Mucosal Immunity in the Human Female Reproductive Tract

Garcia, Marta Rodriguez; Patel, Mickey V.; Shen, Zheng; Fahey, John V.; Biswas, Nabanita; Městecký, Jiří; Wira, Charles R.

doi:10.1016/b978-0-12-415847-4.00108-7

Cited by 11 publications

(7 citation statements)

References 242 publications

(286 reference statements)

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“…The uterine mucosal immune system plays an important role during maternal recognition and establishment of pregnancy. This is accomplished by maintaining a balance between the defense against pathogens and the tolerance toward the allogeneic sperm and semiallogeneic embryo, adapting thereby to different pregnancy-associated events (e.g., implantation, placentation, parturition) and contributing to tissue remodeling ( 1 – 3 ). This balance relies on the complex population of resident immune cells, composed of, e.g., macrophages, natural killer (NK) cells, B and T lymphocytes, regulated by local and systemic signaling, including endocrine insults ( 1 , 2 , 4 , 5 ), and changing during the progression of pregnancy.…”

Section: Introductionmentioning

confidence: 99%

Selected Uterine Immune Events Associated With the Establishment of Pregnancy in the Dog

et al. 2021

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In the dog, implantation takes place at approximately 17 days of embryonal life and, while exposed to relatively high circulating progesterone concentrations, embryos presence is required for the formation of decidua. Furthermore, a balance between pro- and anti-inflammatory responses in conceptus-maternal communication is crucial for the onset of pregnancy. Strikingly, the understanding of such immune mechanisms in canine reproduction is still elusive. Here, canine uterine samples from pre-implantation (day 10–12, E+) and corresponding non-pregnant controls (E–), implantation (day 17, Imp) and post-implantation (day 18–25, Post-Imp) stages of pregnancy were used to investigate the expression and localization of several immune-related factors. The most important findings indicate increased availability of CD4, MHCII, NCR1, IDO1, AIF1, CD25, CCR7, and IL6 in response to embryo presence (E+), while FoxP3 and CCL3 were more abundant in E– samples. Implantation was characterized by upregulated levels of FoxP3, IL12a, ENG, and CDH1, whereas CD4, CCR7, IL8, and -10 were less represented. Following implantation, decreased transcript levels of TNFR1, MHCII, NCR1, TLR4, CD206, FoxP3, and IL12a were observed concomitantly with the highest expression of IL6 and IL1β. MHCII, CD86, CD206, CD163, TNFα, IDO1, and AIF1 were immunolocalized in macrophages, CD4 and Nkp46 in lymphocytes, and some signals of IDO1, AIF1, and TNF-receptors could also be identified in endothelial cells and/or uterine glands. Cumulatively, new insights regarding uterine immunity in the peri-implantation period are provided, with apparent moderated pro-inflammatory signals prevailing during pre-implantation, while implantation and early trophoblast invasion appear to be associated with immunomodulatory and rather anti-inflammatory conditions.

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Section: Introductionmentioning

confidence: 99%

Selected Uterine Immune Events Associated With the Establishment of Pregnancy in the Dog

et al. 2021

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“…However, there is no clear diagnostic marker for PTB and proinflammatory cytokine and chemokine profiles differing among women who deliver pre-term ( Wei et al., 2010 ; Fettweis et al., 2019 ). In addition, elevation of proinflammatory markers including IL-6 and IL-8 are associated with HIV infection risk ( Mlisana et al., 2012 ; Rodriguez Garcia et al., 2015 ). Genital inflammation can lead to an increased risk of STI acquisition, with the infected epithelia being damaged, allowing the pathogens that cause STIs access to deeper tissues ( Passmore et al., 2016 ).…”

Section: Discussionmentioning

confidence: 99%

“…The epithelial barrier function and the physiological properties of the mucosal membranes lining the FRT are crucial in protecting the cervix from BV-associated bacteria ( Rodriguez Garcia et al., 2015 ). One of the key pathophysiological changes during BV is disruption of the epithelial barrier function, which allows pathogenic bacteria to access deeper tissues and induce inflammation ( Muzny et al., 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Immunometabolic Analysis of Mobiluncus mulieris and Eggerthella sp. Reveals Novel Insights Into Their Pathogenic Contributions to the Hallmarks of Bacterial Vaginosis

McKenzie

Maarsingh

Łaniewski

et al. 2021

Front. Cell. Infect. Microbiol.

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The cervicovaginal microbiome plays an important role in protecting women from dysbiosis and infection caused by pathogenic microorganisms. In healthy reproductive-age women the cervicovaginal microbiome is predominantly colonized by protective Lactobacillus spp. The loss of these protective bacteria leads to colonization of the cervicovaginal microenvironment by pathogenic microorganisms resulting in dysbiosis and bacterial vaginosis (BV). Mobiluncus mulieris and Eggerthella sp. are two of the many anaerobes that can contribute to BV, a condition associated with multiple adverse obstetric and gynecological outcomes. M. mulieris has been linked to high Nugent scores (relating to BV morphotypes) and preterm birth (PTB), whilst some bacterial members of the Eggerthellaceae family are highly prevalent in BV, and identified in ~85-95% of cases. The functional impact of M. mulieris and Eggerthella sp. in BV is still poorly understood. To determine the individual immunometabolic contributions of Eggerthella sp. and M. mulieris within the cervicovaginal microenvironment, we utilized our well-characterized human three-dimensional (3-D) cervical epithelial cell model in combination with multiplex immunoassays and global untargeted metabolomics approaches to identify key immune mediators and metabolites related to M. mulieris and Eggerthella sp. infections. We found that infection with M. mulieris significantly elevated multiple proinflammatory markers (IL-6, IL-8, TNF-α and MCP-1) and altered metabolites related to energy metabolism (nicotinamide and succinate) and oxidative stress (cysteinylglycine, cysteinylglycine disulfide and 2-hydroxygluatrate). Eggerthella sp. infection significantly elevated multiple sphingolipids and glycerolipids related to epithelial barrier function, and biogenic amines (putrescine and cadaverine) associated with elevated vaginal pH, vaginal amine odor and vaginal discharge. Our study elucidated that M. mulieris elevated multiple proinflammatory markers relating to PTB and STI acquisition, as well as altered energy metabolism and oxidative stress, whilst Eggerthella sp. upregulated multiple biogenic amines associated with the clinical diagnostic criteria of BV. Future studies are needed to evaluate how these bacteria interact with other BV-associated bacteria within the cervicovaginal microenvironment.

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“…Syndecan-1 regulates various cellular events, including migration, adhesion, proliferation, and growth, by acting as a coreceptor for different growth factors, cytokines, and chemokines [26]. Interferons (IFNs) secreted by cervical fibroblasts stimulate IFN-stimulated genes (ISGs), indicating cervical immune cell involvement in innate immunity by recognizing and responding to pathogens [28]. Cytotoxic T-lymphocytes (CTLs) in the cervix play a critical protective role and maintain their high levels despite menstrual status [28,29].…”

Section: The Immune Environment Of the Healthy Cervixmentioning

confidence: 99%

“…Interferons (IFNs) secreted by cervical fibroblasts stimulate IFN-stimulated genes (ISGs), indicating cervical immune cell involvement in innate immunity by recognizing and responding to pathogens [28]. Cytotoxic T-lymphocytes (CTLs) in the cervix play a critical protective role and maintain their high levels despite menstrual status [28,29]. However, CD3 + , CD4 + , and CD8 + cell populations are significantly smaller in the endocervix than in the ectocervix (as shown in Figure 1A).…”

Section: The Immune Environment Of the Healthy Cervixmentioning

confidence: 99%

TIME Is Ticking for Cervical Cancer

Kumar

Bauer

Stewart

2023

Biology

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Cervical cancer (CC) is a major health problem among reproductive-age females and comprises a leading cause of cancer-related deaths. Human papillomavirus (HPV) is the major risk factor associated with CC incidence. However, lifestyle is also a critical factor in CC pathogenesis. Despite HPV vaccination introduction, the incidence of CC is increasing worldwide. Therefore, it becomes critical to understand the CC tumor immune microenvironment (TIME) to develop immune cell-based vaccination and immunotherapeutic approaches. The current article discusses the immune environment in the normal cervix of adult females and its role in HPV infection. The subsequent sections discuss the alteration of different immune cells comprising CC TIME and their targeting as future therapeutic approaches.

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Mucosal Immunity in the Human Female Reproductive Tract

Cited by 11 publications

References 242 publications

Selected Uterine Immune Events Associated With the Establishment of Pregnancy in the Dog

Selected Uterine Immune Events Associated With the Establishment of Pregnancy in the Dog

Immunometabolic Analysis of Mobiluncus mulieris and Eggerthella sp. Reveals Novel Insights Into Their Pathogenic Contributions to the Hallmarks of Bacterial Vaginosis

TIME Is Ticking for Cervical Cancer

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