Measurement of natural (CD4+CD25high) and inducible (CD4+IL-10+) regulatory T cells in patients with systemic lupus erythematosus

Abstract

Abnormalities of regulatory T cells may play an important role in the loss of self-tolerance, which is a major characteristic of lupus. The objective of this study was to determine the ratio and the number of natural CD4+CD25highFoxp3+ and inducible CD4+IL-10+ regulatory T cells in lupus patients and to search correlation with disease activity. Seventy-two Hungarian lupus patients were enrolled in the study. Fourty-one age- and sex matched healthy donors served as controls. Flow cytometry was used for the quantification of CD4+CD25high Foxp3+ (nTreg) and CD4+IL-10+ (iTreg) cells. The ratio (3.06 ± 1.45%) and the number (0.019 ± 0.012 × 109/L) of nTreg cells decreased in lupus significantly (P < 0.001 in both) as compared to normal controls (4.26 ± 1.01% and 0.039 ± 0.017 × 109/L). The ratio of iTreg cells were significantly higher in patients than in controls (20.92 ± 14.02% versus 15.49 ± 11.65%, P < 0.03), but the number of these cell type did not differ in significant manner (0.314 ± 0.236 × 109/L versus 0.259 ± 0.183 × 109/L). The 19 active patients were characterised by significantly higher disease activity index (SLEDAI 8.63 ± 2.95 versus 1.74 ± 1.68, P < 0.001) and anti-DNA concentration (117.85 ± 145.89 versus 37.36 ± 68.85 IU/mL, P = 0.001) as compered to the 52 inactive patients. Furthermore, active patients required higher dose of methylprednisolon than inactive ones (14.8 ± 10.6 versus 4.8 ± 3.4 mg/day, P < 0.001). However, we did not find statistical significant difference in the number and ratio of the examined cell populations regarding to disease activity. Altered ratio and number of both natural and inducible regulatory T cells may play a role in the pathogenesis of lupus. There are small but appreciable difference in the number of regulatory T cells between inactive patients and healthy controls. It suggests that immunoregulatory deficiencies are present in the inactive stage of the disease also. Lupus (2007) 16, 489—496.

Keywords

CD4+CD25high Foxp3+constitutional IL-10 inducible regulatory T cells SLE

Get full access to this article

View all access options for this article.

References

Tsokos GC , Wong HK , Enyedy EJ , Nambiar MP Immune cell signaling in lupus. Curr Opin Rheumatol 2000; 12: 355—363.

Anolik J. , Sanz I. B cells in human and murine systemic lupus erythematosus. Curr Opin Rheumatol 2004; 16: 505—512.

Goodnoe CC Balancing immunity and tolerance: deleting and tuning lymphocyte repertoires . Proc Natl Acad Sci USA 1996; 93: 2264—2271.

Thornton AM , Shevach EM CD4+CD25+ immunoregulatory T cells suppress polyclonal T-cell activation in vitro by inhibiting interleukin-2 production. J Exp Med 1998; 188: 287—296.

Ng WF , Duggan PJ , Ponchel F. et al. Human CD4+CD25+ cells: a naturally occurring population of regulatory T cells. Blood 2001; 98: 2736—2744.

Stephens LA , Mottet C. , Mason D. Human CD4+CD25+ thymocytes and peripheral T cells have immune suppressive activity. Eur J Immunol 2001; 31: 1247—1254.

Sakaguchi S. , Takahasi T. , Nishizuka Y. Study on cellular events in postthymectomy autoimmune oophoritis in mice. II. Requirement of Lyt-1 cells in normal female mice for the prevention of oophoritis. J Exp Med 1982; 156: 1577—1586.

Lundsgaard D. , Holm TL , Hornum L. , Markholst H. In vivo control of diabetogenic T-cells by regulatory CD4+CD25+ T-cells expressing Foxp3. Diabetes 2005; 54: 1040—1047.

Ramsdell F.

Foxp3 and natural regulatory cells. Key to a cell lineage?

Immunity 2003; 19: 165—168.

10.

Bettelli E. , Dastrange M. , Oukka M. Foxp3 interacts with nuclear factor of activated T cells and NF-kB to repress cytokine gene expression and effector function of T helper cells. Proc Natl Acad Sci USA 2005; 102: 5138—5143.

11.

Bakke AC , Purtzer MZ , Wildin RS Prospective immunological profiling in a case of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX). Clin Exp Immunol 2004; 137: 373—378.

12.

Saito S. , Sasaki Y. , Sakai M. CD4 + CD25high regulatory cells in human pregnancy. J Reprod Immunol 2005; 65: 111—120.

13.

Yoshizawa A. , Ito A. , Li Y. et al. The roles of CD25+CD4+ regulatory T cells in operational tolerance after living donor liver transplantation. Transplant Proc 2005; 37: 37—39.

14.

Vieira PL , Christensen JR , Minaee S. et al. IL-10 secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J Immunol 2004; 172: 5986—5993.

15.

Crispin JC , Martinez A. , Alcocer-Varela J. Quantification of regulatory T cells in patients with systemic lupus erythematosus . J Autoimmun 2003; 21: 273—276.

16.

Liu MF , Wang CR , Fung LL , Wu CR Decreased CD4+CD25+ T cells in peripheral blood of patients with systemic lupus erythematosus. Scand J Immunol 2004; 59: 198—202.

17.

Miyara M. , Amoura Z. , Parizot C. et al. Global natural regulatory T cell depletion in active systemic lupus erythematosus. J Immunol 2005; 175: 8392—8400.

18.

Lee J-H. , Wang L. , Lin Y. , Yang Y. , Lin D. , Chiang B. Inverse correlation between CD4+ regulatory T-cell population and autoantibody levels in paediatric patients with systemic lupus erythematosus. Immunlogy 2006; 117: 280—286.

19.

Soltesz P. , Aleksza M. , Antal-Szalmas P. , Lakos G. , Szegedi G. , Kiss E. Plasmapheresis modulates Th1/Th2 imbalance in patients with systemic lupus erythematosus according measurement of cytoplasmic cytokines. Autoimmunity 2002; 35: 51—56.

20.

Hochberg MC Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725.

21.

Bombardier C. , Gladman D. , Urowitz M. , Caron D. , Chang C. and the Committee on Prognosis Studies in systemic lupus erythematsus. Derivation of SLEDAI. A disease activity index for lupus patients. Arthrtitis Rheum 1992; 35: 630—640.

22.

Sakaguchi S. , Sakaguchi N. , Asano M. , Itoh M. , Toda M. Immunologic self-tolerance maintained by achieved T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995; 155: 1151—1164.

23.

Miyara M. , Amoura Z. , Parizot C. et al. Global natural regulatory T cell depletion in active systemic lupus erythematosus. J Immunol 2005; 175: 8392—8400.

24.

Karagiannidis C. , Akdis M. , Holopainen P. et al. Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma. J Allergy Clin Immunol 2004; 114 (6): 1425—1433.

25.

Valencia X. , Stephens G. , Goldbach-Mansky R. , Wilson M. , Shevach EM , Lipsky PE TNF downmodulates the function of human CD4+CD25hi T-regulatory cells. Blood 2006; 108: 253—261.

26.

Suarez A. , Lopez P. , Gomez J. , Gutierrez C. Enrichment of CD4+CD25+high T cell population in SLE patients treated with glucocorticoids. Ann Rheum Dis 2006; 65: 1512—1517.

27.

La Cava A. , Fang CJ , Singh RP , Ebling F. , Hahn BH Manipulation of immune regulation in systemic lupus erythematosus. Autoimmunity Rev 2005; 4: 515—519.

28.

Hahn BH , Ebling F. , Singh RP , Karpouzas G, La Cava A. Cellular and molecular mechanisms of regulation of autoantibody production in lupus. Ann NY Acad Sci 2005; 1051: 433—441.

29.

Fields ML , Hindowicz BD , Wharton GN et al. The regulation and activation of lupus associated B cells. Immunol Rev 2005; 204: 165—183.

30.

Lee JH , Wang LC , Lin YT , Yang AH , Lin DT , Chiang BL Inverse correlation between CD4+ regulatory T-cell population and antibody levels in paediatric patients with systemic lupus erythematosus. Immunology 2006; 117: 280—286.

31.

Read S. , Malmstrom V. , Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD4+CD25+ regulatory cells that control intestinal role inflammation . J Exp Med 2000; 192: 295—302.

32.

Asseman C. , Mauze S. , Leach MW et al. An essential rple for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med 1999; 190: 995—1004.

33.

Strand V. Biologic agents and innovative interventional approaches in the management of systemic lupus erythematosus. Curr Opin Rheum 1999; 11: 330—340.