Double-negative B cells mediate the causal association between rheumatoid arthritis and interstitial lung disease: a two-step Mendelian randomization mediation study.

Abstract

Background: Rheumatoid arthritis (RA) elevates interstitial lung disease (ILD) risk, yet the underlying mediating immune cells remain unknown. This study sought peripheral immune phenotypes driving the causal pathway from RA to ILD.

Methods: A two-step Mendelian randomization (MR) mediation analysis was performed using European GWAS data: RA (14,361 cases/43,923), 731 immune cell traits, and ILD from FinnGen R13 (6,733 cases/493,453). Step 1 applied inverse variance weighted (IVW) MR to estimate RA effects on immune cells; Step 2 tested immune cell effects on ILD. Mediation was validated via joint significance and parametric bootstrapping (10,000 resamples) with BCa 95% confidence intervals (CIs).

Results: RA exerted a causal risk-increasing effect on ILD (β = 0.166, P = 4.26 × 10⁻⁸). Fifty-three immune traits showed nominal significance in Step 1, 15 passing FDR correction. CD19⁺IgD⁻CD27⁻ DN B cells reached nominal significance (P = 0.028) but not FDR significance (q = 0.512) in Step 1, yet were the only trait significantly associated with ILD in Step 2 (β₂ = 0.060, P = 0.027). Bootstrapping verified a small but significant indirect effect (β = 0.0039, 95% BCa CI 0.0009-0.0153, P = 0.050; mediation proportion = 2.3%), consistent across sensitivity tests.

Conclusions: DN B cells partially mediate the causal RA-ILD relationship. Our genetic evidence highlights B cell dysfunction as a mechanistic link and identifies DN B cells as candidate biomarkers for RA-related interstitial lung complications. Key Points • Rheumatoid arthritis (RA) is associated with elevated interstitial lung disease (ILD) risk, yet the underlying causal pathway remains poorly defined. • A two-step Mendelian randomization mediation design was applied to identify double-negative (DN) B cells (CD19⁺IgD⁻CD27⁻) as a potential mediator linking RA to ILD. • Genetically predisposed RA was causally associated with increased DN B cell proportions, which in turn were associated with higher ILD risk. • These findings indicate DN B cells may serve as a potential immunological link between RA and ILD, meriting further investigation as a candidate direction for early intervention research.