Leveraging accessible genetic datasets, our study embarked on a comprehensive investigation into the possible causal links between 731 immune cell traits and endometritis via MR techniques. This represents a pioneering effort in utilizing MR to assess the influence of a broad spectrum of immune traits on endometritis. We pinpointed 22 immune traits with substantial causal impacts on this condition.The IVW analysis of T cell profiles sheds light on the multifaceted interactions between T cell subpopulations and their impact on endometritis, distinguishing between factors that mitigate or elevate disease risk. One of the most compelling associations identified involves the clear distinction between protective and risk factors related to T cell subpopulations. Protective roles are evident in higher counts of CD39 + CD4 + T cells and CD25 + + CD8 + T cells, alongside increased CD25 expression on CD39 + CD4 regulatory T cells. Higher counts of regulatory and anti-inflammatory T cell subsets are protective, and these associations may reflect the cells’ capacity for regulatory and anti-inflammatory actions, such as hydrolyzing extracellular ATP with CD39 + T cells, which can dampen inflammatory responses within the endometrium16. On the other hand, the analysis identifies potential exacerbators of endometritis, including increased CD4 expression on CD28 + CD4 + T cells and a higher prevalence of effector memory CD4 + T cells, suggesting an overactive adaptive immune response that could intensify inflammation and tissue damage. CD28 is a co-stimulatory molecule that enhances T cell activation and survival, potentially leading to an overactive adaptive immune response and increased inflammation. Effector memory CD4 + T cells are involved in rapid immune responses upon re-exposure to antigens, potentially exacerbating inflammatory processes within the endometrium. Additionally, elevated levels of HLA DR + among T cells and CD8 + T cells imply sustained immune activation, potentially aggravating the condition. These markers indicate an ongoing immune response, which can contribute to chronic inflammation and tissue damage in the endometrium. Li et al. also observed an increase in CD8 + T cells in the endometrium of CE patients11. This nuanced understanding of T cell behavior emphasizes the importance of targeted immunotherapies that enhance protective T cell actions while curbing those that contribute to endometritis, offering a strategic approach to managing the disease’s complex immunological landscape.The results from the B cell panel suggest a complex role of B cells in endometritis, with certain traits acting as protective factors while others potentially increase the risk. The identification of switched memory B cells, characterized by increased absolute counts and CD19 expression, as protective factors (OR < 1) indicates their possible involvement in a beneficial immune response against endometritis. Switched memory B cells are known for their ability to rapidly produce specific antibodies upon re-exposure to antigens17, suggesting that a higher presence of these cells might enhance the body’s capability to fight off infections associated with endometritis. CD19 is a crucial marker for B cell activation, and its expression suggests a robust immune response capability. Additionally, the protective association indicated by increased CD20 expression on IgD + CD38− unswitched memory B cells and a higher percentage of switched memory B cells among lymphocytes further supports the idea that an effective B cell-mediated immune response is crucial in safeguarding against endometritis. Conversely, the potential risk factors identified, such as a higher level of CD20 on CD20− CD38− B cells and a higher percentage of IgD + CD24 + B cells among the B cell population (OR > 1), hint at a more complex scenario. CD20 expression is associated with B cell activation and proliferation, which may contribute to a dysregulated immune response and exacerbate inflammation. These findings indicate that certain subsets of B cells could either be ineffective in combating the infection or might even contribute to a dysregulated immune response, thereby exacerbating the condition. Previous literature has reported that CD20 B cells account for less than 1% of all CD45 cells in the normal endometrium, but can reach up to 25% in endometritis samples18, and the count of CD20 B cells also increases with the severity of endometrial inflammation19. Overall, these findings underscore the nuanced role of B cell immunity in endometritis, highlighting the balance between protective memory responses and potentially maladaptive B cell activities.In addition, the findings suggest an augmented risk associated with two specific DC subtypes: myeloid dendritic cells expressing high levels of CD62L and plasmacytoid dendritic cells (pDCs) in increased numbers. CD62L, a cell adhesion molecule, plays a crucial role in the trafficking and homing of immune cells to inflammation sites20. Elevated CD62L expression on CD62L + myeloid DCs could imply enhanced migratory capacity and interaction with T cells, potentially leading to an intensified inflammatory response within the endometrial tissue. Similarly, the elevated absolute count of plasmacytoid dendritic cells, known for their robust production of type I interferons in response to viral infections, points to an overactive immune response21. The accumulation of pDCs in the endometrium could exacerbate inflammatory processes, further elevating the risk of endometritis (OR: 1.584). Similarly, Li et al. found a notable rise in the levels of mature CD83 + dendritic cells in the endometrium of individuals with CE11. These results underscore the complex interplay between specific dendritic cell subsets and endometritis.The analysis of the NK cell panel yielded a significant finding, revealing a protective association between CD16-CD56 expression on HLA DR + NK cells and a decreased risk of endometritis (OR: 0.563). CD16, a low-affinity Fc receptor, allows NK cells to mediate antibody-dependent cellular cytotoxicity, while CD56 is associated with NK cell adhesion and migration22. Previous studies have indicated that, compared to non-CE patients, there is a significant decrease in the proportion of CD56 + CD16− NK cells in the secretory phase endometrium of CE patients8, supporting our research findings. HLA-DR expression on NK cells indicates enhanced activity, with these cells, like those identified by CD16–CD56, known for elevated IFN-γ secretion23,24. Based on the analysis above, these specific NK cell subsets may play a role in eliminating potential pathogens that lead to the development of endometritis, thereby reducing the inflammatory response and the risk of the disease.The protective factors identified suggest that specific phenotypes of monocytes and macrophages are associated with a decreased risk of developing endometritis. Firstly, the higher percentage of CD11c + CD62L− monocytes was associated with a lower risk of endometritis (OR: 0.612). CD11c is a marker typically associated with dendritic cells but also expressed on certain subsets of monocytes that may have a role in antigen presentation and initiation of immune responses25. The lack of CD62L, an adhesion molecule involved in leukocyte trafficking26, may indicate these monocytes have a reduced capacity for migration into inflamed tissues, potentially mitigating excessive inflammatory responses that could contribute to endometritis. Secondly, the increased expression of CD86 on monocytes (OR: 0.570) highlights the importance of co-stimulatory molecules in the protective immune response. CD86, a co-stimulatory molecule expressed on antigen-presenting cells, is crucial for the activation of T cells27. Its increased expression might enhance the ability of monocytes to effectively initiate immune responses against infections without leading to excessive inflammation that can cause endometritis. Thirdly, a higher percentage of CCR2 expression on CD14 + CD16 + monocytes (OR: 0.552) was also associated with a decreased risk. CCR2 is a chemokine receptor involved in monocyte recruitment to sites of inflammation28. The specific subset of CD14 + CD16 + monocytes is known for its pro-inflammatory properties29. The higher expression of CCR2 might reflect a more controlled recruitment and activity of these cells, preventing an overwhelming inflammatory response. Lastly, the protective association of CD14 expression on monocytic MDSCs (Myeloid-derived suppressor cells) (OR: 0.597) underscores the complex interplay between different immune cells in endometritis. MDSCs are known for their immunosuppressive functions30, and their involvement could help modulate the immune response, preventing excessive inflammation and tissue damage associated with endometritis.The present study has notable strengths and limitations. By leveraging MR, we replicated the outcomes of randomized controlled trials within the context of an observational study. Nevertheless, the utilization of a more permissive threshold for assessing results might have increased the likelihood of type I errors. Moreover, the GWAS datasets were exclusively derived from European samples, which calls for a broader analysis to verify the applicability of our findings to a more varied demographic. The diversity of clinical presentations in endometritis was acknowledged, yet a stratified analysis targeting distinct subgroups was not conducted. Additionally, the large discrepancy in sample size between the number of endometritis cases (159) and controls (247,381) could affect the generalizability of the results. The diversity of clinical presentations in endometritis was acknowledged, yet a stratified analysis targeting distinct subgroups was not conducted. Subsequent investigations should endeavor to classify and scrutinize the data more intricately, particularly concerning the varying degrees of endometritis severity.To summarize, our meticulous MR investigations established a cause-and-effect link between specific immune characteristics and the development of endometritis, underscoring the intricate crosstalk between immune modulation and this gynecological condition. These insights pave the way for further exploration into the immune pathogenesis of endometritis, setting the stage for advanced research into potential immunotherapy approaches.
