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Elevated Production of B Cell Chemokine CXCL13 is Correlated with Systemic Lupus Erythematosus Disease Activity

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Abstract

Introduction

B lymphocyte chemoattractant (BLC/CXCL13), a CXC chemokine, is involved in B1 and B2 cell trafficking for the activation of autoreactive T helper (Th) cells and autoantibody production in target organs during the development of lupus. CXCL13 can induce the trafficking of CXCR5+ T lymphocyte subset designated as follicular helper T lymphocytes (TFH) which are specifically involved in autoantibody production.

Materials and Methods

We herein measured the plasma concentrations of CXCL13, B-cell-activating factor of the TNF family (BAFF), and TFH-cells-related cytokine IL-21 and cell surface expression of TFH-related receptor CXCR5 and IL-21R on CD4+Th and CD19+B cells in 35 systemic lupus erythematosus (SLE) patients and 23 sex- and age-matched control subjects (NC) using enzyme-linked immunosorbent assay and flow cytometry, respectively.

Results and Discussion

Plasma CXCL13, BAFF, and IL-21 concentrations were significantly higher in SLE patients than NC group (all p < 0.0001). Increase in CXCL13 concentration correlated positively and significantly with SLEDAI score in SLE patients (r = 0.399, p = 0.032). Cell surface expression of CXCR5 on Th and B cells and IL-21R on B cells was however significantly lower in SLE patients than controls (both p < 0.01). It may indicate that most differentiated TFH cells migrate out from circulation into lymphoid organ upon activation during the disease development of SLE.

Conclusions

The above results suggest that the elevated production of CXCL13, BAFF, and IL-21 may be associated with the function of TFH for the immunopathogenesis in SLE, and CXCL13 may serve as a potential disease marker of SLE.

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References

  1. Heinlen LD, McClain MT, Merrill J, et al. Clinical criteria for systemic lupus erythematosus precede diagnosis, and associated autoantibodies are present before clinical symptoms. Arthritis Rheum. 2007;56:2344–51.

    Article  PubMed  CAS  Google Scholar 

  2. Kotzin BL. Systemic lupus erythematosus. Cell. 1996;85:303–6.

    Article  PubMed  CAS  Google Scholar 

  3. Viallard JF, Pellegrin JL, Ranchin V, et al. Th1 (IL-2, interferon-gamma (IFN-gamma)) and Th2 (IL-10, IL-4) cytokine production by peripheral blood mononuclear cells (PBMC) from patients with systemic lupus erythematosus (SLE). Clin Exp Immunol. 1999;115:189–95.

    Article  PubMed  CAS  Google Scholar 

  4. Ansel KM, Harris RBS, Cyster JG. CXCL13 is required for B1 cell homing, natural antibody production, and body cavity immunity. Immunity. 2002;16:67–76.

    Article  PubMed  CAS  Google Scholar 

  5. Vissers JL, Hartgers FC, Lindhout E, Figdor CG, Adema GJ. BLC (CXCL13) is expressed by different dendritic cell subsets in vitro and in vivo. Eur J Immunol. 2001;31:1544–9.

    Article  PubMed  CAS  Google Scholar 

  6. Legler DF, Loetscher M, Roos RS, Clark-Lewis I, Baggiolini M, Moser B. B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR1/CXCR5. J Exp Med. 1998;187:655–60.

    Article  PubMed  CAS  Google Scholar 

  7. Ansel KM, Ngo VN, Hyman PL, et al. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature. 2000;406:309–14.

    Article  PubMed  CAS  Google Scholar 

  8. Schaerli P, Willimann K, Lang AB, Lipp M, Loetscher P, Moser B. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J Exp Med. 2000;192:1553–62.

    Article  PubMed  CAS  Google Scholar 

  9. Breitfeld DL, Ohl L, Kremmer EK, et al. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J Exp Med. 2000;192:1545–51.

    Article  PubMed  CAS  Google Scholar 

  10. Vogelzang A, McGuire HM, Yu D, Sprent J, Mackay CR, King C. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity. 2008;29:127–37.

    Article  PubMed  CAS  Google Scholar 

  11. Fazilleau N, Mark L, McHeyzer-Williams LJ, McHeyzer-Williams MG. Follicular helper T cells: lineage and location. Immunity. 2009;30:324–35.

    Article  PubMed  CAS  Google Scholar 

  12. King C, Tangye SG, Mackay CR. T follicular helper (TFH) cells in normal and dysregulated immune responses. Annu Rev Immunol. 2008;26:741–66.

    Article  PubMed  CAS  Google Scholar 

  13. Vinuesa CG, Tangye SG, Moser B, Mackay CR. Follicular B helper T cells in antibody responses and autoimmunity. Nat Rev Immunol. 2005;5:853–65.

    Article  PubMed  CAS  Google Scholar 

  14. Spolski R, Leonard WJ. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu Rev Immunol. 2007;26:57–79.

    Article  CAS  Google Scholar 

  15. Nurieva RI, Chung Y, Hwang D, et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity. 2008;29:138–49.

    Article  PubMed  CAS  Google Scholar 

  16. Sawalha AH, Kaufman KM, Kelly JA, et al. Genetic association of interleukin-21 polymorphisms with systemic lupus erythematosus. Ann Rheum Dis. 2008;67:458–61.

    Article  PubMed  CAS  Google Scholar 

  17. Hayakawa K, Hardy RR. Development and function of B-1 cells. Curr Opin Immunol. 2000;12:346–53.

    Article  PubMed  CAS  Google Scholar 

  18. Sato T, Ishikawa S, Akadegawa K, et al. Aberrant B1 cell migration into the thymus results in activation of CD4 T cells through its potent antigen-presenting activity in the development of murine lupus. Eur J Immunol. 2004;34:3346–58.

    Article  PubMed  CAS  Google Scholar 

  19. Dauphinee M, Tovar Z, Talal N. B cells expressing CD5 are increased in Sjogren’s syndrome. Arthritis Rheum. 1988;31:642–7.

    Article  PubMed  CAS  Google Scholar 

  20. Plater-Zyberk C, Maini RN, Lam K, Kennedy TD, Janossy G. A rheumatoid arthritis B cell subset expresses a phenotype similar to that in chronic lymphocytic leukemia. Arthritis Rheum. 1985;28:971–6.

    Article  PubMed  CAS  Google Scholar 

  21. Ito T, Ishikawa S, Sato T, et al. Defective B1 cell homing to the peritoneal cavity and preferential recruitment of B1 cells in the target organs in a murine model for systemic lupus erythematosus. J Immunol. 2004;172:3628–34.

    PubMed  CAS  Google Scholar 

  22. Ishikawa S, Sato T, Abe M, et al. Aberrant high expression of B lymphocyte chemokine (BLC/CXCL13) by C11b+CD11c+dendritic cells in murine lupus and preferential chemotaxis of B1 cells towards BLC. J Exp Med. 2001;193:1393–402.

    Article  PubMed  CAS  Google Scholar 

  23. Ishikawa S, Matsushima K. Aberrant B1 cell trafficking in a murine model for lupus. Front Biosci. 2007;12:1790–803.

    Article  PubMed  CAS  Google Scholar 

  24. Batten M, Groom J, Cachero TG, et al. BAFF mediates survival of peripheral immature B lymphocytes. J Exp Med. 2000;192:1453–66.

    Article  PubMed  CAS  Google Scholar 

  25. Badr G, Borhis G, Lefevre EA, et al. BAFF enhances chemotaxis of primary human B cells: a particular synergy between BAFF and CXCL13 on memory B cells. Blood. 2008;111:2744–54.

    Article  PubMed  CAS  Google Scholar 

  26. Groom JR, Fletcher CA, Walters SN, et al. BAFF and MyD88 signals promote a lupuslike disease independent of T cells. J Exp Med. 2007;204:1959–71.

    Article  PubMed  CAS  Google Scholar 

  27. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25:1271–7.

    Article  PubMed  CAS  Google Scholar 

  28. Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH. The Committee on Prognosis studies in SLE: Derivation of the SLEDAI: a disease activity index for lupus patients. Arthritis Rheum. 1992;35:630–40.

    Article  PubMed  CAS  Google Scholar 

  29. Mohan C, Adams S, Stanik V, Datta SK. Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus. J Exp Med. 1993;177:1367–81.

    Article  PubMed  CAS  Google Scholar 

  30. Schiffer L, Kümpers P, Davalos-Misslitz AM et al. B-cell-attracting chemokine CXCL13 as a marker of disease activity and renal involvement in systemic lupus erythematosus (SLE). Nephrol Dial Transplant. 2009 doi:10.1093/ndt/gfp343

  31. Rioja I, Hughes FJ, Sharp CH, et al. Potential novel biomarkers of disease activity in rheumatoid arthritis patients: CXCL13, CCL23, transforming growth factor alpha, tumor necrosis factor receptor superfamily member 9, and macrophage colony-stimulating factor. Arthritis Rheum. 2008;58:2257–67.

    Article  PubMed  CAS  Google Scholar 

  32. Fulkerson PC, Zimmermann N, Hassman LM, Finkelman FD, Rothenberg ME. Pulmonary chemokine expression is coordinately regulated by STAT1, STAT6, and IFN-gamma. J Immunol. 2004;173:7565–74.

    PubMed  CAS  Google Scholar 

  33. Morimoto S, Nakano S, Watanabe T, et al. Expression of B-cell activating factor of the tumour necrosis factor family (BAFF) in T cells in active systemic lupus erythematosus: the role of BAFF in T cell-dependent B cell pathogenic autoantibody production. Rheumatology. 2007;46:1083–6.

    Article  PubMed  CAS  Google Scholar 

  34. Mackay F, Schneider P, Rennert P, Browning J. BAFF AND APRIL: a tutorial on B cell survival. Annu Rev Immunol. 2003;21:231–64.

    Article  PubMed  CAS  Google Scholar 

  35. Bubier JA, Sproule TJ, Foreman O, et al. A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice. Proc Natl Acad Sci U S A. 2009;106:1518–23.

    Article  PubMed  Google Scholar 

  36. Linterman MA, Rigby RJ, Wong RK, et al. Follicular helper T cells are required for systemic autoimmunity. J Exp Med. 2009;206:561–76.

    Article  PubMed  CAS  Google Scholar 

  37. Adalid-Peralta L, Mathian A, Tran T, Delbos L, Durand-Gasselin I, Berrebi D, et al. Leukocytes and the kidney contribute to interstitial inflammation in lupus nephritis. Kidney Int. 2008;73:172–80.

    Article  PubMed  CAS  Google Scholar 

  38. Bagaeva LV, Rao P, Powers JM, Segal BM. CXC chemokine ligand 13 plays a role in experimental autoimmune encephalomyelitis. J Immunol. 2006;176:7676–85.

    PubMed  CAS  Google Scholar 

  39. Shi K, Hayashida K, Kaneko M, et al. Lymphoid chemokine B cell-attracting chemokine-1 (CXCL13) is expressed in germinal center of ectopic lymphoid follicles within the synovium of chronic arthritis patients. J Immunol. 2001;166:650–5.

    PubMed  CAS  Google Scholar 

  40. Magliozzi R, Columba-Cabezas S, Serafini B, Aloisi F. Intracerebral expression of CXCL13 and BAFF is accompanied by formation of lymphoid follicle-like structures in the meninges of mice with relapsing experimental autoimmune encephalomyelitis. J Neuroimmunol. 2004;148:11–23.

    Article  PubMed  CAS  Google Scholar 

  41. Ree HJ, Kadin ME, Kikuchi M, Ko YH, Suzumiya J, Go JH. Bcl-6 expression in reactive follicular hyperplasia, follicular lymphoma, and angioimmunoblastic T-cell lymphoma with hyperplastic germinal centers: heterogeneity of intrafollicular T-cells and their altered distribution in the pathogenesis of angioimmunoblastic T-cell lymphoma. Hum Pathol. 1999;30:403–11.

    Article  PubMed  CAS  Google Scholar 

  42. Sabahi R, Anolik JH. B-cell-targeted therapy for systemic lupus erythematosus. Drugs. 2006;66:1933–48.

    Article  PubMed  Google Scholar 

  43. Sun J, Li Z, Feng J, Li Y, Shen B. BAFF-targeting therapy, a promising strategy for treating autoimmune diseases. Eur J Pharmacol. 2008;597:1–5.

    Article  PubMed  CAS  Google Scholar 

  44. Bubier JA, Bennett SM, Sproule TJ, et al. Treatment of BXSB-Yaa mice with IL-21R-Fc fusion protein minimally attenuates systemic lupus erythematosus. Ann N Y Acad Sci. 2007;1110:590–601.

    Article  PubMed  CAS  Google Scholar 

  45. Zheng B, Ozen Z, Zhang X, et al. CXCL13 neutralization reduces the severity of collagen-induced arthritis. Arthritis Rheum. 2005;52:620–6.

    Article  PubMed  CAS  Google Scholar 

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Conflicts of Interest

No conflict of interest has been declared by the authors.

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Authors and Affiliations

  1. Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong

    C. K. Wong, Purple T. Y. Wong, D. P. Chen & Christopher W. K. Lam

  2. Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong

    L. S. Tam & Edmund K. Li

  3. Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau

    Christopher W. K. Lam

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  1. C. K. Wong
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Correspondence to Christopher W. K. Lam.

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Wong, C.K., Wong, P.T.Y., Tam, L.S. et al. Elevated Production of B Cell Chemokine CXCL13 is Correlated with Systemic Lupus Erythematosus Disease Activity. J Clin Immunol 30, 45–52 (2010). https://doi.org/10.1007/s10875-009-9325-5

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