Search

Natural Killer (NK) cells are a vital part of immune surveillance and have been implicated in colorectal cancer development and prognosis. This systematic review aims to distil the literature on NK cells as it relates to colorectal cancer. All published studies over 10 years relating to NK cells and colorectal cancer were reviewed. All studies publishing in English, searchable via pubmed or through reference review and reporting directly on the nature or function of NK cells in colorectal cancer patients were included. Outcomes were determined as alterations or new information regarding NK cells in colorectal cancer patients. Natural killer cells may be implicated in the development of colorectal cancer and may play a role in prognostication of the disease. NK cells are altered by the treatment (both surgical and medical) of colorectal cancer and it seems likely that they will also be a target for manipulation to improve colorectal cancer survival. NK cell morphology and function are significantly affected by the development of colorectal cancer. Observation of NK cell changes may lead to earlier detection and better prognostication in colorectal cancer. Further study is needed into immunological manipulation of NK cells which may lead to improved colorectal cancer survival.

The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by major histocompatibility complex (MHC) class I molecules. Previously, we have shown that genetic or pharmacological inhibition of ERAP1 on murine and human tumor cell lines perturbs the engagement of NK cell inhibitory receptors Ly49C/I and Killer-cell Immunoglobulin-like receptors (KIRs), respectively, by their specific ligands (MHC class I molecules), thus leading to NK cell killing. However, the effect of ERAP1 inhibition in tumor cells was highly variable, suggesting that its efficacy may depend on several factors, including MHC class I typing. To identify MHC class I alleles and KIRs that are more sensitive to ERAP1 depletion, we stably silenced ERAP1 expression in human HLA class I-negative B lymphoblastoid cell line 721.221 (referred to as 221) transfected with a panel of KIR ligands (i.e. HLA-B*51:01, -Cw3, -Cw4 and -Cw7), or HLA-A2 which does not bind any KIR, and tested their ability to induce NK cell degranulation and cytotoxicity. No change in HLA class I surface expression was detected in all 221 transfectant cells after ERAP1 depletion. In contrast, CD107a expression levels were significantly increased on NK cells stimulated with 221-B*51:01 cells lacking ERAP1, particularly in the KIR3DL1-positive NK cell subset. Consistently, genetic or pharmacological inhibition of ERAP1 impaired the recognition of HLA-B*51:01 by the YTS NK cell overexpressing KIR3DL1*001, suggesting that ERAP1 inhibition renders HLA-B*51:01 molecules less eligible for binding to KIR3DL1. Overall, these results identify HLA-B*51:01/KIR3DL1 as one of the most susceptible combinations for ERAP1 inhibition, suggesting that individuals carrying HLA-B*51:01-like antigens may be candidates for immunotherapy based on pharmacological inhibition of ERAP1.

Objective: The aim of this study was to investigate changes in natural killer (NK) cell proportion, NK cell activity, and cytokine levels in children with acute lymphoblastic leukemia (ALL) during and after therapy. Materials and Methods: The study group included 33 ALL patients and the control group consisted of 11 healthy children. The ALL patients were divided into three groups, those who had completed protocol M, receiving maintenance chemotherapy, and whose chemotherapy was discontinued. NK cell cytotoxicity was evaluated at different effector to target (E:T) cell ratios and in lytic units (LU). Expression of CD56, CD3, NKp46, CD2, CD94, NKG2D, and CD16 molecules and levels of the interferon gamma (IFN-γ) and interleukin-15 (IL-15) were measured. Results: NK cell activity at an E:T ratio of 1:1 was higher in patients receiving maintenance chemotherapy compared to the other groups (p0.05). The ratio of CD16+CD56+ cells was smaller in the maintenance chemotherapy group compared to controls (p, Amaç: Bu çalışmanın amacı, akut lenfoblastik lösemili (ALL) çocuklarda tedavi sırasında ve sonrasında doğal öldürücü (NK) hücre oranı, NK hücre aktivitesi ve sitokin düzeylerindeki değişiklikleri araştırmaktır. Gereç ve Yöntem: Çalışma grubu 33 ALL hastasını ve kontrol grubu 11 sağlıklı çocuktan oluştu. ALL hastaları, M protokolünü tamamlayan, idame kemoterapisi alan ve kemoterapisi kesilen olmak üzere üç gruba ayrıldı. NK hücre sitotoksisitesi, farklı efektör-hedef (E:H) hücre oranlarında ve litik birimlerde (LU) değerlendirildi. CD56, CD3, NKp46, CD2, CD94, NKG2D ve CD16 moleküllerinin ekspresyonu ve interferon gamma (IFN-γ) ve interlökin-15 (IL-15) seviyeleri ölçüldü. Bulgular: 1:1 E:H oranında NK hücre aktivitesi idame kemoterapisi alan hastalarda diğer gruplara göre daha yüksek (p0.05). CD16+CD56+ hücrelerin oranı, kontrollere göre idame kemoterapi grubunda daha düşük (p

Study question Does uterine natural killer cell functional activity differ in women with recurrent miscarriage (RM) or implantation failure (RIF) compared to fertile controls? Summary answer There is insufficient data to conclusively determine differences in uterine natural killer (NK) cell activity between women with RM/RIF and controls. What is known already Uterine NK cell (uNK) function is central to maintaining healthy pregnancy by promoting placentation and spiral artery vascular remodelling. The range of uNK activity is diverse and includes cytokine secretion, such as IFN-γ, or angiogenic factors which promote vascular remodelling. Despite an abundance of studies investigating peripheral blood NK cell cytotoxicity, there is limited evidence of uNK cytotoxicity. uNK-trophoblast interactions are facilitated by uNK receptors such as CD94, LILRB1 and KIRs. It is possible that dysfunction of these diverse uNK activities plays a more important role in early pregnancy failure than uNK levels. Study design, size, duration We conducted a systematic review of prospective case-control studies investigating uterine natural killer cell activity in patients with RM or RIF versus controls. The aim was to determine whether there was a distinct variation in uNK activity between RM/RIF and controls. We stratified uNK activity into four broad categories: i) regulation and receptors; ii) cytotoxicity; iii) expression of cytokines; iv) effect on uterine vasculature. Participants/materials, setting, methods The electronic database search included MEDLINE, EMBASE, Web of Science and bibliographies from included articles from inception to December 2020 using a combination of MESH and keywords. Search, screen, and data extraction were performed by two reviewers independently. Quality assessment was conducted with ROBINS-I. Out of 4636 studies screened, 30 studies (1696 women) were analysed for uNK activity. Main results and the role of chance Different methods were used to measure uNK activity including immunohistochemistry, flow cytometry, ELISA, PCR and Western blot. Samples were obtained from endometrium during mid-luteal phase or decidua following surgery. 14 studies reported on uNK phenotypes associated with regulation and receptors. RM/RIF patients, compared to controls, demonstrated a reduced expression of KIR2DL4, KIR2DL3/L2/S2 and inhibitory receptors (NKG2A); whereas there was a higher expression of the activating receptor (NKp46) and CD161. One study reported correlation between FoxP3+ T-cells and CD56+ NK cells but another reported no similar correlation with CD57+/CD56+ ratio. Two studies investigating dNK cytotoxicity, using chromium release or lactate dehydrogenase release assays, concluded higher dNK cytotoxicity in RM patients. Eight studies reported on cytokine expression. Interestingly, two studies found lower expression of IFN-g, but four studies reported otherwise in RM patients. Two studies found a higher ratio of dNK producing IFN-γ/TNF-α to those producing IL–4. The rest of the studies reported lower expression of IL–1RA, IL–10, TNF-α, Lnc–49A and higher expression of granzyme B, perforin and PRF–1. Finally, six studies reported on effect of uNK on vasculature. Among the findings were negative correlation between CD16+ uNK and endometrial IL–6 and VEGF, as well as higher angiogenin, VEGF and bFGF expression. Limitations, reasons for caution Functional activity investigated amongst studies varied significantly; this heterogeneity precluded meta-analysis of the data. Heterogeneity also prohibited definitive conclusions on uNK function and pregnancy outcome. Studies presented data in a combination of qualitative and quantitative analysis and variation was seen in the criteria for inclusion of RM, RIF and controls. Wider implications of the findings: uNK levels alone may be insufficient to guide management of early pregnancy failure. Clarification of underlying functional activity may guide therapeutic intervention and help develop new treatments. This review highlights the need for a greater understanding of the role of uNK activity in healthy pregnancy and early pregnancy failure. Trial registration number N/A

The coordinated activities of innate and adaptive immunity are critical for effective protection against viruses. To counter this, some viruses have evolved sophisticated strategies to circumvent immune cell recognition. In particular, cytomegaloviruses encode large arsenals of molecules that seek to subvert T cell and natural killer cell function via a remarkable array of mechanisms. Consequently, these ‘immunoevasins’ play a fundamental role in shaping the nature of the immune system by driving the evolution of new immune receptors and recognition mechanisms. Here, we review the diverse strategies adopted by cytomegaloviruses to target immune pathways and outline the host’s response.

It is widely accepted that ageing is accompanied by remodelling of the immune system, including reduced numbers of naïve T cells, increased senescent or exhausted T cells, compromise to monocyte, neutrophil and natural killer cell function and an increase in systemic inflammation. In combination these changes result in increased risk of infection, reduced immune memory, reduced immune tolerance and immune surveillance, with significant impacts upon health in old age. More recently it has become clear that the rate of decline in the immune system is malleable and can be influenced by environmental factors such as physical activity as well as pharmacological interventions. This review discusses briefly our current understanding of immunesenescence and then focuses on lifestyle interventions and therapeutic strategies that have been shown to restore immune functioning in aged individuals.

Primary haemophagocytic lymphohistiocytosis (HLH) diseases are a collection of inherited genetic disorders that cause the syndrome of HLH. Great advances have been made in the last 20 years with regard to the discovery of many of the genetic aetiologies of disease. Several advances have also been made on the clinical stage. Accurate screening diagnostics for primary HLH diseases that are superior to traditional Natural Killer cell function testing have been developed and are now available in many countries. There is now grounded clinical experience on which to base routine treatment decisions for patients with HLH. Newer approaches to allogeneic haematopoietic cell transplantation have increased overall patient survival. Despite these advances, however, there is still much work to be done to further improve patient care. This 'How I Treat' article will focus on summarizing current diagnostic, treatment and transplant strategies for patients with primary HLH diseases.

Immune dysfunction is an established risk factor in acute myeloid leukemia (AML). The cytotoxicity of natural killer (NK) cells is greatly impaired in AML, and the profile of NK cell receptors is markedly altered in AML; however, this is not yet well characterized. In this study, we found the downregulation of Siglec-7 could be utilized as a potential marker of NK cell dysfunction in AML. The absolute numbers and percentages of NK cells were declined in the peripheral blood of patients with AML, and the levels of activating receptors NKG2D, NKp46, and NKp30 were reduced in NK cells from patients with AML compared with healthy controls. In contrast, the levels of inhibitory receptors TIM-3, ILT-4, ILT-5, and PD-1 were increased in NK cells from patients with AML. Of note, the level of Siglec-7 in NK cells from patients with AML was significantly lower than that in NK cells from healthy controls, and Siglec-7+ NK cells displayed higher levels of activating receptors and stronger cytotoxicity when compared with Siglec-7- NK cells. Our data indicate that decreased Siglec-7 level may predict NK cell dysfunction in AML, and NK cells may be promising targets of immunotherapy for AML.

Although natural killer (NK) cell function is a hallmark of hemophagocytic lymphohistiocytosis (HLH), there is no standard method or data on its diagnostic value in adults. Thus, we performed a single-center retrospective study of 119 adult patients with suspected HLH. NK cell function was determined using both flowcytometry-based NK-cytotoxicity test (NK-cytotoxicity) and NK cell activity test for interferon-gamma (NKA-IFN&gamma, ). NK cell phenotype and serum cytokine levels were also tested. Fifty (42.0%) HLH patients showed significantly reduced NK cell function compared to 69 non-HLH patients by both NK-cytotoxicity and NKA-IFN&gamma, (p &lt, 0.001 and p = 0.020, respectively). Agreement between NK-cytotoxicity and NKA-IFN&gamma, was 88.0% in HLH patients and 58.0% in non-HLH patients. NK-cytotoxicity and NKA-IFN&gamma, assays predicted HLH with sensitivities of 96.0% and 92.0%, respectively. The combination of NKA-IFN&gamma, and ferritin (&gt, 10,000 &micro, g/L) was helpful for ruling out HLH, with a specificity of 94.2%. Decreased NK-cytotoxicity was associated with increased soluble IL-2 receptor levels and decreased CD56dim NK cells. Decreased NKA-IFN&gamma, was associated with decreased serum cytokine levels. We suggest that both NK-cytotoxicity and NKA-IFN&gamma, could be used for diagnosis of HLH. Further studies are needed to validate the diagnostic and prognostic value of NK cell function tests.

Background Haemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) is a hyperinflammatory syndrome potentially leading to critical illness. Early treatment reduces mortality but diagnosis requires a high index of suspicion. Highly elevated ferritin levels (HEF) >10,000 μg/L are highly specific for HLH/MAS [1] and should prompt consideration of hyperinflammation. Diagnostic guidelines for HLH, requiring the presence of ≥5/8 criteria [2], and classification criteria for MAS complicating systemic juvenile idiopathic arthritis (sJIA) have been published [3]. Objectives To assess recognition of HLH/MAS in a paediatric population with HEF. Methods This retrospective study was conducted at 11 centres under local service evaluation permissions. Biochemistry databases identified patients ≤16 years with serum ferritin >10,000 μg/L during a 3-year period. Each case was assessed against the 2004 HLH criteria and, for patients with sJIA, the 2016 MAS criteria. Due to limited access to some of the laboratory tests, previously-published modified HLH criteria using a threshold of ≥4/5 (excluding tissue haemophagocytosis, decreased natural killer cell function, increased soluble interleukin-2 receptor) were also applied to all patients [4]. Results 153 patients (55.6% male) were identified. Patient diagnoses included: infections (29.4%), rheumatological (17.0%) and malignancies (17.0%). A diagnosis of HLH/MAS was made by the treating clinical team in 39.9% and considered in a further 16.3%. Using all available data, 30/153 (19.6%) met ≥5/8 criteria and 93.3% of these patients were diagnosed with HLH/MAS by the treating team. 56 (36.6%) met ≥4/5 criteria and 33 (58.9%) of these were diagnosed with HLH/MAS by clinicians. HLH/MAS was not documented as being considered in the differential in 23.2%. Of 23 patients with sJIA, 82.6% met MAS classification criteria and 89.5% of these were diagnosed with MAS by the treating clinicians. Overall mortality was 32.7% (50/153) and was 27.9% (17/61) in patients diagnosed with HLH/MAS during their admission. Conclusion Although HEF is highly specific for HLH/MAS, the diagnosis was only made or considered in just over half of paediatric patients with this laboratory result. Increased awareness of this potentially-lethal condition is likely to lead to earlier treatment and reduced mortality. References [1] Allen CE, et al. 2008;50:1227-35. [2] Henter JI, et al. 2007;48:124-31. [3] Ravelli A, et al. 2016;75:481-9. [4] Davi S, et al. 2014;66:2871-80. Disclosure of Interests Ethan Sen: None declared, Beverley Almeida: None declared, Louise Moran: None declared, Charlene Foley: None declared, Nagla Abdelrahman: None declared, Rosie Close: None declared, Ema-Louise Long: None declared, Joshua Bennett: None declared, Jason Palman: None declared, Catriona Anderson: None declared, Kirsty McLellan: None declared, Samundeeswari Deepak: None declared, Kathy Gallagher: None declared, Peter Bale: None declared, Kamran Mahmood: None declared, Clare Pain: None declared, Flora McErlane: None declared, Athimalaipet Ramanan Consultant for: AbbVie, UCB, Sobi, Eli Lilly, Speakers bureau: Speaker fees/honoraria from Abbvie, SOBI, Eli Lilly and UCB, Speakers bureau: AbbVie, UCB, Sobi, Eli Lilly, Rachel Tattersall: None declared

Mesenchymal stem cells (MSCs) are powerful immunomodulators that regulate the diverse functions of immune cells involved in allogeneic reactions, such as T cells and natural killer (NK) cells, through cell-cell contact or secreted factors. Exosomes secreted by MSCs may be involved in their regulatory functions, providing new therapeutic tools. Here, we showed that fetal liver (FL) MSC-derived exosomes inhibit proliferation, activation, and cytotoxicity of NK cells. Exosomes bearing latency associated peptide (LAP), TGFβ, and thrombospondin 1 (TSP1), a regulatory molecule for TGFβ, induced downstream TGFβ/Smad2/3 signaling in NK cells. The inhibition of TGFβ, using a neutralizing anti-TGFβ antibody, restored NK proliferation, differentiation, and cytotoxicity, demonstrating that FL-MSC-derived exosomes exert their inhibition on NK cell function via TGFβ. These results suggest that FL-MSC-derived exosomes regulate NK cell functions through exosome-associated TGFβ.

The following study on natural immunology in schizophrenic patients aims at elucidating differential effects of psychopathological status and neuroleptic treatment. Natural killer (NK-) cell activity and antibody dependent cellular cytotoxity (ADCC) were tested in 24 adolescent schizophrenic patients and compared to 27 adult schizophrenics and healthy controls. Twelve adolescent patients were tested before and after 2 weeks on neuroleptic treatment. Age or psychopathological status did not have a significant impact on NK-activity or ADCC. There were no significant general effects resulting from neuroleptic treatment on NK-activity detectable in patients tested before and during treatment. However, there was a significant negative correlation between the differences of NK-activity (before and during treatment) and the NK-activity before treatment.

Recurrent miscarriage is a condition that affects 1% of all women, and rejection of the fetus by the mother's immune system is thought to be one of the underlying causes. The mechanisms of maternal tolerance vital to a successful pregnancy are not well understood; however, uterine natural killer (uNK) cells are implicated as they comprise over 70% of immune cells in the uterus during early pregnancy. Heme oxygenase‐1 (HO‐1) is an enzyme that is known to be immunosuppressive. Moreover, mice missing HO‐1 have extremely high abortion rates. This study is the first to analyze the effects of HO‐1 deficiency specifically on uNK cells. We posit that an absence of HO‐1 affects normal uNK cell‐mediated immunosuppression, and also possibly their ability to modify uterine spiral arteries supplying blood to the fetus. Our study analyzed embryos from mice lacking or deficient in HO‐1 on days 8, 10, and 12 of pregnancy. Both number of uNK cells and degree of vascularization were analyzed using immunohistochemistry staining. We observed a significantly higher number of uNK cells in one area of the embryo implantation site and a significantly lower number of cells in another, suggesting the uNK cells are failing to localize properly. Analysis of vascularization is currently ongoing. Since women with multiple miscarriages have been shown to down‐regulate HO‐1, confirmation that absence of HO‐1 leads to implantation site abnormalities could pave the way for future clinical treatments.