Localized cyclical variations in immunoproteins in the female genital tract and the implications on the design and assessment of mucosal infection and therapies

Makinde, Julia; Jones, C. K.; Bartolf, Angela; Sibeko, Sengeziwe; Baden, Susan; Cosgrove, Catherine; Shattock, Robin J.

doi:10.1111/aji.12801

Cited by 3 publications

(4 citation statements)

References 43 publications

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“…Interestingly, the lack of a recall response in both splenocytes and tissue occurred in the absence of a significant upregulation of TGFβ, suggesting a minimal T regulatory response. 33 However, the role of estrogen in preventing effective memory induction in the study was confounded by its negative impact on the ability of the attenuated vaccine to produce an effective primary infection. The triple adjuvant combination used to formulate the vaccines used in this study has been shown highly effective at inducing a significant recall response upon in vitro restimulation after only a single subcutaneous immunization in koalas.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the importance of endocrine state during subsequent evaluation of uterine immune capacity has been recently demonstrated. 33 While the current study was not geared toward evaluating the impact of endocrine signaling on the response to vaccination, interpretation of the results must be carried out in the context of this effect. Given rabbits are induced-ovulators, and the present experiment was conducted in the absence of a buck; our animals naturally oscillated between high and low estrogen states without the intervening high progesterone luteal phase.…”

Section: Cell-mediated Response Following Intrauterine Vaccinationmentioning

confidence: 99%

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Intrauterine vaccination induces a dose‐sensitive primary humoral response with limited evidence of recall potential

Pasternak

Hamonic

Kessel

et al. 2018

American J Rep Immunol

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Section: Discussionmentioning

confidence: 99%

Section: Cell-mediated Response Following Intrauterine Vaccinationmentioning

confidence: 99%

Intrauterine vaccination induces a dose‐sensitive primary humoral response with limited evidence of recall potential

Pasternak

Hamonic

Kessel

et al. 2018

American J Rep Immunol

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“…Moreover, for some immune mediators, data interpretation is complicated at times by conflicting results between studies. For example, four studies have observed higher interleukin 6 (IL-6) concentrations during the follicular phase [19,21,23,26], while two other studies have observed higher IL-6 concentrations in the luteal phase [11,12].…”

Section: Rationalementioning

confidence: 99%

Changes in concentrations of cervicovaginal immune mediators across the menstrual cycle: a systematic review and meta-analysis of individual patient data

Hughes

Levy²,

Katz³

et al. 2022

BMC Med

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Background Hormonal changes during the menstrual cycle play a key role in shaping immunity in the cervicovaginal tract. Cervicovaginal fluid contains cytokines, chemokines, immunoglobulins, and other immune mediators. Many studies have shown that the concentrations of these immune mediators change throughout the menstrual cycle, but the studies have often shown inconsistent results. Our understanding of immunological correlates of the menstrual cycle remains limited and could be improved by meta-analysis of the available evidence. Methods We performed a systematic review and meta-analysis of cervicovaginal immune mediator concentrations throughout the menstrual cycle using individual participant data. Study eligibility included strict definitions of the cycle phase (by progesterone or days since the last menstrual period) and no use of hormonal contraception or intrauterine devices. We performed random-effects meta-analyses using inverse-variance pooling to estimate concentration differences between the follicular and luteal phases. In addition, we performed a new laboratory study, measuring select immune mediators in cervicovaginal lavage samples. Results We screened 1570 abstracts and identified 71 eligible studies. We analyzed data from 31 studies, encompassing 39,589 concentration measurements of 77 immune mediators made on 2112 samples from 871 participants. Meta-analyses were performed on 53 immune mediators. Antibodies, CC-type chemokines, MMPs, IL-6, IL-16, IL-1RA, G-CSF, GNLY, and ICAM1 were lower in the luteal phase than the follicular phase. Only IL-1α, HBD-2, and HBD-3 were elevated in the luteal phase. There was minimal change between the phases for CXCL8, 9, and 10, interferons, TNF, SLPI, elafin, lysozyme, lactoferrin, and interleukins 1β, 2, 10, 12, 13, and 17A. The GRADE strength of evidence was moderate to high for all immune mediators listed here. Conclusions Despite the variability of cervicovaginal immune mediator measurements, our meta-analyses show clear and consistent changes during the menstrual cycle. Many immune mediators were lower in the luteal phase, including chemokines, antibodies, matrix metalloproteinases, and several interleukins. Only interleukin-1α and beta-defensins were higher in the luteal phase. These cyclical differences may have consequences for immunity, susceptibility to infection, and fertility. Our study emphasizes the need to control for the effect of the menstrual cycle on immune mediators in future studies.

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“…Other physiological processes or systems such as the immune system [25], fat metabolism [26], etc., all of which could potentially contribute to cancer risk, may also be influenced by this carrier state. Indeed, variations in immune function during the menstrual cycle, especially in sexually active women, are well documented [27][28][29] while a DNA methylation signature in blood cells, but not in buccal cells, is associated with cancer risk [25]. Moreover, lipid and metabolite deregulation was reported in breasts of BRCA1/2 mutation carriers [26].…”

Section: Introductionmentioning

confidence: 99%

Non-Surgical Cancer Risk Reduction in BRCA1 Mutation Carriers: Disabling the Remote Control

Widschwendter

Dubeau

2020

Cancers

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Women-specific cancers are a major health issue, particularly those associated with the BRCA1 germline mutation carrier state, which include triple-negative basal breast carcinomas and high-grade serous ovarian carcinomas (referred to as extra-uterine Müllerian carcinomas). Whereas many chronic diseases can currently be prevented (e.g., cardiovascular diseases), no recent tangible progress was made in cancer prevention of BRCA1 mutation carriers apart from surgical resections of at-risk organs. This lack of progress is largely due to (1) poor understanding of the initiating events triggered by known risk factors in the development of these cancers, (2) the fact that current preventive measures rely on evidence obtained from adjuvant breast cancer treatment that fail to protect against poor prognostic cancers, and (3) problems with using cancer incidence in high-risk women as an ethically justifiable endpoint in cancer prevention trials. Here, we propose that cancer predisposition in BRCA1 mutation carriers is driven, at least in part, by cell-nonautonomous mechanisms (i.e., driven by consequences of this carrier state on hormonal and other systemic factors controlled in organs other than those that are cancer-prone) and that biomarkers of epigenomic reprogramming, hypothesized to be a direct consequence of such cell-nonautonomous mechanisms, are attractive as intermediate surrogate endpoints to assess the efficacy of cancer risk-reducing strategies targeting these mechanisms.

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Localized cyclical variations in immunoproteins in the female genital tract and the implications on the design and assessment of mucosal infection and therapies

Abstract: Our results underscore the need to consider these localized cyclical differences in studies aimed at assessing the outcome of disease and the efficacy of mucosal vaccines and other therapies.

Cited by 3 publications

References 43 publications

Intrauterine vaccination induces a dose‐sensitive primary humoral response with limited evidence of recall potential

Intrauterine vaccination induces a dose‐sensitive primary humoral response with limited evidence of recall potential

Changes in concentrations of cervicovaginal immune mediators across the menstrual cycle: a systematic review and meta-analysis of individual patient data

Non-Surgical Cancer Risk Reduction in BRCA1 Mutation Carriers: Disabling the Remote Control

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