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）：全身性红斑狼疮（SLE）是一种慢性自身免疫性疾病，会影响育儿的妇女。除其他临床表现外，妊娠丧失是常见的情况。研究表明，在结束家人之前被诊断出患有SLE的妇女的孩子少于预期，这主要是由于妊娠丧失。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，而不是早期妊娠丧失（自发流产，SAB）。除了遗传和结构异常外，抗磷脂抗体综合征是妊娠丧失的最精心的预测指标。但是，它占复发性妊娠损失（RPL）的一小部分。 有证据表明，某些RPL病例（包括自身和同种免疫性障碍）可能具有免疫学作用。在正常妊娠期间，胎儿微核，母体和胎儿细胞的双向转移，DNA和蛋白质在正常妊娠期间增加（胎盘的突然，早产性和前宾夕化），胎儿丧失[23]以及终止，大概是由于母胎胎的增加而增加的。因此，以前的妊娠能够获得母体免疫系统获得新型胎儿抗原的机会：同种敏感性可能触发异常的免疫反应，如果无法实现母体外周耐受性，则会导致对随后胚胎的细胞毒性损害。 该应用程序领导团队的一部分Miklos博士开发了特定的ELISA和相应的自动抗原微阵列，以针对由Y-染色体H-Y抗原编码的较小的组织相容性抗原。在46％的RPL患者中，出现了高滴度H-Y抗体的存在，但没有其H-X同源物，并且与随后的活生生中的女性比例降低有关。最近，我们显示出狼疮家族注册表和存储库中狼疮家族的女性比率低于预期的男性：LFRR（LFRR）；但是，H-Y和H-X抗体均未在此或其他SLE组中进行系统的研究。 我们假设，与健康无关的女性相比，SLE患者的多种高素质新颖和传统自身抗体的患病率更频繁地发生。此外，这种抗体与SAB和RPL相关。特别是，SLE患者的男性出生率降低暗示SLE女性的抗男性免疫力，并且在经常使用SAB和RPL的SLE女性中将​​检测到H-Y抗体。我们建议研究这些抗体的患病率及其在SLE患者，姐妹和无关的健康妇女中与SAB和RPL的关联，以开发出最高妊娠风险风险的患者的预测模型。