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Subuhi Sherwani,1 Mohd Wajid Ali Khan2 1Department of Biology, College of Sciences, University of Ha’il, Ha’il 2440, Saudi Arabia; 2Department of Chemistry, College of Sciences, University of Ha’il, Ha’il 2440, Saudi ArabiaCorrespondence: Subuhi SherwaniDepartment of Biology, College of Sciences, University of Ha’il, Ha’il 2440, Saudi ArabiaTel +966-590172770Email susherwani@gmail.comAbstract: The last few months of 2019 witnessed the emergence, rise and rapid spread of a novel coronavirus known as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), causing an acute respiratory disease called coronavirus disease 2019 or Covid-19. Severe pathological manifestations of the disease in the infected population with comorbidities are linked to acute respiratory distress syndrome (ARDS), associated with an exaggerated synthesis and expression of cytokines, leading to a systemic inflammatory response also known as a cytokine storm (CS). Elderly patients (> 60 years of age) showed more deaths in Covid-19 infection. Age-related immune imbalance increases patient susceptibility to CS. In acute Covid-19 infection, it is difficult to minimize or control the overproduction of cytokines; hence, limited medical treatments are effective. This review aims to provide an overview of the current knowledge of involvement of cytokines in SARS-CoV-2 infection, susceptibility factors for the accompanying cytokine storm in severe Covid-19 cases and possible treatment strategies.Keywords: SARS-CoV-2, Covid-19, coronavirus, cytokine storm, inflammation, elderly

Rheumatoid arthritis (RA) is an autoimmune disorder in which increased autoantibody production and enhanced secretion of pro-inflammatory cytokines are the hallmark of the disease. A strictly controlled balance of antibody production and proinflammatory cytokines is the key to the healthy state. A slight tilt in this balance causes proinflammatory diseases. In RA there is an increased production of autoantibodies such as rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA), anti-cartilage type II antibodies, and etc., which have a prominent clinical significance. Furthermore, there is increased secretion of proinflammatory cytokines such as tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), interleukin-1 (IL-1) which have an impact of great magnitude on the RA disease progression and severity. A better understanding of the mechanism of autoantibody production and secretion of cytokines together with crosstalk between immune cells and cytokines can provide us a better insight into the disease pathogenesis as well disease prognosis and management.

International audience; The inherent resistance of cancer stem cells (CSCs) to existing therapies has largely hampered the development of effective treatments for advanced malignancy. To help develop novel immunotherapy approaches that efficiently target CSCs, an experimental model allowing reliable distinction of CSCs and non-CSCs was set up to study their interaction with non-MHC-restricted γδ T cells and antigen-specific CD8 + T cells. Stable lines with characteristics of breast CSC-like cells were generated from ras-transformed human mammary epithelial (HMLER) cells as confirmed by their CD44 hi CD24 lo GD2 + phenotype, their mesenchymal morphology in culture and their capacity to form mammospheres under non-adherent conditions, as well as their potent tumorigenicity, self-renewal and differentiation in xenografted mice. The resistance of CSC-like cells to γδ T cells could be overcome by inhibition of farnesyl pyrophosphate synthase (FPPS) through pretreatment with zoledronate or with FPPS-targeting short hairpin RNA. γδ T cells induced upregulation of MHC class I and CD54/ICAM-1 on CSC-like cells and thereby increased the susceptibility to antigen-specific killing by CD8 + T cells. Alternatively, γδ T-cell responses could be specifically directed against CSC-like cells using the humanised anti-GD2 monoclonal antibody hu14.18K322A. Our findings identify a powerful synergism between MHC-restricted and non-MHC-restricted T cells in the eradication of cancer cells including breast CSCs. Our research suggests that novel immunotherapies may benefit from a two-pronged approach combining γδ T-cell and CD8 + T-cell targeting strategies that triggers effective innate-like and tumour-specific adaptive responses.

Peritonitis remains the major obstacle for the maintenance of long-term peritoneal dialysis and dysregulated host peritoneal immune responses may compromise local anti-infectious defense, leading to treatment failure. Whilst, tissue mononuclear phagocytes, comprising macrophages and dendritic cells, are central to a host response to pathogens and the development of adaptive immune responses, they are poorly characterized in the human peritoneum. Combining flow cytometry with global transcriptome analysis, the phenotypic features and lineage identity of the major CD14+ macrophage and CD1c+ dendritic cell subsets in dialysis effluent were defined. Their functional specialization was reflected in cytokine generation, phagocytosis, and antigen processing/presentation. By analyzing acute bacterial peritonitis, stable (infection-free) and new-starter patients receiving peritoneal dialysis, we identified a skewed distribution of macrophage to dendritic cell subsets (increasing ratio) that associated with adverse peritonitis outcomes, history of multiple peritonitis episodes, and early catheter failure, respectively. Intriguingly, we also noted significant alterations of macrophage heterogeneity, indicative of different maturation and activation states that were associated with different peritoneal dialysis outcomes. Thus, our studies delineate peritoneal dendritic cells from macrophages within dialysate, and define cellular characteristics associated with peritoneal dialysis treatment failure. These are the first steps to unravelling the detrimental adaptive immune responses occurring as a consequence of peritonitis.

Cell-based immunotherapy strategies target tumors directly (via cytolytic effector cells) or aim at mobilizing endogenous anti-tumor immunity. The latter approach includes dendritic cells (DC) most frequently in the form of in vitro cultured peripheral blood monocytes-derived DC. Human blood γδT cells are selective for a single class of non-peptide agonists (“phosphoantigens”) and develop into potent antigen-presenting cells (APC), termed γδT-APC within 1–3 days of in vitro culture. Availability of large numbers of γδT-APC would be advantageous for use as a novel cellular vaccine. We here report optimal γδT cell expansion (>107 cells/ml blood) when peripheral blood mononuclear cells (PBMC) from healthy individuals and melanoma patients were stimulated with zoledronate and then cultured for 14 days in the presence of IL-2 and IL-15, yielding γδT cell cultures of variable purity (77 ± 21 and 56 ± 26%, respectively). They resembled effector memory αβT (TEM) cells and retained full functionality as assessed by in vitro tumor cell killing as well as secretion of pro-inflammatory cytokines (IFNγ, TNFα) and cell proliferation in response to stimulation with phosphoantigens. Importantly, day 14 γδT cells expressed numerous APC-related cell surface markers and, in agreement, displayed potent in vitro APC functions. Day 14 γδT cells from PBMC of patients with cancer were equally effective as their counterparts derived from blood of healthy individuals and triggered potent CD8+ αβT cell responses following processing and cross-presentation of simple (influenza M1) and complex (tuberculin purified protein derivative) protein antigens. Of note, and in clear contrast to peripheral blood γδT cells, the ability of day 14 γδT cells to trigger antigen-specific αβT cell responses did not depend on re-stimulation. We conclude that day 14 γδT cell cultures provide a convenient source of autologous APC for use in immunotherapy of patients with various cancers.

Estrogen metabolites have been implicated in rheumatoid arthritis (RA) and cancer, although the mechanism remains unestablished. Some estrogen metabolites, which are used for the assessment of cancer risk, play an important role in RA. The pathways by which malignancies associated with RA remain elusive. Possible mechanism involves enzymatic or nonenzymatic oxidation of estrogen into catecholestrogen metabolites through semiquinone and quinone redox cycle to produce free radicals that can cause DNA modifications. Modifications of DNA alter its immunogenicity and trigger various immune responses leading to elevated levels of cancer and RA antibodies. However, the role of different estrogen metabolites as a mediator of immune response cannot be ruled out in various immune-related diseases.