Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus

Abstract

IntroductionInterleukin (IL)-17 is a proinflammatory cytokine that is produced largely by a unique CD4+ T-helper (Th) subset called Th17 cells. The development of Th17 cells is suppressed by interferon (IFN)-γ produced by Th1 cells, suggesting cross-regulation between Th17 and Th1 cells. Thus, this study analyzed the balance of CD4+ Th17 and Th1 cell responses in peripheral blood from patients with systemic lupus erythematosus (SLE) and healthy subjects.MethodsTwenty-five adult patients with SLE and 26 healthy subjects matched for gender and age (± 2 years) were recruited. Peripheral blood mononuclear cells (PBMCs) from patients and healthy subjects were stimulated for 4 h ex vivo with phorbol myristate acetate (PMA) and ionomycin. The frequency of CD4+ T cells producing IL-17 and/or IFN-γ was measured by using flow cytometry. Expression of Th17-associated chemokine receptors CCR4 and CCR6 on CD4+ T cells as well as plasma levels of Th17-polarizing cytokines were assessed. Disease activity was evaluated by the SLE disease activity index score (SLEDAI). Unpaired t test and Pearson correlation were used for statistical analyses.ResultsPatients with SLE had an increased frequency of CD4+IL-17+ T cells compared with healthy subjects. However, the frequency of CD4+IFN-γ+ T cells was similar between the two groups, indicating an altered balance of Th17 and Th1 cell responses in SLE. Patients with SLE also had an increased frequency of CD4+CCR4+CCR6+ T cells that are known to produce IL-17. The frequency of CD4+IL-17+ T cells and CD4+CCR4+CCR6+ T cells correlated with disease activity. In measuring plasma levels of the Th17-polarizing cytokines, levels of IL-6 were higher in patients with SLE than in healthy subjects, although levels of IL-1β, IL-21, IL-23, and transforming growth factor (TGF)-β were not different between the two groups.ConclusionsWe demonstrate an enhanced Th17 cell response that correlates with disease activity in patients with SLE, suggesting a role for IL-17 in the pathogenesis of lupus. Our data indicate that the mechanisms involved in balancing Th1 and Th17 regulation, as well as in producing IL-6, are aberrant in SLE, leading to an increased Th17 response. We suggest that CCR4 and CCR6 expression on CD4+ T cells should be considered as markers of disease activity, and that IL-17 blocking may offer a therapeutic target in SLE.

Role of IL-21 in Systemic Lupus Erythematosus

“…The exact source of IL-21 in lupus patients is not known. Notably, TFH and Th17 cells are elevated in the peripheral blood of SLE patients, and positively correlate with disease activity [31,32] [31,33,34]. Thus, current data suggest that TFH and Th17 cells may be the major producers of IL-21 in SLE patients, although this remains to be formally shown.…”

“…Th17 cells produce an array of proinflammatory molecules including IL-1, IL-6, IL-17, IL-21, IL-22, and TNFα [68]. these patients [31,32]. IL-17 is also detectable in the affected skin and kidneys of cutaneous lupus patients [31,33,34].…”

Deficient Leptin Signaling Ameliorates Systemic Lupus Erythematosus Lesions in MRL/Mp-Faslpr Mice

“…SLE patients were recently reported to have increased numbers of IL-17-producing CD4 + T cells in their peripheral blood, with cell number correlating with disease activity (39,40). Furthermore, the levels of ex- pression of CCR4 and CCR6, receptor molecules associated with Th17 cells, were higher in SLE patients than in healthy controls (41). In agreement with findings in human SLE, IL-17-producing T cells are increased in MRL/Mp-Fas lpr mice (32).…”

T Cell Targeted Therapies in Lupus: Do They Make Sense?

“…Serum levels of IL17 and the prevalence of Th17 cells are increased in patients with SLE and have been correlated to disease activity in some studies [6]. Double negative (CD4-CD8-) T cells are also expanded in the peripheral blood of patients with SLE and represent, along with Th17 cells, a major source of IL17 [7].…”