Granulysin‐mediated apoptosis of trophoblasts in blighted ovum and missed abortion

Gulić, Tamara; Laškarin, Gordana; Dominović, Marin; Gačanin, Lana Glavan; Babarović, Emina; Rubeša, Željka; Haller, Herman; Rukavina, Daniel

doi:10.1111/aji.12978

Cited by 8 publications

(12 citation statements)

References 42 publications

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“…cells after T. gondii infection caused an imbalance between inhibitory and activating receptors, thereby contributing to abnormal pregnancy outcomes. The cytotoxic molecules GranzymeA, GranzymeB and Perforin are constitutively produced by NK cells (Trapani et al, 1998;Shirshev et al, 2017;Gulic et al, 2018). Researchers have found that dysfunctional dNK cells release excessive GranzymeB and Perforin which induce pregnancy failure (Trapani et al, 1998;Gulic et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

The Role of Tim-3 on dNK Cells Dysfunction During Abnormal Pregnancy With Toxoplasma gondii Infection

Cui

et al. 2021

Front. Cell. Infect. Microbiol.

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Vertical transmission of Toxoplasma gondii (T. gondii) infection during gestation can result in severe complications such as abortion, congenital malformation, fetal teratogenesis, etc. Immune inhibitory molecule Tim-3 was discovered to be expressed on some decidual immune cells and participates in the maintenance of maternal-fetal tolerance. Dysregulation of Tim-3 expression on decidual NK (dNK) cells was observed in several cases of pregnancy complications, whereas the role of Tim-3 on dNK cells during T. gondii infection remains unclear. In the present study, T. gondii infected Tim-3-/- pregnant mice, and anti-Tim-3 neutralizing antibody treated and infected human dNK cells were successfully established to explore the role of Tim-3 in dysfunction of dNK cells during abnormal pregnancy. Our results illustrated that Tim-3-/- pregnant mice displayed more worse pregnancy outcomes with T. gondii infection compared to infected WT pregnant mice. Also, it demonstrated that Tim-3 expression on dNK cells was significantly down-regulated following T. gondii infection. Data suggested a remarkable activation of dNK cells in Tim-3-/- mice and anti-Tim-3 neutralizing antibody treated and infected groups, with higher ratios of activating receptor NKG2D to inhibitory receptor NKG2A or KIR2DL4, IFN-γ/IL-10, and increased granule production compared with that of the infected group. Mechanism analysis proved that T. gondii-induced Tim-3 down-regulation significantly activated the phosphatidylinositol-3-kinase (PI3K)-AKT and JAK-STAT signaling pathway, by which the GranzymeB, Perforin, IFN-γ, and IL-10 production were further up-regulated. Our research demonstrated that the decrease of Tim-3 on dNK cells caused by T. gondii infection further led to dNK cells function disorder, which finally contributed to the development of abnormal pregnancy outcomes.

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Section: Discussionmentioning

confidence: 99%

The Role of Tim-3 on dNK Cells Dysfunction During Abnormal Pregnancy With Toxoplasma gondii Infection

Cui

et al. 2021

Front. Cell. Infect. Microbiol.

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“…NK cells respond to inflammatory stimuli and are best known for their role in tumor immunosuppression. Phenotypically, NK cells are defined as CD56 + CD16 + CD3 – in humans [28, 30]. NK cell activity depends on the interplay of their activating and inhibiting receptor repertoire [28, 30].…”

Section: The Role Of Nk Cells In Breast Cancermentioning

confidence: 99%

“…Phenotypically, NK cells are defined as CD56 + CD16 + CD3 – in humans [28, 30]. NK cell activity depends on the interplay of their activating and inhibiting receptor repertoire [28, 30]. After activation, NK cells secrete proinflammatory cytokines such as interferon-γ, tumor necrosis factor-α, granulocyte macrophage colony-stimulating factor, and chemokines (CCL1, CCL2, CCL3, CCL4, CCL5 and CXCL8) that can modulate the function of other innate and adaptive immune cells [29, 31, 32].…”

Section: The Role Of Nk Cells In Breast Cancermentioning

confidence: 99%

“…After activation, NK cells secrete proinflammatory cytokines such as interferon-γ, tumor necrosis factor-α, granulocyte macrophage colony-stimulating factor, and chemokines (CCL1, CCL2, CCL3, CCL4, CCL5 and CXCL8) that can modulate the function of other innate and adaptive immune cells [29, 31, 32]. CD94/NK group 2 member A (NKG2A) heterodimer receptor is one of the NK inhibitory receptors that binds to nonclassical minimally polymorphic HLA class I molecules such as HLA-E that is overexpressed in many solid tumors [29, 30]. In addition, HLA-E expression may represent an important regulatory mechanism of tumors to evade immune surveillance [30].…”

Section: The Role Of Nk Cells In Breast Cancermentioning

confidence: 99%

“…CD94/NK group 2 member A (NKG2A) heterodimer receptor is one of the NK inhibitory receptors that binds to nonclassical minimally polymorphic HLA class I molecules such as HLA-E that is overexpressed in many solid tumors [29, 30]. In addition, HLA-E expression may represent an important regulatory mechanism of tumors to evade immune surveillance [30]. Mamessier et al [32] determinate the importance of tolerogenic NK cells in the control of invasive breast tumors resulting in impaired malignant cellular immunogenicity.…”

Section: The Role Of Nk Cells In Breast Cancermentioning

confidence: 99%

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The Role of Innate Immunity in the Pathogenesis of Breast Cancer

Grebić

Gulić

Starčević³

et al. 2020

Breast Care

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Background: Breast carcinoma is the most common malignant disease in the female population and one of the leading causes of death among women worldwide. One crucial hallmark of cancer is chronic inflammation where the immunosuppressive environment is dominant. The immunosuppressive environment is largely achieved by the interaction of tumor cells and infiltrating leukocytes. Summary: Usually, human macrophages and natural killer cells are involved in antitumor immunity. The therapeutic potential of this population against cancers has stimulated their study and led to the discovery of several different tumor-associated macrophages and natural killer cell subsets, each of which is endowed with different immunoregulatory functions. Both heterogeneity and plasticity of the tumor-associated macrophages and natural killer cell compartment, which are both tightly linked to the tumor microenvironment of different breast cancer types. Key Messages: The identification of specific tumor-associated macrophages and natural killer cell subsets endowed with particular functional capabilities might help monitor tumor-mediated responses in breast cancer patients. Currently, one of the most used strategies for breast cancer of newly diagnosed patients is neoadjuvant chemotherapy.

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Upregulated serum granulysin levels in women with antiphospholipid antibody‐associated recurrent miscarriage are downregulated by heparin treatment

Ichikawa

Negishi

Kasano

et al. 2022

Reprod Medicine & Biology

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Purpose Granulysin is a cytotoxic protein that simultaneously activates innate and cellular immunity. The authors aimed to evaluate whether granulysin is associated with the antiphospholipid antibody syndrome and whether heparin changes the granulysin levels. Methods A cohort study was performed with women with antiphospholipid antibody‐positive recurrent pregnancy loss (RPL). The authors examined granulysin levels under RPL and evaluated the changes in serum granulysin levels before and 1 week after the commencement of heparin treatment. Results Serum granulysin levels before heparin treatment were significantly higher in women who tested positive for one or more types of antiphospholipid antibodies (2.75 ± 1.03 vs. 2.44 ± 0.69, p = 0.0341 by Welch's t test), particularly anti‐phosphatidylethanolamine antibodies (IgG: 2.98 ± 1.09 vs. 2.51 ± 0.86, p = 0.0013; IgM: 2.85 ± 1.09 vs. 2.47 ± 0.77, p = 0.0024 by Welch's t test). After heparin treatment for 1 week, serum granulysin levels were significantly reduced ( p = 0.0017 by the paired t test). The miscarriage rate was significantly higher in women whose serum granulysin levels were not reduced by heparin treatment ( p = 0.0086 by Fisher's exact probability test). Conclusion The results suggest that heparin may reduce the incidence of miscarriage by suppressing serum granulysin levels.

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Granulysin‐mediated apoptosis of trophoblasts in blighted ovum and missed abortion

Cited by 8 publications

References 42 publications

The Role of Tim-3 on dNK Cells Dysfunction During Abnormal Pregnancy With Toxoplasma gondii Infection

The Role of Tim-3 on dNK Cells Dysfunction During Abnormal Pregnancy With Toxoplasma gondii Infection

The Role of Innate Immunity in the Pathogenesis of Breast Cancer

Upregulated serum granulysin levels in women with antiphospholipid antibody‐associated recurrent miscarriage are downregulated by heparin treatment

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