#610 Alterations in frequency and function exhausted memory B cells in lupus nephritis and systemic lupus erythematosus

Abstract

Abstract Background and Aims Various B cell abnormalities have been implicated in the pathogenesis of LN, and our previous studies have demonstrated that memory B cells assume pathogenic relevance in disease relapse. Memory B cell exhaustion is a B lymphocyte aberration initially reported in chronic human immunodeficiency virus (HIV) infection, and was later also observed in chronic graft versus host disease (cGVHD) and autoimmune disorders. The pathogenic roles of exhausted memory B cells in LN and disease relapse remains unclear. We will validate the significance role of exhausted B cell in the pathogenesis of LN. Method Classical memory (CD19 + CD21 + CD27+) and exhausted B cells (CD19 + CD21 – CD27–) were measured in LN patients with multiple relapses (MR) (n=15) or no relapse (NR) (n=15) during disease remission. B cell-related cytokines, homing and inhibitory receptors, proliferation and calcium mobilization in classical and exhausted memory B cells were also assessed. Using single-cell RNA sequencing data from NIH and GEO, we also performed bioinformatics analysis to identify genes and pathways relevant to memory and exhausted B cells in SLE, LN and healthy controls. Results The MR group exhibited higher proportion of circulating exhausted memory B cells compared to NR. Blood levels of IL-6, BAFF and IL-21 in MR patients were higher than the NR group. The MR had higher blood levels of Siglec-6, CXCR3 and CD62L than the NR group. Expression of inhibitory receptors CD22, CD85j, CD183 and FCRL4 in exhausted B cells were increased in the MR group compared to the NR group. Exhausted B cells from MR patients also showed decreased proliferation compared to NR patients and impaired calcium mobilization in response to B-cell receptor triggering. STAT1, XAF1, MX1, IFI44L, EPSTI1, LCP1, OAS1, NEAT1, IFI16, IFI44 in exhausted B cells and XAF1, MX1, IFI44L in memory B cells play a pathogenic role in LN patients (Figs. 1 and 2). SLE patients also show increased proportion of exhausted B cells compared to healthy control and the expression of STAT1, XAF1, MX1, IFI44L correlate positively with the proportion of exhausted B cells. Conclusion Our results suggested that altered numbers and function of exhausted B cells may have pathogenic significance in SLE and LN.