Skip to main content

Advertisement

Log in

Plasma concentrations of growth arrest specific protein 6 and the soluble form of its tyrosine kinase receptor Axl in patients with Systemic lupus erythematosus and Behçets disease

  • Original Research
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Purpose

The aim of the present study was to investigate plasma concentrations of Gas6 and its soluble tyrosine kinase receptor sAxl in Systemic lupus erythematosus (SLE) and Behçets disease (BD) patients and to correlate those levels with clinical and laboratory manifestations of the diseases.

Methods

The study included 89 female SLE and 49 male BD patients. Twenty-seven age and sex matched healthy volunteers served as controls. All patients were subjected to full clinical examination, laboratory investigations and assessment of disease activity. Plasma concentrations of Gas6 and sAxl were quantified using ELISA technique.

Results

The level of Gas6 and Axl were significantly altered in the SLE patients (p < 0.001) and in the BD patients (p 0.001 and 0.04 respectively) compared to those of the control. In SLE, the Gas6 was remarkably lower in those with class 1 lupus nephritis and in those with neuropsychiatric manifestations. In the BD patients, the level of Axl was significantly increased in those with neurological disease activity. The number of lymphocytes significantly negatively correlated with the gas6 and Axl levels significantly correlated with the number of neutrophils and negatively with the lymphocytic count in the BD patients.

Conclusion

The plasma concentrations of Gas6 and Axl were significantly altered in SLE and BD patients, suggesting that the Axl receptor shedding is an active process affected by and influences Gas6-mediated Axl-signaling in both diseases. Special attention is required in SLE patients with early lupus nephritis and neuropsychiatric manifestations and BD patients presenting with neurological disease activity. The relation with lymphocytes and neutrophils in BD throws light on the role of gas6 and Axl on their known resistance to cell death. Although the mechanisms responsible for the initiation of BD remain to be clarified, the role of the apoptotic process seems critical throughout the disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Katsiari CG, Liossis SN, Sfikakis PP. The pathophysiologic role of monocytes and macrophages in systemic lupus erythematosus: a reappraisal. Semin Arthritis Rheum. 2010;39:491–503.

    Article  PubMed  CAS  Google Scholar 

  2. Zhao S, Long H, Lu Q. Epigenetic perspectives in systemic lupus erythematosus: pathogenesis, biomarkers, and therapeutic potentials. Clin Rev Allergy Immunol. 2010;39(1):3–9.

    Article  PubMed  Google Scholar 

  3. Wu J, Ekman C, Jönsen A, Sturfelt G, Bengtsson AA, Gottsäter A, et al. Increased plasma levels of the soluble Mer tyrosine kinase receptor in systemic lupus erythematosus relate to disease activity and nephritis. Arthritis Res Ther. 2011;13:R62.

    Article  PubMed  CAS  Google Scholar 

  4. Baumann I, Kolowos W, Voll RE, Manger B, Gaipl U, Neuhuber WL, et al. Impaired uptake of apoptotic cells into tingible body macrophages in germinal centers of patients with systemic lupus erythematosus. Arthritis Rheum. 2002;46:191–201.

    Article  PubMed  Google Scholar 

  5. Munoz LE, Gaipl US, Franz S, Sheriff A, Voll RE, Kalden JR, et al. SLE–a disease of clearance deficiency? Rheumatology (Oxford). 2005;44:1101–7.

    Article  CAS  Google Scholar 

  6. Nagata S, Hanayama R, Kawane K. Autoimmunity and the clearance of dead cells. Cell. 2010;140:619–30.

    Article  PubMed  CAS  Google Scholar 

  7. Pipitone N, Olivieri I, Padula A, D’angelo S, Nigro A, Zuccoli G, et al. Infliximab for the treatment of Neuro-Behçet’s disease: a case series and review of the literature. Arthritis Rheum. 2008;59(2):285–90.

    Article  PubMed  CAS  Google Scholar 

  8. Saadoun D, Wechsler B, Desseaux K, Le Thi Huong D, Amoura Z, Resche-Rigon M, et al. Mortality in Behçet’s disease. Arthritis Rheum. 2010;62(9):2806–12.

    Article  PubMed  CAS  Google Scholar 

  9. Todaro M, Zerilli M, Triolo G, Iovino F, Patti M, Accardo-Palumbo A, et al. NF-kappaB protects Behçet’s disease T cells against CD95-induced apoptosis up-regulating antiapoptotic proteins. Arthritis Rheum. 2005;52(7):2179–91.

    Article  PubMed  CAS  Google Scholar 

  10. Saadoun D, Wechsler B. Behcet’s disease. Orphanet J Rare Dis. 2012;7(1):20.

    Article  PubMed  Google Scholar 

  11. Arimura K, Arima N, Matsushita K, Akimoto M, Park CY, Uozumi K, et al. High incidence of morphological myelodysplasia and apoptotic bone marrow cells in Behçet’s disease. J Clin Immunol. 2007;27(2):145–51.

    Article  PubMed  Google Scholar 

  12. Yang P, Chen L, Zhou H, Zhong H, Wang H, Huang X, et al. Resistance of lymphocytes to Fas-mediated apoptosis in Behçet’s disease and Vogt-Koyangi-Harada syndrome. Ocul Immunol Inflamm. 2002;10(1):47–52.

    Article  PubMed  Google Scholar 

  13. Suh CH, Hilliard B, Li S, Merrill JT, Cohen PL. TAM receptor ligands in lupus: protein S but not Gas6 levels reflect disease activity in systemic lupus erythematosus. Arthritis Res Ther. 2010;12(4):R146.

    Article  PubMed  Google Scholar 

  14. Hafizi S, Dahlback B. Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases. Cytokine & Growth Factor Reviews. 2006;17:295–304.

    Article  CAS  Google Scholar 

  15. Seitz HM, Camenisch TD, Lemke G, Earp HS, Matsushima GK. Macrophages and dendritic cells use different Axl/Mertk/Tyro3 receptors in clearance of apoptotic cells. J Immunol. 2007;178:5635–42.

    PubMed  CAS  Google Scholar 

  16. Lemke G, Rothlin CV. Immunobiology of the TAM receptors. Nat Rev Immunol. 2008;8:327–36.

    Article  PubMed  CAS  Google Scholar 

  17. Wu J, Ekman C, Jönsen A, Sturfelt G, Bengtsson AA, Gottsäter A, et al. Increased plasma levels of the soluble Mer tyrosine kinase receptor in systemic lupus erythematosus relate to disease activity and nephritis. Arthritis Research & Therapy. 2011;13:R62.

    Article  CAS  Google Scholar 

  18. Ekman C, Gottsater A, Lindblad B, Dahlback B. Plasma concentrations of Gas6 and soluble Axl correlate with disease and predict mortality in patients with critical limb ischemia. Clin Biochem. 2010;43(10–11):873–6.

    Article  PubMed  CAS  Google Scholar 

  19. Lemke G, Lu Q. Macrophage regulation by Tyro 3 family receptors. Curr Opin Immunol. 2003;15:31–6.

    Article  PubMed  CAS  Google Scholar 

  20. Caraux A, Lu Q, Fernandez N, Riou S, Di Santo JP, Raulet DH, et al. Natural killer cell differentiation driven by Tyro3 receptor tyrosine kinases. Nat Immunol. 2006;7:747–54.

    Article  PubMed  CAS  Google Scholar 

  21. Cosemans JM, van Kruchten R, Olieslagers S, Schurgers LJ, Verheyen FK, Munnix IC, et al. Potentiating role of Gas6 and TAM receptors in human and murine platelet activation and thrombus stabilization. J Thromb Haemost. 2010;8(8):1797–808.

    Article  PubMed  CAS  Google Scholar 

  22. Ekman C, Linder A, Akesson P, Dahlback B. Plasma concentrations of Gas6 (growth arrest specific protein 6) and its soluble tyrosine kinase receptor sAxl in sepsis and systemic inflammatory response syndromes. Crit Care. 2010;14(4):R158.

    Article  PubMed  Google Scholar 

  23. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25:1271–7.

    Article  PubMed  CAS  Google Scholar 

  24. International Study Group for Behçet’s Disaese. Criteria for diagnosis of Behçet’s disaese. Lancet. 1990;335:1078–80.

    Google Scholar 

  25. Churg J, Sobin DH. Renal disease: classification and atlas of glomerular diseases. Igaku-Shoin, Tokyo, 1982:127–149

  26. Bombardier C, Gladman D, Urowitz M, Caron D, Chang C. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum. 1992;35:630–40.

    Article  PubMed  CAS  Google Scholar 

  27. Aydintuğ AO, Tokgöz G, Ozoran K, Düzgün N, Gürler A, Tutkak H. Elevated levels of soluble intercellular adhesion molecule-1 correlate with disease activity in Behçet’s disease. Rheumatol Int. 1995;15(2):75–8.

    Article  PubMed  Google Scholar 

  28. Scott RS, McMahon EJ, Pop SM, Reap EA, Caricchio R, Cohen PL, et al. Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature. 2001;411(6834):207–11.

    Article  PubMed  CAS  Google Scholar 

  29. Ekman C, Jönsen A, Sturfelt G, Bengtsson AA, Dahlbäck B. Plasma concentrations of Gas6 and sAxl correlate with disease activity in systemic lupus erythematosus. Rheumatology (Oxford). 2011;50(6):1064–9.

    Article  CAS  Google Scholar 

  30. O’Donnell K, Harkes IC, Dougherty L, Wicks IP. Expression of receptor tyrosine kinase Axl and its ligand Gas6 in rheumatoid arthritis: evidence for a novel endothelial cell survival pathway. Am J Pathol. 1999;154(4):1171–80.

    Article  PubMed  Google Scholar 

  31. Slomiany BL, Slomiany A. Delay in oral mucosal ulcer healing by aspirin is linked to the disturbances in p38 mitogen-activated protein kinase activation. J Physiol Pharmacol. 2001;52(2):185–94.

    PubMed  CAS  Google Scholar 

  32. Yanagita M. Gas6, warfarin, and kidney diseases. Clin Exp Nephrol. 2004;8:304–9.

    Article  PubMed  CAS  Google Scholar 

  33. Kahaleh MB. Raynaud phenomenon and the vascular disease in scleroderma. Curr Opin Rheumatol. 2004;16(6):718–22.

    Article  PubMed  Google Scholar 

  34. Yanagita M. The role of the vitamin K-dependent growth factor Gas6 in glomerular pathophysiology. Curr Opin Nephrol Hypertens. 2004;13(4):465–70.

    Article  PubMed  CAS  Google Scholar 

  35. Saadoun D, Wechsler B. Behcet’s disease. Orphanet Journal of Rare Diseases. 2012;7:20.

    Article  PubMed  Google Scholar 

  36. Krueger A, Fas SC, Baumann S, Krammer PH. The role of CD95 in the regulation of peripheral T-cell apoptosis. Immunol Rev. 2003;193:58–69.

    Article  PubMed  CAS  Google Scholar 

  37. Cohen JJ. Apoptosis. Immunol Today. 1993;14:126–30.

    Article  PubMed  CAS  Google Scholar 

  38. Lynch DH, Ramsdell F, Alderson MR. Fas and FasL in the homeostatic regulation of immune responses. Immunol Today. 1995;16:569–74.

    Article  PubMed  CAS  Google Scholar 

  39. Cohen JJ. Apoptosis: mechanisms of life and death in the immune system. J Allergy Clin Immunol. 1999;103:548–54.

    Article  PubMed  CAS  Google Scholar 

  40. Dhein J, Walczak H, Baumler C, Debatin KM, Krammer PH. Autocrine T-cell suicide mediated by APO-1/(Fas/CD95). Nature. 1995;373:438–41.

    Article  PubMed  CAS  Google Scholar 

  41. Kirchhoff S, Muller WW, Krueger A, Schmitz I, Krammer PH. TCR-mediated up-regulation of c-FLIPshort correlates with resistance toward CD95-mediated apoptosis by blocking death-inducing signaling complex activity. J Immunol. 2000;165:6293–300.

    PubMed  CAS  Google Scholar 

  42. Liu H, Pope RM. The role of apoptosis in rheumatoid arthritis. Curr Opin Pharmacol. 2003;3:317–22.

    Article  PubMed  Google Scholar 

  43. Park IK, Giovenzana C, Hughes TL, Yu J, Trotta R, Caligiuri MA. The Axl/Gas6 pathway is required for optimal cytokine signaling during human natural killer cell development. Blood. 2009;113(11):2470–7.

    Article  PubMed  CAS  Google Scholar 

  44. McColl A, Bournazos S, Franz S, Perretti M, Morgan BP, Haslett C, et al. Glucocorticoids induce protein S-dependent phagocytosis of apoptotic neutrophils by human macrophages. J Immunol. 2009;183(3):2167–75.

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of Interest

None

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tamer A. Gheita.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gheita, T.A., Bassyouni, I.H. & Bassyouni, R.H. Plasma concentrations of growth arrest specific protein 6 and the soluble form of its tyrosine kinase receptor Axl in patients with Systemic lupus erythematosus and Behçets disease. J Clin Immunol 32, 1279–1286 (2012). https://doi.org/10.1007/s10875-012-9743-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-012-9743-7

Keywords

Navigation