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）是一种慢性自身免疫性疾病，影响育龄期妇女。在其他临床表现中，流产是常见的。研究表明，在完成家庭之前被诊断患有SLE的妇女的孩子比期望的少，主要是由于怀孕损失。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，而不是早期妊娠丢失（自然流产，Sab）。除了遗传和结构异常，抗磷脂抗体综合征是妊娠丢失的最好的研究预测因子;然而，它占复发性妊娠丢失（RPL）的一小部分。 有证据表明，某些RPL病例可能具有免疫学作用，包括自身免疫和同种免疫紊乱。胎儿微嵌合体，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[23]和终止妊娠中增加，可能是由于母胎输血增加。因此，以前的怀孕，提供母体免疫系统获得新的胎儿抗原：异体致敏，可能会引发异常的免疫反应，导致细胞毒性损伤后续胚胎，如果母体外周耐受性没有实现。 Miklos博士是该应用的领导团队的一员，他开发了针对Y染色体编码的次要组织相容性抗原H-Y抗原的特异性ELISA和相应的自身抗原微阵列。高滴度H-Y抗体的存在，但不是他们的H-X同源物，已被视为在46%的RPL患者，并与降低男性：女性比例在随后的活产。我们最近在狼疮家族登记和储存库（LFRR）中证实了狼疮家族中男性：女性比例低于预期;然而，H-Y和H-X抗体均未在该或其他SLE队列中进行系统研究。 我们推测，多种高滴度的新型和传统的自身抗体的患病率更频繁地发生在SLE患者相比，健康的，无关的妇女。此外，这些抗体与Sab和RPL相关，而不依赖于APL。特别是，SLE患者中男性出生率的下降暗示SLE女性中存在抗男性免疫，并且在频繁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与SAB和RPL之间的SLE患者，他们的姐妹篇，和无关的健康女性，以开发一个预测模型，为患者在最高风险的妊娠损失。