O-078 CD138 expression in the endometrium associates with endometrial timing and inflammatory status but not microbiota composition: a translational analysis of the CERM trial

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Abstract Study question To understand the relationship between endometrial CD138 expression and the reproductive tract microbiota. Summary answer CD138+ staining of endometrium is associated with general delay in endometrial maturation but not the composition of the microbiota. What is known already Chronic endometritis (CE) is a purported cause of recurrent miscarriage (RM). This asymptomatic inflammation of the endometrium has been associated with RM, with several studies demonstrating a higher prevalence than the general population. CE has previous been associated with a reduction in Lactobacilli species and a dysbiotic endometrial microbiota. CD138 is a widely used plasma cell marker utilised to aid the diagnosis of CE. However, CD138, a transmembrane heparan sulfate proteoglycan, is expressed by other cells in human endometrium. Its expression has previously been shown to vary across the menstrual cycle. The implications of this remain under-explored. Study design, size, duration Translational cohort study embedded within a randomised controlled trial with a subset of 103 samples derived from a trial population of 737 women. Participants/materials, setting, methods Women aged ≥18 to < 42 yrs, with a history of two or more first trimester consecutive miscarriages were recruited from specialist Recurrent Pregnancy Loss (RPL) clinics. A timed endometrial biopsy alongside endometrial microbial sampling was performed following ovulation (10±4 days). Additional samples were obtained from the Tommy’s National Reproductive Health Biobank. Samples underwent CD138 immunostaining, histological and molecular dating analysis, immune profiling, cytokine analysis and bacterial metataxonomic profiling with 16S ribosomal RNA (rRNA) sequencing analysis. Main results and the role of chance Non-immune expression of CD138 was demonstrated across all endometrial cell populations. Stromal expression was very high (>200 CD138-positive stromal cells/10mm2) in 26 out of 27 proliferative endometrial samples. While CD138 immunoreactivity in the stroma declines markedly following ovulation (Mann Whitney U-Test; p < 0.005), gene expression analysis demonstrated persistently elevated SDC1 (CD138) transcript levels in a subset of non-immune stromal cells. Immunohistochemistry revealed three patterns of CD138 immunoreactivity: punctate staining, diffuse staining, and a mixed pattern. When compared to CD138 negative samples, conspicuous diffuse staining in the stromal compartment was associated with significantly earlier histological dating (p < 0.01) and lower molecular dating ratios (p < 0.01). Sequencing of paired vaginal and ectocervical swabs and endometrial Tao brush samples collected from 114 patients demonstrated tightly interconnected microbial ecosystems across the low reproductive tract. There was no association between the pattern or severity of CD138 immunoreactivity in luteal phase endometrium and vaginal, ectocervical or endometrial community state types (p < 0.05). Analysis of supernatants of vaginal and ectocervical swabs and Tao Brush revealed an inverse correlation between the pattern and severity of stromal CD138 immunoreactivity in endometrial stroma and secreted levels of TNF-α, CXCL/BRAK and VEGF (q-value < 0.05). Limitations, reasons for caution This study relied on self-reported ovulation testing using commercially available urine LH tests. In addition, multiple statistical testing was utilised across differing data types. The consistency of the results seen, however, adds credence to the findings. Wider implications of the findings This study challenges the assumptions underlying the reliability of CD138 IHC to detect plasma cells infiltration. It suggests the possibility of a confounding relationship of delayed endometrial maturation within the literature on CE to date. CD138-based CE testing and treatment should not therefore be performed outside of a research context. Trial registration number Yes

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