CD71 + erythroid cell expansion in late‐onset systemic lupus erythematosus

Abstract Background Systemic lupus erythematosus (SLE) mainly affects women of reproductive age. Late‐onset SLE patients (lo‐SLE, ≥50 years) are generally indolent and have less severe manifestations. Objective The present study aims to decode molecular differences underlying the distinct clinical presentations between lo‐SLE and early onset SLE patients. Methods In a cohort of 243 treatment‐naïve Chinese SLE female patients, we carried out clinical analysis and experimental validation studies. RNA‐seq was used to identify differentially expressed genes (DEGs) of lo‐SLE patients. Reverse transcription quantitative polymerase chain reaction and flow cytometry were utilized to validate DEGs and enriched cell types. The discovery was further compared to findings in a European cohort. The immunosuppressive function of CD71 + CD235a + erythroid cells (CECs) was evaluated by coculturing peripheral blood mononuclear cells (PBMCs) with CECs. Results Differential expression analysis identified a group of hub upregulated genes in lo‐SLE patients. These genes, overrepresented in erythrocyte differentiation, are highly enriched in CECs. In our Chinese cohort, CECs abundance in peripheral blood was inversely correlated with disease activity. Increased CECs in treatment‐naïve lo‐SLE patients may play an immunosuppressive role by inhibiting CD8⁺ T cell function and IFN‐γ production. This immunosuppressive role was evidenced by the significant suppression of IL‐6, IFN‐γ, and IL‐17A production by healthy donor's PBMCs cocultured with SLE bone marrow‐derived CECs. Conclusions This pioneering study has revealed a panel of CECs genes as potential molecular markers for lo‐SLE, supporting a novel erythroid modulation theory. These novel findings provide valuable insights into previously unrecognized molecular mechanisms underlying the latent disease activity of lo‐SLE.