EBNA2-Driven X Chromosome Amplification and LTB-NF-kB Feedback Explain the 9:1 Female Predominance and Glandular Tropism of Sjogren Syndrome

Abstract

Sjogren syndrome is a systemic autoimmune disease characterized by lymphocytic infiltration of salivary and lacrimal glands, affecting women 9 times more than men. The etiology of this sex bias and the glandular tropism have remained unexplained. We integrate the largest Sjogren GWAS (Khatri et al. 2022, 35 loci) with ChIP-seq data (GSE75503) and scRNA-seq from salivary glands (GSE272409, 82,867 cells, 7 PSS + 6 Sicca) to propose a mechanistic model. EBNA2 from Epstein-Barr virus amplifies RBP-Jk occupancy at TLR7 (2.3x by ChIP-seq; 2.19x in gland, p=0.022) and is associated with RBP-Jk binding at CD40LG, CXorf21, KDM6A, and DDX3X on the X chromosome. TLR7 escapes X-inactivation, meaning women receive a biallelic dose further amplified by EBNA2, explaining the 9:1 female predominance without invoking hormones. In the salivary gland, lymphotoxin beta (LTB) is elevated 3.40x in PSS versus Sicca controls, driving a self-amplifying loop: LTB activates LTBR on stromal cells, signaling through NF-kB2/RELB to produce CXCL13 (29.94x elevated), the master B-cell chemoattractant. CXCL13 recruits B cells expressing CXCR5 (7.40x), which produce more LTB, closing the loop. This feedback mechanism operates only in tissues where CXCL13 is constitutively produced (salivary and lacrimal glands), explaining the gland-specific attack. The Sjogren GWAS provides two genetic hits to the NF-kB pathway (TNFAIP3, TNIP1), and EBV LMP1 provides the third, creating a three-hit mechanism that sustains the inflammatory loop. The model predicts that CXCL13 neutralization or LTBR blockade should interrupt the cycle.