Evaluation of BCL6 and SIRT1 as Non-Invasive Diagnostic Markers of Endometriosis

Sansone, Alison M.; Hisrich, Brooke V.; Young, Richard B.; Abel, William F.; Bowens, Zachary; Blair, Bailey B.; Funkhouser, Avery T.; Schammel, David P.; Green, Lisa J.; Lessey, Bruce A.; Blenda, Anna V.

doi:10.3390/cimb43030096

Cited by 23 publications

(15 citation statements)

References 45 publications

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“…A GC-like B-cell (FAS + IgD − BCL6 + ) population was also identified, representing 12.2 ± 8.6% of all endometrial B cells. Previous studies demonstrated that endometrial B-cell lymphoma-6 (BCL6) protein levels are significantly higher in patients with RPL, unexplained infertility or endometriosis (eutopic endometrium) when compared with controls ( Evans-Hoeker et al , 2016 ; Almquist et al , 2017 ; Fox et al , 2020 ; Sansone et al , 2021 ). However, BCL6 expression is not limited to endometrial B cells, therefore, it is not yet clear whether the up-regulation of BCL6 is a reflection of the existence and/or involvement of GC-like B cells in the endometrial environment.…”

Section: Discussionmentioning

confidence: 99%

The role of endometrial B cells in normal endometrium and benign female reproductive pathologies: a systematic review

Shen

O’Donnell

Leon

et al. 2021

Human Reproduction Open

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STUDY QUESTION What are the similarities and differences in endometrial B cells in the normal human endometrium and benign reproductive pathologies? SUMMARY ANSWER Endometrial B cells typically constitute less than 5% of total endometrial CD45+ lymphocytes, and no more than 2% of total cells in the normal endometrium, and while their relative abundance and phenotypes vary in benign gynaecological conditions current evidence is inconsistent. WHAT IS KNOWN ALREADY B cells are vitally important in the mucosal immune environment and have been extensively characterised in secondary lymphoid organs and tertiary lymphoid structures (TLSs), with the associated microenvironment germinal centre. However, in the endometrium, B cells are largely overlooked, despite the crucial link between autoimmunity and reproductive pathologies and the fact that B cells are present in normal endometrium and in benign female reproductive pathologies, scattered or in the form of lymphoid aggregates (LAs). A comprehensive summary of current data investigating B cells will facilitate our understanding of endometrial B cells in the endometrial mucosal immune environment. STUDY DESIGN, SIZE, DURATION This systematic review retrieved relevant studies from four databases (MEDLINE, EMBASE, Web of Science Core Collection, CINAHL) from database inception until November 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS The search strategy combined the use of subject headings and relevant text words related to ‘endometrium’, ‘B cells’ and B cell derivatives such as ‘antibody’ and ‘immunoglobulin’. Non-benign diseases were excluded using cancer related free-text terms, and searches were limited to English language and human subjects. Only peer-reviewed research papers were included. Each paper was graded as ‘Good’, ‘Fair’, or ‘Poor’ quality based on the NEWCASTLE-OTTAWA quality assessment scale. Only ‘Good’ quality papers were included. MAIN RESULTS AND THE ROLE OF CHANCE Twenty-seven studies met the selection criteria and were included in this review: 10 cross-sectional studies investigated B cells in the normal endometrium; and 17 case-control studies compared the characteristics of endometrial B cells in control and benign female reproductive pathologies including endometritis, endometriosis, infertility, abnormal uterine bleeding, endometrial polyps and uterine fibroids. In all studies, B cells were present in the endometrium, scattered or in the form of LAs. CD20+ B cells were more abundant in patients with endometritis, but the data were inconsistent as to whether B cell numbers were increased in endometriosis and patients with reproductive pathologies. LIMITATIONS, REASONS FOR CAUTION Although only “good” quality papers were included in this systematic review, there are variations in patients’ age, diagnostic criteria for different diseases and sample collection time among included studies. Additionally, a large number of the included studies only used immunohistochemistry as the identification method for endometrial B cells, which may fail to provide an accurate representation of the numbers of endometrial B cells. WIDER IMPLICATIONS OF THE FINDINGS Histological studies found that endometrial B cells are either scattered or surrounded by T cells in LAs: the latter structure seems to be under hormonal control throughout the menstrual cycle and resembles TLSs that have been observed in other tissues. Further characterisation of endometrial B cells and LAs could offer insights to endometrial B cell function, particularly in the context of autoimmune-associated pathologies such as endometriosis. Additionally, clinicians should be aware of the limited value of diagnosing plasma cell infiltration using only CD138. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by Finox Biotech. The authors have no conflicts of interests to declare. PROSPERO REGISTRATION NUMBER This systematic review was registered in PROSPERO in January 2020 (PROSPERO ID: CRD42020152915).

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Section: Discussionmentioning

confidence: 99%

The role of endometrial B cells in normal endometrium and benign female reproductive pathologies: a systematic review

Shen

O’Donnell

Leon

et al. 2021

Human Reproduction Open

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“…High expression of the gene encoding transcriptional repressor BCL6 (B-cell lymphoma 6) in the endometrium allows the detection of endometritis associated with endometriosis [ 161 ]. Elevated BCL6 and aromatase levels are associated with progesterone resistance and estrogen dominance in women with endometriosis [ 129 ].…”

Section: Inflammation-related Molecules In Pathologically Altered End...mentioning

confidence: 99%

Inflammation-Related Molecules at the Maternal–Fetal Interface during Pregnancy and in Pathologically Altered Endometrium

Sieg¹,

Kiewisz

Podolak

et al. 2022

CIMB

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The blastocyst expresses paternally derived alloantigens and induces inflammation during implantation. However, it is necessary for the onset of pregnancy. An abnormal response might result in a pathological course of pregnancy or pregnancy failure. On the other hand, a state of maternal immune tolerance is necessary to ensure the normal development of pregnancy by suppressing inflammatory processes. This article discusses recognized mechanisms and the significance of inflammatory processes for embryo implantation and pregnancy establishment. We would also like to present disorders involving excessive inflammatory response and their influence on events occurring during embryo implantation. The chain of correlation between the processes responsible for embryo implantation and the subsequent physiological course of pregnancy is complicated. Many of those interrelationships are still yet to be discovered. Undoubtedly, their recognition will give hope to infertile couples for the emergence of new treatments that will increase the chance of giving birth to a healthy child.

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“…Initially described as a proto-oncogene and transcriptional repressor implicated in the pathogenesis of B-cell lymphoma, BCL6 has recently been identified as a promising tissular biomarker which could be used to diagnose women affected by endometriosis [ 1 , 2 , 3 , 4 ]. The recent identification of actors acting in conjunction with BCL6, and the delineation of several target genes have helped to better determine its biological functions [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…While alternative methods such as medical imaging, genetic tests, or biomarkers are aimed at alleviating invasive diagnosis, none of them can adequately substitute for surgery at present [ 23 , 24 , 25 , 26 , 27 ]. Recent studies have identified a promising tissular biomarker called B-cell lymphoma 6 (BCL6), which could be used to diagnose women affected by endometriosis [ 1 , 2 , 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…BCL6 is a promising candidate as a unique diagnostic tissular biomarker for the detection of endometriosis in women. On the contrary, use of BCL6 as a protein biomarker in bodily fluids (such as serum and urine) for a less invasive diagnosis of endometriosis is not appropriate [ 2 ]. Furthermore, this factor was also overexpressed in the endometrium of women who suffer from unexplained infertility, recurrent miscarriages, or implantation failure during in vitro fertilization cycles [ 28 , 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

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Comparison of Morphological and Digital-Assisted Analysis for BCL6 Endometrial Expression in Women with Endometriosis

Squatrito

Blacher

Henry

et al. 2022

JCM

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BCL6 (B-cell lymphoma 6) is a proto-oncogene and transcriptional repressor initially described as being involved in B-cell lymphoma. Recently, this factor has been identified as a promising tissue biomarker which could be used to diagnose women affected by endometriosis. Previous studies used HSCORE for BCL6 staining quantification in the endometrium. However, this semi-quantitative technique of analysis has some limitations, including a lack of objectivity, robustness, and reproducibility that may lead to intra- and inter-observer variability. Our main goal was to develop an original computer-assisted method to quantify BCL6 staining from whole-slide images reliably. In order to test the efficiency of our new digital method of quantification, we compared endometrial BCL6 expression between fertile and infertile women without or with different stages of endometriosis by using the widely used HSCORE analysis and our new automatic digital image analysis. We find a higher expression of BCL6 in the endometrium of infertile women with endometriosis and women with stage IV endometriosis. Furthermore, we demonstrate a significant correlation between the two types of independent measurements, indicating the robustness of results and also the reliability of our computer-assisted method for BCL6 quantification. In conclusion, our work, by using this original computer-assisted method, enables BCL6 quantification more objectively, reliably, robustly, and promptly compared to HSCORE analysis.

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Evaluation of BCL6 and SIRT1 as Non-Invasive Diagnostic Markers of Endometriosis

Cited by 23 publications

References 45 publications

The role of endometrial B cells in normal endometrium and benign female reproductive pathologies: a systematic review

The role of endometrial B cells in normal endometrium and benign female reproductive pathologies: a systematic review

Inflammation-Related Molecules at the Maternal–Fetal Interface during Pregnancy and in Pathologically Altered Endometrium

Comparison of Morphological and Digital-Assisted Analysis for BCL6 Endometrial Expression in Women with Endometriosis

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