Beyond Uterine Natural Killer Cell Numbers in Unexplained Recurrent Pregnancy Loss: Combined Analysis of CD45, CD56, CD16, CD57, and CD138

Changes in the number and cytotoxic potential of uterine Natural Killer (uNK) cells have been associated with reduced fertility. To provide a better characterization of immunophenotypes in the endometrium of women with uRPL (unexplained recurrent pregnancy loss), we examined the applicability of a set of five immune cell markers. The concentration (cells/mm²) of CD45⁺ leukocytes, CD56⁺ uNK cells, and CD138⁺ plasma cells as well as of CD16⁺ and CD57⁺ cells, which indicate high cytotoxic uNK cells, were assessed by immunohistochemistry in endometrial biopsies from 61 uRPL patients and 10 controls. Control fertile endometria presented 90-300 CD56⁺ uNK cells/mm². uRPL cases were classified in subgroups of low (uRPL-CD56^low < 90 cells/mm²), normal (uRPL-CD56^normal 90-300 cells/mm²), and high uNK cell counts (uRPL-CD56^high > 300 cells/mm²). Some cases from the uRPL-CD56^low and uRPL-CD56^normal subgroups showed elevated proportions of cytotoxic CD16⁺ and CD57⁺ cells in relation to CD56⁺ cells. In the uRPL-CD56^high subgroup, the CD57/CD56 ratio was reduced in most samples and the CD16/CD56 ratio was unaltered. Analysis of CD138 excluded the influence of chronic endometritis on these observations. Our results reinforce a link between uRPL and a dysfunctional endometrial environment associated with distinct immune cell profiles.