Causal association of immune cells and endometritis: a Mendelian randomization study

doi:10.21203/rs.3.rs-4254941/v1

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Causal association of immune cells and endometritis: a Mendelian randomization study

https://doi.org/10.21203/rs.3.rs-4254941/v1

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published 22 Oct, 2024

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Background: Research exploring the link between immune cell profiles and the development of endometritis remains scant. This gap necessitates further study to decode the complex interrelations influencing this condition.

Methods: In this analysis, we leveraged two-sample Mendelian randomization to examine the causal ties between the phenotypes of immune cells and the incidence of endometritis. Our evaluation hinged on data from 3,757 participants hailing from Sardinia, focusing on a diverse array of 731 immune phenotypes, and cross-referenced with endometritis data sourced from the UK Biobank. To ensure rigor, we performed sensitivity analyses, utilized MR-Egger and MR-Presso to check for pleiotropy, and applied Cochran's Q test for assessing the heterogeneity of our findings.

Results: Our investigation identified numerous immune characteristics associated with endometritis. For certain immune traits, a lower risk of endometritis was observed, including: Absolute Counts of CD39+ CD4+ T cells, CD25+ CD39+ CD4 regulatory T cells, and CD25++ CD8+ T cells; Absolute Counts of Switched Memory B cells; CD19 expression on IgD+ CD38dim and Switched Memory B cells; CD20 expression on IgD+ CD38- Unswitched Memory B cells; percentage of Switched Memory B cells among lymphocytes; CD16-CD56 expression on HLA DR+ Natural Killer cells; percentage of CD11c+ CD62L- monocytes; CD86 expression on monocytes; CCR2 expression on CD14+ CD16+ monocytes; and CD14 expression on Monocytic Myeloid-Derived Suppressor Cells, with Odds Ratios (ORs) between 0.413 and 0.703. On the contrary, increased risks of endometritis were linked with: the percentage of Effector Memory CD4+ T cells within the CD4+ T cell population; percentages of HLA DR+ T cells and HLA DR+ CD8+ T cells among T cells; CD4 expression on CD28+ CD4+ T cells; CD20 expression on CD20- CD38- B cells; percentage of IgD+ CD24+ B cells within the B cell population; CD62L expression on CD62L+ myeloid Dendritic Cells; and Absolute Counts of Plasmacytoid Dendritic Cells, with ORs from 1.473 to 2.677, indicating these traits potentially elevate the risk of developing endometritis.

Conclusion: Our research delineates distinct causal links between specific immune cell phenotypes and endometritis, offering groundbreaking perspectives that could contribute to the pinpointing of new therapeutic avenues for this condition.

Biological sciences/Computational biology and bioinformatics

Biological sciences/Immunology/Inflammation

Mendelian randomization

immune cells

endometritis

causality

SNP

Endometritis is characterized as an infection or inflammation of the endometrium, with two main types: acute and chronic ^[1]. This condition has been linked to adverse reproductive outcomes, including unexplained infertility, implantation failure, and recurrent miscarriage ^[2–4].

Individuals suffering from acute endometritis typically report symptoms such as elevated temperatures and discomfort in the lower abdomen, often accompanied by an increase in white blood cells or higher levels of markers indicating inflammation in the blood ^[5]. Nonetheless, diagnosing this condition can be challenging when it's in its initial stages or if the infection is mild, as the clinical manifestations may not be distinct ^[6].

Chronic endometritis (CE) represents a disruption in the balance between the endometrial microbiota and the immune defense of the host, evidenced by the significant infiltration of plasmacytes within the stromal regions of the endometrium ^[7]. This condition is prevalent among women of reproductive age and can be precipitated by sexual intercourse, inadequate uterine procedures, or the introduction of harmful pathogens, among various other causes ^[8].

Nevertheless, prevailing detection methods have proven unsuccessful in detecting microorganisms in over half of infertile women with CE ^[9]. Consequently, some researchers propose that the primary pathophysiological foundation of endometritis lies in the interplay between microorganisms and endometrial immunity, extending beyond the mere presence of microorganisms in the endometrium ^[10].

The intricate interplay between the immune system and cellular components within the uterine microenvironment plays a pivotal role in the pathogenesis of endometritis. Li et al.'s research revealed a significant elevation of uterine CD68 macrophages, CD8 T cells, CD83 mature dendritic cells, and Foxp3 regulatory T cells in CE patients ^[11]. Kitazawa et al.'s study demonstrated that the endometrium of CE patients had significantly more Th1 cells among CD4 cells compared to non-CE patients. Additionally, Chen et al.'s research identified significant differences in the abundance of CD4 T cells and macrophages in the endometrium between CE and non-CE patients. Although the connection between immune inflammation and endometritis is pertinent, the existing findings regarding their association have been inconclusive, likely attributed to constraints such as limited sample sizes, design flaws in studies, and the presence of confounding factors.

Utilizing genetic variations as instrumental variables, Mendelian Randomization (MR) emerges as a powerful tool for investigating causal relationships between immune cell signatures and endometritis. The critical aspect of MR lies in ensuring the rationality of the causal sequence ^{[12, 13]}. Earlier studies pointed to links between certain immune cell behaviors and endometritis, hinting at a possible connection. This research adopts an extensive MR approach to delve into the potential causal ties between specific immune cell patterns and endometritis.

MR analysis

To investigate the causal link between immune characteristics and endometritis, we conducted a two-sample Mendelian Randomization analysis, mainly using the IVW approach. By setting a p-value threshold below 0.05, we identified 22 immune traits with a causal connection to endometritis, distributed across various cell panels: 7 in T cell panels, 9 in B cell panels, 1 in dendritic cell (DC) panels, 1 in natural killer (NK) cell panels, and 4 in monocyte panels. (Supplementary Table 1, Fig. 2–3).

In the analysis of T cell profiles, the IVW method revealed several protective associations against endometritis. Specifically, a lower risk was observed with higher absolute counts of CD39 + CD4 + T cells (OR: 0.614, 95% CI: 0.388 − 0.973), higher CD25 expression on CD39 + CD4 regulatory T cells (OR: 0.507, 95% CI: 0.286 − 0.900), and higher absolute counts of CD25 + + CD8 + T cells (OR: 0.703, 95% CI: 0.497 − 0.996). Conversely, increased risks were associated with higher levels of CD4 expression on CD28 + CD4 + T cells (OR: 1.870, 95% CI: 1.192 − 2.934), a greater percentage of effector memory CD4 + T cells among the CD4 + T cell population (OR: 2.109, 95% CI: 1.147 − 3.876), and higher percentages of HLA DR + T cells (OR: 1.482, 95% CI: 1.009 − 2.178) and HLA DR + CD8 + T cells among T cells (OR: 1.473, 95% CI: 1.029 − 2.108). (Supplementary Table 1, Fig. 2–3).

In the B cell panel, protective factors for endometritis included a higher absolute count of switched memory B cells (OR: 0.494, 95% CI: 0.298 − 0.818), increased CD19 expression on IgD + CD38dim B cells (OR: 0.553, 95% CI: 0.323 − 0.945), and more CD19 expression on switched memory B cells (OR: 0.613, 95% CI: 0.384 − 0.980). Additionally, a lower risk was seen with increased CD20 expression on IgD + CD38- unswitched memory B cells (OR: 0.618, 95% CI: 0.417 − 0.917) and a higher percentage of switched memory B cells among lymphocytes (OR: 0.424, 95% CI: 0.235 − 0.766). The forward scatter (FSC-A) on B cells also indicated a protective effect (OR: 0.413, 95% CI: 0.202 − 0.843). On the other hand, a potential risk factor for endometritis was a higher level of CD20 on CD20- CD38- B cells (OR: 2.677, 95% CI: 1.039 − 6.898) and a higher percentage of IgD + CD24 + B cells among the B cell population (OR: 2.043, 95% CI: 1.196 − 3.490). (Supplementary Table 1, Fig. 2–3).

Looking at the dendritic cell panel, an increased risk of endometritis was suggested by a higher level of CD62L expression on CD62L + myeloid dendritic cells (OR: 1.769, 95% CI: 1.105 − 2.832) and a higher absolute count of plasmacytoid dendritic cells (OR: 1.584, 95% CI: 1.007 − 2.491). (Supplementary Table 1, Fig. 2–3).

Within the NK cell panel, a protective association was found for CD16-CD56 expression on HLA DR + NK cells (OR: 0.563, 95% CI: 0.364 − 0.870), indicating a decreased risk of endometritis. (Supplementary Table 1, Fig. 2–3).

Lastly, in the monocyte/macrophage cell panel, several protective factors were highlighted. A lower risk of endometritis was associated with a higher percentage of CD11c + CD62L- monocytes (OR: 0.612, 95% CI: 0.375 − 0.997), increased CD86 expression on monocytes (OR: 0.570, 95% CI: 0.338 − 0.962), and a higher percentage of CCR2 expression on CD14 + CD16 + monocytes (OR: 0.552, 95% CI: 0.339 − 0.897). Additionally, CD14 expression on monocytic myeloid-derived suppressor cells was also found to be protective (OR: 0.597, 95% CI: 0.394 − 0.904). (Supplementary Table 1, Fig. 2–3).

Sensitivity analysis

Evaluations using MR-Egger intercept and global MR-PRESSO methods did not detect evidence of horizontal pleiotropy or heterogeneity in the associations between immunophenotypes and endometritis, as outlined in Supplementary Tables 2–4. Moreover, the robustness of our MR findings was confirmed through a leave-one-out sensitivity analysis, which demonstrated that the exclusion of any particular SNP associated with both immunophenotypes and endometritis did not substantially alter the aggregate results (refer to Supplementary Fig. 1).

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. 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. 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 endometrium ^[14]. 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. Additionally, elevated levels of HLA DR + among T cells and CD8 + T cells imply sustained immune activation, potentially aggravating the condition. Li et al. also observed an increase in CD8 + T cells in the endometrium of CE patients ^[11]. 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 antigens ^[15], suggesting that a higher presence of these cells might enhance the body's capability to fight off infections associated with endometritis. 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. These results may indicate that certain subsets of B cells could either be ineffective in combating the infection or might even contribute to a dysregulated immune response that exacerbates 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 samples ^[16], and the count of CD20 B cells also increases with the severity of endometrial inflammation ^[17]. 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 sites ^[18]. 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 response ^[19]. 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 CE ^[11]. 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 migration ^[20]. 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 patients ^[8], 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 secretion ^{[21, 22]}. 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 responses ^[23]. The lack of CD62L, an adhesion molecule involved in leukocyte trafficking ^[24], 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 cells ^[25]. 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 inflammation ^[26]. The specific subset of CD14 + CD16 + monocytes is known for its pro-inflammatory properties ^[27]. 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 (OR: 0.597) underscores the complex interplay between different immune cells in endometritis. MDSCs are known for their immunosuppressive functions ^[28], and their involvement could help modulate the immune response, preventing excessive inflammation and tissue damage associated with endometritis.

The present research boasts notable strengths and constraints. 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. 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.

Research Framework

Our investigation explored the causative link between 731 immune cell markers (spanning 7 categories) and endometritis, employing a two-sample MR approach. MR leverages genetic variants as proxies for risk factors, necessitating that chosen instrumental variables (IVs) adhere to three principal criteria for reliable causal deduction: (1) a direct connection between the genetic variants and the exposure; (2) no association of the genetic variants with any confounders linking the exposure and the outcome; (3) the genetic variants influence the outcome solely through the exposure. Ethical clearance for the incorporated studies was obtained from the appropriate boards, with participants giving their informed consent.

Immune cells sample

A publicly accessible database, spanning entries GCST0001391 to GCST0002121, provides GWAS information for 731 immune phenotypes analyzed in this research ^[29]. Utilizing data from 3,757 individuals from Sardinia, approximately 22 million genetic variants were analyzed to establish associations with autoimmune conditions within the immunological trait GWAS dataset. This compiled GWAS dataset encompasses various measures: 118 counts of absolute cells (AC), 389 values of median fluorescence intensity (MFI) indicative of surface antigen levels, 32 morphological attributes (MP), and 192 counts of relative cells (RC), indicating the proportion of different cell types.

Endometritis sample

Endometritis-related GWAS findings were derived from UK Biobank's released datasets (https://www.ebi.ac.uk/gwas/studies/GCST90044301). The GWAS statistics encompassed 11,842,647 loci variations from 159 cases and 247,381 controls.

Choosing Instrumental Variables

Recent studies have established a significance threshold of 1 × 10^-5 for the instrumental variables (IVs) linked to each immune trait ^[29]. To guarantee dependable outcomes, a cut-off for significant linkage disequilibrium (LD) impact was set (r^2 < 0.001) ^[30], utilizing the 10000 Genomes Project as the reference. For every IV, the explained phenotypic variance (PVE) and F statistic were computed to evaluate the IV's robustness and to sidestep the issue of weak instrument bias. Moreover, IVs with an F statistic exceeding 10 were considered robust and were kept for further examination to reduce the skewness caused by feeble instruments. SNPs related to exposure and outcome were synchronized to ensure consistent effect estimates for identical effect alleles. Palindromic SNPs showing intermediate allele frequencies (EAFs > 0.42) or those with mismatched alleles were eliminated ^[31].

Analysis of Data

A spectrum of MR analyses was undertaken, including methods such as MR Egger, inverse-variance weighted (IVW), weighted median, weighted mode, simple mode, and MR-PRESSO. The IVW technique is particularly widely applied ^[32].

To probe into the variance, heterogeneity tests were conducted using both MR Egger and IVW methods. The Cochrane’s Q value was used to evaluate the genetic instruments' variability, with a p-value above 0.05 indicating insignificant diversity. The MR Egger regression was employed to investigate horizontal pleiotropy, where a p-value over 0.05 suggests no signs of such pleiotropy ^[33].

To explore the influence of directional pleiotropy, we examined each SNP for potential links with secondary traits via the GWAS Catalog. MR analyses were then redone, excluding SNPs tied to other traits. Leave-one-out sensitivity tests were also performed on significant results to check if a particular SNP was responsible for the observed causative link. The overall study layout is illustrated in Fig. 1. All analyses were conducted using the R software, version 4.2.1. The MR analysis was performed using the R libraries "TwoSampleMR" and "MR-PRESSO" ^[34]. Additionally, R facilitated the visualization of data through various charts.

Author contributions statement

Jing-wei Li crafted the manuscript and, together with Ren-tao Wan, synthesized and examined the data. Qing-dong Liu and Hong-lin Xu contributed to refining and amending the manuscript. The project was conceived and overseen by Qi Chen. The final manuscript received the endorsement of all contributors.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

The study utilized data sourced from published literature and the publicly accessible GWAS platform (https://gwas.mrcieu.ac.uk/), which are freely available for use.

Competing interests

The authors declare no competing interests.

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No competing interests reported.

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Causal association of immune cells and endometritis: a Mendelian randomization study

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