Objectives: We determined the expression of ITGAL, PRF1, KIR2DL4, CD70, and CD40LG in patients with SLE and performed correlations with the global DNA methylation status and the levels of three DNA methylation enzymes and two methyl CpG-binding domain (MBD) proteins. Patients and Methods: CD4+ T cells were isolated from 35 SLE patients and 30 healthy controls. DNA deoxymethylcytosine content was measured by an enzyme-linked immunosorbent assay (ELISA). Transcript levels of ITGAL, PRF1, KIR2DL4, CD70, CD40LG, DNMT1, DNMT3A, DNMT3B, MBD2, and MBD4 were quantified by real-time reverse-transcription polymerase chain reaction (RT-PCR). Results: SLE patients had significantly elevated transcript levels of ITGAL (18.61±22.17 vs. 7.33±9.17, p = 0.042), PRF1 (21.67±26.34 vs. 10.67±11.65, p = 0.039), and CD70 (1.45±1.63 vs. 0.67±0.28, p = 0.011). A positive correlation was observed between transcript levels of CD40LG and ITGAL (r = 0.477, p = 0.004) as well as between CD40LG and PRF1 (r = 0.557, p = 0.001). Transcript levels of KIR2DL4 were higher than controls' but it did not reach statistical significance (1.36±3.52 vs. 0.22±0.79, p = 0.560). A tight relationship with global DNA hypomethylation as well as with the expression of most of the DNA methylation-related genes was observed, especially for ITGAL, PRF1, and CD40LG. Conclusions: ITGAL, PRF1, and CD70 are overexpressed in SLE CD4+ T cells. The tight association of CD40LG with ITGAL and PRF1 leads us to infer that it probably contributes to the pathogenesis of the disease. The apparent simultaneous regulation between their expression and the global DNA hypomethylation as well as with the transcription of many DNA methylation-related enzymes, reinforces the idea that epigenetic mechanisms are responsible for the deregulation of ITGAL, PRF1, and CD40LG. © 2012 Balada et al.