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

• Published in: European journal of immunology 2023-07, Vol.53 (7), p.e2250319-n/a
• Main Authors: Moneta, Gian Marco, Bracaglia, Claudia, Caiello, Ivan, Farroni, Chiara, Pires Marafon, Denise, Carlomagno, Raffella, Hiraki, Linda, Vivarelli, Marina, Gianviti, Alessandra, Carbogno, Simone, Ferlin, Walter, Min, Cristina, Silverman, Earl, Carsetti, Rita, De Benedetti, Fabrizio, Marasco, Emiliano
• Format: Article
• Language: English
• Subjects: Autoimmune diseases; Childhood; Children; CXCL10 protein; Humans; IFN‐γ; Interferon; Interferon Type I; Interferon-gamma - metabolism; Lupus; Lupus Erythematosus, Systemic; Lupus Nephritis; Lymphocytes B; Morbidity; Nephritis; Serum levels; SLE; Systemic lupus erythematosus; Therapeutic targets; Transcription Factors; T‐bet+ B cells
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.202250319

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. Patients with childhood‐onset systemic lupus erythematosus (cSLE) have an increased activity of both IFNα and IFNγ as suggested by upregulated of IFN‐regulated genes in peripheral blood: in vitro the two cytokines potentiate the activity of one another. IFNγ, but not IFNα, induces the expression of T‐bet in B cells. Activity of IFNγ is associated with renal involvement, whereas IFNα correlates with skin activity.