A Novel B Cell Marker and Therapeutic Target in Lupus

描述（由申请人提供）：系统性红斑狼疮（SLE）治疗后，致病性自身抗体经常返回，表明长寿命浆细胞（PC）对此类干预不敏感。因此，消除它们是治疗的关键目标。这些研究的目的是验证p -选择糖蛋白配体-1 （PSGL-1）作为狼疮浆细胞的新标记物，并作为狼疮的治疗靶点。这项工作是基于观察到在生发中心（B细胞记忆和PC形成的部位）分化为抗体分泌细胞的B细胞亚群表达PSGL-1，其在PC上的表达高度上调。待验证的假设是，在抗体分泌细胞上的PSGL-1表达在其运输到骨髓和脾红髓中发挥重要作用，从而使其存活。为了解决这一假设，计划了三个具体目标。首先，我们将评估免疫后正常小鼠PC上PSGL-1的表达和功能。接下来，类似的研究将在狼疮易感小鼠中进行，随后阻断PSGL1与其配体的相互作用，询问PC向生存利基的运输是否被改变，导致生存率降低。最后，PSGL- 1+CD38hi PC将在狼疮患者的外周血中被表征，并将其数量与疾病活动性相关联，以努力

DESCRIPTION (provided by applicant): Pathogenic utoantibodies often return following treatment in systemic lupus erythematosus (SLE), suggesting that long-lived plasma cells (PC) are not sensitive to such interventions. Therefore, their elimination is a key therapeutic goal in treatment. The goal of these studies is to validate P-selection glycoprotein ligand-1 (PSGL-1) as a novel marker for plasma cells in lupus, and as a therapeutic target in SLE. This work is based upon the observation that a subset of B cells differentiating into antibody secreting cells in germinal centers, the site of B cell memory and PC formation, express PSGL-1, with its expression highly upregulated on PC. The hypothesis to be tested is that PSGL-1 expression on antibody-secreting cells plays an important role in their trafficking to the bone marrow and splenic red pulp, niches for their survival. To address this hypothesis, three specific aims are planned. First, PSGL-1 expression and function on PC in normal mice following immunization will be assessed. Next, similar studies will be carried in lupus-prone mice, followed by blockade of PSGL1 interactions with its ligands, asking if PC trafficking to survival niches is altered, leading to diminished survival. Finally, PSGL- 1+CD38hi PC will be characterized in the peripheral blood of lupus patients, correlating their numbers with disease activity in an effort to support the idea that PSGL-1 on PC is an appropriate therapeutic target in SLE.