A specific molecular profiling of secreted rheumatoid factors in Sjögren’ s disease patients with lymphoma

OBJECTIVE: To perform proteomic analysis of secreted IgM-Rheumatoid factor (RF) in patients with Sjogren's disease (SjD) with and without lymphoma to determine if a specific RF molecular profile is associated with lymphoma occurrence. METHODS: We studied 23 RF+ SjD patients from the ASSESS cohort. Eleven had lymphoma (cases), including five collected prior to lymphoma diagnosis (pre-lymphoma), and twelve had no lymphoma (controls). Cases and controls were matched for age and gender. Serum RF heavy chains were purified and analyzed using de novo mass spectrometry and database matching. IGHV subfamilies were identified, and amino acid sequences compared between cases and controls. Full RF sequences were used for structural modeling and affinity prediction. RESULTS: We observed a progressive enrichment of detectable immunoglobulin heavy chain variable region (VH) subfamilies among circulating RFs, with over-representation of VH1-69 RFs in SjD patients with lymphoma compared to those without lymphoma. We observed fewer somatic mutations in VH 1-69 RFs from pre lymphoma SjD patients whilst IGHV3 family RFs contained a greater number of unique mutations. Focused on VH 1-69s, we identified convergence of mutations amongst all patients and identified less frequent antigen-interacting mutations in pre lymphoma patients. CONCLUSION: This study suggests changes in the serum RF antibody repertoire in SjD patients prior to and following lymphoma diagnosis, offering new insights into the serum clonal dynamics of the disease. Compositional changes in circulating RF clones may warrant further investigation in larger, independent cohorts to assess their potential value as a predictive biomarker for lymphoma.