Global Natural Regulatory T Cell Depletion in Active Systemic Lupus Erythematosus

Abstract

The immune defect that could account for the multisystemic involvement that characterizes systemic lupus erythematosus (SLE) remains unknown. We hypothesized that iterative disease flares correspond to a recurrent defect in the peripheral immune suppression exerted by naturally occurring T regulatory cells (Tregs). Surprisingly, Tregs isolated from lupus patients show the same phenotypic and functional characteristics as corresponding cells found in healthy controls. A decrease in the proportion of circulating Tregs among other CD4+ T cells is nevertheless evidenced in active patients when this group is compared with healthy controls (0.57 ± 0.24%, n = 45 vs 1.29 ± 0.38%, n = 82, p < 0.0001) or with inactive patients (1.22 ± 0.67%, n = 62, p < 0.0001). In contrast, the proportion of Tregs in other systemic autoimmune diseases such as primary Sjögren syndrome and inflammatory myopathy does not significantly differ from controls’ values (1.15 ± 0.46%, n = 21, p = 0.09 and 1.16 ± 0.44%, n = 16, p = 0.43, respectively). Lupus Tregs do not accumulate in either the lymph nodes or the diseased kidneys and are not killed by a circulating soluble factor, but demonstrate in vitro a heightened sensitivity to Fas-induced apoptosis. Finally, we show that the extent of Treg depletion correlates with the clinical severity of the flare. SLE flares are therefore associated with a global Treg depletion and not with a phenomenon of tissue redistribution. In summary, we suggest that the physiopathology of SLE could be tied to a defect in the homeostatic control of the Treg subpopulation.

Low number of regulatory T cells in skin lesions of patients with cutaneous lupus erythematosus

“…Our finding of a normal frequency and normal apoptosis sensitivity of Treg differs from previously published data in patients with SLE and, therefore, distinguishes patients with CLE from patients with an active flare of a systemic manifestation of the disease (14-17,32). However, more work needs to be performed with regard to the suppressive activity of Treg, because our study in CLE patients and the study by Miyara et al (16) in SLE patients did not demonstrate a significant reduction in suppressive activity of Treg, while other groups of investigators demonstrated reduced suppressive activity of Treg in patients with SLE, as reported at several meetings (31,32,35).…”

“…Recently, we reported that the majority of CD4ϩ,CD25 high Treg are highly sensitive to CD95L-mediated apoptosis, in contrast to Tcon (29). Moreover, Miyara et al (16) suggested a loss of Treg due to enhanced sensitivity of Treg to CD95L-mediated apoptosis in SLE. Therefore, we purified CD4ϩ,CD25 high Treg and CD4ϩ,CD25Ϫ Tcon from patients with various subtypes of CLE and tested the sensitivity of these cells to CD95L, in a kill assay as described previously (29).…”

“…Peripheral blood was obtained from patients with various subtypes of CLE (SCLE, DLE, LET) (n ϭ 12) as well as from normal healthy donors (n ϭ 18) and separated by Ficoll gradient centrifugation. The detection of Treg by analysis of CD4ϩ,CD25 high cells has produced conflicting results in patients with SLE (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)31,32). Therefore, we used a new intracellular staining method to directly visualize Foxp3ϩ Treg by flow cytometry, which was performed according to the manufacturer's protocol, as described previously (25).…”

“…In recent studies, several groups of investigators detected a decrease in the number of naturally occurring Treg during active flares of SLE and considered this decrease to be an important pathogenic feature (14)(15)(16)(17). Interestingly, a significantly reduced level of Treg has also been observed to correlate with autoantibody production and the onset of a lupus-like disease in different murine models (18,19).…”

“…In this study, we were interested in applying these new tools to patients with CLE, because a reduction in the number of CD4ϩ,CD25 high T cells has been consistently reported in patients with a systemic manifestation of the disease (14)(15)(16)(17). Moreover, no systematic analysis of tissue-specific Treg distribution in patients with CLE or SLE has been reported.…”