Abstract
Objective Uncontrolled plasma cell (PC) expansion and hypergammaglobulinemia are hallmarks of B cell hyperactivity in the autoimmune disease Systemic Lupus erythematosus (SLE). While the presence of autoantibodies, in particular anti-nuclear antibodies (ANAs), is another hallmark of the disease, their link to B cell hyperactivity remains unknown. Our goal was to investigate the relationship between PC expansion, hypergammaglobulinemia, and specific autoantibody production.
Methods SLE patients from two cohorts were included as primary analysis cohort (US) and replication cohort (Europe), respectively. B cell subsets were determined by flow cytometry in fresh blood, whereas Ig and autoantibody levels were determined in serum by ELISA. Disease endotypes were calculated based on the frequencies of PC relative to total B cells, CD27+ B cells in healthy individuals.
Results We identified a subgroup of SLE patients with higher frequencies of circulating PC. In particular, this was observed in the frequency relative to memory B cells (high PC/CD27). Importantly, this phenotype was consistent over time in most patients. This disease endotype was characterized by higher levels of total IgG and IgA and a broader anti-nuclear antibody (ANA) response, suggesting that the high PC/CD27 endotype reflects B cell hyperactivity. This subgroup of SLE patients frequently displayed presence of Sm/RNP autoantibodies (29 vs 80%, OR: 9.167 (2.966–26.04)). Furthermore, patients with this disease endotype exhibited a more severe disease course. Interestingly, these characteristics were less prominent or absent in groupings based on total plasma cell percentages or absolute plasma cell counts, suggesting the PC/CD27 frequency in particular represents a distinct disease endotype. Results were validated in the independent replication cohort.
Conclusions Our study presents a novel disease endotype in SLE, characterized by a distinct distribution of the B cell compartment, hypergammaglobulinemia, and distinct serological (auto)antibody characteristics. This patient phenotype therefore signifies B cell hyperactivity and the higher disease activity in this patient group suggests a potential role in the pathogenesis of SLE. These findings may assist in the development of B cell targeted therapies for SLE patients.
