Human hypofunctional NCF1 variant aggravates salivary gland immunopathology in Sjögren’s disease by promoting switched memory B-cell recruitment and long-lived plasma cell differentiation

OBJECTIVES: We assessed the role of a systemic lupus erythematosus causal, hypofunctional variant, neutrophil cytosolic factor 1 (NCF1)-p.Arg90His (p.R90H) substitution, in Sjögren's disease (SjD). METHODS: Association between NCF1-H90 and SjD was assessed in case-control cohorts. Peripheral blood mononuclear cells (PBMCs) and minor salivary gland (MSG) from patients with Sjögren's Syndrome type A antigen (SSA)+ SjD were assessed using cytometry by time-of-flight and single-cell RNA sequencing, respectively. RESULTS: = 1.15E-55, odds ratio [OR] = 2.58), exhibiting a more robust association in patients with SSA+ SjD (OR = 3.37 in Chinese and OR = 2.60 in European Americans). In a longitudinal observational cohort, patients with homozygous H90 SjD at baseline had lower levels of complement C4 and higher scores on labial salivary gland biopsy, European Alliance of Associations for Rheumatology (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI), and EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI). These patients with H90 SjD sustained elevated ESSDAI and ESSPRI scores during follow-up years with decreased survival. The 0, 1, and 2 copies of H90 carriage in SjD PBMCs exhibited dose-dependent decreases in switched memory B cells, which might be recruited by fibroblasts into MSG, and further differentiated into long-lived Immunoglobulin G (IgG+) plasma cells, resulting in elevated serum SSA+ IgG levels and greater disease severity. In a retrospective belimumab-treated SSA+ female cohort, homozygous H90 patients showed significantly greater improvement in ESSDAI, C4 levels, and serum SSA+ IgG levels, supporting the role of NCF1-H90 as a predictive biomarker for enhanced response to B-cell-targeted therapy. CONCLUSIONS: Low NCF1 activity increases the risk of severe SSA+ SjD by driving switched memory B-cell trafficking and IgG+ plasma cell differentiation, revealing targetable pathways in SSA+ SjD.