Divergent gene signatures and neutrophil enrichment in lymph nodes of inflammatory arthritis patients

Background: Lymph node (LN) studies in anti-cyclic citrullinated protein antibodies (ACPA) positive rheumatoid arthritis (RA) patients have revealed notable alterations in adaptive immune cell populations. However, it remains unclear whether similar changes occur in seronegative inflammatory arthritis, such as psoriatic arthritis (PsA) or ACPA-negative RA. This study investigates molecular and cellular alterations in LN biopsies from ACPA-positive RA patients, ACPA-negative inflammatory arthritis (IA) patients, and healthy controls (HCs). Methods: Ultrasound-guided LN biopsies were collected from 25 HCs, 14 ACPA positive RA patients and 45 ACPA negative IA patients (including various IA subtypes). Whole LN tissue biopsies were analyzed by transcriptome analyses, quantitative PCR and immunohistochemistry. Results: Distinct LN gene expression profiles were identified in ACPA-positive RA and ACPA-negative IA patients compared to HCs. ACPA-positive RA patients exhibited upregulation of genes associated with adaptive immunity, while ACPA-negative IA patients showed higher expression of genes related to innate immune cell function. Subsequent qPCR analysis confirmed increased mRNA expression of Cathepsin G, a serine protease highly expressed by neutrophils, in ACPA negative IA patients. Immunohistochemistry demonstrated significantly elevated CD15 + neutrophil presence in LNs from IA patients compared to HCs, irrespective of ACPA status and diagnosis (RA or PsA). Conclusions: This study provides novel insights into the immune landscape of lymph nodes in inflammatory arthritis, emphasizing an unexpected role for neutrophils in IA patients. Future research should explore the functional implications of neutrophils within these uninfected lymph nodes to better understand their contribution to the pathogenesis of inflammatory arthritis.