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IL-35 Contributing to Immune Tolerance in Normal Pregnancy

IL-35 Contributing Immune Tolerance Normal Pregnancy
IL-35 – Normal Pregnancy

A study published in PLoS One indicates that normal pregnancy is associated with increased levels of interleukin (IL)-35, whereas recurrent spontaneous abortions are linked to low levels of this cytokine, suggesting the involvement of this cytokine in the maintenance of immune tolerance during pregnancy.

Pregnancy is a major challenge for the maternal immune system. The foreign antigens expressed by the fetus can even stimulate the immune system. In this complex immunological dilemma, the maternal immune system actively responds to fetal antigens with the help of endocrine pathways.

Regulatory T cells (Treg) play an important role in maintaining immune tolerance, inhibiting progression of autoimmune disease and preventing excessive inflammatory response. Additionally, a specific role in the maintenance of fetal immune tolerance has been widely reported for these cells in both humans and mice.

Cytokine pathways are considered to be the major mechanism for immunosuppression of Tregs. Inhibitory cytokines include IL-10, TGF-β and IL-35.

Interleukin-35 identified in 2007 is a major immunosuppressive and anti-inflammatory cytokine along with IL-10 and TGF-β.

Interleukin-35 belongs to the IL-12 family of cytokines, composed of two subunits – p35 and EBI3, which are shared with other IL-12 family members, specifically IL-12 and IL-27. Interleukin-35 is produced mostly by CD4+ Foxp3+ Treg cells, but also by regulatory B cells and tolerogenic dendritic cells.

The cytokine exerts its immunosuppressive and anti-inflammatory effects by up-regulating regulatory T cells, and by inhibiting of both T helper (Th)1 and Th17 immune responses.

Interleukin-35 is implicated in autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, and in the pathogenesis of asthma.

Interleukin-35 is also implicated in cancer growth by enhancing angiogenesis and TGF-β production, and where it is utilized as suppressive mechanism by inhibiting the recruitment of effector anti-tumor T cells and suppressing their function.

In regards to pregnancy, it appears that first-trimester human trophoblast cells express and secrete IL-35, whereas in women with idiopathic recurrent pregnancy loss, IL-35 is lower compared to fertile controls.

Although IL-10, TGF-β and IL-35 are all inhibitory, the extent of their suppression, and of their non-overlapping functions, needs further clarification. There is a general consensus that Tregs increase in decidual tissue, peripheral blood and lymphoid organs during pregnancy and mediate maternal tolerance to the fetus. However, information on the level of serum IL-35 and its potential role in pregnancy remains limited.

In the PLoS One study, Chao-yan Yue, Bin Zhang, and Chun-mei Ying from the Department of Laboratory Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China, investigated the serum levels of inhibitory cytokines Interleukin-35, IL-10 and TGF-β in both normal pregnancies and non-pregnant females, and whether IL-35 is associated with the pathogenesis of recurrent spontaneous abortion.

The authors demonstrate that inhibitory cytokines Interleukin-35, IL-10 and TGF-β were elevated to different extents during pregnancy, and IL-35 plays an important role in maternal-fetal immune tolerance.

In the first trimester of pregnancy, the increased immunosuppressive factors were mainly Interleukin-35 and TGF-β; in the second and third trimesters of pregnancy the main immunosuppressive factor was IL-35. During recurrent spontaneous abortion, IL-35 decreased significantly.

In early pregnancy, the IL-35 level positively correlated with estradiol (E2) levels, and the authors speculate that this might reflect the effects of estrogens on Tregs proliferation.

On the other hand, serum Interleukin-35 levels in recurrent spontaneous abortion was significantly lower when compared to that in normal early pregnancy.

These results results indicate that increased IL-35 in normal pregnancy may provide immune protection for the fetus, and insufficient IL-35 is involved in the recurrent spontaneous abortion pathogenesis, so IL-35 associated with the establishment and maintenance of maternal-fetal tolerance during a successful pregnancy.

It has been reported that first-trimester human trophoblast cells expressed and secreted interleukin-35, which might be of benefit to the suppressive capacity of maternal immune cells. In women with history of idiopathic recurrent pregnancy loss, IL-35 was found to be significantly lower compared to fertile controls

Thus, this study implicates IL-35 in the maintenance of immune tolerance during normal pregnancy. This is achieved, as specified by the authors, most likely through “Treg augmentation during pregnancy”.

This may also suggest new therapeutic approaches in infertility, miscarriage and/or pregnancy complications.

Source: PLoS One, 2015; 10(6): e0128219
Read more: PLoS One

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