. & Johnson, J.P. A simpler sort of antibody. Proc. Natl. Acad. Sci. USA 91, 893–896 (1994).

    Article  CAS  Google Scholar 

  12. Sun, M., Li, L., Gao, Q.S. & Paul, S. Antigen recognition by an antibody light chain. J. Biol. Chem. 269, 734–738 (1994).

    CAS  PubMed  Google Scholar 

  13. Ledbetter, J.A., Fell, H.P., Grosmaire, L.S., Norris, N.A. & Tsu, T.T. An immunoglobulin light chain dimer with CD4 antigen specificity. Mol. Immunol. 24, 1255–1261 (1987).

    Article  CAS  Google Scholar 

  14. Schechter, I. & Ziv, E. Binding of 2,4-dinitrophenyl derivatives by the light chain dimer obtained from immunoglobulin A produced by MOPC-315 mouse myeloma. Biochemistry 15, 2785–2790 (1976).

    Article  CAS  Google Scholar 

  15. Painter, R.G., Sage, H.J. & Tanford, C. Contributions of heavy and light chains of rabbit immunoglobulin G to antibody activity. I. Binding studies on isolated heavy and light chains. Biochemistry 11, 1327–1337 (1972).

    Article  CAS  Google Scholar 

  16. Tribbick, G., Edmundson, A.B., Mason, T.J. & Geysen, H.M. Similar binding properties of peptide ligands for a human immunoglobulin and its light chain dimer. Mol. Immunol. 26, 625–635 (1989).

    Article  CAS  Google Scholar 

  17. Thiagarajan, P. et al. Monoclonal antibody light chain with prothrombinase activity. Biochemistry 39, 6459–6465 (2000).

    Article  CAS  Google Scholar 

  18. Sun, M., Gao, Q.S., Li, L. & Paul, S. Proteolytic activity of an antibody light chain. J. Immunol. 153, 5121–5126 (1994).

    CAS  PubMed  Google Scholar 

  19. Kitamura, D., Roes, J., Kuhn, R. & Rajewsky, K. A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature 350, 423–426 (1991).

    Article  CAS  Google Scholar 

  20. Kalesnikoff, J. et al. Monomeric IgE stimulates signaling pathways in mast cells that lead to cytokine production and cell survival. Immunity 14, 801–811 (2001).

    Article  CAS  Google Scholar 

  21. Asai, K. et al. Regulation of mast cell survival by IgE. Immunity 14, 791–800 (2001).

    Article  CAS  Google Scholar 

  22. Yamaguchi, M. et al. IgE enhances mouse mast cell Fc(epsilon)RI expression in vitro and in vivo: Evidence for a novel amplification mechanism in IgE-dependent reactions. J. Exp. Med. 185, 663–672 (1997).

    Article  CAS  Google Scholar 

  23. Hsu, C. & MacGlashan, D., Jr. IgE antibody up-regulates high affinity IgE binding on murine bone marrow-derived mast cells. Immunol. Lett. 52, 129–134 (1996).

    Article  CAS  Google Scholar 

  24. Sheets, E.D., Holowka, D. & Baird, B. Critical role for cholesterol in Lyn-mediated tyrosine phosphorylation of FcepsilonRI and their association with detergent-resistant membranes. J. Cell. Biol. 145, 877–887 (1999).

    Article  CAS  Google Scholar 

  25. Meade, R., Van Loveren, H., Parmentier, H., Iverson, G.M. & Askenase, P.W. The antigen-binding T cell factor PCl-F sensitizes mast cells for in vitro release of serotonin. Comparison with monoclonal IgE antibody. J. Immunol. 141, 2704–2713 (1988).

    CAS  PubMed  Google Scholar 

  26. Huang, Z.Q. & Sanders, P.W. Localization of a single binding site for immunoglobulin light chains on human Tamm-Horsfall glycoprotein. J. Clin. Invest. 99, 732–736 (1997).

    Article  CAS  Google Scholar 

  27. Tsuji, R.F. et al. Required early complement activation in contact sensitivity with generation of local C5-dependent chemotactic activity, and late T cell interferon γ: A possible initiating role of B cells. J. Exp. Med. 186, 1015–1026 (1997).

    Article  CAS  Google Scholar 

  28. Takai, T., Li, M., Sylvestre, D., Clynes, R. & Ravetch, J.V. FcR γ chain deletion results in pleiotrophic effector cell defects. Cell 76, 519–529 (1994).

    Article  CAS  Google Scholar 

  29. Maeda, A., Kurosaki, M. & Kurosaki, T. Paired immunoglobulin-like receptor (PIR)-A is involved in activating mast cells through its association with Fc receptor γ chain. J. Exp. Med. 188, 991–995 (1998).

    Article  CAS  Google Scholar 

  30. Lee, K.H., Ono, M., Inui, M., Yuasa, T. & Takai, T. Stimulatory function of gp49A, a murine Ig-like receptor, in rat basophilic leukemia cells. J. Immunol. 165, 4970–4977 (2000).

    Article  CAS  Google Scholar 

  31. Pirozzi, G., Terry, R.W., Epstein, D. & Labow, M.A. Identification and characterization of a novel surface antigen gene induced in mast cells activated through the high affinity IgE receptor. J. Immunol. 155, 5811–5818 (1995).

    CAS  PubMed  Google Scholar 

  32. Smith, D.A., Monk, P.N. & Partridge, L.J. Antibodies against human CD63 activate transfected rat basophilic leukemia (RBL-2H3) cells. Mol. Immunol. 32, 1339–1344 (1995).

    Article  CAS  Google Scholar 

  33. Echtenacher, B., Mannel, D.N. & Hultner, L. Critical protective role of mast cells in a model of acute septic peritonitis. Nature 381, 75–77 (1996).

    Article  CAS  Google Scholar 

  34. Biedermann, T. et al. Mast cells control neutrophil recruitment during T cell-mediated delayed-type hypersensitivity reactions through tumor necrosis factor and macrophage inflammatory protein 2. J. Exp. Med. 192, 1441–1452 (2000).

    Article  CAS  Google Scholar 

  35. Secor, V.H., Secor, W.E., Gutekunst, C.A. & Brown, M.A. Mast cells are essential for early onset and severe disease in a murine model of multiple sclerosis. J. Exp. Med. 191, 813–822 (2000).

    Article  CAS  Google Scholar 

  36. Woolley, D.E. & Tetlow, L.C. Mast cell activation and its relation to proinflammatory cytokine production in the rheumatoid lesion. Arthritis Res. 2, 65–74 (2000).

    Article  CAS  Google Scholar 

  37. Geba, G.P. et al. Delayed-type hypersensitivity in mast cell-deficient mice: Dependence on platelets for expression of contact sensitivity. J. Immunol. 157, 557–565 (1996).

    CAS  PubMed  Google Scholar 

  38. Askenase, P.W. & Tsuji, R.F. B-1 B cell IgM antibody initiates T cell elicitation of contact sensitivity. Curr. Top. Microbiol. Immunol. 252, 171–177 (2000).

    CAS  PubMed  Google Scholar 

  39. Fagnart, O.C., Sindic, C.J. & Laterre, C. Free κ and λ light chain levels in the cerebrospinal fluid of patients with multiple sclerosis and other neurological diseases. J. Neuroimmunol. 19, 119–132 (1988).

    Article  CAS  Google Scholar 

  40. Moutsopoulos, H.M., Steinberg, A.D., Fauci, A.S., Lane, H.C. & Papadopoulos, N.M. High incidence of free monoclonal λ light chains in the sera of patients with Sjogren's syndrome. J. Immunol. 130, 2663–2665 (1983).

    CAS  PubMed  Google Scholar 

  41. Solling, K., Solling, J. & Romer, F.K. Free light chains of immunoglobulins in serum from patients with rheumatoid arthritis, sarcoidosis, chronic infections and pulmonary cancer. Acta Med. Scand. 209, 473–477 (1981).

    Article  CAS  Google Scholar 

  42. Rozniecki, J.J., Hauser, S.L., Stein, M., Lincoln, R. & Theoharides, T.C. Elevated mast cell tryptase in cerebrospinal fluid of multiple sclerosis patients. Ann. Neurol. 37, 63–66 (1995).

    Article  CAS  Google Scholar 

  43. Marone, G. Mast cells in rheumatic disorders: Mastermind or workhorse? Clin. Exp. Rheumatol. 16, 245–249 (1998).

    CAS  PubMed  Google Scholar 

  44. Karimi, K., Redegeld, F.A., Heijdra, B. & Nijkamp, F.P. Stem cell factor and interleukin-4 induce murine bone marrow cells to develop into mast cells with connective tissue type characteristics in vitro. Exp. Hematol. 27, 654–662 (1999).

    Article  CAS  Google Scholar 

  45. Lukacs, N.W. et al. The role of stem cell factor (c-kit ligand) and inflammatory cytokines in pulmonary mast cell activation. Blood 87, 2262–2268 (1996).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank C. Beukelman for his initial help with the high performance gel filtration experiments; C. Vallinga, D. Kegler, P. van Schaaik, S. de Jager, A. van Houwelingen and B. Blokhuis for expert technical assistance; C. Burger for performing the electron microscopy studies; C. Milstein for providing the oxazolone-specific antibody producing hybridoma; H. Metzger and N. Bloksma for helpful suggestions and critical reading of the manuscript; A. Dvorak for evaluation and discussion of the electron microscopical studies. This work was supported by grants from the Royal Dutch Academy of Arts and Sciences, GlaxoSmithKline, the Netherlands and Fornix Biosciences, the Netherlands.

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Authors and Affiliations

  1. Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

    Frank A. Redegeld, Maurice W. van der Heijden, Mirjam Kool, Bianca M. Heijdra, Aletta D. Kraneveld, Andries S. Koster & Frans P. Nijkamp

  2. National Institute of Public Health and the Environment, Bilthoven, The Netherlands

    Johan Garssen, Henk Van Loveren & Paul Roholl

  3. Department of Molecular Genetics, Chiba University, Chuo-ku, Chiba, Japan

    Takashi Saito

  4. Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

    J. Sjef Verbeek & Jill Claassens

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Correspondence to Frank A. Redegeld.

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This research is being sponsored in part by Fornix Biosciences, Lelystad, the Netherlands.

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Redegeld, F., van der Heijden, M., Kool, M. et al. Immunoglobulin-free light chains elicit immediate hypersensitivity-like responses. Nat Med 8, 694–701 (2002). https://doi.org/10.1038/nm722

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