Table 3 Immune cells changes associated with RSA

uNKs

/

The expression of angiogenins, VEGF-A, and bFGF in CD56 + uNK cells of women with recurrent abortion was significantly increased, which led to endometrial vascular changes that were not conducive to embryo implantation.

[83]

dNKs

down

DSC autophagy promotes DSC adhesion and NK cell residence in the decidua during early pregnancy. Inhibition of autophagy results in reduced DSC adhesion, inadequate enrichment of dNK cells, and increased embryo absorption, which can lead to recurrent abortion.

[84]

NK cells

up

The level of NK cell toxicity measured in women with RSA during pregnancy is significantly higher than that in normal pregnant women. The use of IVIG can reduce the percentage of NK cells and cytotoxicity in patients with RSA and improve pregnancy outcomes.

[85]

NK cells

up

Inhibition of trophoblast autophagy enhances the cytotoxicity of NK cells and may impede trophoblast invasion by targeting IGF-2 and PEG10, respectively, ultimately leading to abortion.

[86]

pNKs

/

The abundance of NKG2C and the deletion of LILRB1 on pNKs are associated with miscarriage, indicating that NKG2C and LILRB1 on pNKs may serve as predictors of miscarriage.

[87]

dMφ

/

Grim-19 expression decreased in decidual macrophages of patients with RSA and was negatively correlated with autophagy. Grim-19 deficiency affects the function of macrophages, leading to increased pro-inflammatory cytokines and phagocytosis activity due to enhanced autophagy, leading to excessive inflammation at the mother-fetal interface.

[88]

dMφ

down

Metabolic inactivation of ENPP2-LPA and inadequate dMφ autophagy result in a decreased dMφ retention rate and an elevated risk of spontaneous abortion.

[89]

dMφ

/

Section 5 is involved in M2 polarization of macrophages through interaction with STAT6. The absence of Sect. 5 in decidual macrophages may lead to early pregnancy loss by disrupting EVT invasion and immune tolerance at the maternal-fetal interface, indicating a potential pathogenic mechanism of URSA related to immune factors.

[90]

M1 macrophages

up

LPS induced decidua inflammation in mice and promoted M1-like polarization of macrophages. Meanwhile, LPS inhibited the expression of Rev-erbα in macrophages. Activation of Rev-erbα reduces the LPS-induced abortion rate in mice and diminishes M1 polarization in macrophages.

[91]

M1 macrophages

up

M1 macrophages are abundant in stages of spontaneous abortion and unexplained RSA, while M2 macrophages are significantly increased in the luteal phase and in the endometrium of normal pregnancy.

[92]

M1 macrophages

up

M1 macrophages induced by extracellular vesicle (EV) miR-196a-5p derived from trophoblasts negatively regulate the proliferation, migration, and apoptosis of trophoblasts through TNF-α, playing a significant role in the pathogenesis of RSA.

[93]

M1 macrophages

up

CTRP6 can induce the polarization of M1 macrophages through the PPAR-γ/NF-κB pathway and glycolytic reprogramming. This process regulates the migration and invasion of trophoblast cells, contributing to the pathogenesis of RSA.

[94]

M2 macrophages

down

Low levels of FBP (fructose-1,6-diphosphate) were observed in plasma and decidual tissue were observed in patients with unexplained recurrent spontaneous abortion. In a spontaneous abortion mouse model, FBP supplementation significantly improved embryo loss by upregulating decidual COX-2 M2-like macrophage differentiation induced by IL-27.

[95]

Th1/Th2 cells

up

There were no significant differences in IFN-γ-producing Th1 and IL-4-producing Th2 cell levels between fertile and infertile women. However, Th1 cell levels and Th1/Th2 cell ratios were significantly higher in women with ≥ 4 ET cycles and ≥ 2 pregnancy losses compared to fertile women and generally infertile women.

[96]

Th1/Th2 cells

up

Blocking Gal-9 can promote the secretion of Th1-derived cytokines in co-culture, enhance the Th1/Th2 immune imbalance in abortion patients, and recombinant Gal-9 can increase Th2 expression, which is conducive to maintaining a normal pregnancy.

[97]

Th1/Th2 cells

up

Intravenous immunoglobulin (IVIG) enables T cells to shift to a Th2 type response and cytokine secretion, which can reduce the Th1/Th2 ratio, thereby improving pregnancy outcomes.

[98]

Th1/Th2 cells

up

psCD83 plays a crucial role in regulating immune tolerance and protecting the fetus by facilitating the shift of Th1/Th2 cytokines towards Th2 and promoting the generation of Treg cells at the maternal-fetal interface in pregnant mice. This process helps mitigate LPS-induced abortion in pregnant mice.

[99]

Treg cells

down

The proportion of pSTAT3 cells in decidual Treg cells increased significantly in patients with URSA. Overphosphorylation of STAT3 impairs the proliferation, inhibition, and cytokine secretion of Treg cells. Inhibition of STAT3 phosphorylation can restore these functions.

[100]

Th17 cells

up

In the decidual stromal cells of women with RSA, IL-7 levels are elevated while IL-7R expression is decreased. The IL-7/IL-7R signaling pathway is implicated in RSA by upregulating Th17 immunity and downregulating Treg immunity.

[101]

iNKTs

up

αGC can rapidly induce fetal absorption and activate decidual iNKT cells, which induce abortion in mice in an IFNγ-dependent manner.

[102]

PBDCs

/

Frequency and dysfunction of PBDCs subsets in the myeloid system, along with disturbances in regulatory T cell (Treg) frequency, are associated with miscarriage.

[103]

mDCs

up

Higher total DC, mDC, and CD86 DC levels were observed in women with RSA, while lower CD200 DC levels were noted, tentatively establishing a significant association between elevated mDC levels and RSA.

[104]

pDCs

up

Baicalin can alleviate embryonic absorption in RSA mice by inhibiting the STAT5-ID2 pathway, which reverses conventional DCs to plasmacytoid DCs and modulates the expression of functional molecules.

[105]

pDCs

up

The ratio of pDCs to transcription activator STAT3 and transcription factor 4 (Tcf4/E2-2) in peripheral blood mononuclear cells and decidua of RSA patients was decreased. Additionally, there was a significant positive mRNA correlation between pDCs and STAT3. Increased miR-6875-5p is involved in RSA by inhibiting the STAT3/E2-2 signaling pathway and reducing pDCs differentiation.

[106]

B cells

up

B-cells induced by IL-10 are associated with favorable pregnancy outcomes due to their role in modulating autoantibody production. Furthermore, a correlation has been observed between reduced IL-10-induced B-cell levels and an increase in autoantibodies in patients experiencing recurrent miscarriages.

[107]

B cells

/

In abortion-prone mice, the initial phases of pregnancy are characterized by a decrease in IL-35 production by B cells, both locally and systemically. Similarly, lower levels of IL-35 have been observed in women who have experienced RSA. These findings suggest a potential role for B-cell-derived IL-35 in the maintenance of pregnancy.

[108]