Human miscarriage is associated with increased number of CD26 decidual lymphocytes.

Dipeptidyl peptidase-IV (DPP-IV, CD26), a serine protease with broad distribution in mammalian tissues and known activity in serum, participates in T-cell activation and promotes a Th1-like cytokine response. Previous data on murine abortion indicate that DPP-IV may play a critical role in pregnancy failure by inducing a Th1 local response. Here, we investigated the possible participation of DPP-IV in the onset of human spontaneous abortion (SA). The systemic (peripheral blood) and local (decidua) percentages of CD4(+), CD8(+), CD26(+) and CD56(+) cells as well as the number of Th1 lymphocytes (CCR5(+) cells) were assessed in samples from women after SAs (n = 20) and from women with normally progressing pregnancies (NPs) (n = 27) using flow cytometry and immunohistochemistry. We further measured the DPP-IV activity and concentrations of Th1 (interferon-gamma and tumour necrosis factor-alpha), Th2 [interleukin-4 (IL-4), IL-10] and Th3 (transforming growth factor-beta2) cytokines in serum samples. We could not find any difference in the number of CD4(+), CD8(+), CD26(+), CD26(+)/CD4(+) or CD8(+)/CD26(+) blood cells between NP and SA patients. No differences in the Th1, Th2 or Th3 cytokine levels could be observed between both groups. However, the percentages of decidual CD26(+) lymphocytes as well as the number of decidual Th1 cells were significantly higher in SA samples compared to samples from patients with NP. Our data support the hypothesis that CD26(+) decidual lymphocytes with DPP-IV activity may play a critical role in SAs, as previously suggested in an abortion mice model. This abortive effect may be mediated by enhancing the levels of Th1 abortogenic cytokines only locally.

Upregulation of decidual P-selectin expression is associated with an increased number of Th1 cell populations in patients suffering from spontaneous abortions.

A multicascade of leukocyte-endothelial cell interactions is involved in the trafficking of inflammatory lymphocytes into tissue. The primary contact between leukocytes and endothelium is mediated by selectins. Ligands for P-Selectin are preferentially expressed on Th1 cells and thereby allow migration of these inflammatory cells through the vessel wall. Since a peripheral and local Th1-type cytokine profile is present in spontaneous human abortion (SA), opposed by a Th2 dominant situation in normal pregnancies (NP), we investigated (1) the phenotype of peripheral Th1 cells by flow cytometry, as well as the Th1-type cytokine levels by ELISA, (2) the decidual expression of P- and E-Selectin by immunohistochemistry (IHC), and (3) the phenotype of decidual immunocompetent cells by IHC in patients with NP or SA. We observed enhanced production of IFN-gamma and TNF-alpha in CD8(+), CD3(+), and CD56(+) blood cells, as well as an increase in the number of CCR5(+) cells in patients suffering from SA compared to those with NP. No difference was detectable with respect to the serum levels of the two cytokines. Using IHC methods, we observed increased staining intensity of P-Selectin(+) vessels in samples of SA patients. E-Selectin was only weakly expressed in decidual endothelial cells, with no difference between NP and SA. In SA samples, E-Selectin(+) stromal cells were exclusively present. We further detected increased numbers of decidual CD8(+), CD3(+), CCR5(+), and CD56(+) cells in SA patients. We propose that Th1 lymphocyte migration into decidua is enhanced in SA due to upregulated P-Selectin expression in decidual vessels. This increase of Th1-producing lymphocytes might be involved in the rejection of trophoblasts.