Mast Cell Activation Syndrome in COVID-19 and Female Reproductive Function: Theoretical Background vs. Accumulating Clinical Evidence

Szukiewicz, Dariusz; Wojdasiewicz, Piotr; Watroba, Mateusz; Szewczyk, Grzegorz

doi:https://doi.org/10.1155/2022/9534163

Journal of Immunology Research

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Review Article | Open Access

Volume 2022 | Article ID 9534163 | https://doi.org/10.1155/2022/9534163

Mast Cell Activation Syndrome in COVID-19 and Female Reproductive Function: Theoretical Background vs. Accumulating Clinical Evidence

Dariusz Szukiewicz,¹Piotr Wojdasiewicz,¹Mateusz Watroba,¹and Grzegorz Szewczyk¹

Academic Editor: Baohui Xu

Received03 Mar 2022

Revised19 May 2022

Accepted01 Jun 2022

Published22 Jun 2022

Abstract

Coronavirus disease 2019 (COVID-19), a pandemic disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, can affect almost all systems and organs of the human body, including those responsible for reproductive function in women. The multisystem inflammatory response in COVID-19 shows many analogies with mast cell activation syndrome (MCAS), and MCAS may be an important component in the course of COVID-19. Of note, the female sex hormones estradiol (E₂) and progesterone (P4) significantly influence mast cell (MC) behavior. This review presents the importance of MCs and the mediators from their granules in the female reproductive system, including pregnancy, and discusses the mechanism of potential disorders related to MCAS. Then, the available data on COVID-19 in the context of hormonal disorders, the course of endometriosis, female fertility, and the course of pregnancy were compiled to verify intuitively predicted threats. Surprisingly, although COVID-19 hyperinflammation and post-COVID-19 illness may be rooted in MCAS, the available clinical data do not provide grounds for treating this mechanism as significantly increasing the risk of abnormal female reproductive function, including pregnancy. Further studies in the context of post COVID-19 condition (long COVID), where inflammation and a procoagulative state resemble many aspects of MCAS, are needed.

1. Short Introduction: Signaling the Problem

COVID-19, a pandemic disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, can affect virtually all systems and organs of the human body, including those responsible for reproductive function in women [1]. Considering COVID-19 as a multisystem inflammatory response, the disease may reveal close analogy with conditions related to upregulation of the secretory activity of mast cells (MCs) with increased susceptibility to degranulation or mast cell activation syndrome (MCAS) [2]. The relationship between COVID-19 and reproductive function in women becomes clearer after taking into account the fact that female sex hormones, including estradiol (E₂) and progesterone (P4), significantly influence mast cell (MC) behavior [3].

2. MCs and MC-Derived Mediators in a Woman’s Reproductive System and Placenta

MCs are very special cells of the immune system derived from pluripotent cells of the myeloid lineage and are widely distributed in connective tissues throughout the body, including the reproductive system and placental tissue of women [4–6]. Unlike other white blood cells, MCs present in blood are immature in the form of MC progenitors generated from CD34⁺ hematopoietic stem cells, and these cells become fully competent after recruitment into the tissue at target localization [7]. Terminal differentiation of MCs occurs under the influence of c-kit ligand (CD117) and cytokine stem cell factor (SCF) in the local site microenvironment containing other distinct cytokines (e.g., IL-3 and IL-33), especially growth factors [8]. Thus, heterogeneity of the population of MCs is decisively observed because they reach their full maturity at the target site. This heterogeneity includes significant differences in the cell ultrastructure, morphology, mediator content, and surface receptors [9]. For example, based on the secretory granule content, human MCs are described as either MC_TC, which contains two serine proteases (tryptase and chymase) together with carboxypeptidase and cathepsin G, or MC_T, which contain only tryptase [10, 11]. The release of key mediators during the activation and degranulation of MCs, including COVID-19-related MC activation, may significantly affect the course of many physiological and pathological reproductive processes in the human body, primarily influencing the permeability of vessels and vascular tone and indirectly modulating electrolyte and water balance or contents of the extracellular matrix [12, 13]. Interestingly, the majority of the key physiological processes in the female reproductive tract, including menstruation, follicle development, ovulation, implantation, pregnancy, labor, and postpartum remodeling, consist of a readily visible inflammatory background [14]. Research successively provides new data. At present, the demonstrated roles of MCs and MC-derived mediators in the human female reproductive system in health and disease are summarized in Table 1.

It is worth noting the presence of MCs in neuroendocrine organs within the female reproductive system, such as ovaries and uterus, where the role of MCs still requires a better understanding [83]. Moreover, the functional status of MCs may be modulated by the female sex hormones E2 and progesterone P4 [3]. For example, NLRP3 inflammasome activation of MCs by estrogen via the nuclear-initiated signaling pathway contributes to the immune inflammatory response in endometriosis and further spreading of the disease [84]. MCs express E2 (ERα, ERβ, and G protein-coupled estrogen receptor (GPER) and P4 receptors (PR-A and PR-B) and further respond to these hormones, which causes changes in MC cell number, distribution, and degranulation in ovarian tissue [3, 85]. E2 and P4 upregulate chemokine receptor expression on MCs and promote their migration into the fetal-maternal interface with subsequent increased production of MC mediators. During the process of oocyte ovulation, E2-induced MC degranulation seems to be a crucial releasing factor, whereas P4 action is required in the peri-implantation period to initiate uterine spiral artery remodeling by decidual MCs [67, 86–88].

3. Secretory Activity of MCs: Main Categories of the Mediators, the Mechanisms of Activation and Degranulation

MCs together with adjacent dendritic cells act as sentinels for tissue damage and pathogen invasion by the release of various mediators from different compartments following diverse stimuli [89]. However, the interactions of MCs with viruses and viral products can have detrimental consequences, leading to a cytokine storm, as described in SARS-CoV-2 infection [90].

Contrary to the popular belief that MC degranulation is nonspecific based on an all-or-none law process in which many mediators are released, it is now apparent that specific mediators are secreted in response to particular stimuli or pathologic states [91].

MC mediators can be divided into three overlapping categories: preformed mediators, newly synthesized lipid mediators, and cytokines, including chemokines (Table 2).

MC secretory granules or secretory lysosomes reveal heterogeneity, and their heterogenous nature reflects many factors, including the tissue of residence and the species, health status and, to some degree, age of the individual [117, 118]. Following MC activation, preformed mediators are rapidly (within seconds to minutes) released into the extracellular environment. Degranulation with or without de novo synthesis of the mediator dominates the secretory profile of MCs; however, other options are also described therein, including de novo synthesized mediator release without degranulation [117] Table 2.

The typical and best-known mode of MC activation with the release of their granule content is associated with allergic reactions mediated via E class immunoglobulin (IgE) binding to the high-affinity receptor for immunoglobulin E (FcεRI) expressed on the MC surface [119]. Tetrameric FcεRI consists of the IgE-binding α-chain, the multimembrane spanning the β-chain, and a disulfide-linked homodimer of the γ-subunit (FcεRγ). The signaling pathway induced after FcεRI binds with IgE includes the activation of Lyn, one of several Src-family tyrosine kinases in immune cells, which phosphorylates tyrosines in its immunoreceptor tyrosine base activation motifs (ITAMs) on the β and γ chains of FcϵRI. Next, Lyn induces Syk tyrosine kinases to phosphorylate the signaling proteins that serve as the linkers for T cell activation (e.g., LAT1 and LAT2) [120]. Hydrolysis of phosphatidylinositol-4,5-bisphosphate leads to the formation of inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG), the second messengers for mobilizing intracellular calcium from the endoplasmic reticulum [121]. The influx of calcium ions produces both activation and translocation (toward the nucleus of the cell) of NF-κB with subsequent transcription of genes encoding various cytokines, including IL-1, IL-2, IL-6, IL-8, IL-12, IL-13, and TNFα [122]. The zinc finger transcription factor Zeb2 (also named Sip1, Zfhx1b) regulates both early and late MC responses related to FcεRI-mediated degranulation [123]. Complementary to the Lyn signaling pathway, another member of the Src family of tyrosine kinases, Fyn, is involved in the regulation of MC degranulation upon FcϵRI activation. Fyn is involved in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway, which ultimately leads to cytokine production and MC chemotaxis [124].

MCs also express FcγR, a receptor for IgG. The signal from FcγR can crosstalk with FcϵRI because the γ-chain homodimer is identical in FcγRI and FcϵRI [119]. In addition to the mentioned FcϵRI and FcγR, MCs express other receptors involved in their activation and/or immune response. Some of the most important receptors include Fc receptors for IgA and IgG; a G protein-coupled receptor known as MRGPRX2; angiotensin-converting enzyme 2 (ACE2) receptor; Toll-like receptors (TLRs) and other receptors for pathogen-associated molecular patterns (PAMPs); receptors for cytokines/chemokines, corticotropin releasing hormone, estrogen and progesterone; and complement receptors (e.g., C3a protein) [125–127]. Evidence indicates that the spike protein (S protein) is the main viral structure that SARS-CoV-2 uses to fuse with and enter human host cells by binding to the ACE2 receptor. This binding is followed by activation of the enzyme furin. Furin plays a vital role for the virus because the spike protein of SARS-CoV-2 must be cleaved by furin or furin-like proteases to become fully functional [128, 129]. Despite the fact that ACE2 is widely expressed in many different cells, including MCs, and is the one major receptor for SARS-CoV-2, other host receptors and/or coreceptors that promote the entry of the virus into cells have been reported recently [129].

Receptors with a documented role in MC activation and degranulation in the context of possible triggering by coronavirus/COVID-19 are shown in Figure 1. (i)The best-known mode of MC activation with degranulation and subsequent allergic reactions is mediated via IgE binding to FcεRI expressed on the MC surface. MCs also express FcγR (not marked in the figure), a receptor for IgG. The signal from FcγR can crosstalk with FcϵRI because the γ-chain homodimer is identical in FcγRI and FcϵRI [119](ii)The spike protein (S protein) is the main viral structure that SARS-CoV-2 uses to fuse with and enter human host cells by binding to ACE2 [128, 130]. MCs express the renin-angiotensin system, the ectoprotease ACE2 required for SARS-CoV-2 binding, and serine proteases, including TMPRSS2, required for priming of the corona spike protein [130]. Such triggers could lead to secretion of multiple proinflammatory mediators selectively, without release of histamine or tryptase [131](iii)IL-33 expression in response to SARS-CoV-2 correlates with seropositivity in COVID-19 convalescent individuals [132]. IL-33 needs the specific receptor ST2L and IL-1RAcP heterodimer for its binding, which stimulates the production of different types of cytokines and chemokines that have crucial roles in the exacerbation of allergic diseases and inflammation. Moreover, IL-33 augments IgE-mediated MC activation and potently enhances the human MC reactivity to C3a and C5a (degranulation, cytokine, and chemokine release), independent of changes in C3aR or C5aR receptor expression or the level of Ca2+ influx [133](iv)Elevated CRH level in COVID-19 may activate CRHR on MCs influencing vascular permeability. It was demonstrated that even COVID-19-related psychological stress is capable of inducing MC-related diseases, including mastocytosis. Psychological stress, by stimulating the release of corticotrophin releasing hormone (CRH) into the serum, can induce MC degranulation [134](v)Circulating S1P emerged as negative biomarker of severity/mortality of COVID-19 patients [135]. S1P generation induces calcium mobilization leading to MC degranulation. S1P affects immune cell function mostly by acting through its receptor S1P2R at the cell membrane but it can also induce S1P receptor-independent responses in the cells where it is generated(vi)Development of clinical COVID-19 involves dysfunctional MC activation and histamine release. It was suggested that histamine signaling pathway may be a potential therapeutic target to prevent COVID-19 from progressing to acute respiratory distress syndrome (ARDS) [136]. All known histamine receptors are expressed on MCs, but H1 and H4 have important roles in the progression and modulation of histamine-mediated allergic/inflammatory diseases(vii)Human MCs possess opioid receptors, which when stimulated trigger degranulation. The opioid system consists of four types of receptors: mu (Mμ), delta (δ), kappa (κ), and opioid receptor like-1 (ORL1) [137]. Opioid receptors may also be capable of modulating IgE-mediated histamine release [138](viii)TSLPR signaling is required for MC development and aggravates allergic reactions through the activation of mouse double minute 2 homolog (MDM2) and signal transducer and activator of transcription 6 (STAT6). TSLPR is formed by the signaling complex: TSLP and IL-7Rɑ [139](ix)PAF is generated by cells involved in host defense in a variety of inflammatory conditions in which MCs accumulate. PAF is capable of activating MCs and inducing a chemotactic response. COVID-19 manifestations, including pulmonary microthrombosis and inflammation, are mediated via PAF receptor [140](x)MRGPRX2 is a novel, low-affinity and low-selectivity receptor, to activate MCs in an IgE-independent manner [141]. This receptor has been cited as a therapeutic target for COVID-19 [142](xi)MCs respond to TLR ligands by secreting cytokines, chemokines, and lipid mediators, and some studies have found that TLR ligands can also cause degranulation, although this finding is contentious [143](xii)Several clinical investigations revealed that chemokines are directly involved in the different stages of SARS-CoV-2 infection [144]. At least nine chemokine receptors (CXCR1, CXCR2, CXCR3, CXCR4, CX3CR1, CCR1, CCR3, CCR4, and CCR5) have been described to be expressed by human MCs of different origins [145](xiii)Tryptase released from MCs can activate PAR-2 in an autocrine or paracrine manner [146]. It was suggested that PAR by proteases plays a role in COVID-19-induced hyperinflammation [147–149](xiv)Purinergic P2X ionotropic nucleotide receptors are ligand-gated ion channels activated by extracellular ATP and selective for monovalent and divalent cations (Na+, K+, and Ca2+), whereas purinergic G protein-coupled receptors P2Y are stimulated by nucleotides such as adenosine triphosphate, adenosine diphosphate, uridine triphosphate, uridine diphosphate, and UDP-glucose [150, 151]. Purinergic signaling is involved in the pathophysiology of several viral infections which makes the purinergic system a potential target of investigation in COVID-19 [152](xv)CD48 is in the CD2 subfamily of the immunoglobulin (Ig) superfamily and shares many structural features with other Ig family members. CD48 expression increases under inflammatory conditions [153]

Abbreviations in Figure 1 are as follows: ACE2: angiotensin-converting enzyme 2 receptor; CD48: cluster of differentiation 48 also known as B-lymphocyte activation marker (BLAST-1); CRHR: corticotropin-releasing hormone receptor; CRs: C3aR, C5aR—complement receptors; FcεRI: high-affinity receptor for the Fc region of immunoglobulin E (IgE); GPER: G protein-coupled estrogen receptor; HRs: H1-H4—histamine receptors; IgE: E class immunoglobulin; IL-1RAcP: IL-1 receptor accessory protein; IL-33: interleukin-33; IL-7Rɑ: IL-7 receptor ɑ chain; ST2L: suppression of tumorigenicity 2, IL-33 receptor; MRGPRX2: Mas-related G-protein-coupled receptor X2; P2X: ligand-gated ion channels (ionotropic receptors); P2Y: metabotropic purinergic receptors; PAF receptor: platelet-activating factor receptor; PAR2: protease-activated receptor 2; S1P2R: sphingosine-1-phosphate receptor 2; TLRs: Toll-like receptors; TMPRSS2: transmembrane serine protease 2; TSLP: thymic stromal lymphopoietin; TSLPR: thymic stromal lymphopoietin receptor.

Participating in intracellular signaling and promoting the production of proinflammatory cytokines involved in the regulation of the innate immune response, reactive oxygen species (ROS) stimulate MC degranulation via high-affinity receptors to IgE (FcεRI) [154]. Although ROS are intermediaries released during normal oxygen metabolism, deleterious effects of oxidative stress associated with an overabundance of ROS are also well documented with regard to female reproductive tissues in the context of an inflammatory background of infertility [155]. In healthy individuals, ROS and antioxidants are maintained in a balanced state, and the antioxidant systems in the ovary and endometrium are sufficient to limit the production of ROS, inactivate them, and repair cell damage [156, 157].

A local increase in the concentration of MC mediators in surroundings containing other MCs upregulates the secretory activity of these MCs, including susceptibility to degranulation. Such an activation syndrome may occur with an unchanged number of MCs as nonclonal MC activation syndrome (nc-MCAS) or together with MC hyperplasia in the form of MC activation syndrome (MCAS) [158–160]. Thus, changes in hormone and cytokine receptor expression caused by MC hyperplasia may be important when comparing MC activation in MCAS vs. nc-MCAS [160]. As proteases, mast cell tryptases are the only currently available convenient marker of human mast cell activation and burden [161]. Of note, tryptases are the most abundant proteases of the human MCs, comprising up to 20% of cellular protein [162]. Nevertheless, the major component of the granules that represents at least 30% of their dry weight is heparin, which is synthesized by MCs as a proteoglycan [109].

Notably, epigenetic mechanisms are also involved in MC activation and proliferation [163]. Numerous microRNAs (miRNAs) or small single-stranded noncoding RNA molecules containing 18 to 25 nucleotides that function in RNA silencing and posttranscriptional regulation of gene expression have been examined in the context of MC biology [164]. Acting via FcϵRI alone or together with increased levels of interleukins (IL-33, IL-10), the respective mRNAs may trigger signals for increased MC degranulation (miR-142-3p, miR-126), PI3K/Akt signaling pathway-dependent increased Ca²⁺ influx with degranulation (miR-155), or reduced MC migration with proliferation and increased degranulation (miR-221/222) [127, 165–167].

As a pandemic disease, COVID-19 raises interest in many aspects of female reproductive health effects [1, 168]. Knowledge on this subject is constantly being generated, and there is evidence that MC activation together with the induction of a cytokine storm may play a vital role in the pathomechanism of some reproductive disorders accompanying COVID-19 [2, 11]. The potential sites of these disorders are pointed in Figure 2.

Figure 2

The potential sites of mast cell activation syndrome (MCAS) that may affect female reproductive function. There are indications to believe that SARS-CoV-2 infection and related COVID-19 may produce release of MC mediators from MC sources within female reproductive organs and other related to reproduction organs, such as 1: hypothalamus; 2: pituitary gland; 3: thyroid gland; 4: endometrial tissue outside the uterus (endometriotic foci); 5: peritoneal fluid; 6: uterus (endometrium, myometrium), 7: fallopian tube; 8: ovary; and 9: blastocyst, placenta, and decidua. Surprisingly, in majority of cases, histologic rationale for increased risk of MCAS (i.e., presence of mast cells in the respective organs) is not confirmed by pathophysiology (i.e., clearly proven relationship: MCAS⟶reproductive disorder), and so far, clinical data do not support that COVID-19 triggers MCAS in female reproductive system. See the main text (Section 4) for details.

4.1. Hormonal Disorders

Hormonal disorders during COVID-19 vary, just as the response to SARS-CoV-2 infection varies [169, 170]. The changes in hormonal activities concern both the hormones directly regulating the menstrual cycle (luteinizing hormone (LH), follicle-stimulating hormone (FSH), and the female sex hormones E₂ and P4) and the hormones that may indirectly modulate its course (e.g., prolactin, thyroid-stimulating hormone (TSH), androgens, and glucocorticoids) [169, 171]. It was reported that approximately one-fifth of COVID-19 patients exhibited a menstrual volume decrease or cycle prolongation, approximately one-fifth exhibited menorrhagia, and approximately 30% experienced new dysmenorrhea [172, 173]. Considering the inflammatory background of menstruation, these last two symptoms and the worsening of already existing heavy menstrual bleeding or/and premenstrual symptoms may indicate the involvement of MC activation in the pathogenesis of cytokine storms in COVID-19 [2, 173]. Since P4, androgens, and glucocorticoids reveal natural immunosuppressive properties, it should be realized that E₂ is implicated in the immune response as an enhancer, including MC activation [174–177].

Among the estrogen receptors, GPER is responsible for the various running fast nongenomic effects of estrogens, including degranulation of MCs [178].

Unlike after activation of genomic pathways by classical nuclear ERα and ERβ receptor stimulation, nongenomic cellular responses to estrogen are initiated at the plasma membrane and result in rapid activation of second messenger-triggered cytoplasmic signal transduction cascades. Ultimately, after E2 binds to GPER, it mobilizes intracellular calcium and synthesizes phosphatidylinositol (3,4,5)-trisphosphate (PIP3) in the nucleus [179]. After estrogen binding, GPER may functionally cross-react with diverse cell signaling systems, such as the epidermal growth factor receptor (EGFR) pathway, the Notch signaling pathway, and the mitogen-activated protein kinases (MAPK) pathway [180].

Paradoxically, despite the risk of cytokine storms following MC degranulation, the net effect of E₂-related modulation of immune cells may be beneficial in SARS-CoV-2 infection. Based on preliminary research results, women with high levels of E₂ exhibited a lower risk of developing severe COVID-19 symptoms and a lower incidence of death [181]. On the other hand, serum E₂ levels in patients with COVID-19 may reflect the severity of infection, as any acute critical illness can lead to suppression of the hypothalamic–pituitary–ovarian axis, biochemically manifesting as low FSH, LH and E₂ [182]. Thus, the mechanisms of E₂ action in viral infections, including COVID-19, should be further comprehensively studied to provide a rationale for therapeutic strategies.

Thyroid hormones are vital for the proper functioning of the female reproductive system given that they modulate the metabolism and development of ovarian, uterine, and placental tissues. Hyperthyroidism is common in female patients with COVID-19 and coexists with thyroid-stimulating hormone (TSH) suppression that seems to be related to increased levels of the proinflammatory cytokine IL-6 [183, 184]. Based on recent studies, activation of MCs with a significantly higher number of degranulated MCs and histamine-induced overexpression of glycoprotein CD86 on antigen-presenting cells within thyroid gland tissue may be responsible for hyperthyroidism [185]. Moreover, MCs can synthesize and store TSH and the thyroid hormone triiodothyronine (T3) [186]. More research is needed to determine whether MCAS-related hyperthyroidism in COVID-19 has a significant impact on reproductive function in women.

4.2. Women with Endometriosis

Endometriosis is an estrogen-dependent and progesterone- (P4-) resistant inflammatory disorder of unknown etiology that affects 5–10% of women of reproductive age and is characterized by the presence of endometrial tissue outside the uterine cavity [187]. Patients with endometriotic foci (lesions) constitute up to 80% of women with pelvic pain and 20-50% of women with infertility. MCs are very prevalent in endometriosis tissue, and many MCs appear to be activated and degranulated. MCs and their products, tryptase, histamine, and many other proinflammatory cytokines, could contribute significantly to several features of endometriosis [76]. It was proposed that MCs represent a therapeutic target in endometriosis to assure better control of endometriosis inhibition and symptom relief [82]. Not surprisingly, endometriosis is included in the list of symptoms and findings in MCAS [76, 84]. Despite the existence of undoubted dysfunction of the immune system in endometriosis, no evidence is available that shows that those with endometriosis are at an increased risk of contracting COVID-19. It is likely that endometriosis does not increase the susceptibility to COVID-19 infections but alters the manifestation of the disease [188]. The prevalence of the disease may depend on the interaction between the virus and the individual's immune system, but further studies are required in this regard. However, although not confirmed, women with thoracic endometriosis (in the lungs and/or diaphragm) may be at increased risk [189]. The manifestation of COVID-19 may be altered in endometriosis with a slightly decreased frequency of asymptomatic infection and fever and an increased frequency of rare symptoms (i.e., sore throat, nasal congestion, cough, shortness of breath, headache, weakness, and muscle pain, reduced sense of smell and/or taste, and ocular problems) [190]. Further studies involving a larger group of patients are needed. On the other hand, exacerbations in pelvic pain may be experienced due to high levels of inflammatory/pain mediators as well as pauses in medical or allied health treatment or postponement of surgical treatments. Evidence that COVID-19 by itself accelerates the progression/development of endometriosis is not available [190].

4.3. Female Fertility and the Course of Pregnancy

Despite the fact that fertility (including low sperm count, low sperm quality, and reduced sperm mobility) and sexual function may be disrupted in a portion of male patients as a result of SARS-CoV-2 infection [191, 192], there is no evidence that a history of asymptomatic or mild SARS-CoV-2 infection in females may negatively affect normal female fertility or affect embryo laboratory outcomes or clinical outcomes in assisted reproductive technology (ART) treatments [168, 172, 193, 194]. Moreover, to date, cohort studies of SARS-CoV-2-positive mothers, including both asymptomatic mothers and those with mild symptoms, did not reveal adverse effects on the mothers or neonates regardless of the timing of the infection (i.e., first, second, or third trimester) [194–196]. Naturally, in severe COVID-19 among pregnant women requiring critical care, higher complication rates should be expected, and these increased rates are particularly related to a higher incidence of iatrogenic prematurity due to induction of preterm delivery in the face of the threat to the mother's life [197].

This finding is puzzling considering that genes encoding the SARS-CoV-2 angiotensin-converting enzyme 2 (ACE2) receptor, which is required for virus entry, and transmembrane serine protease 2 (TMPRSS2), which is required for spike (S) protein priming, are coexpressed in the trophoblast of the blastocyst and the syncytiotrophoblast and hypoblast of the implantation stages, which develop into tissues that interact with the maternal blood supply for nutrient exchange [198, 199]. This finding may demonstrate a high risk of vertical transmission among SARS-CoV-2 infections (see later in this section). However, as data continue to accumulate, the final findings may depend on the number of SARS-CoV-2-positive patients tested. To date, there are no comprehensive reviews or completed meta-analyses that explore the association between COVID-19 and female fertility, especially in the context of MC activation. The strength of such activation should be proportional to the strength of ACE2 and TMPRSS2 coexpression.

Ongoing studies are focused on demonstrating the adverse effects of SARS-CoV-2 infection on ovarian reserve function (mean AMH decline, elevation of basal FSH or LH, and abnormal FSH/LH ratio), changed uterine receptivity due to affected endometrial thickness and/or morphology, disturbed subendometrial blood flow and/or uterine spiral artery blood flow, and altered fallopian tube function and menstrual status [1].

It is crucial to identify cells simultaneously expressing ACE2 and TMPRSS2. Based on the latest results, it can be assumed that the female reproductive tract has a low concentration of SARS-CoV-2 receptors or, more precisely, ACE2 and TMPRSS2 are coexpressed on the same cells [200]. These results suggest that the myometrium, uterus, ovaries, and fallopian tube are likely not susceptible to infection by SARS-CoV-2. In another study on preconceptional human endometrium, analysis of cell entry factors for SARS-CoV-2 (including ACE2 and TMPRSS2) by single-cell RNA-sequencing (scRNAseq) revealed a low risk of infection [201]. In contrast to the mentioned papers, coexpression of the SARS-CoV-2 entry molecules ACE2 and TMPRSS2 has been confirmed within the human ovarian cortex and medulla, including oocytes of different stages and granulosa cells [202]. Regarding the latter two locations, no marked difference in ACE2 or TMPRSS2 expression was observed between young and old ovaries and ovaries with low and high reserves [202]. Thus, SARS-CoV-2 may potentially target specific ovarian cells and affect ovarian function. Moreover, recent research suggests the possibility of noncanonical cell entry machinery for SARS-CoV-2 based on the new putative receptors/co-factors identified [201]. For example, in vitro studies have demonstrated interactions between the spike protein of SARS-CoV-2 and the innate immune system, including C-lectin type receptors (CLR), Toll-like receptors (TLR) and neuropilin-1 (NRP1), and the nonimmune receptor glucose-regulated protein 78 (GRP78), which are constantly expression in female reproductive tissues [203]. At the level of the endometrium across the menstrual cycle, alternative potential cell entry machinery components include BSG, ANPEP, CD209, CLEC4G, TMPRSS4, TMPRSS11A, FURIN, CTSB, CTSL, and IFITM1 [200]. All of the abovementioned receptors/cofactors can also be important in the context of the further mutagenic activity of SARS-CoV-2.

There are many unknowns regarding the vertical transmission of SARS-CoV-2 through the placenta. In general, hematogenous spread as a mechanism of infection and transmission across the placenta into the fetal circulation appears unlikely due to inefficient viral replication in placental tissues. The majority of newborns delivered from SARS-CoV-2-positive mothers test negative following delivery, suggesting that protective mechanisms exist within the placenta [204]. Placental tissues showed significantly lower expression of both ACE2 and TMPRSS2 compared with adult lung tissues. Placental samples expressed low to no ACE2, whereas TMPRSS2 seemed to be present at variable levels in the chorionic villi [205]. The possibilities that a time window exists during pregnancy during which ACE2 and TMPRSS2 are coexpressed and that individual variability may influence the strength of this coexpression cannot be excluded. One possible reason for discordant results within the published literature may be the widespread presence of Fc receptors in the human placenta, as these are known to bind antibodies to varying affinities and may therefore lead to nonspecific staining [206, 207].

It was discovered that placental cytotrophoblasts and syncytiotrophoblasts express ACE2 from 7 weeks onward, suggesting that SARS-CoV-2 could cross into the placenta at any gestational age [208]. Studies of ACE2 and TMPRSS2 coexpression in the developing embryo up to day 14 (from surplus IVF human embryos) revealed the colocalization of these genes, raising concern about increased susceptibility to SARS-CoV-2 fetal infection in the early stages of embryonic development [198]. Despite the clearly confirmed possibility of SARS-CoV-2 infection during the peri-implantation period, the transplacental route of viral transmission seems to be uncommon, especially in the antenatal period. It was reported that term placenta expresses low to no ACE2. Lack of this key protein for SARS-CoV-2 infection makes it difficult for the virus to pass from the maternal blood to the fetus or amniotic fluid [209]. However, in the case of vertical transmission in which the viral genome was detected in term placentas, these cases were associated with a strong maternal proinflammatory response [207, 209–211]. Local degranulation of MCs may be highly responsible for these pathologic findings [6, 13]. Thus, SARS-CoV-2 can be associated with a rare set of placental lesions that can lead to fetal demise, preterm birth, or growth restriction. The massive placental damage is indirectly induced by the virus with subsequent trophoblast necrosis and massive inflammation in the villous chamber; in a similar manner, diffuse alveolar damage is noted in adults infected by SARS-CoV-2 [210]. Again, placental MCs may represent an important source of mediators that can activate other immune cell types during SARS-CoV-2 infection, and these cells have the potential to be a major contributor to the spread of the virus in cases of vertical transmission [14, 119]. Demonstrable placental SARS-CoV-2 placentitis is an uncommon but readily recognizable complication of maternal COVID-19 with potential use as a marker of vertical transmission [211].

In contrast to term placenta, single-cell transcriptomic studies of the early placenta (6–14 weeks of gestation) revealed stable coexpression of ACE2 and TMPRSS2 in stromal and perivascular cells in the decidua and villous cytotrophoblasts and syncytiotrophoblasts. This finding may suggest that women infected early in pregnancy could potentially pass SARS-CoV-2 to the fetus through the transplacental route [207].

Interestingly, the gastrointestinal tract may also be important for the route of vertical transmission given the high coexpression of both ACE2 and TMPRSS2 in the human fetal intestine across the first and, particularly, the second trimester. Intrauterine infection through the gastrointestinal tract requires SARS-CoV-2 entry into the fetal gastrointestinal lumen through fetal swallowing of infected amniotic fluid [207]. Developing MCs were detected in the mucosa of the fetal gastrointestinal tract, but their possible role in vertical transmission was not investigated [212].

Although the course of SARS-CoV-2 infection is asymptomatic in 70-80% of cases, observed symptoms in the vast majority of pregnant woman are benign, and the risk of vertical transmission is negligible, monitoring for adverse consequences of COVID-19 during pregnancy is reasonable [213]. Both the mother and especially the child may show long-term health effects of maternal immune system activation (including MCAS) in response to SARS-CoV-2 [205, 214]. The available data do not currently demonstrate an increased teratogenic potential of SARS-CoV-2, and limited evidence has not demonstrated any association between COVID-19 and an increased risk of miscarriage [215].

5. Concluding Remarks

Pregnant women do not appear to be more likely to contract SARS-CoV-2 than the general population or women of childbearing age [216]. However, intensive care admission and invasive ventilation are more common among pregnant women with COVID-19 compared with infected nonpregnant women of the same age [215, 217]. Analogous to respiratory function, it cannot be excluded that the cytokine storm accompanying SARS-CoV-2 infection and MCAS during COVID-19 may indirectly affect female reproductive function, especially in more severe cases [38, 204, 205]. The demonstrated roles of MCs and MC mediators in the human female reproductive system in health and disease have been presented elsewhere (see Table 1). Neutralization of upstream histamine, a major mediator derived from MCs, inhibits the nuclear translocation of NF-κB, thereby preventing the release of the proinflammatory cytokines interleukin- (IL-) 1β, TNF-α, IL-6, and IL-10 [218]. This effect has been successfully used in the MC-targeted treatment of chronic dyspareunia, vaginitis, and dysfunctional uterine bleeding [219]. Despite the fact that COVID-19 hyperinflammation and post-COVID-19 illness may be rooted in MCAS, the available clinical data do not provide grounds for treating this mechanism as a significant threat to female reproductive functions, including pregnancy [214]. Understandably, severe COVID-19 reduces female fertility and has been associated with impaired fetal growth during pregnancy, an approximate 2-fold increased risk of stillbirth, 3-fold increased risk of preterm birth (likely influenced by iatrogenic deliveries) and prematurity-related worse perinatal outcomes [215].

It should be noted that the pathophysiological spectrum of MCAS is extremely broad and heterogeneous with a strong female predilection. The above and environmental changes inducing epigenetic mechanisms may explain the increasing incidence of MCAS, which is estimated to be up to 17% [220]. Specific research in the pregnant or postpartum MCAS population related to SARS-CoV-2 infection and COVID-19 has not been performed to date. Data continue to accumulate, including those regarding the long-term influence of COVID-19 on the course of both preexisting and SARS-CoV-2-induced MCAS and female fertility. This is especially true for cases of so-called long COVID or post-acute COVID-19 when females experience lingering COVID-19 symptoms for weeks and months after this initial or acute phase of the infection [221]. It is noteworthy that long COVID with high residual cardiovascular risk and persistence of blood chemistry of inflammation and procoagulative state resembles many aspects of MCAS [222]. For example, in both pathologies, NLRP3 inflammasome (hyper)activation may be crucial in the consolidation of coagulation disorders within the female reproductive organs [223, 224]. Further studies are needed to determine whether MCAS-related clotting disorders (e.g., microcoagulopathy) are subjected to long-term modulation by SARS-CoV-2 infection with possible consequences on female reproductive function.

Abbreviations

5-HT:	5-Hydroxytryptamine, serotonin
αV-β3:	Member of the integrin family, also known as a vitronectin receptor
ACE:	Angiotensin-converting enzyme
ACE2:	Angiotensin-converting enzyme 2 receptor
Akt:	Protein kinase B
AMH:	Anti-Mullerian hormone
ANPEP:	Cell membrane alanyl aminopeptidase
ART:	Assisted reproductive technology
bFGF:	Basic fibroblast growth factor
CCL2:	C-C motif chemokine ligand 2, monocyte chemoattractant protein-1 (MCP-1)
CCL8:	C-C motif chemokine 8
CCL17:	C-C motif chemokine ligand 17
CCL22:	C-C motif chemokine ligand 22
CCR1:	C-C chemokine receptor type 1
CD117:	The c-kit protooncogene product
CLEC4G:	C-type lectin domain family 4 member G
CLR:	C-type lectin receptors
COVID-19:	Coronavirus Disease 2019
CRH:	Corticotropin-releasing hormone
CTSL:	Lysosomal cysteine peptidase cathepsin L
CTSB:	Cathepsin B
CX3CL1:	C-X3-C motif chemokine ligand 1 or fractalkine
CXCL8:	C-X-C motif chemokine ligand 8 or interleukin 8 (IL-8)
CXCL10:	C-X-C motif chemokine ligand 10, also known as interferon-gamma-induced protein 10 (IP-10)
CXCL11:	C-X-C motif chemokine ligand 11
DAG:	Diacylglycerol
E2:	Estradiol
ECM:	Extracellular matrix
EGFR:	Epidermal growth factor receptor
ERα, ERβ:	Estrogen receptors alpha, beta
ET-1:	Endothelin 1
FcεRIα:	High-affinity IgE receptor
FGR:	Fetal growth restriction
FSH:	Follicle-stimulating hormone
GM-CSF:	Granulocyte-macrophage colony-stimulating factor
GPER:	G protein-coupled estrogen receptor
GRP78:	Glucose regulated protein 78
H1, H2, H3, H4:	Histamine receptors: H1 H2, H3 and H4, respectively
HLA-G:	Human leukocyte antigen
IFITM1:	Interferon-induced transmembrane protein 1
IgE:	E class immunoglobulin
IL-1, IL-3, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-31, IL-33:	Interleukins
IP3:	Inositol-1,4,5-triphosphate
ITAMs:	Immunoreceptor tyrosine-based activation motifs
IUD:	Contraceptive intrauterine device
IVF:	In vitro fertilization
JAK3:	Janus kinase 3 of the killer cell Ig-like receptor (KIR)
LAD2:	Laboratory of allergic diseases 2 human MCs
LAT1, LAT2:	Linkers for activation of T cells family, member 1 and 2, respectively
LH:	Luteinizing hormone
LIF:	Leukemia inhibitory factor
LTs (LTC4, LTD4, LTE4, LTB4):	Leukotrienes: LTC4, LTD4, LTE4, LTB4
MAPK:	Mitogen-activated protein kinases
MC, MCs:	Mast cell, mast cells
MCAS:	Mast cell activation syndrome
MCP-1/CCL2:	Monocyte chemoattractant protein-1
MCT:	Tryptase+ but chymase– MC subtype
MCTC:	Tryptase+ and chymase+ MC subtype
miRNAs (e.g., miR-142-3p, miR-126, miR-155, and miR-221/222):	MicroRNAs
MRGPRX2:	Mas-related G-protein coupled receptor member X2
MMPs:	Metalloproteinases
mTOR:	Mammalian target of rapamycin (mTOR)
nc-MCAS:	Nonclonal MC activation syndrome
NGF:	Nerve growth factor
NLRP3:	Inflammasome (NOD-, LRR-, and pyrin domain-containing protein 3)
NRP1:	Neuropilin-1
NF-κB:	Nuclear factor kappa-light-chain-enhancer of activated B cells
P4:	Progesterone
p75NTR:	Low-affinity receptor for neurotrophins
PAF:	Platelet-activating factor
PAMPs:	Pathogen-associated molecular patterns
PCO:	Polycystic ovaries
PDGF:	Platelet-derived growth factor
PGs:	Prostaglandins
PIP3:	Phosphatidylinositol (3,4,5)-trisphosphate
PR-A, PR-B:	progesterone (P4) receptors A, B
ROS:	Reactive oxygen species
SARS-CoV-2:	Severe acute respiratory syndrome coronavirus 2
SCF:	Stem cell factor
scRNAseq:	Single-cell RNA-sequencing
GF-β1, TGF-β2:	Transforming growth factors: β1 and β2, respectively
Th2 cell:	T helper type 2 cell
TLRs:	Toll-like receptor
TMPRSS2, TMPRSS4, TMPRSS11A:	Transmembrane serine proteases: 2, 4 and 11A, respectively
TNF-α:	Tumor necrosis factor α
TrkA:	Neurotrophic tyrosine kinase receptor (NTRK1)
TSH:	Thyroid-stimulating hormone
Ucn:	Urocortin
VEGF:	Vascular endothelial growth factor
Zeb2:	Zinc finger E-box-binding homeobox 2 or Smad interacting protein 1 (Sip1)

Data Availability

Data availability issue does not apply to this review paper. All data are from the published papers and are included in the references.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

References

F. Li, H. Lu, Q. Zhang et al., “Impact of COVID-19 on female fertility: a systematic review and meta-analysis protocol,” BMJ Open., vol. 11, no. 2, article e045524, 2021.
View at: Publisher Site | Google Scholar
T. C. Theoharides and P. Conti, “COVID-19 and multisystem inflammatory syndrome, or is it mast cell activation syndrome?” J Biol Regul Homeost Agents, vol. 34, no. 5, pp. 1633–1636, 2020.
View at: Publisher Site | Google Scholar
O. Zierau, A. C. Zenclussen, and F. Jensen, “Role of female sex hormones, estradiol and progesterone, in mast cell behavior,” Front Immunol., vol. 3, p. 169, 2012.
View at: Publisher Site | Google Scholar
P. Valent, C. Akin, K. Hartmann et al., “Mast cells as a unique hematopoietic lineage and cell system: from Paul Ehrlich's visions to precision medicine concepts,” Theranostics., vol. 10, no. 23, pp. 10743–10768, 2020.
View at: Publisher Site | Google Scholar
S. K. Lee, C. J. Kim, D. J. Kim, and J. H. Kang, “Immune cells in the female reproductive tract,” Immune Netw., vol. 15, no. 1, pp. 16–26, 2015.
View at: Publisher Site | Google Scholar
W. M. Purcell and T. H. Hanahoe, “A novel source of mast cells: the human placenta,” Agents Actions., vol. 33, no. 1-2, pp. 8–12, 1991.
View at: Publisher Site | Google Scholar
G. Csaba, “Mast cell, the peculiar member of the immune system: a homeostatic aspect,” Acta Microbiol Immunol Hung., vol. 62, no. 3, pp. 207–231, 2015.
View at: Publisher Site | Google Scholar
J. Grootens, J. S. Ungerstedt, G. Nilsson, and J. S. Dahlin, “Deciphering the differentiation trajectory from hematopoietic stem cells to mast cells,” Blood Adv., vol. 2, no. 17, pp. 2273–2281, 2018.
View at: Publisher Site | Google Scholar
B. Frossi, F. Mion, R. Sibilano, L. Danelli, and C. E. M. Pucillo, “Is it time for a new classification of mast cells? What do we know about mast cell heterogeneity?” Immunol Rev., vol. 282, no. 1, pp. 35–46, 2018.
View at: Publisher Site | Google Scholar
D. Atiakshin, I. Buchwalow, V. Samoilova, and M. Tiemann, “Tryptase as a polyfunctional component of mast cells,” Histochem Cell Biol., vol. 149, no. 5, pp. 461–477, 2018.
View at: Publisher Site | Google Scholar
D. Atiakshin, I. Buchwalow, and M. Tiemann, “Mast cell chymase: morphofunctional characteristics,” Histochem Cell Biol., vol. 152, no. 4, pp. 253–269, 2019.
View at: Publisher Site | Google Scholar
K. Woidacki, F. Jensen, and A. C. Zenclussen, “Mast cells as novel mediators of reproductive processes,” Front Immunol., vol. 4, p. 29, 2013.
View at: Publisher Site | Google Scholar
F. M. Menzies, M. C. Shepherd, R. J. Nibbs, and S. M. Nelson, “The role of mast cells and their mediators in reproduction, pregnancy and labour,” Hum Reprod Update., vol. 17, no. 3, pp. 383–396, 2011.
View at: Publisher Site | Google Scholar
Y. Negishi, Y. Shima, T. Takeshita, and R. Morita, “Harmful and beneficial effects of inflammatory response on reproduction: sterile and pathogen-associated inflammation,” Immunol Med., vol. 44, no. 2, pp. 98–115, 2021.
View at: Publisher Site | Google Scholar
J. Goto, N. Kanayama, T. Asahina, Y. Okada, T. Kobayashi, and T. Terao, “Induction of follicular growth by exogenous interleukin-8,” Hum Reprod., vol. 12, no. 12, pp. 2729–2734, 1997.
View at: Publisher Site | Google Scholar
D. Szukiewicz, M. Pyzlak, J. Klimkiewicz, G. Szewczyk, and D. Maslinska, “Mast cell-derived interleukin-8 may be involved in the ovarian mechanisms of follicle growth and ovulation,” Inflamm Res., vol. 56, Suppl 1, pp. S35–S36, 2007.
View at: Publisher Site | Google Scholar
S. L. Field, T. Dasgupta, M. Cummings, and N. M. Orsi, “Cytokines in ovarian folliculogenesis, oocyte maturation and luteinisation,” Mol Reprod Dev., vol. 81, no. 4, pp. 284–314, 2014.
View at: Publisher Site | Google Scholar
D. Szukiewicz, J. Klimkiewicz, M. Pyzlak, G. Szewczyk, and D. Maslinska, “Locally secreted histamine may regulate the development of ovarian follicles by apoptosis,” Inflamm Res., vol. 56, Suppl 1, pp. S33–S34, 2007.
View at: Publisher Site | Google Scholar
A. Krishna, K. Beesley, and P. F. Terranova, “Histamine, mast cells and ovarian function,” J Endocrinol., vol. 120, no. 3, pp. 363–371, 1989.
View at: Publisher Site | Google Scholar
D. Szukiewicz, G. Szewczyk, J. Klimkiewicz, M. Pyzlak, and D. Maslinska, “The role of histamine and its receptors in the development of ovarian follicles in vitro,” Inflamm Res., vol. 55, Suppl 1, pp. S49–S50, 2006.
View at: Publisher Site | Google Scholar
A. M. Galvão, D. Skarzynski, and G. Ferreira-Dias, “Luteolysis and the auto-, paracrine role of cytokines from tumor necrosis factor α and transforming growth factor β superfamilies,” Vitam Horm., vol. 107, pp. 287–315, 2018.
View at: Publisher Site | Google Scholar
U. Heider, I. Pedal, and K. Spanel-Borowski, “Increase in nerve fibers and loss of mast cells in polycystic and postmenopausal ovaries,” Fertil Steril., vol. 75, no. 6, pp. 1141–1147, 2001.
View at: Publisher Site | Google Scholar
A. Krishna, A. al Rifai, B. Hubner, P. Rother, and K. Spanel-Borowski, “Increase in calcitonin gene related peptide (CGRP) and decrease in mast cells in dihydroepiandrosterone (DHEA)-induced polycystic rat ovaries,” Anat Embryol (Berl)., vol. 203, no. 5, pp. 375–382, 2001.
View at: Publisher Site | Google Scholar
H. M. Chang, H. C. Wu, Z. G. Sun, F. Lian, and P. C. K. Leung, “Neurotrophins and glial cell line-derived neurotrophic factor in the ovary: physiological and pathophysiological implications,” Hum Reprod Update., vol. 25, no. 2, pp. 224–242, 2019.
View at: Publisher Site | Google Scholar
J. K. Chan, A. Magistris, V. Loizzi et al., “Mast cell density, angiogenesis, blood clotting, and prognosis in women with advanced ovarian cancer,” Gynecol Oncol., vol. 99, no. 1, pp. 20–25, 2005.
View at: Publisher Site | Google Scholar
S. A. Oldford and J. S. Marshall, “Mast cells as targets for immunotherapy of solid tumors,” Mol Immunol., vol. 63, no. 1, pp. 113–124, 2015.
View at: Publisher Site | Google Scholar
D. E. A. Komi and F. A. Redegeld, “Role of mast cells in shaping the tumor microenvironment,” Clin Rev Allergy Immunol., vol. 58, no. 3, pp. 313–325, 2020.
View at: Publisher Site | Google Scholar
B. I. Glukhovets, I. I. Ukhov, and S. S. Lebedev, “Tsiklicheskie izmeneniia tuchno-kletochnoĭ reaktsii i krovenosnykh kapilliarov v stenke matochnykh trub u zhenshchin [Cyclic changes in mast cell response and capillaries in the wall of the Fallopian tubes of women],” Arkh Anat Gistol Embriol., vol. 79, no. 9, pp. 55–58, 1980.
View at: Google Scholar
R. Sandvei, A. L. Wollen, P. R. Flood, and C. Anker, “Mast cells in the tubal wall in women using an intrauterine contraceptive device,” Br J Obstet Gynaecol., vol. 93, no. 7, pp. 758–764, 1986.
View at: Publisher Site | Google Scholar
E. Oral, D. L. Olive, and A. Arici, “The peritoneal environment in endometriosis,” Hum Reprod Update., vol. 2, no. 5, pp. 385–398, 1996.
View at: Publisher Site | Google Scholar
M. G. D. Broi, R. A. Ferriani, and P. A. Navarro, “Ethiopathogenic mechanisms of endometriosis-related infertility,” JBRA Assisted Reproduction, vol. 23, no. 3, pp. 273–280, 2019.
View at: Publisher Site | Google Scholar
V. Borelli, M. Martinelli, S. Luppi et al., “Mast cells in peritoneal fluid from women with endometriosis and their possible role in modulating sperm function,” Front Physiol., vol. 10, p. 1543, 2020.
View at: Publisher Site | Google Scholar
L. Drudy, B. L. Sheppard, and J. Bonnar, “The ultrastructure of mast cells in the uterus throughout the normal menstrual cycle and the postmenopause,” J Anat, vol. 14, no. 1, p. 51, 1991.
View at: Publisher Site | Google Scholar
E. Sivridis, A. Giatromanolaki, N. Agnantis, and P. Anastasiadis, “Mast cell distribution and density in the normal uterus -- metachromatic staining using lectins,” Eur J Obstet Gynecol Reprod Biol., vol. 98, no. 1, pp. 109–113, 2001.
View at: Publisher Site | Google Scholar
M. Al-Jefout, K. Black, L. Schulke et al., “Novel finding of high density of activated mast cells in endometrial polyps,” Fertil Steril., vol. 92, no. 3, pp. 1104–1106, 2009.
View at: Publisher Site | Google Scholar
T. El-Hamarneh, A. J. Hey-Cunningham, M. Berbic, M. Al-Jefout, I. S. Fraser, and K. Black, “Cellular immune environment in endometrial polyps,” Fertil Steril., vol. 100, no. 5, pp. 1364–1372, 2013.
View at: Publisher Site | Google Scholar
F. Jensen, M. Woudwyk, A. Teles et al., “Estradiol and progesterone regulate the migration of mast cells from the periphery to the uterus and induce their maturation and degranulation,” PLoS One., vol. 5, no. 12, article e14409, 2010.
View at: Publisher Site | Google Scholar
D. Elieh Ali Komi, F. Shafaghat, and G. Haidl, “Significance of mast cells in spermatogenesis, implantation, pregnancy, and abortion: cross talk and molecular mechanisms,” Am J Reprod Immunol, vol. 83, no. 5, p. e13228, 2020.
View at: Publisher Site | Google Scholar
K. Woidacki, A. C. Zenclussen, and F. Siebenhaar, “Mast cell-mediated and associated disorders in pregnancy: a risky game with an uncertain outcome?” Front Immunol., vol. 5, p. 231, 2014.
View at: Publisher Site | Google Scholar
H. Saito, “Role of mast cell proteases in tissue remodeling,” Chem Immunol Allergy., vol. 87, pp. 80–84, 2005.
View at: Publisher Site | Google Scholar
T. Matsuno, S. Toyoshima, T. Sakamoto-Sasaki et al., “Characterization of human decidual mast cells and establishment of a culture system,” Allergol Int., vol. 67, pp. S18–S24, 2018.
View at: Publisher Site | Google Scholar
Y. Derbala, H. Elazzamy, M. Bilal et al., “Mast cell-induced immunopathology in recurrent pregnancy losses,” Am J Reprod Immunol., vol. 82, no. 1, article e13128, 2019.
View at: Publisher Site | Google Scholar
C. Ueshima, T. R. Kataoka, M. Hirata et al., “Possible involvement of human mast cells in the establishment of pregnancy via killer cell Ig-like receptor 2DL4,” Am J Pathol., vol. 188, no. 6, pp. 1497–1508, 2018.
View at: Publisher Site | Google Scholar
T. R. Kataoka, C. Ueshima, M. Hirata, S. Minamiguchi, and H. Haga, “Killer immunoglobulin-like receptor 2DL4 (CD158d) regulates human mast cells both positively and negatively: possible roles in pregnancy and cancer metastasis,” Int J Mol Sci., vol. 21, no. 3, p. 954, 2020.
View at: Publisher Site | Google Scholar
G. Szewczyk, D. Szukiewicz, J. Klimkiewicz, M. Pyzlak, A. Szewczyk, and K. Krajewska, “Influence of histamine on the process of human trophoblast differentiation,” Inflamm Res., vol. 54, Suppl 1, pp. S78–S79, 2005.
View at: Publisher Site | Google Scholar
M. Yin, P. Zhu, H. Luo, and R. Xu, “The presence of mast cells in the human endometrium pre- and post-insertion of intrauterine devices,” Contraception., vol. 48, no. 3, pp. 245–254, 1993.
View at: Publisher Site | Google Scholar
C. H. Chou, S. U. Chen, C. T. Shun, P. N. Tsao, Y. S. Yang, and J. H. Yang, “Divergent endometrial inflammatory cytokine expression at peri-implantation period and after the stimulation by copper intrauterine device,” Sci Rep., vol. 5, no. 1, p. 15157, 2015.
View at: Publisher Site | Google Scholar
R. E. Garfield, A. M. Irani, L. B. Schwartz, E. Bytautiene, and R. Romero, “Structural and functional comparison of mast cells in the pregnant versus nonpregnant human uterus,” Am J Obstet Gynecol., vol. 194, no. 1, pp. 261–267, 2006.
View at: Publisher Site | Google Scholar
E. Bytautiene, Y. P. Vedernikov, G. R. Saade, R. Romero, and R. E. Garfield, “Degranulation of uterine mast cell modifies contractility of isolated myometrium from pregnant women,” Am J Obstet Gynecol., vol. 191, no. 5, pp. 1705–1710, 2004.
View at: Publisher Site | Google Scholar
D. Szukiewicz, D. Maslinska, J. Stelmachów, and E. Wojtecka-Lukasik, “Biogenetic amines in placental tissue. Relation to the contractile activity of the human uterus. Preliminary communication,” Clin Exp Obstet Gynecol., vol. 22, no. 1, pp. 66–70, 1995.
View at: Google Scholar
R. Mitani, K. Maeda, R. Fukui et al., “Production of human mast cell chymase in human myometrium and placenta in cases of normal pregnancy and preeclampsia,” Eur J Obstet Gynecol Reprod Biol., vol. 101, no. 2, pp. 155–160, 2002.
View at: Publisher Site | Google Scholar
P. D'Orléans-Juste, M. Houde, G. A. Rae, G. Bkaily, E. Carrier, and E. Simard, “Endothelin-1 (1-31): from chymase-dependent synthesis to cardiovascular pathologies,” Vascul Pharmacol., vol. 49, no. 2-3, pp. 51–62, 2008.
View at: Publisher Site | Google Scholar
A. Norström, N. Vukas Radulovic, M. Bullarbo, and E. Ekerhovd, “Mast cell involvement in human cervical ripening,” Eur J Obstet Gynecol Reprod Biol., vol. 238, pp. 157–163, 2019.
View at: Publisher Site | Google Scholar
M. Kurihara-Shimomura, T. Sasahira, H. Shimomura, A. K. Bosserhoff, and T. Kirita, “Mast cell chymase promotes angiogenesis and lymphangiogenesis mediated by activation of melanoma inhibitory activity gene family members in oral squamous cell carcinoma,” Int J Oncol., vol. 56, no. 5, pp. 1093–1100, 2020.
View at: Publisher Site | Google Scholar
D. A. de Souza, A. C. Borges, A. C. Santana, C. Oliver, and M. C. Jamur, “Mast cell proteases 6 and 7 stimulate angiogenesis by inducing endothelial cells to release angiogenic factors,” PLoS One., vol. 10, no. 12, article e0144081, 2015.
View at: Publisher Site | Google Scholar
D. Szukiewicz, A. Szukiewicz, D. Maslinska, P. Poppe, M. Gujski, and M. Olszewski, “Mast cells and histamine in intrauterine growth retardation--relation to the development of placental microvessels,” Inflamm Res., vol. 48, no. 1, pp. 41-42, 1999.
View at: Publisher Site | Google Scholar
D. Szukiewicz, A. Szukiewicz, D. Maslinska, G. Szewczyk, and M. Watroba, “Mast cell-derived vascular endothelial growth factor (VEGF) and microvascular density in diabetic placentae,” Inflamm Res., vol. 52, pp. s9–10, 2003.
View at: Publisher Site | Google Scholar
G. Szewczyk, D. Maślińska, D. Szukiewicz, W. Śmiertka, J. Klimkiewicz, and M. Pyzlak, “Histamine H4 receptors in human placenta in diabetes-complicated pregnancy,” Inflamm Res., vol. 56, Suppl 1, pp. S31–S32, 2007.
View at: Publisher Site | Google Scholar
M. M. Faas and P. De Vos, “Innate immune cells in the placental bed in healthy pregnancy and preeclampsia,” Placenta., vol. 69, pp. 125–133, 2018.
View at: Publisher Site | Google Scholar
Y. Wang and J. S. Alexander, “Role of chymase in preeclampsia,” Curr Vasc Pharmacol., vol. 11, no. 5, pp. 606–615, 2013.
View at: Publisher Site | Google Scholar
G. Szewczyk, M. Pyzlak, J. Klimkiewicz, W. Smiertka, M. Miedzińska-Maciejewska, and D. Szukiewicz, “Mast cells and histamine: do they influence placental vascular network and development in preeclampsia?” Mediators Inflamm., vol. 2012, article 307189, 5 pages, 2012.
View at: Publisher Site | Google Scholar
D. Szukiewicz, A. Szukiewicz, D. Maslinska, M. Gujski, P. Poppe, and J. Mazurek-Kantor, “Mast cell number, histamine concentration and placental vascular response to histamine in preeclampsia,” Inflamm Res., vol. 48, pp. 39-40, 1999.
View at: Publisher Site | Google Scholar
G. Szewczyk, M. Pyzlak, W. Smiertka, J. Klimkiewicz, and D. Szukiewicz, “Does histamine influence differentiation of trophoblast in preeclampsia?” Inflamm Res., vol. 57, Suppl 1, pp. 71-72, 2008.
View at: Publisher Site | Google Scholar
N. Meyer, K. Woidacki, M. Knöfler et al., “Chymase-producing cells of the innate immune system are required for decidual vascular remodeling and fetal growth,” Sci Rep., vol. 7, no. 1, p. 45106, 2017.
View at: Publisher Site | Google Scholar
Z. M. Wu, H. Yang, M. Li et al., “Pro-inflammatory cytokine-stimulated first trimester decidual cells enhance macrophage-induced apoptosis of extravillous trophoblasts,” Placenta., vol. 33, no. 3, pp. 188–194, 2012.
View at: Publisher Site | Google Scholar
M. Pyzlak, G. Szewczyk, D. Szukiewicz, and A. Szczesniak, “Histamine influence on apoptosis in trophoblast cell cultures,” Inflamm Res., vol. 59, Suppl 2, pp. S213–S215, 2010.
View at: Publisher Site | Google Scholar
Z. Liu, B. A. Kilburn, R. E. Leach, R. Romero, B. C. Paria, and D. R. Armant, “Histamine enhances cytotrophoblast invasion by inducing intracellular calcium transients through the histamine type-1 receptor,” Mol Reprod Dev., vol. 68, no. 3, pp. 345–353, 2004.
View at: Publisher Site | Google Scholar
K. Needham, M. Fadia, J. E. Dahlstrom, K. Harrington, B. Shadbolt, and S. Robson, “Significance of mast cell distribution in placental tissue and membranes in spontaneous preterm birth,” J Inflamm Res., vol. Volume 9, pp. 141–145, 2016.
View at: Publisher Site | Google Scholar
M. S. Abelius, U. Enke, F. Varosi et al., “Placental immune response to apple allergen in allergic mothers,” J Reprod Immunol., vol. 106, pp. 100–109, 2014.
View at: Publisher Site | Google Scholar
A. L. Mikkelsen, C. Felding, L. G. Larsen, B. Andersen, and P. Sander, “Mast cells in the placenta. Is there a relation to the development of atopic disease in infants before 18 months of age?” J Perinat Med., vol. 22, no. 4, pp. 273–278, 1994.
View at: Publisher Site | Google Scholar
K. Straubinger, S. Paul, O. Prazeres da Costa et al., “Maternal immune response to helminth infection during pregnancy determines offspring susceptibility to allergic airway inflammation,” J Allergy Clin Immunol, vol. 134, no. 6, pp. 1271–1279.e10, 2014.
View at: Publisher Site | Google Scholar
N. Papadogiannakis, M. Joerink, E. Rindsjö, A. Scheynius, and J. Alm, “Placental inflammation, lifestyle, maternal and early child sensitisation to allergens - the assessment of lifestyle and allergic disease during infancy birth cohort,” Acta Paediatr., vol. 108, no. 5, pp. 927–932, 2019.
View at: Publisher Site | Google Scholar
V. Anaf, C. Chapron, I. El Nakadi, V. De Moor, T. Simonart, and J. C. Noël, “Pain, mast cells, and nerves in peritoneal, ovarian, and deep infiltrating endometriosis,” Fertil Steril., vol. 86, no. 5, pp. 1336–1343, 2006.
View at: Publisher Site | Google Scholar
T. H. Zhu, G. Zou, S. J. Ding et al., “Mast cell stabilizer ketotifen reduces hyperalgesia in a rodent model of surgically induced endometriosis,” J Pain Res., vol. 12, pp. 1359–1369, 2019.
View at: Publisher Site | Google Scholar
O. J. D'Cruz and F. M. Uckun, “Targeting mast cells in endometriosis with Janus kinase 3 inhibitor, JANEX-1,” Am J Reprod Immunol., vol. 58, no. 2, pp. 75–97, 2007.
View at: Publisher Site | Google Scholar
T. H. Zhu, S. J. Ding, T. T. Li, L. B. Zhu, X. F. Huang, and X. M. Zhang, “Estrogen is an important mediator of mast cell activation in ovarian endometriomas,” Reproduction., vol. 155, no. 1, pp. 73–83, 2018.
View at: Publisher Site | Google Scholar
D. Kirchhoff, S. Kaulfuss, U. Fuhrmann, M. Maurer, and T. M. Zollner, “Mast cells in endometriosis: guilty or innocent bystanders?” Expert Opin Ther Targets., vol. 16, no. 3, pp. 237–241, 2012.
View at: Publisher Site | Google Scholar
D. Kempuraj, N. Papadopoulou, E. J. Stanford et al., “Increased numbers of activated mast cells in endometriosis lesions positive for corticotropin-releasing hormone and urocortin,” Am J Reprod Immunol., vol. 52, no. 4, pp. 267–275, 2004.
View at: Publisher Site | Google Scholar
K. Norrby, “Evidence of a dual role of endogenous histamine in angiogenesis,” Int J Exp Pathol., vol. 76, no. 2, pp. 87–92, 1995.
View at: Google Scholar
S. Xue, H. Tang, G. Zhao et al., “C-C Motif Chemokine 8 promotes angiogenesis in vascular endothelial cells,” Vascular., vol. 29, no. 3, pp. 429–441, 2021.
View at: Publisher Site | Google Scholar
T. Li, J. Wang, X. Guo et al., “Possible involvement of crosstalk between endometrial cells and mast cells in the development of endometriosis via CCL8/CCR1,” Biomed Pharmacother., vol. 129, p. 110476, 2020.
View at: Publisher Site | Google Scholar
M. M. Binda, J. Donnez, and M. M. Dolmans, “Targeting mast cells: a new way to treat endometriosis,” Expert Opin Ther Targets., vol. 21, no. 1, pp. 67–75, 2017.
View at: Publisher Site | Google Scholar
T. C. Theoharides, “Neuroendocrinology of mast cells: challenges and controversies,” Exp Dermatol., vol. 26, no. 9, pp. 751–759, 2017.
View at: Publisher Site | Google Scholar
X. Guo, X. Xu, T. Li et al., “NLRP3 inflammasome activation of mast cells by estrogen via the nuclear-initiated signaling pathway contributes to the development of endometriosis,” Front Immunol., vol. 12, p. 749979, 2021.
View at: Publisher Site | Google Scholar
K. Jaiswal and A. Krishna, “Effects of hormones on the number, distribution and degranulation of mast cells in the ovarian complex of mice,” Acta Physiol Hung., vol. 84, no. 2, pp. 183–190, 1996.
View at: Google Scholar
G. Schmidt, C. Owman, and N. O. Sjöberg, “Cellular localization of ovarian histamine, its cyclic variations, and histaminergic effects on ovulation in the rat ovary perfused in vitro,” Reproduction, vol. 82, no. 2, pp. 409–417, 1988.
View at: Publisher Site | Google Scholar
P. Hamouzova, P. Cizek, A. Bartoskova, R. Vitasek, and F. Tichy, “Changes in the mast cell distribution in the canine ovary and uterus throughout the oestrous cycle,” Reprod Domest Anim., vol. 55, no. 4, pp. 479–485, 2020.
View at: Publisher Site | Google Scholar
A. Schumacher, D. J. Sharkey, S. A. Robertson, and A. C. Zenclussen, “Immune cells at the fetomaternal interface: how the microenvironment modulates immune cells to foster fetal development,” J Immunol., vol. 201, no. 2, pp. 325–334, 2018.
View at: Publisher Site | Google Scholar
J. S. Marshall, L. Portales-Cervantes, and E. Leong, “Mast cell responses to viruses and pathogen products,” Int J Mol Sci., vol. 20, no. 17, p. 4241, 2019.
View at: Publisher Site | Google Scholar
G. Conti, N. Giannitto, F. L. De Luca et al., “Kawasaki disease and cardiac involvement: an update on the state of the art,” J Biol Regul Homeost Agents, vol. 34, pp. 1629–1632, 2020.
View at: Publisher Site | Google Scholar
S. N. Abraham and A. L. St John, “Mast cell-orchestrated immunity to pathogens,” Nat Rev Immunol., vol. 10, no. 6, pp. 440–452, 2010.
View at: Publisher Site | Google Scholar
S. J. Galli, N. Gaudenzio, and M. Tsai, “Mast cells in inflammation and disease: recent progress and ongoing concerns,” Annu Rev Immunol., vol. 38, pp. 49–77, 2020.
View at: Publisher Site | Google Scholar
R. B. Silver, A. C. Reid, C. J. Mackins et al., “Mast cells: a unique source of renin,” Proc Natl Acad Sci U S A., vol. 101, no. 37, pp. 13607–13612, 2004.
View at: Publisher Site | Google Scholar
K. Maaninka, S. D. Nguyen, M. I. Mäyränpää et al., “Human mast cell neutral proteases generate modified LDL particles with increased proteoglycan binding,” Atherosclerosis., vol. 275, pp. 390–399, 2018.
View at: Publisher Site | Google Scholar
K. M. Heutinck, I. J. ten Berge, C. E. Hack, J. Hamann, and A. T. Rowshani, “Serine proteases of the human immune system in health and disease,” Mol Immunol., vol. 47, no. 11-12, pp. 1943–1955, 2010.
View at: Publisher Site | Google Scholar
G. Peljer, M. Abrink, M. Ringvall, and S. Wernersson, “Mast cell proteases,” Adv Immunol., vol. 95, pp. 167–255, 2007.
View at: Publisher Site | Google Scholar
G. Peljer, E. Ronnberg, I. Waern, and S. Wernersson, “Mast cell proteases: multifaceted regulators of inflammatory disease,” Blood., vol. 115, no. 24, pp. 4981–4990, 2010.
View at: Publisher Site | Google Scholar
G. H. Caughey, “Mast cell proteases as pharmacological targets,” Eur J Pharmacol., vol. 778, pp. 44–55, 2016.
View at: Publisher Site | Google Scholar
J. Wang, S. Sjöberg, T. T. Tang et al., “Cathepsin G activity lowers plasma LDL and reduces atherosclerosis,” Biochim Biophys Acta., vol. 1842, no. 11, pp. 2174–2183, 2014.
View at: Publisher Site | Google Scholar
E. Tiligada and M. Ennis, “Histamine pharmacology: from Sir Henry Dale to the 21st century,” Br J Pharmacol., vol. 177, no. 3, pp. 469–489, 2020.
View at: Publisher Site | Google Scholar
M. Walter and H. Stark, “Histamine receptor subtypes: a century of rational drug design,” Front Biosci, vol. S4, no. 2, pp. 461–488, 2012.
View at: Publisher Site | Google Scholar
E. B. Thangam, E. A. Jemima, H. Singh et al., “The role of histamine and histamine receptors in mast cell-mediated allergy and inflammation: the hunt for new therapeutic targets,” Front Immunol., vol. 9, p. 1873, 2018.
View at: Publisher Site | Google Scholar
Y. Hattori, K. Hattori, and N. Matsuda, “Regulation of the cardiovascular system by histamine,” Handb Exp Pharmacol., vol. 241, pp. 239–258, 2017.
View at: Publisher Site | Google Scholar
A. Bonnin and P. Levitt, “Fetal, maternal, and placental sources of serotonin and new implications for developmental programming of the brain,” Neuroscience., vol. 197, pp. 1–7, 2011.
View at: Publisher Site | Google Scholar
S. Ranzil, D. W. Walker, A. J. Borg, E. M. Wallace, P. R. Ebeling, and P. Murthi, “The relationship between the placental serotonin pathway and fetal growth restriction,” Biochimie., vol. 161, pp. 80–87, 2019.
View at: Publisher Site | Google Scholar
N. M. Kushnir-Sukhov, J. M. Brown, Y. Wu, A. Kirshenbaum, and D. D. Metcalfe, “Human mast cells are capable of serotonin synthesis and release,” J Allergy Clin Immunol., vol. 119, no. 2, pp. 498-499, 2007.
View at: Publisher Site | Google Scholar
M. Ritter, H. El-Nour, M. A. Hedblad et al., “Serotonin and its 5-HT1 receptor in human mastocytosis,” Immunopharmacol Immunotoxicol., vol. 34, no. 4, pp. 679–685, 2012.
View at: Publisher Site | Google Scholar
K. M. Nautiyal, C. A. Dailey, J. L. Jahn et al., “Serotonin of mast cell origin contributes to hippocampal function,” Eur J Neurosci., vol. 36, no. 3, pp. 2347–2359, 2012.
View at: Publisher Site | Google Scholar
E. Rönnberg, F. R. Melo, and G. Pejler, “Mast cell proteoglycans,” J Histochem Cytochem., vol. 60, no. 12, pp. 950–962, 2012.
View at: Publisher Site | Google Scholar
B. Mulloy, R. Lever, and C. P. Page, “Mast cell glycosaminoglycans,” Glycoconj J., vol. 34, no. 3, pp. 351–361, 2017.
View at: Publisher Site | Google Scholar
J. L. Zehnder and S. J. Galli, “Mast-cell heparin demystified,” Nature., vol. 400, no. 6746, pp. 714-715, 1999.
View at: Publisher Site | Google Scholar
M. N. A. Sahid and T. Kiyoi, “Mast cell activation markers for in vitro study,” J Immunoassay Immunochem., vol. 41, no. 4, pp. 778–816, 2020.
View at: Publisher Site | Google Scholar
B. Liu, J. Yang, W. Luo et al., “Prostaglandin D₂ is the major cyclooxygenase-1-derived product in prepartum mouse uteri where it mediates an enhanced in vitro myometrial contraction,” Eur J Pharmacol., vol. 813, pp. 140–146, 2017.
View at: Publisher Site | Google Scholar
T. Nakamura and T. Murata, “Regulation of vascular permeability in anaphylaxis,” Br J Pharmacol., vol. 175, no. 13, pp. 2538–2542, 2018.
View at: Publisher Site | Google Scholar
T. C. Theoharides, K. D. Alysandratos, A. Angelidou et al., “Mast cells and inflammation,” Biochim Biophys Acta., vol. 1822, no. 1, pp. 21–33, 2012.
View at: Publisher Site | Google Scholar
D. Elieh Ali Komi, S. Wöhrl, and L. Bielory, “Mast cell biology at molecular level: a comprehensive review,” Clin Rev Allergy Immunol., vol. 58, no. 3, pp. 342–365, 2020.
View at: Publisher Site | Google Scholar
T. C. Moon, A. D. Befus, and M. Kulka, “Mast cell mediators: their differential release and the secretory pathways involved,” Front Immunol., vol. 5, p. 569, 2014.
View at: Publisher Site | Google Scholar
T. C. Moon, C. D. St Laurent, K. E. Morris et al., “Advances in mast cell biology: new understanding of heterogeneity and function,” Mucosal Immunol, vol. 3, no. 2, pp. 111–128, 2010.
View at: Publisher Site | Google Scholar
R. Sibilano, B. Frossi, and C. E. Pucillo, “Mast cell activation: a complex interplay of positive and negative signaling pathways,” Eur J Immunol., vol. 44, no. 9, pp. 2558–2566, 2014.
View at: Publisher Site | Google Scholar
C. Tkaczyk, S. Iwaki, D. D. Metcalfe, and A. M. Gilfillan, “Roles of adaptor molecules in mast cell activation,” Chem Immunol Allergy., vol. 87, pp. 43–58, 2005.
View at: Publisher Site | Google Scholar
T. Ishizaka, J. R. White, and H. Saito, “Activation of basophils and mast cells for mediator release,” Int Arch Allergy Appl Immunol., vol. 82, no. 3-4, pp. 327–332, 1987.
View at: Publisher Site | Google Scholar
T. Liu, L. Zhang, D. Joo, and S. C. Sun, “NF-κB signaling in inflammation,” Signal Transduct Target Ther, vol. 2, p. 17023, 2017.
View at: Publisher Site | Google Scholar
E. A. Barbu, J. Zhang, E. H. Berenstein, J. R. Groves, L. M. Parks, and R. P. Siraganian, “The transcription factor Zeb2 regulates signaling in mast cells,” J Immunol., vol. 188, no. 12, pp. 6278–6286, 2012.
View at: Publisher Site | Google Scholar
M. S. Kim, H. S. Kuehn, D. D. Metcalfe, and A. M. Gilfillan, “Activation and function of the mTORC1 pathway in mast cells,” J Immunol., vol. 180, no. 7, pp. 4586–4595, 2008.
View at: Publisher Site | Google Scholar
P. L. Quan, M. Sabaté-Brescó, Y. Guo, M. Martín, and G. Gastaminza, “The multifaceted Mas-related G protein-coupled receptor member X2 in allergic diseases and beyond,” Int J Mol Sci., vol. 22, no. 9, p. 4421, 2021.
View at: Publisher Site | Google Scholar
U. Blank, H. Huang, and T. Kawakami, “The high affinity IgE receptor: a signaling update,” Curr Opin Immunol., vol. 72, pp. 51–58, 2021.
View at: Publisher Site | Google Scholar
D. O. Lyons and N. A. Pullen, “Beyond IgE: alternative mast cell activation across different disease states,” Int J Mol Sci., vol. 21, no. 4, p. 1498, 2020.
View at: Publisher Site | Google Scholar
J. Lu and P. D. Sun, “High affinity binding of SARS-CoV-2 spike protein enhances ACE2 carboxypeptidase activity,” J Biol Chem., vol. 295, no. 52, pp. 18579–18588, 2020.
View at: Publisher Site | Google Scholar
Q. Zhang, R. Xiang, S. Huo et al., “Molecular mechanism of interaction between SARS-CoV-2 and host cells and interventional therapy,” Signal Transduct Target Ther., vol. 6, no. 1, p. 233, 2021.
View at: Publisher Site | Google Scholar
T. C. Theoharides, “COVID-19, pulmonary mast cells, cytokine storms, and beneficial actions of luteolin,” Biofactors., vol. 46, no. 3, pp. 306–308, 2020.
View at: Publisher Site | Google Scholar
T. C. Theoharides, “Potential association of mast cells with coronavirus disease 2019,” Ann Allergy Asthma Immunol., vol. 126, no. 3, pp. 217-218, 2021.
View at: Publisher Site | Google Scholar
M. A. Stanczak, D. E. Sanin, P. Apostolova et al., “IL-33 expression in response to SARS-CoV-2 correlates with seropositivity in COVID-19 convalescent individuals,” Nat Commun., vol. 12, no. 1, p. 2133, 2021.
View at: Publisher Site | Google Scholar
P. W. West, R. Bahri, K. M. Garcia-Rodriguez et al., “Interleukin-33 amplifies human mast cell activities induced by complement anaphylatoxins,” Front Immunol., vol. 11, p. 615236, 2021.
View at: Publisher Site | Google Scholar
T. C. Theoharides, “The impact of psychological stress on mast cells,” Ann Allergy Asthma Immunol., vol. 125, no. 4, pp. 388–392, 2020.
View at: Publisher Site | Google Scholar
G. Marfia, S. Navone, L. Guarnaccia et al., “Decreased serum level of sphingosine-1-phosphate: a novel predictor of clinical severity in COVID-19,” EMBO Mol Med, vol. 13, no. 1, article e13424, 2021.
View at: Publisher Site | Google Scholar
M. Ennis and K. Tiligada, “Histamine receptors and COVID-19,” Inflamm Res., vol. 70, no. 1, pp. 67–75, 2021.
View at: Publisher Site | Google Scholar
R. Al-Hasani and M. R. Bruchas, “Molecular mechanisms of opioid receptor-dependent signaling and behavior,” Anesthesiology., vol. 115, no. 6, pp. 1363–1381, 2011.
View at: Publisher Site | Google Scholar
K. E. Barke and L. B. Hough, “Opiates, mast cells and histamine release,” Life Sci., vol. 53, no. 18, pp. 1391–1399, 1993.
View at: Publisher Site | Google Scholar
N. R. Han, H. A. Oh, S. Y. Nam et al., “TSLP induces mast cell development and aggravates allergic reactions through the activation of MDM2 and STAT6,” J Invest Dermatol., vol. 134, no. 10, pp. 2521–2530, 2014.
View at: Publisher Site | Google Scholar
C. Demopoulos, S. Antonopoulou, and T. C. Theoharides, “COVID-19, microthromboses, inflammation, and platelet activating factor,” Biofactors., vol. 46, no. 6, pp. 927–933, 2020.
View at: Publisher Site | Google Scholar
Y. N. Mi, N. N. Ping, and Y. X. Cao, “Ligands and signaling of Mas-related G protein-coupled receptor-X2 in mast cell activation,” Rev Physiol Biochem Pharmacol., vol. 179, pp. 139–188, 2021.
View at: Publisher Site | Google Scholar
H. Y. Lam, V. Tergaonkar, A. P. Kumar, and K. S. Ahn, “Mast cells: therapeutic targets for COVID-19 and beyond,” IUBMB Life., vol. 73, no. 11, pp. 1278–1292, 2021.
View at: Publisher Site | Google Scholar
H. Sandig and S. Bulfone-Paus, “TLR signaling in mast cells: common and unique features,” Front Immunol., vol. 3, p. 185, 2012.
View at: Publisher Site | Google Scholar
B. A. Khalil, N. M. Elemam, and A. A. Maghazachi, “Chemokines and chemokine receptors during COVID-19 infection,” Comput Struct Biotechnol J., vol. 19, pp. 976–988, 2021.
View at: Publisher Site | Google Scholar
M. Juremalm and G. Nilsson, “Chemokine receptor expression by mast cells,” Chem Immunol Allergy., vol. 87, pp. 130–144, 2005.
View at: Publisher Site | Google Scholar
J. Li, S. Jubair, S. P. Levick, and J. S. Janicki, “The autocrine role of tryptase in pressure overload-induced mast cell activation, chymase release and cardiac fibrosis,” IJC Metab Endocr., vol. 10, pp. 16–23, 2016.
View at: Publisher Site | Google Scholar
H. S. Palmer, E. B. Kelso, J. C. Lockhart et al., “Protease-activated receptor 2 mediates the proinflammatory effects of synovial mast cells,” Arthritis Rheum., vol. 56, no. 11, pp. 3532–3540, 2007.
View at: Publisher Site | Google Scholar
S. Nagashima, A. A. Dutra, M. P. Arantes et al., “COVID-19 and lung mast cells: the Kallikrein-Kinin activation pathway,” Int J Mol Sci, vol. 23, no. 3, p. 1714, 2022.
View at: Publisher Site | Google Scholar
S. Subramaniam, W. Ruf, and M. Bosmann, “Advocacy of targeting protease-activated receptors in severe coronavirus disease 2019,” Br J Pharmacol., vol. 179, no. 10, pp. 2086–2099, 2022.
View at: Publisher Site | Google Scholar
Z. G. Gao, Q. Wei, M. P. Jayasekara, and K. A. Jacobson, “The role of P2Y(14) and other P2Y receptors in degranulation of human LAD2 mast cells,” Purinergic Signal., vol. 9, no. 1, pp. 31–40, 2013.
View at: Publisher Site | Google Scholar
Z. G. Gao and K. A. Jacobson, “Purinergic signaling in mast cell degranulation and asthma,” Front Pharmacol., vol. 8, p. 947, 2017.
View at: Publisher Site | Google Scholar
M. L. M. Franciosi, M. D. M. Lima, M. R. C. Schetinger, and A. M. Cardoso, “Possible role of purinergic signaling in COVID-19,” Mol Cell Biochem., vol. 476, no. 8, pp. 2891–2898, 2021.
View at: Publisher Site | Google Scholar
S. L. McArdel, C. Terhorst, and A. H. Sharpe, “Roles of CD48 in regulating immunity and tolerance,” Clin Immunol., vol. 164, pp. 10–20, 2016.
View at: Publisher Site | Google Scholar
M. A. Chelombitko, A. V. Fedorov, O. P. Ilyinskaya, R. A. Zinovkin, and B. V. Chernyak, “Role of reactive oxygen species in mast cell degranulation,” Biochemistry (Mosc)., vol. 81, no. 12, pp. 1564–1577, 2016.
View at: Publisher Site | Google Scholar
J. Donnez, M. M. Binda, O. Donnez, and M. M. Dolmans, “Oxidative stress in the pelvic cavity and its role in the pathogenesis of endometriosis,” Fertil Steril., vol. 106, no. 5, pp. 1011–1017, 2016.
View at: Publisher Site | Google Scholar
F. Zal, F. Khademi, R. Taheri, and Z. Mostafavi-Pour, “Antioxidant ameliorating effects against H2O2-induced cytotoxicity in primary endometrial cells,” Toxicol Mech Methods., vol. 28, no. 2, pp. 122–129, 2018.
View at: Publisher Site | Google Scholar
A. Mancini, C. Bruno, E. Vergani, C. d’Abate, E. Giacchi, and A. Silvestrini, “Oxidative stress and low-grade inflammation in polycystic ovary syndrome: controversies and new insights,” Int J Mol Sci., vol. 22, no. 4, p. 1667, 2021.
View at: Publisher Site | Google Scholar
J. C. Cardet, M. C. Castells, and M. J. Hamilton, “Immunology and clinical manifestations of non-clonal mast cell activation syndrome,” Curr Allergy Asthma Rep., vol. 13, no. 1, pp. 10–18, 2013.
View at: Publisher Site | Google Scholar
A. Giannetti, E. Filice, C. Caffarelli, G. Ricci, and A. Pession, “Mast cell activation disorders,” Medicina (Kaunas)., vol. 57, no. 2, p. 124, 2021.
View at: Publisher Site | Google Scholar
A. I. Petra, S. Panagiotidou, J. M. Stewart, P. Conti, and T. C. Theoharides, “Spectrum of mast cell activation disorders,” Expert Rev Clin Immunol., vol. 10, no. 6, pp. 729–739, 2014.
View at: Publisher Site | Google Scholar
J. H. Butterfield, A. Ravi, and T. Pongdee, “Mast cell mediators of significance in clinical practice in mastocytosis,” Immunol Allergy Clin North Am., vol. 38, no. 3, pp. 397–410, 2018.
View at: Publisher Site | Google Scholar
L. B. Schwartz, A. M. Irani, K. Roller, M. C. Castells, and N. M. Schechter, “Quantitation of histamine, tryptase, and chymase in dispersed human T and TC mast cells,” J Immunol., vol. 138, no. 8, pp. 2611–2615, 1987.
View at: Google Scholar
G. J. Molderings, “Transgenerational transmission of systemic mast cell activation disease-- genetic and epigenetic features,” Transl Res., vol. 174, pp. 86–97, 2016.
View at: Publisher Site | Google Scholar
H. S. Kim, Y. Kawakami, K. Kasakura, and T. Kawakami, “Recent advances in mast cell activation and regulation,” F1000Res, vol. 9, p. 196, 2020.
View at: Publisher Site | Google Scholar
Y. Yamada, K. Kosaka, T. Miyazawa, K. Kurata-Miura, and T. Yoshida, “miR-142-3p enhances FcεRI-mediated degranulation in mast cells,” Biochem Biophys Res Commun., vol. 443, no. 3, pp. 980–986, 2014.
View at: Publisher Site | Google Scholar
Y. Bao, S. Wang, Y. Gao et al., “MicroRNA-126 accelerates IgE-mediated mast cell degranulation associated with the PI3K/Akt signaling pathway by promoting Ca²⁺ influx,” Exp Ther Med., vol. 16, no. 3, pp. 2763–2769, 2018.
View at: Publisher Site | Google Scholar
R. J. Mayoral, M. E. Pipkin, M. Pachkov, E. van Nimwegen, A. Rao, and S. Monticelli, “MicroRNA-221-222 regulate the cell cycle in mast cells,” J Immunol., vol. 182, no. 1, pp. 433–445, 2009.
View at: Publisher Site | Google Scholar
R. Li, T. Yin, F. Fang et al., “Potential risks of SARS-CoV-2 infection on reproductive health,” Reprod Biomed Online., vol. 41, no. 1, pp. 89–95, 2020.
View at: Publisher Site | Google Scholar
V. Kantroo, S. Bhattacharya, A. Dhingra, and S. Kalra, “Pulmocrinology: interplay of pulmonary and endocrine diseases,” J Pak Med Assoc., vol. 71, no. 3, pp. 1033–1038, 2021.
View at: Google Scholar
T. Ciarambino, O. Para, and M. Giordano, “Immune system and COVID-19 by sex differences and age,” Womens Health, vol. 17, p. 174550652110222, 2021.
View at: Publisher Site | Google Scholar
A. Selek, M. Güçlü, and Ş. E. Bolu, “COVID-19 pandemic: what about the gonads?” Hormones, vol. 20, no. 2, pp. 259–268, 2021.
View at: Publisher Site | Google Scholar
K. Li, G. Chen, H. Hou et al., “Analysis of sex hormones and menstruation in COVID-19 women of child-bearing age,” Reprod Biomed Online., vol. 42, no. 1, pp. 260–267, 2021.
View at: Publisher Site | Google Scholar
N. Phelan, L. A. Behan, and L. Owens, “The impact of the COVID-19 pandemic on women's reproductive health,” Front Endocrinol, vol. 12, p. 642755, 2021.
View at: Publisher Site | Google Scholar
M. Vasiadi, D. Kempuraj, W. Boucher, D. Kalogeromitros, and T. C. Theoharides, “Progesterone inhibits mast cell secretion,” Int J Immunopathol Pharmacol., vol. 19, no. 4, pp. 787–794, 2006.
View at: Publisher Site | Google Scholar
A. Kasperska-Zajac, Z. Brzoza, and B. Rogala, “Dehydroepiandrosterone and dehydroepiandrosterone sulphate in atopic allergy and chronic urticaria,” Inflammation., vol. 31, no. 3, pp. 141–145, 2008.
View at: Publisher Site | Google Scholar
E. Oppong, N. Flink, and A. C. Cato, “Molecular mechanisms of glucocorticoid action in mast cells,” Mol Cell Endocrinol., vol. 380, no. 1-2, pp. 119–126, 2013.
View at: Publisher Site | Google Scholar
M. Cutolo, S. Capellino, A. Sulli et al., “Estrogens and autoimmune diseases,” Ann N Y Acad Sci., vol. 1089, no. 1, pp. 538–547, 2006.
View at: Publisher Site | Google Scholar
D. Jacenik and W. M. Krajewska, “Significance of G protein-coupled estrogen receptor in the pathophysiology of irritable bowel syndrome, inflammatory bowel diseases and colorectal cancer,” Front Endocrinol, vol. 11, p. 390, 2020.
View at: Publisher Site | Google Scholar
J. Luo and D. Liu, “Does GPER really function as a G protein-coupled estrogen receptor in vivo?” Front Endocrinol, vol. 11, p. 148, 2020.
View at: Publisher Site | Google Scholar
M. Pupo, M. Maggiolini, and A. M. Musti, “GPER mediates non-genomic effects of estrogen,” Methods Mol Biol., vol. 1366, pp. 471–488, 2016.
View at: Publisher Site | Google Scholar
A. Ramírez-de-Arellano, J. Gutiérrez-Franco, E. Sierra-Diaz, and A. L. Pereira-Suárez, “The role of estradiol in the immune response against COVID-19,” Hormones (Athens)., vol. 20, no. 4, pp. 657–667, 2021.
View at: Publisher Site | Google Scholar
R. Pal and M. Banerjee, “COVID-19 and the endocrine system: exploring the unexplored,” J Endocrinol Invest., vol. 43, no. 7, pp. 1027–1031, 2020.
View at: Publisher Site | Google Scholar
A. Lania, M. T. Sandri, M. Cellini, M. Mirani, E. Lavezzi, and G. Mazziotti, “Thyrotoxicosis in patients with COVID-19: the THYRCOV study,” Eur J Endocrinol., vol. 183, no. 4, pp. 381–387, 2020.
View at: Publisher Site | Google Scholar
I. Muller, D. Cannavaro, D. Dazzi et al., “SARS-CoV-2-related atypical thyroiditis,” Lancet Diabetes Endocrinol., vol. 8, no. 9, pp. 739–741, 2020.
View at: Publisher Site | Google Scholar
V. V. Zdor, B. I. Geltser, M. G. Eliseikina et al., “Roles of thyroid hormones, mast cells, and inflammatory mediators in the initiation and progression of autoimmune thyroid diseases,” Int Arch Allergy Immunol., vol. 181, no. 9, pp. 715–726, 2020.
View at: Publisher Site | Google Scholar
E. Landucci, A. Laurino, L. Cinci, M. Gencarelli, and L. Raimondi, “Thyroid hormone, thyroid hormone metabolites and mast cells: a less explored issue,” Front Cell Neurosci, vol. 13, p. 79, 2019.
View at: Publisher Site | Google Scholar
D. Szukiewicz, A. Stangret, C. Ruiz-Ruiz et al., “Estrogen- and progesterone (P4)-mediated epigenetic modifications of endometrial stromal cells (EnSCs) and/or mesenchymal stem/stromal cells (MSCs) in the etiopathogenesis of endometriosis,” Stem Cell Rev Rep., vol. 17, no. 4, pp. 1174–1193, 2021.
View at: Publisher Site | Google Scholar
B. Moazzami, S. Chaichian, S. Samie et al., “Does endometriosis increase susceptibility to COVID-19 infections? A case-control study in women of reproductive age,” BMC Womens Health., vol. 21, no. 1, p. 119, 2021.
View at: Publisher Site | Google Scholar
M. Leonardi, A. W. Horne, K. Vincent et al., “Self-management strategies to consider to combat endometriosis symptoms during the COVID-19 pandemic,” Hum Reprod Open, vol. 2020, no. 2, article hoaa028, 2020.
View at: Publisher Site | Google Scholar
M. Leonardi, A. W. Horne, M. Armour et al., “Endometriosis and the coronavirus (COVID-19) pandemic: clinical advice and future considerations,” Front. Reprod. Health, vol. 2, 2020.
View at: Publisher Site | Google Scholar
A. Agolli, Z. Yukselen, O. Agolli et al., “SARS-CoV-2 effect on male infertility and its possible pathophysiological mechanisms,” Discoveries, vol. 9, no. 2, article e131, 2021.
View at: Publisher Site | Google Scholar
A. Ardestani Zadeh and D. Arab, “COVID-19 and male reproductive system: pathogenic features and possible mechanisms,” J Mol Histol., vol. 52, no. 5, pp. 869–878, 2021.
View at: Publisher Site | Google Scholar
M. Wang, Q. Yang, X. Ren et al., “Investigating the impact of asymptomatic or mild SARS-CoV-2 infection on female fertility and _in vitro_ fertilization outcomes: a retrospective cohort study,” EClinicalMedicine., vol. 38, p. 101013, 2021.
View at: Publisher Site | Google Scholar
L. Zupin, L. Pascolo, G. Zito, G. Ricci, and S. Crovella, “SARS-CoV-2 and the next generations: which impact on reproductive tissues?” J Assist Reprod Genet., vol. 37, no. 10, pp. 2399–2403, 2020.
View at: Publisher Site | Google Scholar
S. Cosma, A. R. Carosso, J. Cusato et al., “Coronavirus disease 2019 and first-trimester spontaneous abortion: a case- control study of 225 pregnant patients,” Am J Obstet Gynecol, vol. 224, no. 4, pp. 391.e1–391.e7, 2021.
View at: Publisher Site | Google Scholar
N. la Cour Freiesleben, P. Egerup, K. V. R. Hviid et al., “SARS-CoV-2 in first trimester pregnancy: a cohort study,” Human Reproduction, vol. 36, no. 1, pp. 40–47, 2020.
View at: Publisher Site | Google Scholar
A. Khalil, E. Kalafat, C. Benlioglu et al., “SARS-CoV-2 infection in pregnancy: a systematic review and meta-analysis of clinical features and pregnancy outcomes,” EClinicalMedicine., vol. 25, p. 100446, 2020.
View at: Publisher Site | Google Scholar
B. A. T. Weatherbee, D. M. Glover, and M. Zernicka-Goetz, “Expression of SARS-CoV-2 receptor ACE2 and the protease TMPRSS2 suggests susceptibility of the human embryo in the first trimester,” Open Biol., vol. 10, no. 8, p. 200162, 2020.
View at: Publisher Site | Google Scholar
M. Hoffmann, H. Kleine-Weber, S. Schroeder et al., “SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor,” Cell, vol. 181, no. 2, pp. 271–280.e8, 2020.
View at: Publisher Site | Google Scholar
J. Goad, J. Rudolph, and A. Rajkovic, “Female reproductive tract has low concentration of SARS-CoV2 receptors,” PLoS One., vol. 15, no. 12, article e0243959, 2020.
View at: Publisher Site | Google Scholar
F. Vilella, W. Wang, I. Moreno, B. Roson, S. R. Quake, and C. Simon, “Single-cell RNA sequencing of SARS-CoV-2 cell entry factors in the preconceptional human endometrium,” Hum Reprod., vol. 36, no. 10, pp. 2709–2719, 2021.
View at: Publisher Site | Google Scholar
M. Wu, L. Ma, L. Xue et al., “Co-expression of the SARS-CoV-2 entry molecules ACE2 and TMPRSS2 in human ovaries: identification of cell types and trends with age,” Genomics., vol. 113, no. 6, pp. 3449–3460, 2021.
View at: Publisher Site | Google Scholar
L. K. Gadanec, K. R. McSweeney, T. Qaradakhi, B. Ali, A. Zulli, and V. Apostolopoulos, “Can SARS-CoV-2 virus use multiple receptors to enter host cells?” Int J Mol Sci., vol. 22, no. 3, p. 992, 2021.
View at: Publisher Site | Google Scholar
H. S. Rad, J. Röhl, N. Stylianou et al., “The effects of COVID-19 on the placenta during pregnancy,” Front Immunol., vol. 12, p. 743022, 2021.
View at: Publisher Site | Google Scholar
A. C. Tallarek, C. Urbschat, L. Fonseca Brito et al., “Inefficient placental virus replication and absence of neonatal cell-specific immunity upon Sars-CoV-2 infection during pregnancy,” Front Immunol., vol. 12, p. 698578, 2021.
View at: Publisher Site | Google Scholar
F. Saji, M. Koyama, and N. Matsuzaki, “Current topic: human placental Fc receptors,” Placenta., vol. 15, no. 5, pp. 453–466, 1994.
View at: Publisher Site | Google Scholar
M. A. Beesley, J. R. Davidson, F. Panariello et al., “COVID-19 and vertical transmission: assessing the expression of ACE2/TMPRSS2 in the human fetus and placenta to assess the risk of SARS-CoV-2 infection,” BJOG, vol. 129, no. 2, pp. 256–266, 2022.
View at: Publisher Site | Google Scholar
V. Faure-Bardon, P. Isnard, N. Roux et al., “Protein expression of angiotensin-converting enzyme 2, a SARS-CoV-2-specific receptor, in fetal and placental tissues throughout gestation: new insight for perinatal counseling,” Ultrasound Obstet Gynecol., vol. 57, no. 2, pp. 242–247, 2021.
View at: Publisher Site | Google Scholar
M. Li, L. Chen, J. Zhang, C. Xiong, and X. Li, “The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single-cell transcriptome study,” PLoS One., vol. 15, no. 4, article e0230295, 2020.
View at: Publisher Site | Google Scholar
A. Bouachba, F. Allias, B. Nadaud et al., “Placental lesions and SARS-Cov-2 infection: diffuse placenta damage associated to poor fetal outcome,” Placenta., vol. 112, pp. 97–104, 2021.
View at: Publisher Site | Google Scholar
L. Linehan, K. O'Donoghue, S. Dineen, J. White, J. R. Higgins, and B. Fitzgerald, “SARS-CoV-2 placentitis: an uncommon complication of maternal COVID-19,” Placenta., vol. 104, pp. 261–266, 2021.
View at: Publisher Site | Google Scholar
X. Y. Chen, X. M. Jia, Y. S. Jia, X. R. Chen, H. Z. Wang, and W. Q. Qi, “Development and distribution of mast cells and neuropeptides in human fetus duodenum,” World J Gastroenterol., vol. 10, no. 22, pp. 3349–3352, 2004.
View at: Publisher Site | Google Scholar
E. I. Ortiz, E. Herrera, A. De La Torre, and Royal College of Obstetricians and Gynaecologists, “Coronavirus (COVID-19) infection and pregnancy,” Colombia Médica, vol. 51, 2020.
View at: Google Scholar
L. B. Afrin, L. B. Weinstock, and G. J. Molderings, “Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome,” Int J Infect Dis., vol. 100, pp. 327–332, 2020.
View at: Publisher Site | Google Scholar
J. Allotey, E. Stallings, M. Bonet et al., “Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis,” The BMJ, vol. 370, 2021.
View at: Google Scholar
A. B. Docherty, E. M. Harrison, C. A. Green et al., “Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study,” BMJ., vol. 369, p. m1985, 2020.
View at: Publisher Site | Google Scholar
J. Collin, E. Byström, A. Carnahan, and M. Ahrne, “Public Health Agency of Sweden's Brief Report: pregnant and postpartum women with severe acute respiratory syndrome coronavirus 2 infection in intensive care in Sweden,” Acta Obstet Gynecol Scand., vol. 99, no. 7, pp. 819–822, 2020.
View at: Publisher Site | Google Scholar
A. Peddapalli, M. Gehani, A. M. Kalle, S. R. Peddapalli, A. E. Peter, and S. Sharad, “Demystifying excess immune response in COVID-19 to reposition an orphan drug for down-regulation of NF-κB: a systematic review,” Viruses., vol. 13, no. 3, p. 378, 2021.
View at: Publisher Site | Google Scholar
L. B. Afrin, T. T. Dempsey, L. S. Rosenthal, and S. R. Dorff, “Successful mast-cell-targeted treatment of chronic dyspareunia, vaginitis, and dysfunctional uterine bleeding,” J Obstet Gynaecol., vol. 39, no. 5, pp. 664–669, 2019.
View at: Publisher Site | Google Scholar
S. R. Dorff and L. B. Afrin, “Mast cell activation syndrome in pregnancy, delivery, postpartum and lactation: a narrative review,” J Obstet Gynaecol., vol. 40, no. 7, pp. 889–901, 2020.
View at: Publisher Site | Google Scholar
D. Acanfora, C. Acanfora, M. M. Ciccone et al., “The cross-talk between thrombosis and inflammatory storm in acute and long-COVID-19: therapeutic targets and clinical cases,” Viruses., vol. 13, no. 10, p. 1904, 2021.
View at: Publisher Site | Google Scholar
S. Chanchal, A. Mishra, M. K. Singh, and M. Z. Ashraf, “Understanding inflammatory responses in the manifestation of prothrombotic phenotypes,” Frontiers in Cell and Developmental Biology, vol. 8, p. 73, 2020.
View at: Publisher Site | Google Scholar
M. Bazrafkan, E. Hosseini, M. Nazari, C. A. Amorim, and M. R. Sadeghi, “NLRP3 inflammasome: a joint, potential therapeutic target in management of COVID-19 and fertility problems,” Journal of Reproductive Immunology, vol. 148, p. 103427, 2021.
View at: Publisher Site | Google Scholar
Z. Zhang, F. Wang, and Y. Zhang, “Expression and contribution of NLRP3 inflammasome during the follicular development induced by PMSG,” Frontiers in Cell and Developmental Biology, vol. 7, p. 256, 2019.
View at: Publisher Site | Google Scholar

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Copyright © 2022 Dariusz Szukiewicz et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Journal of Immunology Research

Mast Cell Activation Syndrome in COVID-19 and Female Reproductive Function: Theoretical Background vs. Accumulating Clinical Evidence

Abstract

1. Short Introduction: Signaling the Problem

2. MCs and MC-Derived Mediators in a Woman’s Reproductive System and Placenta

3. Secretory Activity of MCs: Main Categories of the Mediators, the Mechanisms of Activation and Degranulation

4. COVID-19-Related MCAS or nc-MCAS and Possible Consequences for Female Reproductive Function

4.1. Hormonal Disorders

4.2. Women with Endometriosis

4.3. Female Fertility and the Course of Pregnancy

5. Concluding Remarks

Abbreviations

Data Availability

Conflicts of Interest

References

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