Stratification of systemic lupus erythematosus with IGHV4-34 in unswitched memory B cells

Abstract Objectives Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies. Antibody affinities are defined by immunoglobulins, which include the immunoglobulin heavy-chain variable region (IGHV) genes, but the relationship between SLE and IGHV has not been fully elucidated. This study aimed to investigate the association between clinical features of SLE and IGHV. Methods We recruited SLE patients, collected their peripheral blood. B cells from SLE patients were sorted into naïve B cells, unswitched memory (USM) B cells, switched memory (SM) B cells, double negative (DN) B cells, and plasmablasts. RNA-seq was performed to analyse IGHV gene usage, calculating the frequency of clonotypes that use IGHV4–34. The interactions between IGHV4-34 usage and clinical features were analysed by regression analysis, and the threshold for stratifying SLE patients by IGHV4-34 usage was determined by receiver operating characteristic (ROC) analysis. Results IGHV4-34 usage in USM B cells had a significant association with disease activity. ROC curve analysis revealed the threshold of IGHV4-34 usage in USM B cells which distinguished patients with low complement levels from the other patients. High IGHV4-34 usage in USM B cells was associated with arthritis, hematuria, proteinuria, rash and fever. Achievement of a lupus low disease activity state (LLDAS), SLE disease activity index 2000 (SLEDAI-2K) score, and physician global assessment (PGA) score showed worse values in the high IGHV4-34 usage group. Among those who achieved LLDAS under tacrolimus treatment, patients with high IGHV4-34 usage in USM B cells had a higher flare rate. Conclusion IGHV4-34 usage in USM B cells is a potential biomarker of SLE and for patient stratification.