Antibody Mediated Spontaneous Abortion in Lupus Pregnancies

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种影响育龄妇女的慢性自身免疫性疾病。在其他临床表现中，妊娠丢失是常见的。研究表明，在成家之前被诊断为SLE的女性生育的孩子比预期的要少，主要是由于流产。过去对SLE相关妊娠发病率的研究主要集中在妊娠晚期并发症，而不是早期妊娠丢失（自然流产，Sab）。除了遗传和结构异常外，抗磷脂抗体综合征是研究最充分的流产预测因子；然而，它只占复发性妊娠丢失（RPL）的一小部分。有证据表明，某些RPL病例可能具有免疫作用，包括自身和同种免疫紊乱。胎儿微嵌合，即正常妊娠期间母体和胎儿细胞、DNA和蛋白质的双向转移，在复杂妊娠（胎盘早剥、早产和先兆子痫）、胎儿丢失和终止妊娠（可能是由于母胎输血增加）中增加。因此，以前的怀孕使母体免疫系统能够接触到新的胎儿抗原：同种异体致敏，可能引发异常的免疫反应，如果母体外周耐受不能实现，就会导致后续胚胎的细胞毒性损伤。Miklos博士是该应用领导团队的一员，开发了针对Y染色体编码的小组织相容性抗原H-Y抗原的特异性ELISA和相应的自身抗原微阵列。在46%的RPL患者中发现了高滴度的H-Y抗体，而不是它们的H-X同源物，并与随后活产的男女比例下降有关。我们最近在狼疮家庭登记和存储库（LFRR）中证明了狼疮家庭的男女比例低于预期；然而，H-Y和H-X抗体均未在本研究或其他SLE队列中进行系统研究。我们假设，与健康、无血缘关系的女性相比，SLE患者中出现多种高滴度新型和传统自身抗体的频率更高。此外，这些抗体与Sab和RPL相关，独立于APL。特别是SLE患者中男性出生率的下降与SLE女性的抗男性免疫有关，并且在SLE女性中频繁出现Sab和RPL时可以检测到H-Y抗体。我们建议研究这些抗体在SLE患者、其姐妹和无亲缘关系的健康女性中的流行程度及其与SAB和RPL的关系，以便为流产风险最高的患者建立预测模型。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects women during the childbearing years. Among other clinical manifestations, pregnancy loss is a common occurrence. Studies have shown that women diagnosed with SLE prior to completing their families have fewer children than desired, largely due to pregnancy loss. Past research into SLE related pregnancy morbidity has focused largely on late pregnancy complications rather than early pregnancy loss (spontaneous abortion, Sab). Aside from genetic and structural abnormalities, the antiphospholipid antibody syndrome is the most well studied predictor of pregnancy loss; however, it accounts for a small fraction of recurrent pregnancy loss (RPL). Evidence suggests a possible immunologic role for some cases of RPL, including both auto- and alloimmune disturbances. Fetal micro-chimerism, the bi-directional transfer of maternal and fetal cells, DNA, and proteins during normal pregnancy, is increased in complicated pregnancies (placental abruption, prematurity, and pre-eclampsia), fetal loss [23], and termination, presumably due to increased maternal-fetal transfusion. Previous pregnancies, therefore, afford the maternal immune system access to novel fetal antigens: allo-sensitization that may trigger abnormal immune responses, leading to cytotoxic damage to subsequent embryos if maternal peripheral tolerance is not achieved. Dr. Miklos, part of the leadership team of this application, has developed specific ELISA and corresponding autoantigen microarrays against minor histocompatibility antigens encoded by the Y- chromosome, H-Y antigens. Presence of high titer H-Y antibodies, but not their H-X homologues, has been seen in 46% of patients with RPL and is associated with a decreased male:female ratio in subsequent live births. We have recently demonstrated a lower than expected male:female ratio in lupus families in the Lupus Family Registry and Repository (LFRR); however, neither H-Y nor H-X antibodies have been systematically studied in this or other SLE cohorts. We hypothesize that the prevalence of multiple high-titer novel and traditional autoantibodies occurs more frequently in SLE patients compared to healthy, unrelated women. Further, such antibodies are associated with Sab and RPL independent of APL. In particular, decreased male birth rates among SLE patients implicate anti-male immunity in SLE women, and H-Y antibodies will be detected in SLE women with frequent Sab and RPL. We propose to study the prevalence of these antibodies and their associations with SAB and RPL among SLE patients, their sisters, and unrelated healthy women in order to develop a predictive model for patients at highest risk for pregnancy loss.