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复发，表明长寿浆细胞（PC）对此类干预不敏感。因此，它们的消除是治疗中的关键治疗目标。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志物，以及作为SLE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形成的位点）分化成抗体分泌细胞的B细胞亚群表达PSGL-1，其表达在PC上高度上调。待检验的假设是抗体分泌细胞上的PSGL-1表达在其向骨髓和脾红髓的运输中起重要作用，骨髓和脾红髓是其存活的小生境。为了解决这一假设，计划了三个具体目标。首先，评估免疫后正常小鼠PC上PSGL-1的表达和功能。接下来，将在狼疮易感小鼠中进行类似的研究，然后阻断PSGL 1与其配体的相互作用，询问PC向生存壁龛的运输是否改变，导致生存减少。最后，将在狼疮患者的外周血中表征PSGL- 1+ CD 38 hi PC，将它们的数量与疾病活动性相关联，以努力 支持PC上的PSGL-1是SLE的适当治疗靶点的观点。 公共卫生相关性：在脾脏和其他淋巴器官中产生抗体的B细胞对正常和自身免疫反应至关重要。关于这些细胞在自身免疫中的生物学，包括其成熟和功能的要求，以及如何阻断后者作为自身免疫性疾病的潜在疗法，还有很多东西有待了解。拟议研究的结果应该有助于解决这些问题，并促进人类自身免疫反应如何发展以及如何在治疗上消除这些反应的知识。

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. PUBLIC HEALTH RELEVANCE: B cells that produce antibodies in the spleen and other lymphoid organs are critical for normal and autoimmune responses. Much remains to be learned about the biology of these cells in autoimmunity, including the requirements for their maturation and function, and how to block the latter as a potential therapy for autoimmune diseases. The results of the proposed studies should help address these issues, and advance knowledge of how autoimmune responses develop in humans and how they can be abrogated therapeutically.