Regulatory B cell expansion and type 1 innate lymphoid cell suppression characterise immune modulation in paediatric lupus nephritis

RMD Open. 2026 May 13;12(2):e006492. doi: 10.1136/rmdopen-2025-006492.

ABSTRACT

OBJECTIVE: B-cell activating factor (BAFF) is essential for B-cell survival and innate immune activation, and its dysregulation contributes to the pathogenesis of lupus nephritis (LN). This study investigated whether BAFF-pathway inhibition alters the balance between regulatory B cells (Bregs) and type 1 innate lymphoid cells (ILC1s) in paediatric LN.

METHODS: In this prospective, open-label randomised study, 60 paediatric patients with biopsy-confirmed class III/IV LN were randomised to standard therapy (mycophenolate mofetil and corticosteroids; n=30) or standard therapy plus the belimumab (10 mg/kg intravenously every 4 weeks for 6 months; n=30). Ten healthy children and three patients with biopsy-confirmed minimal change disease served as controls. Flow cytometry quantified IL-10-producing Bregs and circulating ILC1s. Clinically indicated paired renal biopsies (n=3) underwent transcriptomic and immunofluorescence analyses.

RESULTS: Belimumab was associated with greater increases in serum C3, reductions in antidouble-stranded DNA titres, decreased proteinuria, improved Systemic Lupus Erythematosus Disease Activity Index 2000 scores and reduced corticosteroid exposure. Belimumab expanded memory B cells and IL-10-producing CD19⁺CD5⁺ and CD19⁺CD24^hi+CD38^hi+ Bregs, with enhanced suppression of CD4⁺ T cell proliferation. Treatment reduced circulating and renal ILC1s, downregulated interferon (IFN)-stimulated genes and modulated inflammatory pathways. Serum cytokine profiling showed decreased IFN-γ, interleukin (IL)-17A, IL-10 and BAFF levels, alongside increased IL-35. Phosphorylation of the aryl hydrocarbon receptor and signal transducer and activator of transcription 3 (STAT3) in Bregs was partially restored.

CONCLUSIONS: BAFF inhibition in paediatric LN is associated with rebalancing of innate and adaptive immunity through enhancement of Breg function and suppression of ILC1-driven inflammation.

PMID:42128531 | DOI:10.1136/rmdopen-2025-006492