Antibody Mediated Spontaneous Abortion in Lupus Pregnancies

狼疮妊娠中抗体介导的自然流产

• 批准号: 8639720
• 负责人: ELIZA F CHAKRAVARTY
• 金额: $ 10.18万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8639720
• 关键词: Abruptio Placentae; Accounting; Affect; Algorithms; Alloimmunization; Antibodies; Antibody Specificity; Antigens; Antiphospholipid Antibodies; Antiphospholipid Syndrome; Attention; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocyte Epitopes; Biological Assay; Birth Rate; Blood; Blood Transfusion; Characteristics; Child; Child Rearing; Chimerism; Classification; Clinical; Clinical Data; Confounding Factors (Epidemiology); Cutaneous; DNA; Data; Databases; Diagnosis; Discipline of obstetrics; Disease; Embryo; Enzyme-Linked Immunosorbent Assay; Family; Family-Based Registry; Female; Fetal Proteins; Foundations; Gender; Genetic; Goals; H-Y Antigen; H-Y antibody; Habitual Abortion; High-Risk Pregnancy; Homologous Gene; Housing; Immune; Immune response; Immune system; Immunity; Immunologics; Infertility; Intervention; Intrauterine Blood Transfusion; Kidney; Leadership; Left; Live Birth; Lupus; Lupus Coagulation Inhibitor; Measures; Mediating; Medical Research; Microarray Analysis; Minor Histocompatibility Antigens; Molecular Abnormality; Morbidity - disease rate; Oklahoma; Participant; Patients; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy loss; Prevalence; Prevalence Study; Production; Protein Microchips; Proteins; Recurrence; Relative (related person); Reproductive History; Research; Resources; Risk; Role; Sampling; Serologic tests; Serum; Sister; Source; Source Code; Spontaneous abortion; System; Systemic Lupus Erythematosus; Thrombophilia; Woman; Y Chromosome; adverse outcome; base; body system; child bearing; chronic autoimmune disease; cohort; cytotoxic; embryo/fetus antigen; fetal; fetus cell; high risk; male; meetings; novel; offspring; peripheral tolerance; predictive modeling; premature; public health relevance; repository; reproductive

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.

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，妊娠流产是一种常见现象。研究表明，在组建家庭之前被诊断患有系统性红斑狼疮的女性生育的孩子数量少于预期，这主要是由于流产。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之外，抗磷脂抗体综合征是研究最多的流产预测因素。然而，它仅占复发性流产 (RPL) 的一小部分。 有证据表明，某些 RPL 病例可能具有免疫学作用，包括自身免疫紊乱和同种免疫紊乱。胎儿微嵌合现象（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）、胎儿流产和终止妊娠中会增加[23]。推测是由于母胎输血增加。因此，以前的妊娠使母体免疫系统能够接触到新的胎儿抗原：同种异体致敏可能会引发异常的免疫反应，如果未达到母体外周耐受性，则会导致对后续胚胎的细胞毒性损伤。 Miklos 博士是该应用领导团队的成员，他开发了针对 Y 染色体 H-Y 抗原编码的次要组织相容性抗原的特异性 ELISA 和相应的自身抗原微阵列。 46% 的 RPL 患者存在高滴度 H-Y 抗体，但不存在 H-X 同源物，并且与随后活产中男女比例下降相关。我们最近在狼疮家族登记和存储库 (LFRR) 中证明狼疮家族的男女比例低于预期；然而，H-Y 和 H-X 抗体都没有在这个或其他 SLE 队列中进行系统研究。 我们假设，与健康、无关的女性相比，SLE 患者中多种高滴度新型和传统自身抗体的流行率更高。此外，此类抗体与Sab和RPL相关，独立于APL。特别是，SLE 患者中男性出生率的下降暗示 SLE 女性存在抗男性免疫力，并且在频繁出现 Sab 和 RPL 的 SLE 女性中会检测到 H-Y 抗体。我们建议研究 SLE 患者、其姐妹以及无关的健康女性中这些抗体的患病率及其与 SAB 和 RPL 的关系，以便为流产风险最高的患者开发预测模型。