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Basophils and the T helper 2 environment can promote the development of lupus nephritis

Nature Medicine volume 16, pages 701–707 (2010)Cite this article

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Abstract

In systemic lupus erythematosus (SLE), self-reactive antibodies can target the kidney (lupus nephritis), leading to functional failure and possible mortality. We report that activation of basophils by autoreactive IgE causes their homing to lymph nodes, promoting T helper type 2 (TH2) cell differentiation and enhancing the production of self-reactive antibodies that cause lupus-like nephritis in mice lacking the Src family protein tyrosine kinase Lyn (Lyn−/− mice). Individuals with SLE also have elevated serum IgE, self-reactive IgEs and activated basophils that express CD62 ligand (CD62L) and the major histocompatibility complex (MHC) class II molecule human leukocyte antigen-DR (HLA-DR), parameters that are associated with increased disease activity and active lupus nephritis. Basophils were also present in the lymph nodes and spleen of subjects with SLE. Thus, in Lyn−/− mice, basophils and IgE autoantibodies amplify autoantibody production that leads to lupus nephritis, and in individuals with SLE IgE autoantibodies and activated basophils are factors associated with disease activity and nephritis.

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Figure 1: The lupus-like nephritis in Lyn−/− mice is IL-4 and IgE dependent.
Figure 2: IgE, basophils and IL-4 regulate autoantibody production in Lyn−/− mice, and basophils alter the kidney cytokine environment.
Figure 3: Autoreactive IgEs and IgE-CICs are present in the sera of aged Lyn−/− mice.
Figure 4: Basophils from aged Lyn−/− mice upregulate CD62L expression, home to secondary lymphoid tissues and express membrane BAFF and MHC II.
Figure 5: dsDNA-specific IgE and IgE-specific IgG are associated with human SLE disease activity and lupus nephritis.
Figure 6: Basophils in individuals with SLE are active, upregulate CD62L and HLA-DR and home to secondary lymphoid organs.

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References

  1. Rahman, A. & Isenberg, D.A. Systemic lupus erythematosus. N. Engl. J. Med. 358, 929–939 (2008).

    Article  CAS  Google Scholar 

  2. Moser, K.L., Kelly, J.A., Lessard, C.J. & Harley, J.B. Recent insights into the genetic basis of systemic lupus erythematosus. Genes Immun. 10, 373–379 (2009).

    Article  CAS  Google Scholar 

  3. Masutani, K. et al. Predominance of TH1 immune response in diffuse proliferative lupus nephritis. Arthritis Rheum. 44, 2097–2106 (2001).

    Article  CAS  Google Scholar 

  4. Balomenos, D., Rumold, R. & Theofilopoulos, A.N. Interferon-γ is required for lupus-like disease and lymphoaccumulation in MRL-lpr mice. J. Clin. Invest. 101, 364–371 (1998).

    Article  CAS  Google Scholar 

  5. Peng, S.L., Szabo, S.J. & Glimcher, L.H. T-bet regulates IgG class switching and pathogenic autoantibody production. Proc. Natl. Acad. Sci. USA 99, 5545–5550 (2002).

    Article  CAS  Google Scholar 

  6. Zeng, D., Liu, Y., Sidobre, S., Kronenberg, M. & Strober, S. Activation of natural killer T cells in NZB/W mice induces TH1-type immune responses exacerbating lupus. J. Clin. Invest. 112, 1211–1222 (2003).

    Article  CAS  Google Scholar 

  7. Nalbandian, A., Crispin, J.C. & Tsokos, G.C. Interleukin-17 and systemic lupus erythematosus: current concepts. Clin. Exp. Immunol. 157, 209–215 (2009).

    Article  CAS  Google Scholar 

  8. Pernis, A.B. TH17 cells in rheumatoid arthritis and systemic lupus erythematosus. J. Intern. Med. 265, 644–652 (2009).

    Article  CAS  Google Scholar 

  9. Valencia, X., Yarboro, C., Illei, G. & Lipsky, P.E. Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J. Immunol. 178, 2579–2588 (2007).

    Article  CAS  Google Scholar 

  10. Zhao, X.F. et al. Increased serum interleukin 17 in patients with systemic lupus erythematosus. Mol. Biol. Rep. 37, 81–85 (2010).

    Article  Google Scholar 

  11. Akahoshi, M. et al. TH1/TH2 balance of peripheral T helper cells in systemic lupus erythematosus. Arthritis Rheum. 42, 1644–1648 (1999).

    Article  CAS  Google Scholar 

  12. Heine, G. et al. A shift in the TH1/TH2 ratio accompanies the clinical remission of systemic lupus erythematosus in patients with end-stage renal disease. Nephrol. Dial. Transplant. 17, 1790–1794 (2002).

    Article  CAS  Google Scholar 

  13. Shimizu, S. et al. Membranous glomerulonephritis development with TH2-type immune deviations in MRL/lpr mice deficient for IL-27 receptor (WSX-1). J. Immunol. 175, 7185–7192 (2005).

    Article  CAS  Google Scholar 

  14. Tiller, T. et al. Autoreactivity in human IgG+ memory B cells. Immunity 26, 205–213 (2007).

    Article  CAS  Google Scholar 

  15. Tsuiji, M. et al. A checkpoint for autoreactivity in human IgM+ memory B cell development. J. Exp. Med. 203, 393–400 (2006).

    Article  Google Scholar 

  16. Atta, A.M., Sousa, C.P., Carvalho, E.M. & Sousa-Atta, M.L. Immunoglobulin E and systemic lupus erythematosus. Braz. J. Med. Biol. Res. 37, 1497–1501 (2004).

    Article  CAS  Google Scholar 

  17. Odom, S. et al. Negative regulation of immunoglobulin E–dependent allergic responses by Lyn kinase. J. Exp. Med. 199, 1491–1502 (2004).

    Article  CAS  Google Scholar 

  18. Charles, N. et al. Lyn kinase controls basophil GATA-3 transcription factor expression and induction of TH2 cell differentiation. Immunity 30, 533–543 (2009).

    Article  CAS  Google Scholar 

  19. Beavitt, S.J. et al. Lyn-deficient mice develop severe, persistent asthma: Lyn is a critical negative regulator of TH2 immunity. J. Immunol. 175, 1867–1875 (2005).

    Article  CAS  Google Scholar 

  20. Hibbs, M.L. et al. Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease. Cell 83, 301–311 (1995).

    Article  CAS  Google Scholar 

  21. Nishizumi, H. et al. Impaired proliferation of peripheral B cells and indication of autoimmune disease in lyn-deficient mice. Immunity 3, 549–560 (1995).

    Article  CAS  Google Scholar 

  22. Yu, C.C., Yen, T.S., Lowell, C.A. & DeFranco, A.L. Lupus-like kidney disease in mice deficient in the src family tyrosine kinases Lyn and Fyn. Curr. Biol. 11, 34–38 (2001).

    Article  CAS  Google Scholar 

  23. Lu, R. et al. Genetic associations of LYN with systemic lupus erythematosus. Genes Immun. 10, 397–403 (2009).

    Article  CAS  Google Scholar 

  24. Liossis, S.N. et al. B-cell kinase lyn deficiency in patients with systemic lupus erythematosus. J. Investig. Med. 49, 157–165 (2001).

    Article  CAS  Google Scholar 

  25. Kopf, M. et al. Disruption of the murine IL-4 gene blocks TH2 cytokine responses. Nature 362, 245–248 (1993).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  28. 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 

  29. Seshan, S.V. & Jennette, J.C. Renal disease in systemic lupus erythematosus with emphasis on classification of lupus glomerulonephritis: advances and implications. Arch. Pathol. Lab. Med. 133, 233–248 (2009).

    PubMed  Google Scholar 

  30. Sinico, R.A. et al. Anti-C1q autoantibodies in lupus nephritis. Ann. NY Acad. Sci. 1173, 47–51 (2009).

    Article  CAS  Google Scholar 

  31. Toran, E.J. & Lee, C.M. Isolation and analysis of nephritic-producing immune complexes in Plasmodium berghei–infected mice. J. Natl. Med. Assoc. 87, 693–699 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Perrigoue, J.G. et al. MHC class II–dependent basophil-CD4+ T cell interactions promote TH2 cytokine–dependent immunity. Nat. Immunol. 10, 697–705 (2009).

    Article  CAS  Google Scholar 

  33. Sokol, C.L. et al. Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response. Nat. Immunol. 10, 713–720 (2009).

    Article  CAS  Google Scholar 

  34. Yoshimoto, T. et al. Basophils contribute to TH2-IgE responses in vivo via IL-4 production and presentation of peptide–MHC class II complexes to CD4+ T cells. Nat. Immunol. 10, 706–712 (2009).

    Article  CAS  Google Scholar 

  35. American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Response Criteria. The American College of Rheumatology response criteria for systemic lupus erythematosus clinical trials: measures of overall disease activity. Arthritis Rheum. 50, 3418–3426 (2004).

  36. Hauswirth, A.W. et al. Recombinant allergens promote expression of CD203c on basophils in sensitized individuals. J. Allergy Clin. Immunol. 110, 102–109 (2002).

    Article  CAS  Google Scholar 

  37. Singh, R.R., Ebling, F.M., Sercarz, E.E. & Hahn, B.H. Immune tolerance to autoantibody-derived peptides delays development of autoimmunity in murine lupus. J. Clin. Invest. 96, 2990–2996 (1995).

    Article  CAS  Google Scholar 

  38. Kyttaris, V.C., Katsiari, C.G., Juang, Y.T. & Tsokos, G.C. New insights into the pathogenesis of systemic lupus erythematosus. Curr. Rheumatol. Rep. 7, 469–475 (2005).

    Article  CAS  Google Scholar 

  39. Holmdahl, R., Tarkowski, A. & Jonsson, R. Involvement of macrophages and dendritic cells in synovial inflammation of collagen induced arthritis in DBA/1 mice and spontaneous arthritis in MRL/lpr mice. Autoimmunity 8, 271–280 (1991).

    Article  CAS  Google Scholar 

  40. Levesque, M.C. Translational mini-review series on B cell–directed therapies: recent advances in B cell–directed biological therapies for autoimmune disorders. Clin. Exp. Immunol. 157, 198–208 (2009).

    Article  CAS  Google Scholar 

  41. Schroeder, J.T. & MacGlashan, D.W. New concepts: the basophil. J. Allergy Clin. Immunol. 99, 429–433 (1997).

    Article  CAS  Google Scholar 

  42. Mukai, K. et al. Basophils play a critical role in the development of IgE-mediated chronic allergic inflammation independently of T cells and mast cells. Immunity 23, 191–202 (2005).

    Article  CAS  Google Scholar 

  43. Sokol, C.L., Barton, G.M., Farr, A.G. & Medzhitov, R. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat. Immunol. 9, 310–318 (2008).

    Article  CAS  Google Scholar 

  44. Denzel, A. et al. Basophils enhance immunological memory responses. Nat. Immunol. 9, 733–742 (2008).

    Article  CAS  Google Scholar 

  45. Chen, K. et al. Immunoglobulin D enhances immune surveillance by activating antimicrobial, proinflammatory and B cell–stimulating programs in basophils. Nat. Immunol. 10, 889–898 (2009).

    Article  CAS  Google Scholar 

  46. Lin, H. et al. Omalizumab rapidly decreases nasal allergic response and FcɛRI on basophils. J. Allergy Clin. Immunol. 113, 297–302 (2004).

    Article  CAS  Google Scholar 

  47. Burmeister Getz, E., Fisher, D.M. & Fuller, R. Human pharmacokinetics/pharmacodynamics of an interleukin-4 and interleukin-13 dual antagonist in asthma. J. Clin. Pharmacol. 49, 1025–1036 (2009).

    Article  Google Scholar 

  48. De Carli, M., D'Elios, M.M., Zancuoghi, G., Romagnani, S. & Del Prete, G. Human TH1 and TH2 cells: functional properties, regulation of development and role in autoimmunity. Autoimmunity 18, 301–308 (1994).

    Article  CAS  Google Scholar 

  49. Kono, D.H., Balomenos, D., Park, M.S. & Theofilopoulos, A.N. Development of lupus in BXSB mice is independent of IL-4. J. Immunol. 164, 38–42 (2000).

    Article  CAS  Google Scholar 

  50. Peng, S.L., Moslehi, J. & Craft, J. Roles of interferon-γ and interleukin-4 in murine lupus. J. Clin. Invest. 99, 1936–1946 (1997).

    Article  CAS  Google Scholar 

  51. Lee, H.Y. et al. Altered frequency and migration capacity of CD4+CD25+ regulatory T cells in systemic lupus erythematosus. Rheumatology (Oxford) 47, 789–794 (2008).

    Article  CAS  Google Scholar 

  52. Miyajima, H. et al. IgE allotypes in sera of mice with autoimmune diseases and in mice with graft-versus-host disease after transfusion or bone marrow transplantation. Int. Arch. Allergy Immunol. 111, 152–155 (1996).

    Article  CAS  Google Scholar 

  53. Hochberg, M.C. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 40, 1725 (1997).

    Article  CAS  Google Scholar 

  54. Tan, E.M. et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 25, 1271–1277 (1982).

    Article  CAS  Google Scholar 

  55. Liu, F.T. et al. Monoclonal dinitrophenyl-specific murine IgE antibody: preparation, isolation and characterization. J. Immunol. 124, 2728–2737 (1980).

    CAS  PubMed  Google Scholar 

  56. Kepley, C.L., Craig, S.S. & Schwartz, L.B. Identification and partial characterization of a unique marker for human basophils. J. Immunol. 154, 6548–6555 (1995).

    CAS  PubMed  Google Scholar 

  57. McEuen, A.R., Buckley, M.G., Compton, S.J. & Walls, A.F. Development and characterization of a monoclonal antibody specific for human basophils and the identification of a unique secretory product of basophil activation. Lab. Invest. 79, 27–38 (1999).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank J. Daruwalla and G. Souto-Adeva (Office of the Clinical Director, NIAMS) for human samples, data input and analysis and H.C. Oettgen (Harvard University) for providing the Igh-7−/− mice. We also thank M. Hourseau for human sample preparation and L.B. Schwartz (Virginia Commonwealth University) and A.F. Walls (University of Southampton) for the gift of human basophil–specific monoclonal antibodies. We acknowledge the support of the Laboratory Animal Care and Use Section and the Flow Cytometry Section of the Office of Science and Technology, NIAMS. This research was supported by the intramural programs of NIAMS and National Institute of Dental and Craniofacial Research, NIH.

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Authors and Affiliations

  1. Laboratory of Molecular Immunogenetics, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland, USA

    Nicolas Charles & Juan Rivera

  2. Office of the Clinical Director, NIAMS, NIH, Bethesda, Maryland, USA

    Donna Hardwick

  3. Department of Nephrology, Institut National de la Santé et de la Recherche Médicale U699, Assistance Publique–Hôpitaux de Paris, Université Paris Diderot, Hôpital Bichat, Paris, France

    Eric Daugas

  4. Sjogren's Syndrome Clinic, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland, USA

    Gabor G Illei

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Contributions

N.C. and J.R. conceived and directed the project, designed experiments and wrote the manuscript. N.C. conducted experiments. D.H., E.D. and G.G.I. provided SLE patient history, samples and analysis.

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Correspondence to Juan Rivera.

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Charles, N., Hardwick, D., Daugas, E. et al. Basophils and the T helper 2 environment can promote the development of lupus nephritis. Nat Med 16, 701–707 (2010). https://doi.org/10.1038/nm.2159

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