Intravenous Immunoglobulin Suppresses Abortion Relates to an Increase in the CD44bright NK Subset in Recurrent Pregnancy Loss Model Mice

Abstract

Recurrent pregnancy loss (RPL), which mostly is of unknown etiology (unexplained RPL, uRPL), is defined as three or more consecutive spontaneous abortions. Some women with uRPL display a higher fraction and cytotoxicity of natural killer (NK) cells in the periphery and endometrium. Therefore, some uRPL cases have been explained by autoimmune abnormalities. The efficacy of intravenous immunoglobulin (IVIg) for uRPL has been confirmed in several clinical trials; however, its mechanism remains unknown, mainly because the abortion mechanism remains to be elucidated. In the present study, we analyzed the mechanisms of both abortion and IVIg action using a uRPL mouse model in which abortion was induced by lipopolysaccharide injection. IVIg attenuated the abortion rate in the uRPL model mice. The suppressive effect of IVIg was maximized by high dose administration early after lipopolysaccharide injection. Specifically, we discovered the presence of two distinct uterine NK (uNK) subsets: CD44(bright) and CD44(mid) In uRPL model mice, we observed an increase in the number of CD44(bright) uNK cells, while the CD44(mid) uNK subset remained unchanged. Furthermore, when abortion was reduced by IVIg administration, the cell number of the CD44(bright) uNK subset did not increase, which might allow differentiating pathological from normal uNK cells based on CD44 expression. Based on these results, we propose not only an effective administration protocol of IVIg to the uRPL model mice, but also a novel mechanism of abortion related to the increase in the CD44(bright) subset and of IVIg, which suppresses the increase of the CD44(bright) subset.

Histone deacetylase 9 deficiency exaggerates uterine M2 macrophage polarization

“…As a result, using PerCp‐Cy5.5‐conjugated anti‐mouse CD45, PE‐conjugated anti‐mouse F4/80 and APC‐conjugated anti‐mouse CD206 antibodies, CD45 + F4/80 + CD206 − M1 and CD45 + F4/80 + CD206 + M2 macrophage subpopulations were identified both in the spleen and the uterus on gd6 (Figure 1A ). Next, we used a low‐dose LPS‐induced abortion model (0.5 μg per mouse) 21 , 22 to investigate the dynamic changes of M1 and M2 macrophages after LPS treatment for 1, 3, 6, 12 and 24 hours. The results showed an overall increasing tendency of M1 cells, a decreasing trend of M2 cells and an increase in M1/M2 ratio, and significant differences between LPS‐injected mice and the control group were observed at 6 hours and afterwards (Figure 1B,C , and Figure S1 ).…”

“…In order to study the abortion mechanism caused by M1/M2 imbalance, rescue experiments utilizing in vivo LPS‐induced abortion model are needed. Since high as well as low doses of LPS can induce abortion in mice, 22 we set up to optimize the treatment conditions. Mice were ip injected with different doses of LPS (0.5, 1.2, 1.5, 2 or 4 μg in 100 μL PBS per mouse) on gd6.…”

Intravenous immunoglobulin treatment in women with four or more recurrent pregnancy losses: A double-blind, randomised, placebo-controlled trial

“… 31 Similarly, a high dose of intact type- immunoglobulin in an early period reduced miscarriages through NK cells in a mouse model of miscarriage induced by lipopolysaccharide. 32 High-dose IVIG treatment starting at 4–5 weeks of gestation might effectively restore normal immune environment, while the treatment starting at 6 weeks of gestation would be too late to yield the efficacy to restore fecundity. Modification of immune function by a high dose of IVIG during early pregnancy might reduce the number of miscarriages in humans, but the mechanism is still unknown and further investigation is required.…”

Omega‐3 fatty acid supplements and recurrent miscarriage: A perspective on potential mechanisms and clinical evidence

“…A recent study identified a novel subset of NK cells, CXCR4 + CD56 bright decidual NK cells, which are insufficiently expressed in RM patients and RM model mice; in addition, adoptive transfer of these cells to NK cell‐deficient mice improves pregnancy outcomes (Tao et al, 2021). Notably, several studies conducted with a mouse model of RM suggested that the modulation of NK cells in abortion‐prone mice is able to promote pregnancy outcomes (Li et al, 2017; Nagamatsu et al, 2018; Rezaei Kahmini et al, 2020; Tanaka et al, 2016). T cells are also critical modulators of immunity.…”