SLE Antibody-Secreting Cells Are Characterized by Enhanced Peripheral Maturation and Survival Programs [AIRR]

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by multiple autoantibodies, some of which are present in high titers in a sustained, B cell-independent fashion consistent with their generation from long-lived plasma cells (LLPC). Active SLE displays high numbers of circulating antibody-secreting cells (ASC). Understanding the mechanisms of generation and survival of SLE ASC would contribute important insight into disease pathogenesis and novel targeted therapies. We studied the properties of SLE ASC through a systematic analysis of their phenotypic, molecular, structural, and functional features. Our results indicate that in active SLE, relative to healthy post-immunization responses, blood ASC contain a much larger fraction of newly generated mature CD19-CD138+ASC similar to bone marrow (BM) LLPC. SLE ASC were characterized by morphological and structural features of premature maturation. Additionally, SLE ASC express high levels of CXCR4 and CD138, and molecular programs consistent with increased longevity based on pro-survival and attenuated pro-apoptotic pathways.Notably, SLE ASC demonstrate autocrine production of APRIL and IL-10 and experience prolonged in vitro survival. Combined, our findings indicate that SLE ASC are endowed with enhanced peripheral maturation, survival and BM homing potential suggesting that these features likely underlie BM expansion of autoreactive PC. Overall design: To investigate the question of whether different types of ASC arise from distinct B cell precursors or whether a common precursor might generate different ASC progeny through separate differentiation pathways, or instead through sequential maturation. Sorted ASC populations (Pop 2, Pop 3, Pop 4 and Pop 5) from active SLE patients were used to extract the total cellular RNA by using the RNeasy Mini Kit (Qiagen, Inc. Valencia, CA) according to the manufacturer's protocol. Approximately 400 pg of RNA was subjected to reverse transcription using the iScript RT kit. Resulting cDNA products were combined with 50 nM VH1- VH6 specific primers and 250 nM Ca, Cm, and Cg specific primers in a 25 µl PCR reaction.