Persistently active interferon‐γ pathway and expansion of T‐bet⁺ B cells in a subset of patients with childhood‐onset systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease causing significant morbidity and mortality, despite important improvements in its management in the last decades. The objective of this work is to investigate the role of IFN‐γ in the pathogenesis of childhood‐onset systemic lupus erythematosus (cSLE), evaluating the crosstalk between IFN‐α and IFN‐γ and the expression of T‐bet, a transcription factor induced by IFN‐γ, in B cells of patients with cSLE. Expression levels of both IFN‐α and IFN‐γ‐induced genes were upregulated in patients with cSLE. We found increased serum levels of CXCL9 and CXCL10 in patients with cSLE. Type I IFN score decreased with initiation of immunosuppressive treatment; conversely, type II IFN score and levels of CXCL9 were not significantly affected by immunosuppressive treatment. Type II IFN score and CXCL9 were significantly higher in patients with lupus nephritis. We observed the expansion of a population of naïve B cells expressing T‐bet in a cluster of patients with cSLE. IFN‐γ, but not IFN‐α, induced the expression of T‐bet in B cells. Our data suggest that IFN‐γ is hyperactive in cSLE, especially in patients with lupus nephritis, and it is not modulated by therapy. Our data reinforce the potential of IFN‐γ as a therapeutic target in SLE.

Th1-related transcription factors and cytokines in systemic lupus erythematosus

“…Plasmacytoid dendritic cells (pDCs) from SLE patients treated with prostaglandin E2 (PGE 2 ) inhibited the expression of IFNα, and coculturing PGE 2 -treated pDCs with Th1 cells significantly suppressed secretion of IFNγ, indicating that IFNα is involved in PGE 2 -mediated inhibition of Th1 response ( 12 ). Furthermore, childhood-onset SLE (cSLE) patients showed a high expression of IFNα and IFNγ as compared with controls, and IFNγ stimulation induced expression of T-bet in B cells ( 13 ).…”

“…There were more percentages of naive B cells, double-negative (DN) B cells expressing T-bet in SLE patients as compared with controls, and T-bet + DN B cells expressing CD11c ( 13 ). A proportion of T-bet + naive B cells were related to IFNγ expression in SLE patients.…”

“…A proportion of T-bet + naive B cells were related to IFNγ expression in SLE patients. Patients with a higher proportion of T-bet + naive B cells had a much higher SLE disease activity index (SLEDAI) score, correlating with a higher expression of ANA and anti-dsDNA antibodies and lower disease duration ( 13 ). Age-associated B cells (ABCs) are a novel subset of activated B cells, which are involved in protective antiviral response and pathogenesis of autoimmunity.…”