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T Cells in Systemic Lupus Erythematosus

Mindy S. Lo, MD, PhD, and George C. Tsokos, MD  |  Issue: August 2011  |  

As technology continues to advance, it may soon be possible to measure methylation patterns and other gene expression profiles easily, perhaps even as a bedside point-of-care test. Such a profile could be readily applied in clinical practice as a biomarker to predict disease activity, organ system involvement, and response to targeted therapy. Small-molecule inhibitors that target specific aberrations of gene expression in SLE could then be selectively used depending on a patient’s profile. The few examples discussed here (such as inhibitors of Syk, CaMKIV, and ROCK) have already shown activity in proof-of-principle experiments with immune cells from SLE patients as well as in some animal models. These types of drugs offer additional advantages over the current biologic agents in terms of ease of administration and dosing and will hopefully have fewer side effects than broader immunosuppression. Thus, a gene expression profile could be used to develop an individualized regimen using specific targeted therapies, moving us toward the ultimate goal of personalized medicine for SLE. the rheumatologist

Dr. Lo is a pediatric rheumatology fellow at Children’s Hospital Boston. Dr. Tsokos is chief of the rheumatology division at Beth Israel Deaconess Medical Center and a professor at Harvard Medical School, both in Boston.

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References

  1. Kyttaris VC, Zhang Z, Kampagianni O, Tsokos GC. Calcium signaling in systemic lupus erythematosus T cells: A treatment target. Arthritis Rheum. 2011;63:2058-2066.
  2. Deng GM, Liu L, Bahjat FR, Pine PR, Tsokos GC. Suppression of skin and kidney disease by inhibition of spleen tyrosine kinase in lupus-prone mice. Arthritis Rheum. 2010; 62:2086-2092.
  3. Enyedy EJ, Nambiar MP, Liossis SN, Dennis G, Kammer GM, Tsokos GC. Fc epsilon receptor type I gamma chain replaces the deficient T cell receptor zeta chain in T cells of patients with systemic lupus erythematosus. Arthritis Rheum. 2001; 44:1114-1121.
  4. Tenbrock K, Tsokos GC. Transcriptional regulation of IL-2 in SLE T cells. Int Rev Immunol. 2004; 23:333-345.
  5. Ichinose K, Juang YT, Crispin JC, Kis-Toth K, Tsokos GC. Suppression of autoimmunity and organ pathology in lupus-prone mice upon inhibition of calcium/calmodulin-dependent protein kinase IV. Arthritis Rheum. 2011; 63:523-529.
  6. Stohl W, Elliott JE, Li L, Podack ER, Lynch DH, Jacob CO. Impaired nonrestricted cytolytic activity in systemic lupus erythematosus: Involvement of a pathway independent of Fas, tumor necrosis factor, and extracellular ATP that is associated with little detectable perforin. Arthritis Rheum. 1997; 40:1130-1137.
  7. Lee JH, Wang LC, Lin YT, Yang YH, Lin DT, Chiang BL. Inverse correlation between CD4+ regulatory T cell population and autoantibody levels in paediatric patients with systemic lupus erythematosus. Immunology. 2006;117:280-286.
  8. Scalapino KJ, Daikh DI. Suppression of glomerulonephritis in NZB/NZW lupus-prone mice by adoptive transfer of ex vivo expanded regulatory T cells. PLoS One. 2009;4:e6031.
  9. Desai-Mehta A, Lu L, Ramsey-Goldman R, Datta SK. Hyperexpression of CD40L by B and T cells in human lupus and its role in pathogenic autoantibody production. J Clin Invest. 1996; 97:2063-2073.
  10. Sidiropoulos PI, Boumpas DT. Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients. Lupus. 2004;13:391-397.
  11. Wang A, Guilpain P, Chong BF, et al. Dysregulated expression of CXCR4/CXCL12 in subsets of patients with systemic lupus erythematosus. Arthritis Rheum. 2010;62:3436-3446.
  12. Li Y, Harada T, Juang YT, et al. Phosphorylated ERM is responsible for increased T cell polarization, adhesion, and migration in patients with systemic lupus erythematosus. J Immunol. 2007;178:1938-1947.
  13. Chong BF, Mohan C. Targeting the CXCR4/CXCL12 axis in systemic lupus erythematosus. Expert Opin Ther Targets. 2009;13:1147-1153.
  14. Crispin JC, Keenan BT, Finnell MD, et al. Expression of CD44 variant isoforms CD44v3 and CD44v6 is increased on T cells from patients with systemic lupus erythematosus and is correlated with disease activity. Arthritis Rheum. 2010; 62:1431-1437.
  15. Biswas PS, Gupta S, Chang E, et al. Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice. J Clin Invest. 2010; 120:3280-3295.
  16. Apostolidis SA, Crispin JC, Tsokos GC. IL-17-producing T cells in lupus nephritis. Lupus. 2011; 20:120-124.
  17. Anand A, Dean GS, Quereshi K, Isenberg DA, Lydyard PM. Characterization of CD3+ CD4- CD8- T cells in patients with systemic lupus erythematosus: activation markers. Lupus. 2002;11:493-500.
  18. Mok CC. Biomarkers for lupus nephritis. J Biomed Biotechnol. 2010; 2010:638413. Epub Apr 19.
  19. Fernandez DR, Telarico T, Bonilla E, et al. Activation of mammalian target of rapamycin controls the loss of TCRzeta in lupus T cells through HRES-1/Rab4-regulated lysosomal degradation. J Immunol. 2009; 182:2063-2073.
  20. Fernandez DR, Perl A. mTOR signaling: A central pathway to pathogenesis in systemic lupus erythematosus? Discov Med. 2010; 9:173-178.
  21. Juang YT, Peoples C, Kafri R, et al. A systemic lupus erythematosus gene expression array in disease diagnosis and classification: a preliminary report. Lupus. 2011; 20:243-249.
  22. Jeffries M, Dozmorov M, Tang Y, Merrill JT, Wren JD, Sawalha AH. Genome-wide DNA methylation patterns in CD4+ T cells from patients with systemic lupus erythematosus. Epigenetics. 2011;6:epub ahead of print.
  23. Richardson B, Scheinbart L, Strahler J, Gross L, Hanash S, Johnson M. Evidence for impaired T cell DNA methylation in systemic lupus erythematosus. Arthritis Rheum. 1990;33:1665-1673.
  24. Sunahori K, Juang YT, Kyttaris VC, Tsokos GC. Promoter hypomethylation results in increased expression of protein phosphatase 2A in T cells from patients with systemic lupus erythematosus. J Immunol. 2011;186:4508-4517.
  25. Mishra N, Reilly CM, Brown DR, Ruia P, Gilkeson GS. Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse. J Clin Invest. 2003; 111:539-552.

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