Autoantibody blockade in neonatal lupus

摘要 抗干燥综合征抗原A（SSA）自身抗体主要见于干燥综合征患者， 综合征和系统性红斑狼疮（SLE），其中它们代表有用的诊断标志物， 病理学意义尚待阐明。重要的是，抗SSA自身抗体的存在， 怀孕的母亲与患新生儿狼疮的高风险有关， 心脏传导系统的损害。产妇继发先天性心脏传导阻滞的发生 抗SSA自身抗体的血清阳性与高达30%的儿童死亡率有关， 在64%的病例中，在出生后的第一年内植入了起搏器。这种高发病率和可怕的 预后多年来没有改变，主要是因为难以减轻产妇抗- SSA自身抗体导致胎儿心脏受损。在这里，我们建议抑制SSA自身抗体 在怀孕母亲的生产，以防止心脏组织损伤，在他们的胎儿。在初步 数据表明瘦素是小鼠抗SSA自身抗体产生的促进剂， 瘦素抑制在减少循环抗SSA自身抗体中的功效，我们旨在测试瘦素是否 抗SSA阳性妊娠小鼠的拮抗作用可减少新生儿狼疮中胎儿心脏组织的损伤， 描绘了潜在的机制。这些研究的目的是对一种新的药物进行临床前概念验证。 新生儿狼疮的干预方式，以改善结局并限制高度致残/致命性 这种情况的后果。

ABSTRACT Anti-Sjögren's syndrome antigen A (SSA) autoantibodies are primarily found in patients with Sjögren's syndrome and systemic lupus erythematosus (SLE), where they represent a useful diagnostic marker whose pathological significance remains to be clarified. Importantly, the presence of anti-SSA autoantibodies in pregnant mothers associates with a high risk to bear children that develop neonatal lupus with irreversible damage of the heart conduction system. The development of congenital heart block secondary to maternal seropositivity for anti-SSA autoantibodies associates with child mortality rate of up to 30% and the requirement of a pacemaker within the first year of life in about 64% of the cases. This elevated morbidity and dire prognosis have not changed in years mainly because of the difficulty to reduce the burden of maternal anti- SSA autoantibodies that cause the damage to the fetal heart. Here we propose to inhibit SSA autoantibody production in pregnant mothers for the prevention of heart tissue injury in their fetuses. Building on preliminary data that identified leptin as a promoter of the production of anti-SSA autoantibodies in mice and that showed the efficacy of leptin inhibition in reducing circulating anti-SSA autoantibodies, we aim to test whether leptin antagonism in anti-SSA-positive pregnant mice can reduce fetal heart tissue injury in neonatal lupus, and delineate the underlying mechanisms. Goal of these studies is to have a preclinical proof-of-concept of a new modality of intervention in neonatal lupus, to improve outcomes and to limit the highly disabling/fatal consequences of this condition.