Excessive Production of IFN-γ in Patients with Systemic Lupus Erythematosus and Its Contribution to Induction of B Lymphocyte Stimulator/B Cell-Activating Factor/TNF Ligand Superfamily-13B

Abstract

Expression and immunological significance of IFN-γ, a pivotal cytokine in murine lupus, have not been clearly demonstrated in human systemic lupus erythematosus (SLE). In the present study we investigated the expression of IFN-γ in peripheral blood T cells from patients with SLE and its role in the production of the soluble B lymphocyte stimulator (sBLyS). Peripheral blood T cells from patients with SLE expressed significantly larger amounts of IFN-γ in response to stimulation with anti-CD3 mAb plus anti-CD28 mAb than those from normal controls as shown by three analytical methods, including ELISA, flow cytometry, and quantitative RT-PCR. The ratio of IFN-γ-producing T cells to effector memory T cells in CD3+CD4+ and CD3+CD8+ populations in patients with SLE was significantly higher than that of normal controls. The T-box expressed in T cells (T-bet) mRNA/GATA-binding protein-3 (GATA-3) mRNA ratio was significantly higher in patients with SLE than in normal controls. T cell culture supernatants from patients with SLE contained significantly higher sBLyS-inducing activity than normal controls; this was almost completely inhibited by the addition of anti-human IFN-γ mAb. Percentages of BLyS-expressing peripheral blood monocytes in patients with SLE were significantly higher than those of normal controls. Monocytes from patients with SLE produced significantly larger amounts of sBLyS in response to IFN-γ than those from normal controls. Taken together, these data strongly indicate that the overexpression of IFN-γ in peripheral blood T cells contributes to the immunopathogenesis of SLE via the induction of sBLyS by monocytes/macrophages, which would promote B cell activation and maturation.

Th17 and natural Treg cell population dynamics in systemic lupus erythematosus

“…Previous findings supported the notion that Th1 cytokines could play an important role in inflammation and tissue injury and are correlated with the development of SLE and, in particular, lupus glomerulonephritis (43)(44)(45)(46). We detected IL-17ϩ T cells in MRL/lpr mouse kidneys (data not shown), but whether Th17 cells are implicated in these forms of SLE requires further investigation.…”

“…Although a substantial population of IL-17ϩ cells could be detected in lesional skin from patients with active SLE, and IFN␥ϩ cells infiltrated to a lesser extent, we should not conclude that Th1 cells were not implicated in such tissue inflammation. Both the Th17 and Th1 cytokines might be involved in the pathogenesis of active SLE (41,(43)(44)(45)(46), albeit via different mechanisms. Recent studies showed that Th17 and Th1 cells might be involved at different stages during the development of the inflammation (48).…”

Biomarkers in systemic lupus erythematosus: challenges and prospects for the future

“…Elevated BAFF/BLys levels appeared to correlate with increased total IgG and autoantibody (particularly anti-dsDNA) levels [Cheema et al 2001;Pers et al 2005], and, in some studies, with increased disease activity (as measured by SLEDAI) [Becker-Merok et al 2006]. A recent study has shown that excessive productions of IFNγ by activated T cells may be responsible for the induction of BAFF/BLyS production by monocytes and macrophages in lupus patients [Harigai et al 2008].…”

B cells biology in systemic lupus erythematosus—from bench to bedside

“…IFN/ can also lower activation threshold for autoreactive B cells, enhance B cell resistance to Fas-mediated apoptosis and prolong its survival [155]. Harigai et al [156] also found IFN could induce more Blys production and release from lupus monocytes to promote B cells activation. IL-6 is critical for the differentiation of B cells and promotes the survival of plasmablasts/plasma cells.…”