Assessment of sperm antigen specific T regulatory cells in women with recurrent miscarriage

Abstract

Background and aims

The prevalence of recurrent miscarriage (RM) is about 1–3% of women; the pathogenesis of RM is not fully understood yet. This study aims to assess the sperm antigen specific regulatory T cells (Treg) in women with RM.

Methods

A group of women with RM was recruited into this study. The sperm antigen was extracted from the semen samples of each woman's husband. The sperm antigen specific T cell response was assessed by flow cytometry.

Results

Low frequency of sperm specific Tregs and high frequency of T helper (Th)1 cells were detected in RM women as compared with women without RM. The sperm specific Tregs in RM women expressed less Ubc13. Knockdown of Ubc13 from Tregs converted the Tregs to effector T cells.

Conclusions

Immune deregulation may play an important role in RM.

Introduction

About 1–3% of women may have three or more consecutive miscarriages before 20 week gestation; such a condition is termed as recurrent miscarriage (RM) [1]. Although RM is not a fatal disease, it compromises both physical and mental health and causes economic loss [2]. The pathogenesis of RM are not fully understood yet.

The cause of RM is multi-factorial. It is likely that certain maternal immune responses against the fetus at the maternal–fetal interface contribute to these pregnancy losses. Cumulative reports indicate that underlying etiologic causes of RM include coagulation disorders, abnormal embryonic karyotype, placental abnormality, endometrial defects, endocrine disorders, infectious agents, environmental factors [3], uterine malformation [4], cervical incompetence [5] and endocrine disorders [6]. However, the etiology in an approximate 50% of cases of RM remains undetermined.

It seems that immune factors, such as the decreased maternal tolerance, contribute to RM [7]. Regulatory T cells (Treg) are a major component in the immune tolerance. A number of subtypes of Treg have been described, such as the CD4⁺ CD25⁺ Foxp3⁺ Tregs, Tr1 cells, Th3 cells, etc. [8]. The major function of Treg is to suppress other effector T cell's activities to avoid inducing the unnecessary immune injury [9]. On the other hand, Tregs also contribute to the establishment and maintenance of the immune tolerance [10]. Tregs play a critical role in the organ/tissue transplantation [11]. The fertilized ovum contains paternal material that is a kind of foreign antigen and has potential to induce an immune rejection response [12]; however, which does not happen under normal physiological condition because the rapid development of the specific immune tolerance [13]. Decreased frequency of Tregs in women is noted in the women with RM [14], [15], [16]. Skewed T helper (Th)1 dominant is also reported in RM women [17].

The functional status of Tregs is also an important factor in the maintenance of immune tolerance in the body. A critical factor of Treg cells is the expression of Foxp3, which is a master transcription factor required for the differentiation, maintenance and suppressive functions of Tregs [18]. The deficiency in Foxp3 causes aberrant activation and homeostasis of T cells, which results in multiple organ inflammation [18]. The E2 ubiquitin-conjugating enzyme Ubc13 is involved in the function of the T cell receptor. Ubc13 conjugates the Lys63 (K63)-linked polyubiquitin chains that is critical for activation of the IκB (inhibitor of NF-κB) kinase IKK and its downstream transcription factor NF-κB [19]. The Ubc13-IKK signaling axis is required for expression of Treg signature genes and is required for the expression of the Treg functional factors, including IL-10 and SOCS1 [20]. In this study, we found less frequency of sperm antigen specific Treg, the existing Tregs had less Ubc13 as compared to healthy subjects and a skewed sperm antigen specific Th1 dominant in a group of women with RM.