Abstract
Unexplained recurrent spontaneous abortion (URSA) is an alloimmune disease associated with the failure of fetal-maternal immunologic tolerance in which the regulatory T lymphocytes (Treg) play a pivotal role. It is well known that Forkhead box P3 (Foxp3) is a crucial regulatory factor for the development and function of Treg cells. It has also been established that deficiency of the Foxp3 gene suppresses the regulatory function of Treg cells. To determine if functional polymorphisms at the Foxp3 loci are associated with URSA in humans, we genotyped four common polymorphisms of Foxp3 gene in 146 unrelated URSA patients and 112 healthy women. The results showed that rs3761548A/C and rs2232365A/G polymorphisms were significantly associated with URSA. Additionally, we found that the allelic distribution of rs5902434 del/ATT in URSA group was slightly different from that in the control group. We conclude that functional polymorphisms of the Foxp3 gene may confer an important susceptibility to URSA in the Chinese Han population, probably by altering Foxp3 function and/or its expression.
Highlights
Recurrent spontaneous abortion (RSA), which is defined as two or more consecutive pregnancy losses before the 20th week of gestation from the last menstrual period, occurs in approximately 1% to 5% of women at reproductive age [1, 2]
It has been proposed that unexplained recurrent spontaneous abortion (URSA) belongs to an alloimmune disease associated with the failure of fetal-maternal immunologic tolerance [4, 5]
The diagnosis of “unexplained” abortion was made by the following practical guidelines [8]: (1) uterus and cervical abnormalities were excluded by pelvic examination, ultrasound, and a diagnostic hysteroscopy; (2) chlamydia and ureaplasma were excluded by Cervical mucus culturing; (3) chromosome problems were excluded by Karyotypes of abortion couples and abortuses; (4) luteal function defect, hyperprolactinemia, and hyperandrogenemia were excluded by comprehensive hormonal examinations; (5) endocrine diseases, for example, diabetes, hyperthyroidism, and hypothyroidism, were excluded; (6) autoimmune factors associated with systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS) such as antinuclear antibodies (ANA), lupus anticoagulant (LA), and anticardiolipin antibodies (ACL) were tested in three consecutive visits every other month; (7) all male partners had normal semen status
Summary
Recurrent spontaneous abortion (RSA), which is defined as two or more consecutive pregnancy losses before the 20th week of gestation from the last menstrual period, occurs in approximately 1% to 5% of women at reproductive age [1, 2]. Many known causes of RSA including anatomic (15%), infectious (1%–2%), hormonal (20%), immunological (20%), and genetic (2%–5%) have been identified, a significant number of cases (approximately 40%–50%) do not have known causes, and these cases are called unexplained recurrent spontaneous abortion (URSA) [3]. It has been proposed that URSA belongs to an alloimmune disease associated with the failure of fetal-maternal immunologic tolerance [4, 5]. A reduced suppressive capacity of Treg cells has been implicated in URSA patients [10]. It is the reduced numbers and/or functional deficiency of CD4+CD25+Treg cells that cause the predisposition to miscarriage
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