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“There is many a slip twist the cup and the lip” is a proverb that dates back to the 3rd century. This proverb comes to mind while writing a review on pregnancy loss; so many complications can occur between fertilization and development of the embryo through the long period of gestation until successful delivery of the baby. These include failure of implantation of the embryo, spontaneous miscarriage in the first trimester, pre-eclampsia in the second trimester, premature rupture of fetal membranes, pre-term labour, and pre-term delivery. The maternal immune system which does a phenomenal job of protecting the host from a daunting variety of infections, sometimes also mounts adverse reactions that complicate pregnancy and endanger the fetus. Maternal immune reactions that can adversely affect pregnancy have been shown to be mediated by lymphocytes, macrophages and natural killer cells, and by cytokines secreted by these cellular effectors. This review summarizes the deleterious effects of cytokines leading to recurrent spontaneous miscarriage, pre-eclampsia and pre-term delivery, which are the major complications of pregnancy. It then goes on to discuss the potential use of progesterone and dydrogesterone, an orally-administered progestogen, as immunomodulatory molecules that can be considered for the prevention and/or treatment of these complications.

We sought to investigate the influence of SARS-CoV-2 infection on the cytokine profiles of peripheral blood mononuclear cells (PBMCs) and neutrophils from coronavirus disease 2019 (COVID-19) intensive care unit (ICU) patients. Neutrophils and PBMCs were separated and stimulated with the mitogen phytohemagglutinin. Culture supernatants of mitogen-stimulated PBMCs and neutrophils from 88 COVID-19 ICU patients and 88 healthy controls were evaluated for levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-α, IFN-γ, interleukin (IL)-2, -4, -5, -6, -9, -10, -12, -17A, and tumor necrosis factor (TNF)-α using anti-cytokine antibody MACSPlex capture beads. Cytokine profiles of PBMCs showed significantly lower levels of GM-CSF, IFN-γ, IL-6, IL-9, IL-10, IL-17A, and TNF-α (p < 0.0001) in COVID-19 ICU patients. In contrast, COVID-19 ICU patients showed higher median levels of IL-2 (p < 0.001) and IL-5 (p < 0.01) by PBMCs. As for neutrophils, COVID-19 ICU patients showed significantly lower levels of GM-CSF, IFN-γ, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-17A, IL-12, TNF-α (p < 0.0001), and IFN-α (p < 0.01). T-helper (Th)1:Th2 cytokine ratios revealed lower inflammatory cytokine for PBMCs and neutrophils in COVID-19 ICU patients. Cytokine production profiles and Th1:Th2 cytokine ratios suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has an immunomodulatory effect on PBMCs and neutrophils. This study also suggests that the increased levels of several cytokines in the serum are not sourced from PBMCs and neutrophils.

Fawaz Y Azizieh,1 Diaa Shehab,2 Khaled Al Jarallah,2 Olusegun Mojiminiyi,3 Renu Gupta,4 Raj Raghupathy51Department of Mathematics and Natural Sciences, International Centre for Applied Mathematics and Computational Bioengineering, Gulf University for Science and Technology, Kuwait City, Kuwait; 2Department of Medicine, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait; 3Department of Pathology, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait; 4Department of Radiology, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait; 5Department of Microbiology, Faculty of Medicine, Kuwait University, Kuwait City, KuwaitObjective: In addition to some well-characterized bone turnover markers (BTMs), cytokines and adipokines have also been suggested to be linked to osteoporosis seen in menopause. However, there is much controversy on the possible association between these markers and bone mineral density (BMD). This study was aimed at measuring circulatory levels of selected cytokines, adipokines and BTMs in postmenopausal women with normal and low BMD.Methods: The study population included 71 post-menopausal women, of whom 25 had normal BMD, 31 had osteopenia and 13 had osteoporosis. Circulatory levels of selected pro-resorptive (TNF-α, IL-1β, IL-6, IL-8, IL-12, IL-17), anti-resorptive (IFN-γ, IL-4, IL-10, IL-13, TGF-β) and five adipokine markers (adiponectin, adipsin, lipocalin-2/NGAL, PAI-1 and resistin) were measured using the Multiplex system and read on the Magpix ELISA platform. Further, two bone turnover markers (PINP, CTX) as well as estradiol levels were assayed from the same samples.Results: While circulatory levels of cytokines were comparable between groups, women with low BMD had statistically significantly higher median circulatory levels of adipokines as compared to those with normal BMD. Further, while levels of CTX were not different between the two groups; PINP, PINP/CTX ratio and estradiol levels were significantly lower in women with low BMD. Levels of adiponectin, PINP, PINP/CTX ratio and estradiol correlated significantly with BMD of the hip and spine.Conclusion: The associations between various markers and BMD are complex and multivariate. Our data provide insights into the possible use of circulatory levels of cytokines, adipokines and bone turnover markers on the pathogenesis of postmenopausal osteoporosis because of the well-documented effects of these molecules on bone tissue and their relevance to osteoporosis.Keywords: cytokines, adipokines, BTM, osteoporosis, menopause

Its semi-allogeneic nature renders the conceptus vulnerable to attack by the maternal immune system. Several protective mechanisms operate during gestation to correct the harmful effects of anti-fetal immunity and to support a healthy pregnancy outcome. Pregnancy is characterized by gross alterations in endocrine functions. Progesterone is indispensable for pregnancy and humans, and it affects immune functions both directly and via mediators. The progesterone-induced mediator - PIBF - acts in favor of Th2-type immunity, by increasing Th2 type cytokines production. Except for implantation and parturition, pregnancy is characterized by a Th2-dominant cytokine pattern. Progesterone and the orally-administered progestogen dydrogesterone upregulate the production of Th2-type cytokines and suppress the production of Th1 and Th17 cytokine production in vitro. This is particularly relevant to the fact that the Th1-type cytokines TNF-α and IFN-γ and the Th17 cytokine IL-17 have embryotoxic and anti-trophoblast activities. These cytokine-modulating effects and the PIBF-inducing capabilities of dydrogesterone may contribute to the demonstrated beneficial effects of dydrogesterone in recurrent spontaneous miscarriage and threatened miscarriage. IL-17 and IL-22 produced by T helper cells are involved in allograft rejection, and therefore could account for the rejection of paternal HLA-C-expressing trophoblast. Th17 cells (producing IL-17 and IL-22) and Th22 cells (producing IL-22) exhibit plasticity and could produce IL-22 and IL-17 in association with Th2-type cytokines or with Th1-type cytokines. IL-17 and IL-22 producing Th cells are not harmful for the conceptus, if they also produce IL-4. Another important protective mechanism is connected with the expansion and action of regulatory T cells, which play a major role in the induction of tolerance both in pregnant women and in tumour-bearing patients. Clonally-expanded Treg cells increase at the feto-maternal interface and in tumour-infiltrating regions. While in cancer patients, clonally-expanded Treg cells are present in peripheral blood, they are scarce in pregnancy blood, suggesting that fetal antigen-specific tolerance is restricted to the foeto-maternal interface. The significance of Treg cells in maintaining a normal materno-foetal interaction is underlined by the fact that miscarriage is characterized by a decreased number of total effector Treg cells, and the number of clonally-expanded effector Treg cells is markedly reduced in preeclampsia. In this review we present an overview of the above mechanisms, attempt to show how they are connected, how they operate during normal gestation and how their failure might lead to pregnancy pathologies.

Fawaz Azizieh,1 Khulood O Alyahya,2 Raj Raghupathy3 1Department of Mathematics and Natural Sciences, Gulf University for Science and Technology, Kuwait City, Kuwait; 2Science Department, College of Basic Education, Public Authority for Applied Education and Training, Kuwait City, Kuwait; 3Department of Microbiology, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait Background: No one can deny that the biological importance of vitamin D is much beyond its classical role in bone metabolism. Several recent publications have highlighted its potential role in the functioning of the immune system. The overall objective of this study was to look into possible correlations between levels of vitamin D and inflammatory markers in sera of healthy adult women. These markers included proinflammatory cytokines (interleukin [IL]-1β, IL-6, IL-8, IL-17, interferon [IFN]-γ, and tumor necrosis factor [TNF]-α), anti-inflammatory cytokines (IL-4, IL-10, and IL-13), as well as C-reactive protein (CRP) as a general indicator of inflammation. Methods: Venous blood samples were collected from 118 healthy adult women and serum levels of vitamin D, CRP, proinflammatory cytokines (IL-1β, IL-6, IL-8, IL-17, IFN-γ, and TNF-α), and anti-inflammatory cytokines (IL-4, IL-10, and IL-13) were measured. Results: There were no significant direct correlations between serum levels of vitamin D and any of the inflammatory markers measured. However, subjects with deficient levels of vitamin D and high CRP produced significantly higher levels of the proinflammatory cytokines (TNF-α and IL-8) as compared to subjects with low CRP levels with nondeficient and deficient levels of vitamin D. Further, the anti-inflammatory/proinflammatory ratios suggest a role of vitamin D in maintaining an anti-inflammatory environment at low levels of CRP, an association that is weaker at high CRP levels in subjects with subclinical inflammatory situations. Conclusion: These data point to a possible role of vitamin D as a contributing factor in balancing cytokines toward an anti-inflammatory role in inflammatory situations. Keywords: vitamin D, cytokines, adult women, CRP, Kuwait

Abstract Background Cytokine production and histopathological changes occur in the lungs of mice after intranasal inoculation with Campylobacter jejuni, but the levels of cytokines in different organs to which C. jejuni disseminates have not been studied. Findings Adult BALB/c mice were intranasally inoculated with C. jejuni 81–176 (test) or phosphate-buffered saline (control) (n=16 per group). The levels of cytokines in the organs (spleen, liver, and small and large intestines) to which C. jejuni disseminated were measured by ELISA. Two cytokine patterns were observed. First, increased proinflammatory cytokines, TNF-α, IL-1, and IL-2, were followed by anti-inflammatory cytokines, IL-4 and IL-10 in the spleen and large intestine. Second, in the liver and small intestine, there was a predominant production of anti-inflammatory cytokines, IL-4 and IL-10, with some increase in IL-2 levels. In the spleen and intestines, the levels of pro- and anti-inflammatory cytokines were concurrently increased. Conclusion Dissemination of C. jejuni is associated with the production of different cytokine profiles in different tissues, with the proinflammatory response appearing in the spleen and large intestine at an earlier time point than in the liver and small intestine. The organs produce different cytokine profiles in response to C. jejuni dissemination. These preliminary findings should be confirmed with a study involving a larger group of animals.