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Natural killer (NK) cells, the large granular lymphocytes differentiated from the common lymphoid progenitors, were discovered in early 1970’s. They are members of innate immunity and were initially defined by their strong cytotoxicity against virus-infected cells and by their important effector functions in anti-tumoral immune responses. Nowadays, NK cells are classified among the recently discovered innate lymphoid cell subsets and have capacity to influence both innate and adaptive immune responses. Therefore, they can be considered as innate immune cells that stands between the innate and adaptive arms of immunity. NK cells don’t express T or B cell receptors and are recognized by absence of CD3. There are two major subgroups of NK cells according to their differential expression of CD16 and CD56. While CD16 + CD56 dim subset is best-known by their cytotoxic functions, CD16 - CD56 bright NK cell subset produces a bunch of cytokines comparable to CD4 + T helper cell subsets. Another subset of NK cells with production of interleukin (IL)-10 was named as NK regulatory cells, which has suppressive properties and could take part in immune-regulatory responses. Activation of NK cells is determined by a delicate balance of cell-surface receptors that have either activating or inhibitory properties. On the other hand, a variety of cytokines including IL-2, IL-12, IL-15, and IL-18 influence NK cell activity. NK-derived cytokines and their cytotoxic functions through induction of apoptosis take part in regulation of the immune responses and could contribute to the pathogenesis of many immune mediated diseases including ankylosing spondylitis, Behçet’s disease, multiple sclerosis, rheumatoid arthritis, psoriasis, systemic lupus erythematosus and type-1 diabetes. Dysregulation of NK cells in autoimmune disorders may occur through multiple mechanisms. Thanks to the rapid developments in biotechnology, progressive research in immunology enables better characterization of cells and their delicate roles in the complex network of immunity. As NK cells stand in between innate and adaptive arms of immunity and “bridge” them, their contribution in inflammation and immune regulation deserves intense investigations. Better understanding of NK-cell biology and their contribution in both exacerbation and regulation of inflammatory disorders is a requisite for possible utilization of these multi-faceted cells in novel therapeutic interventions.

Objective: Acute lymphoblastic leukemia (ALL) is the most prevalent type of cancer in children. Minimal residual disease (MRD) is still the most important indicator of clinical results and relapse after chemotherapy. Multidrug resistance is the main obstacle to successful treatment. Multidrug resistance-related protein 1 (MRP1) may play a key role in throwing the chemical drug out of cells leading to therapy resistance. This study aims to detect MRP1 protein in the bone marrow cells of children with B-ALL and determine its value as a prognostic factor in comparison with other factors such as DNA index and MRD obtained by flow cytometric measurement. Methods: Bone marrow samples were obtained from children who are diagnosed as B-ALL (n=20) at day 0 (diagnosis) and 15 of therapy. Risk groups’ classification is based on discrimination of age and white cell count on day 0. The expressions of MRP1 levels and DNA index at diagnosis and MRD on the 15th day of treatment in the bone marrow were detected by using flow cytometry. The B-ALL blast cells were stained using anti-CD10, -CD19, -CD20, -CD34, -CD45 monoclonal antibodies. MRP1 content of cells was detected in an intracellular manner. Results: There was no statistically significant difference in MRP1 expression between risk groups and the other prognostic factor as Flow MRD and DNA index. Conclusion: The utilization of MRP1 as a predictive factor may not provide information on the B-ALL prognosis. Our results can help to better understand the nature of MRP1 in B-ALL patients.

Erroneous immune responses in COVID-19 could have detrimental effects, which makes investigation of immune network underlying COVID-19 pathogenesis a requisite. This study aimed to investigate COVID-19 related alterations within the frame of innate and adaptive immunity. Thirty-four patients clinically diagnosed with mild, moderate and severe COVID-19 disease were enrolled in this study. Decreased ILC1 and increased ILC2 subsets were detected in mild and moderate patients compared to healthy controls. NK cell subsets and cytotoxic capacity of NK cells were decreased in severe patients. Moreover, CD3 + T cells were reduced in severe patients and a negative correlation was found between CD3 + T cells and D-dimer levels. Likewise, moderate and severe patients showed diminished CD3 + CD8 + T cells. Unlike T and NK cells, plasmablast and plasma cells were elevated in patients and IgG and IgA levels were particularly increased in severe patients. Severe patients also showed elevated serum levels of pro-inflammatory cytokines such as TNF-α, IL-6 and IL-8, reduced intracellular IFN-γ and increased intracellular IL-10 levels. Our findings emphasize that SARS-CoV-2 infection significantly alters immune responses and innate and acquired immunity are differentially modulated in line with the clinical severity of the disease. Elevation of IL-10 levels in NK cells and reduction of CD3 + and CD8 + T cells in severe patients might be considered as a protective response against the harmful effect of cytokine storm seen in COVID-19.

The modulatory effect of C-Vx, a novel therapeutic agent, on the immune system of COVID-19 patients was investigated. The functions of T and NK cells of COVID-19 patients with different disease severity were evaluated by flow cytometry in response to C-Vx stimulation. The levels of pro- and anti-inflammatory cytokines were detected by multiplex assay in supernatants after cell culture with C-Vx. Bradykinin, IRF3, and IFN-α levels were also measured by ELISA in the presence or absence of C-Vx stimulation. As a result, increased CD107a expression was observed on NK cells in response to C-Vx addition. The proliferation of T cell subsets was increased by C-Vx, decreasing by disease severity. IL-4 and IL-10 levels were elevated while IFN-γ and IL-17 levels were reduced in T cells following C-Vx stimulation. However, the levels of pro-inflammatory IL-1β, IL-6, IL-8, IFN-γ and GM-CSF were significantly increased upon C-Vx stimulation. IFN-α levels tended to increase after incubation with C-Vx. These findings support an immunomodulatory action of C-Vx on the immune system of patients with a mild and moderate phase of COVID-19.

Behçet’s disease (BD) is a systemic, autoinflammatory, chronic disorder which affects various parts of the body in genetically susceptible individuals. BD has a multi-factorial etiopathogenesis which encompasses both innate and adaptive arms of immunity. NK cells, which kill virus-infected or malign cells and provide interaction between adaptive and innate immune system, are also known to involve in the pathogenesis of autoimmune/autoinflammatory diseases including BD. NK cells function in immune responses via the signals obtained from surface-expressed activating and inhibitory receptors. In this study, we aimed to explore NK cell activation status by measuring the levels of activation marker CD69 and activating receptors NKG2D, NKp30, and NKp46 as well as proliferative and cytotoxic capacities in response to stimulation with interleukin (IL)-15-combined cytokines in BD patients. CD4+ and CD8+ T cell responses were also evaluated to compare with those of NK cells. As a result, the expression of activating receptors on NK cells was demonstrated to be varied among patients with active and inactive BD and healthy controls. The proliferation levels of NK cells were elevated in BD patients, especially in inactive phase of disease compared to healthy controls. Additionally, CD107a levels of inactive BD patients were detected to be lower in comparison with healthy controls and active BD patients. These findings suggest that BD patients in active and inactive phases display different activation status of NK cells which indicate NK cells might be associated with immune attacks and remissions during the course of BD.

The proliferation of antigen-specific lymphocyte clones, the initial step in acquired immunity, is vital for effector functions. Proliferation tests both in immunology research and diagnosis are gaining attendance gradually, while the use of adult healthy individuals as controls of pediatric patients is a question. This study aimed to investigate and compare mitogen-stimulated proliferation responses of total lymphocytes and T- and B-lymphocyte subsets in adult and children healthy donors. Nineteen children and 20 adult healthy donors were enrolled in this study. Peripheral blood mononuclear cells (PBMCs) purified from peripheral blood samples of the donors, by Ficoll gradient centrifugation, were stained with CFSE and were cultured in a 37 ℃ CO2 incubator for 120 h with the absence or existence of polyclonal activators: PHA and CD-Mix. After cell culture, PBMCs were stained with monoclonal antibodies against CD4 and CD19, and proliferation percentages of CD4+ T and CD19+ B cells, together with total lymphocytes were determined by flow cytometry. This study revealed similarities between children and adult age groups, concerning mitogenic stimulation of the lymphocytes. The only difference was a significantly high proliferation of pediatric CD4+ T cells in response to PHA. CD4+ T cell responses against PHA were inversely correlated with altering age. When pediatric individuals were distributed into age groups of 0–2 years, 3–5 years, and 6–18 years, PHA responses of CD4+ cells were found to be diminished with advancing age. These findings propose the possibility of enrollment of adult healthy individuals as controls for pediatric patients.