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Objectives High titres (> 12.5 AU) of IgA2 anti-dsDNA autoantibodies are associated with response to rituximab followed by belimumab. This study aimed to investigate IgA2+ B cells in SLE using 5’ single-cell RNA-sequencing (scRNA-seq).Methods Five SLE patients and three healthy controls (HC) were screened for IgA2 dsDNA autoantibodies by ELISA. All SLE patients had high titres of IgA2 dsDNA autoantibodies (> 12.5 AU). PBMCs were isolated from these donors and live CD19+IgD- B cells were sorted and analysed via 5’ scRNA-seq (10X Genomics), capturing an average of 5,834 cells per sample.Results Nine distinct B cell clusters were identified in the single-cell data, including the double-negative clusters DN2 and DN3 which were significantly expanded in the SLE patients (p = 0.036). IgA1+ B cells were broadly distributed across these clusters, whereas IgA2+ B cells were predominantly identified in the plasmablast and class-switched memory B cell clusters. In the SLE patients IgA2+ B cells had the highest frequency of somatic hypermutation (SHM) compared to all other subclasses, whereas IgG2+ B cells exhibited the highest SHM frequency in the HCs. Expanded IgA2+ B cells were predominantly associated with IgA1+ precursors in HCs and SLE patients. Differential gene expression analysis revealed an elevated IFN signature in SLE IgA1+ B cells compared to SLE IgA2+ B cells, whilst genes associated with gut homing (e.g. CCR9) were enriched in SLE IgA2+ B cells.Abstract PO:06:166 Figure 1Figure 1. B cell repertoire and transcriptomic features of different isotypes in SLE patients and healthy donors. (A) Somatic hypermutation frequency (SHM) across the isotype subclasses in HCs. (B) SHM frequencies across the isotype subclasses in SLE patients. (C) A comparison of the summed expression of interferon (IFN) genes in IgA1 and IgA2 B cells in HCs and SLE patients.Conclusions This study reveals distinct molecular and repertoire signatures of IgA1+ and IgA2+ B cells in SLE. Notably, IgA1+ B cells exhibit enhanced IFN signalling, which is consistent with their association with mucocutaneous disease. In contrast, IgA2+ B cells demonstrate extensive somatic hypermutation.