Low Natural Killer Cell Activity Research Articles

Markers of hemophagocytic lymphohistiocytosis are associated with survival in critically ill patients

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): This work was supported by the Association for the Promotion of Research on Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) and the Ludwig Boltzmann Cluster for Cardiovascular Research Background/Introduction Patients admitted to the intensive care unit (ICU) often show systemic immune dysregulation paired with significantly increased inflammatory activity. Haemophagocytic lymphohistiocytosis (HLH) represents a rare syndrome characterized by fever, inflammation, cytopenia, and organ dysfunction. Inappropriate survival of cytotoxic T cells as well as histiocytes triggers cytokine storm, accompanied by the occurrence of hemophagocytosis and multi-organ failure. prevalence of HLH in critical illness continues to be a topic of discussion but most certainly remains underreported. This circumstance often leads to delays in the necessary immunosuppressive therapy due to difficulty in early diagnosis. Purpose In the present study, we aimed to illuminate the prospective value of the individual HLH criteria in a cohort of critically ill patients. Although the prevalence of this syndrome might be low, isolated markers of HLH could help to assess the extent of inflammatory activation and further be of use in predicting the outcome of patients admitted to the ICU. Methods This was a prospective, observational cohort study. 176 consecutive patients admitted to a cardiac ICU were included over the course of one year. Available HLH criteria were recorded except for biopsy samples of bone marrow and measurements of low or absent natural killer cell activity. For soluble CD25 (sCD25) a specific ELISA kit was used according to the manufacturer's instructions. Results The median age was 67.51 years (IQR: 57.50-77.41) and 38.64% of the included patients were female. The total 30-day mortality was calculated to be 25.57% and positivity for two or more criteria of HLH was found to be associated with depicted mortality (p = 0.033). Analyzing the individual parameters, only sCD25 was found to be a predictor of death within the first 30 days (p < 0.001). The combination of triglycerides and fibrinogen did not predict outcomes. However, low fibrinogen values were found to possess prognostic merit in regard to mortality (p= 0.019). In multivariate analysis, both sCD25 and fibrinogen remained a significant predictor of 30-day survival after adjustment for age, sex, and BMI (sCD25 p < 0.001, fibrinogen p = 0.042). Finally, the addition of fibrinogen was able to improve the prognostic value of the SAPS II score significantly (ROC curve, SAPS II – AUC: 0.790, SAPS II & fibrinogen – AUC: 0.827, p = 0.045). Conclusion We provided evidence for the prognostic value of certain markers of HLH in critically ill patients. Positivity for two or more criteria was found to be associated with an increased 30-day mortality. Moreover, sCD25 and fibrinogen independently predicted outcomes in multivariate analysis after adjustment for age, sex, and BMI. The addition of fibrinogen was able to improve the prognostic properties of the SAPS II score.Figure 1Figure 2

Decreased natural killer cell activity as a potential predictor of hypertensive incidence.

Blood pressure is closely linked with immune function. This study examined the association between natural killer (NK) cell activity (NKA) and blood pressure and the development of hypertension according to NKA levels. This study enrolled 1543 adults who underwent NKA measurement and serial health check-ups at a medical center in Korea. NKA was estimated as the concentration of IFN-γ in the incubated whole blood containing a patented stimulatory cytokine. The participants were categorized into quartiles according to their NKA levels. Participants without hypertension were followed up, and the development of hypertension was compared according to the quartiles. The prevalence of hypertension was not different among the NKA quartiles, whereas blood pressures significantly decreased, followed by an increment of quartiles (systolic blood pressure of 119.0 in Q1 and 117.0 in Q4, P-trend = 0.018). Over a mean follow-up period of 2.13 years, hypertension developed in 156 of 1170 individuals without baseline hypertension. The hazard ratio of Q4 compared with Q1 was 0.625 (95% CI: 0.397-0.983; p = 0.042). In conclusion, our findings indicate a correlation between lower NKA and higher blood pressure and the development of incident hypertension. This may suggest a potential protective role of NK cells against endothelial dysfunction. Further research is necessary to elucidate the specific relationship between immune functions and endothelial function.

Macrophage activation syndrome: a review of recent renal findings

The pathogenesis of Macrophage activation syndrome consists of excessive macrophage and T-cell activation, leading to the uncontrolled release of cytokines and chemokines, which can cause multi-organ dysfunction. The diagnostic criteria for MAS include fever, splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, low or absent natural killer cell activity, elevated ferritin levels, and elevated soluble interleukin-2 receptor levels. Kidney involvement in this disease included glomerular changes, including mesangial expansion, endocapillary proliferation, and thrombotic microangiopathy. Renal biopsy in MAS may also show evidence of macrophage infiltration and activation, such as the presence of hemophagocytic macrophages within the glomeruli and interstitium. These macrophages may contain phagocytosed erythrocytes, platelets, and other cells, indicating ongoing hemophagocytosis. The presence of hemophagocytic macrophages on renal biopsy is highly suggestive of MAS and can help differentiate it from other causes of acute kidney injury (AKI). Management of macrophage activation syndrome-associated kidney involvement involves treating the underlying autoimmune disorder and controlling the systemic inflammation. This may include the use of immunosuppressive medications, such as corticosteroids, disease-modifying anti-rheumatic drugs, and biological agents. Supportive measures, such as renal replacement therapy, may be necessary in severe cases of renal dysfunction.

Association between resting heart rate and low natural killer cell activity: a cross-sectional study.

Resting heart rate (RHR), a simple physiological indicator, has been demonstrated to be associated with inflammation and even metabolic disorders. This study aimed to investigate whether RHR is associated with natural killer cell activity (NKA) in a large population of healthy adults using a novel assay to measure NKA. This cross-sectional study included 7,500 subjects in the final analysis. NKA was estimated by measuring the amount of interferon-gamma (IFN-γ) released by activated natural killer cells; low NKA was defined as IFN-γ level <500 pg/mL. Subjects were categorized into four groups according to RHR as follows: C1 (≤ 60 bpm), C2 (60-70 bpm), C3 (70-80 bpm), and C4 (≥ 80 bpm). Individuals with higher RHR exhibited poorer metabolic and inflammatory profiles, with the prevalence of low NKA being highest in the highest RHR category. Compared with C1 as reference, the fully adjusted odd ratios (ORs) [95% confidence intervals (CIs)] for low NKA were significantly higher in C3 (OR: 1.37, 95% CI: 1.08-1.75) and C4 (OR: 1.55, 95% CI: 1.20-2.00). In addition, RHR was shown to exert indirect effects on NKA upon consideration of the mediation effect of serum cortisol in path analysis. Our findings confirm a significant link between elevated RHR and low NKA, and suggest the usefulness of RHR, a simple indicator reflecting increased sympathetic nervous system activity and stress, in predicting reduced immune function.

Influence of immunosuppressive drugs on natural killer cells in therapeutic drug exposure in liver transplantation.

Natural killer (NK) cells are enriched in the liver and are the main regulators in liver transplantation regarding rejection or tolerance, viral infection, or tumor recurrence. Immunosuppression consists of a triple drug standard regimen comprising tacrolimus (TAC) and corticosteroids (CS) with either mycophenolate mofetil (MMF) or sirolimus (SIR)/everolimus (EVE). The aim of this study was to evaluate the impact of trough levels of these regimens under clinical conditions and exposure on human NK-cell activity and function in order to better understand the antiviral and anti-tumor effects of mammalian target of rapamycin inhibitor (mTORI). Peripheral blood mononuclear cells (PBMCs) were collected from liver transplant recipients and healthy controls. Number and phenotypes of NK cells in vivo were analyzed by flow cytometry. In this study we simulated the immunosuppressive microenvironment in vitro. PBMCs were cultured at the clinically effective plasma concentration of drugs for 3 d to detect the effect of immunosuppressants on NK cells. Drug type and concentration: single drug [EVE, 5 ng/mL; SIR, 5 ng/mL; TAC, 5 ng/mL; cyclosporine A (CSA), 125 ng/mL; MMF, 15 µg/mL; CS, 0.5 µg/mL] and combined immunosuppressants (Group 1: TAC, 5 ng/mL + MMF, 15 µg/mL + CS, 0.5 µg/mL; Group 2: TAC, 5 ng/mL + SIR, 5 ng/mL + CS, 0.5 µg/mL; Group 3: TAC, 5 ng/mL + EVE, 5 ng/mL + CS, 0.5 µg/mL). In addition, NK cells were sorted from PBMCs and treated under the above conditions to detect NK cell killing function and RNA transcription characteristics. CS significantly impaired the cytolytic activity of NK cells, followed by MMF and SIR/EVE. CS and TAC/CSA significantly decreased the secretion of IFN-γ and CD107a. NK cell function in liver transplant recipients was most pronouncedly inhibited by a triple immunosuppressive regimen, with CS playing the most prominent role compared with the other drugs. The MMF-containing regimen demonstrated a significant increase in the expression of suppressive genes, especially of the Siglec7/9 family. The SIR group had stronger NK cell activity compared with that of the MMF group, although liver transplantation patients have lower NK cell activity and function. Despite an overall comparable immunosuppressive efficiency in terms of prevention of acute rejection, a mTORIs-including regimen might be considered as having less impact on NK cell function.

The role of natural killer cell activity as a milestone in oncologic outcome after curative resection of pancreatic adenocarcinoma.

The objective of this study was to investigate differences in oncologic outcomes of patients with pancreas cancer according to natural killer cell activity (NKA). A total of 118 patients who underwent curative resection for primary pancreas cancer in two hospitals were analyzed. NKA change pattern was analyzed. Difference in disease-free survival or overall survival was investigated by dividing subjects into two groups based on a normal NKA value for each period. NKA value decreased after surgery compared to the value measured at admission. It recovered to normal levels at 5 weeks postoperatively. The low NKA (less than 250 pg/mL) group at admission, 5 weeks postoperatively, and before 1st chemotherapy had significantly poorer disease-free survival than the normal NKA group. In multivariate analysis, NKA values less than 250 pg/mL at admission (odds ratio = 2.267, p = 0.023) and N 1 or N2 category (odds ratio = 2.478, p = 0.023) were significant factors associated with recurrence after curative resection. NKA in patients with pancreatic cancer demonstrated noticeable changes after surgery. Immunologically predisposed patients with a low NKA value had a high risk of early recurrence and a poor prognosis, although pancreatic cancer was surgically removed.

Low Muscle and High Fat Percentages Are Associated with Low Natural Killer Cell Activity: A Cross-Sectional Study.

This study aimed to investigate whether body fat and muscle percentages are associated with natural killer cell activity (NKA). This was a cross-sectional study, conducted on 8058 subjects in a medical center in Korea. The association between the muscle and fat percentage tertiles and a low NKA, defined as an interferon-gamma level lower than 500 pg/mL, was assessed. In both men and women, the muscle mass and muscle percentage were significantly low in participants with a low NKA, whereas the fat percentage, white blood cell count, and C-reactive protein (CRP) level were significantly high in those with a low NKA. Compared with the lowest muscle percentage tertile as a reference, the fully adjusted odd ratios (ORs) (95% confidence intervals (CIs)) for a low NKA were significantly lower in T2 (OR: 0.69; 95% CI: 0.55-0.86) and T3 (OR: 0.74; 95% CI: 0.57-0.95) of men, and T3 (OR: 0.76; 95% CI: 0.59-0.99) of women. Compared with the lowest fat percentage tertile as a reference, the fully adjusted OR was significantly higher in T3 of men (OR: 1.31; 95% CI: 1.01-1.69). A high muscle percentage was significantly inversely associated with a low NKA in men and women, whereas a high fat percentage was significantly associated with a low NKA in men.

EVALUATION OF THE ACTIVITY OF PERIPHERAL BLOOD NATURAL KILLER CELLS IN HEALTHY SUBJECTS AND BREAST CANCER PATIENTS

Objectives: To study Natural Killer (NK) cell activity (NK-IFNg) and some indicators related to immunological characteristics of peripheral blood NK cells in healthy people and breast cancer patients. Methods: We evaluated NK cell activity through its secretory characteristics (NK-IFNg) using ATGen's commercial NK VUE TestÒ (ATGen kit) on 35 healthy subjects (medical staff) and 132 cancer patients treated at Vietnam National Cancer Hospital from August 2020 to February 2023. At the same time, we collected peripheral blood samples to conduct immunological characterization of peripheral blood NK cells based on the flow cytometer system (number, expression of the activation and inhibitory receptors such as NKG2A, NKG2D), and some other biomarkers (CEA, CA 15.3). Results: The secretory activity of peripheral blood NK cells (NKA-IFNγ) in breast cancer patients (1,013.46 ± 1,115.87 pg/mL) was statistically significantly lower than that in the healthy group ( 2,571.38 ± 827.52 pg/mL) ( ± SD) (p &lt; 0.001). The proportion of breast cancer patients with NKA-IFNγ activity of a very low level (≤ 200 pg/mL) was 40.9% and that of the healthy subjects was 0%. There was no relationship between NKA-IFNγ and peripheral blood NK cell count, and the expression levels of the activating receptor NKG2D and the inhibitory receptor NKG2A. Patients with CEA and CA 15.3 serum levels above the normal limits accounted for relatively low percentages (10.6% and 6.1%). Conclusion: Breast cancer patients with very low NK cell activity accounted for a significant proportion (40.9%). NKA-IFNγ activity could be used as a potential tool for monitoring the immune system health status of breast cancer patients before and after receiving treatment interventions.

Relationship between Serum Cortisol, Dehydroepiandrosterone Sulfate (DHEAS) Levels, and Natural Killer Cell Activity: A Cross-Sectional Study.

The adrenal steroid hormones, cortisol and dehydroepiandrosterone sulfate (DHEAS), are associated with the immune system in opposite actions. This study aimed to investigate the relationship between cortisol and DHEAS serum concentrations, their ratio (CDR), and natural killer cell activity (NKA). This cross-sectional study included 2275 subjects without current infection or inflammation in the final analyses. NKA was estimated by measuring the amount of interferon-gamma (IFN-γ) released by activated natural killer cells; low NKA was defined as IFN-γ level < 500 pg/mL. Cortisol, DHEAS levels, and CDRs were categorized by quartiles in men, premenopausal women, and postmenopausal women. Compared with the lowest quartile as reference, the adjusted odd ratios (ORs) and 95% confidence intervals (CIs) for low NKA of the highest cortisol and CDR group were 1.66 (1.09-2.51) and 1.68 (1.11-2.55) in men, 1.58 (1.07-2.33) and 2.33 (1.58-3.46) in premenopausal women, and 2.23 (1.28-3.87) and 1.85 (1.07-3.21) in postmenopausal women. Only in premenopausal women, the highest DHEAS group showed significantly lower risk of low NKA (OR: 0.51, 95% CI: 0.35-0.76). HPA axis activation indicated as high cortisol level, CDR was significantly associated with low NKA, while high DHEAS levels were inversely associated with low NKA in premenopausal women.

The prognostic impact of NKA dynamics in first-line treatment of metastatic colorectal cancer.

e15514 Background: Metastatic colorectal cancer (mCRC) remains a therapeutic challenge and new markers hold high priority. Natural Killer (NK) cells are immune cells with potent antitumor properties. The association between neoplastic development and level of effector functions of this cell type is well known. Moreover, it is recognized that NK cells are subject to tumor-mediated immune suppression. The present study aimed at elucidating a potential relationship between NK cell activity (NKA) and response to folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) in mCRC. Methods: NKA was analyzed in patients enrolled in a randomized trial of mCRC receiving FOLFOXIRI and either tocotrienol or placebo as first-line treatment. Blood (1 mL) was sampled into NK Vue tubes at baseline and before treatment cycles 2-3, placed at 37°C for 24 hours, and after incubation, the level of interferon-γ (IFNγ) in the plasma was a surrogate measure for NKA. A cutoff of 250 pg/mL IFNγ distinguished normal and low NKA. The endpoints were response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: A total of 70 patients were enrolled in the randomized clinical trial. The results showed that tocotrienol had no effect on either RR (p = 0.62), PFS (p = 0.52), or OS (p = 0.80). Patients were classified into two groups according to the dynamics of NKA measured at the available time points. Patients that dropped from a normal to a low level of NKA in samples taken between baseline and before cycle 3 and patients with continuous low NKA (IFNγ &lt; 250 pg/mL) were categorized as NKA-low. The NKA-high group included patients that increased from an abnormal to a normal level of NKA and patients that remained within the normal range (IFNγ &gt; 250pg/mL) in all available samples. The RR in the two groups were 38% (8/21) and 69% (24/35), respectively (p = 0.0496). The median PFS was 186 days (95% confidence interval (CI) 136-225 days, n = 23) for the NKA-low group and 252 days (95% CI 223-305 days, n = 37) for NKA-high (p = 0.0005). The hazard ratio (HR) was 2.65 (95% CI 1.28-5.50). After adjusting for age, performance status (PS), and tumor location, NKA remained an independent prognostic factor for PFS (HR = 3.32, 95% CI 1.67-6.61, p = 0.001). Median OS was 408 days (95% CI 219-679 days, n = 23) and 1051 days (95% CI 645-1225 days, n = 37), respectively (p = 0.0034). For OS, the NKA-low group also showed a poor prognosis, HR 2.23 (95% CI 1.17-4.25). NKA dynamics remained an independent prognostic marker for OS after adjusting for age, PS, and tumor location (HR = 2.74, 95% CI 1.50-5.03, p = 0.001). Conclusions: The results suggest that NKA dynamics within the first two cycles of treatment may hold relevant prognostic information in first-line treatment of mCRC. The possible causative relationship between NKA and treatment effect needs further elucidation, but calls for experimental trials combining chemotherapy with NK cell therapy in mCRC.

Natural killer cell activity level in colorectal cancer screening in an average risk population.

Increased natural killer cell activity (NKCA) is linked to reduced risk of colorectal cancer (CRC). Several prior studies have investigated the association of NKCA and the incidence of CRC in high-risk subjects. The aim of our study was to investigate NKCA sensitivity in diagnosing advanced neoplasia (AN) and CRC in an average risk population. NKCA was assessed by an enzyme-linked immunosorbent assay (ELISA) blood test in average risk subjects with a range of 25-2500 pg/ml set for ELISA. NKCA higher than 200 pg/ml was defined as negative. The performance of NKCA was evaluated using measures such as sensitivity, specificity, negative and positive predictive values (NPV, PPV), clinical utility index, etc. In addition, odds ratios for developing CRC using logistic regression models were calculated. NKCA was evaluated in 354 average risk individuals (mean age: 58.5 years; 36.2% male). The diagnostic accuracy of NKCA for CRC and AN was 75.5% and 72.3% respectively, with 96.4% NPV. The NKCA test demonstrated a good negative clinical utility index for CRC and AN (0.664 and 0.741, respectively). Individuals with low NKCA had 6.84 times higher odds of having CRC (95% CI: 2.31-20.27; p < 0.001). NKCA was higher in men vs. women (548.5 pg/ml vs. 500.0 pg/ml) and lower in smokers (412 pg/ml vs. 544 pg/ml), non-exercisers (413 pg/ml vs. 653.5 pg/ml), alcohol users (389 pg/ml vs. 476 pg/ml), and native Kazakhs and other Asian ethnic groups (446 pg/ml vs. 514 pg/ml). A high NKCA level has potential ability to rule out CRC and AN in an average risk population.

Prognostic value of natural killer cell activity for patients with HER2 + advanced gastric cancer treated with first-line fluoropyrimidine-platinum doublet plus trastuzumab.

We aimed to evaluate the prognostic value of natural killer (NK) cell activity for patients with HER2 + advanced gastric cancer (AGC) treated with first-line fluoropyrimidine-platinum doublet plus trastuzumab. Forty-one patients with HER2 + AGC who received fluoropyrimidine-platinum doublet plus trastuzumab as first-line treatment were prospectively enrolled. NK cell activity was evaluated using the NK Vue®. The median age was 63.5years, and 31 patients (75.6%) were male. Patients with low baseline NK cell activity (≤ median, n = 21) were associated worse progression-free survival (PFS) and overall survival (OS) compared with patients with high baseline NK cell activity (> median, n = 20) with a median PFS of 4.21 vs. 9.53months (P < 0.001), and median OS of 8.15months vs. 17.82months (P = 0.025), respectively. In the multivariate analysis, low baseline NK cell activity was independently associated with poor PFS (HR 4.35, P = 0.007). NK cell activity recovered to a normal range in nine patients (47.4%) with a low baseline NK cell activity (n = 19) after two cycles of treatment. The median PFS and OS among patients with recovered NK cell activity were significantly better than that among patients with persistently low NK cell activity (PFS, P = 0.038; OS, P = 0.003). Our results demonstrated the prognostic value of baseline NK cell activity for patients with HER2 + AGC treated with fluoropyrimidine-platinum doublet plus trastuzumab. The association between treatment outcomes and dynamic changes in NK cell activity suggests that NK cell treatment may improve treatment outcomes, especially for patients with low baseline NK cell activity.

Changes in natural killer cell activity after surgery and predictors of its recovery–failure

We evaluated the changes in natural killer cell activity (NKA) during the entire treatment period of patients with resectable biliopancreatic cancers and investigated the predictors of the failure of recovery of NKA after surgery. A total of 202 patients who underwent curative resection for biliopancreatic cancer were enrolled in the study. NKA levels were measured six times during the treatment period. We investigated whether there was any difference in postoperative NKA recovery according to the period-by-time NKA value. NKA decreased after surgery (mean, 40 pg/ml) compared to the NKA value at admission (200.2 pg/ml), then began to increase from 3 weeks after surgery (139.7 pg/ml) and rose to normal NKA levels at 5 weeks (217.1 pg/ml). The pattern of NKA changes was distinct according to the NKA values at admission. In multivariate analysis, NKA values of less than 250 pg/ml at admission (odds ratio = 5.898, p = 0.044) were a predictor of NKA recovery failure 5 weeks after surgery. NKA rapidly decreased after curative surgery for biliopancreatic cancer and recovered to normal levels about 5 weeks later. Clinicians should be aware and cautious that patients with low NKA at admission may fail to recover NKA postoperatively.

A Rare Case of Hemophagocytic Lymphohistiocytosis of Unknown Etiology

Abstract:Hemophagocytic lymphohistiocytosis (HLH) is an uncommon cytokine storm syndrome marked which can cause high mortality. In adults, acquired HLH usually has an underlying infectious, autoimmune or malignant process that triggers the syndrome. In this case report, we present a 64-year old Caucasian male presenting with productive cough, fevers, weight loss and altered mental status who was ultimately found to have HLH of unknown etiology.Introduction:According to the 2008 diagnostic criteria, HLH is established by a molecular diagnosis of pathologic mutation or through clinical and laboratory findings of fever, splenomegaly, cytopenias, hypertriglyceridemia and/or hypofibrinogenemia, tissue diagnosis of hemophagoyctosis in the bone marrow, spleen or lymph nodes, low or absent natural killer cell activity, elevated ferritin (>500 ng/ mL), and soluble CD 25 > 2400 U/mL. As a cytokine storm syndrome, HLH is often confused for sepsis, macrophage-activation syndrome (MAS) and other multi-organ system failures. Early recognition of HLH can prompt timely treatment and improve morbidity and mortality. Current therapeutic options include immunosuppression, immune modulation, chemotherapy, and biological response modification followed by bone marrow transplant.Case Report:A 64-year old Caucasian gentleman presented to the Emergency Department with complaints of lethargy, weakness, progressive dyspnea on exertion, productive cough of whitish sputum and a fever of 102.5 F. His past medical history was significant for non-insulin dependent diabetes, CAD s/p stent 14 years prior, hypertension, and atrial fibrillation. He had a 14 pack year smoking history and had quit smoking 13 years prior. On review of systems, he admitted to a 5 lbs weight loss over the past 3 months, intermittent bouts of confusion and recent leg swelling. Deep venous thrombosis was excluded by his primary care physician, a week prior to admission. While in the ED, a CBC showed pancytopenia, marked by a white blood cell count of 2.7 and anemia with hemoglobin of 10.1. A CXR was performed showing bilateral pulmonary nodules; a CT scan of his chest and abdomen showed extensive pulmonary nodules and moderate splenomegaly. The patient was started on empiric antibiotics for presumed pneumonia with concerns of sepsis.An exhaustive approach for a possible malignant etiology of the patient's lymphadenopathy was initiated on the second day of hospitalization. A CT-guided lung biopsy and bone marrow biopsy were initially conducted which were negative for any abnormal cells. Additionally, a PET-CT, VATS procedure, and several more bone marrow biopsies were performed, without any explanation for his symptoms. An extensive rheumatologic work up only showed mild positivity for anti-cardiolipin IgG and beta-2 glycoprotein 1 antibody IgA positivity. Infectious work up for Rickettsia, Histoplasmosis, Blastomycosis, Bartonella, Syphillis, Tuberculosis, Babesiosis, fungal, viral, and other potential infectious etiologies were unrevealing. Of interest, the patient had one AFB positive sample from his VATS procedure after two weeks, however this specimen was concluded to be non-correlative. All repeat AFB cultures and sputum analyses were negative. His hospital course was prolonged and complicated by bouts of altered mental status, continuing fevers and worsening pancytopenia.Approximately three hospital hospital re-admissions for sepsis-like syndrome, a splenectomy was performed with pathology showing hemophagocytosis. At the time of the splenectomy, an elevated ferritin value of > 70000 was noted, and fibrinogen levels were low. The patient was additionally found to have an elevated IL-2R. Thus, a diagnosis of HLH was made given pancytopenia, ferritin of 70000, elevated triglycerides, hypofibrinogenemia, elevated IL-2R, splenomegaly, hemophagocytosis on splenectomy and fevers. The patient was treated with etoposide and dexamethasone by his oncology, per protocol, to which his cytopenia, ferritin and fibrinogen improved.Conclusion:HLH is a rare disease entity that is often confused for sepsis syndrome. An extensive work up is urgent and necessary to adequately treat patients to reduce morbidity and mortality. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Effects of Bacillus firmus e volumine ex muris cellulae 6x on cytolytic activity of natural killer cells in vitro

Natural killer (NK) cells are among the first in defense of the innate immune system by eliminating a variety of abnormal or stressed cells such as cancer cells or virus-infected cells. Individuals who exhibit low cytolytic NK cell activity are believed to be at higher risk of viral infection, tumorigenesis, and various other diseases of the immune system. Therefore, restoration of impaired NK cell function might be an essential step in immunostimulatory therapy of immunocompromised patients. Bacillus firmus is a non-pathogenic gram-positive bacterium of the environment, which possesses various immunomodulatory properties in vitro and in vivo. This retrospective study reports on the effect of B. firmus on the activity of NK cells in vitro. Basal cytolytic NK cell activity against tumor cells among peripheral blood mononuclear cells (PBMCs) of routine patients was determined in a standardized NK cell cytotoxicity assay. The impact of cultivation of PBMCs with B. firmus preparation Bacillus firmus e volumine ex muris cellulae (Bacillus firmus (evc)) 6x on tumor cell killing by NK cells was monitored in relation to basal NK cell activity. This study showed that stimulation of PBMCs with Bacillus firmus (evc) 6x in vitro led to a significant increase in NK cell function. Substantial improvement in cytolytic NK cell activity (more than 1.3-fold of basal activity) was much more pronounced for patients with compromised NK cell function. Due to its immunostimulatory mode of action, Bacillus firmus (evc) may be of particular importance in therapy of patients with NK cell deficiency.

Immunosurveillance of Cancer and Viral Infections with Regard to Alterations of Human NK Cells Originating from Lifestyle and Aging.

Natural killer (NK) cells are cytotoxic immune cells with an innate capacity for eliminating cancer cells and virus- infected cells. NK cells are critical effector cells in the immunosurveillance of cancer and viral infections. Patients with low NK cell activity or NK cell deficiencies are predisposed to increased risks of cancer and severe viral infections. However, functional alterations of human NK cells are associated with lifestyles and aging. Personal lifestyles, such as cigarette smoking, alcohol consumption, stress, obesity, and aging are correlated with NK cell dysfunction, whereas adequate sleep, moderate exercise, forest bathing, and listening to music are associated with functional healthy NK cells. Therefore, adherence to a healthy lifestyle is essential and will be favorable for immunosurveillance of cancer and viral infections with healthy NK cells.

Insights on Immune Function in Free-Ranging Green Sea Turtles (Chelonia mydas) with and without Fibropapillomatosis.

Simple SummarySea turtles are susceptible to several herpesviruses that are linked to dermatologic diseases, including fibropapillomatosis (FP) and lung-eye-trachea disease. Aside from obvious skin lesions, a number of other sublethal impacts occur in response to these diseases, such as reduced immune function. In this study, we found no relationship between disease presence or severity and T-cell proliferation in green turtles from Florida, USA, at least until the moderate stages of FP; however, natural killer cell activity, a measure of innate immune function, was significantly reduced in turtles with FP compared to tumor-free individuals. This is the first study to examine natural killer cell activity in relation to FP, improving upon our understanding of altered immune system function associated with this disease.Chelonid alphaherpesviruses 5 and 6 (ChHV5 and ChHV6) are viruses that affect wild sea turtle populations. ChHV5 is associated with the neoplastic disease fibropapillomatosis (FP), which affects green turtles (Chelonia mydas) in panzootic proportions. ChHV6 infection is associated with lung-eye-trachea disease (LETD), which has only been observed in maricultured sea turtles, although antibodies to ChHV6 have been detected in free-ranging turtles. To better understand herpesvirus prevalence and host immunity in various green turtle foraging aggregations in Florida, USA, our objectives were to compare measures of innate and adaptive immune function in relation to (1) FP tumor presence and severity, and (2) ChHV5 and ChHV6 infection status. Free-ranging, juvenile green turtles (N = 45) were captured and examined for external FP tumors in Florida’s Big Bend, Indian River Lagoon, and Lake Worth Lagoon. Blood samples were collected upon capture and analyzed for ChHV5 and ChHV6 DNA, antibodies to ChHV5 and ChHV6, in vitro lymphocyte proliferation using a T-cell mitogen (concanavalin A), and natural killer cell activity. Despite an overall high FP prevalence (56%), ChHV5 DNA was only observed in one individual, whereas 20% of turtles tested positive for antibodies to ChHV5. ChHV6 DNA was not observed in any animals and only one turtle tested positive for ChHV6 antibodies. T-cell proliferation was not significantly related to FP presence, tumor burden, or ChHV5 seroprevalence; however, lymphocyte proliferation in response to concanavalin A was decreased in turtles with severe FP (N = 3). Lastly, green turtles with FP (N = 9) had significantly lower natural killer cell activity compared to FP-free turtles (N = 5). These results increase our understanding of immune system effects related to FP and provide evidence that immunosuppression occurs after the onset of FP disease.

Eating Healthy Might Help the Immune System Fight Cancer

Obesity has been known for years to be a major health problem. Rates of obesity have been steadily increasing all over the world. Many factors, including healthy eating habits and exercise, play important roles in controlling obesity. In our study, we compared the function of cells of the immune system called natural killer (NK) cells between healthy and obese groups of mice. We found that obese mice have lower numbers of NK cells and that NK cells from obese mice are less functional. Lower NK cell activity is related to a higher risk of infections and cancer in the obese group. This research could show a relationship between what we eat and our ability to defend ourselves against diseases like cancer.

An autoimmune storm: A case based literature review of successful management of lupus-polymyositis overlap syndrome complicated by multiple organ failure

Overlap syndromes of Connective tissues diseases is a rare and under-studied disorder. This syndrome can be complicated by multiple life-threatening complications like hepatitis, pancreatitis, macrophage activation syndrome and Acute Respiratory Distress syndrome. We report a 22-year-old Hispanic male with no remarkable past medical history who presented to the hospital with abdominal pain, myalgia, arthralgia, and persistent fever for two weeks and was found to have tachycardia, pancytopenia, transaminitis and an elevated lipase. The patient was initially evaluated for acute pancreatitis and hepatitis due to binge drinking and presumptive viral infection. Infectious work up was unrevealing, and the patient continued to deteriorate. The autoimmune panel came back significant for highly elevated Antinuclear Antibody (ANA) and Anti Double Stranded DNA antibody (dsDNA), low complement, high inflammatory markers, ferritin, elevated Creatine Kinase (CK), positive Anti Mi 2 antibody, low Natural Killer (NK) cell activity and elevated CD25. Patient was subsequently diagnosed with Lupus- Polymyositis overlap syndrome. Acute lupus flare was considered as the trigger for pancreatitis and hepatitis. The hospital course was complicated by Acute Respiratory Distress Syndrome (ARDS) due to Lupus pneumonitis, encephalopathy, and Macrophage Activation Syndrome (MAS). Patient was treated successfully with steroid pulse therapy, Cyclophosphamide, plasmapheresis, artificial ventilation, and extracorporeal membrane oxygenation (ECMO). We believe that this case is unique as it represented a diagnostic challenge as the Lupus-Polymyositis overlap syndrome is a rare entity, and it initially manifested in an extensively complicated pattern which is unusual. Moreover, this case was not only a diagnostic challenge but also a treatment conundrum due to multiple life-threatening complications the patient had during this hospitalization. In this review, we intend to discuss the management of this challenging and rarely reported connective tissue disease overlap syndrome.

Effect of Daily Intake of Heat-Killed Lactobacillus plantarum HOKKAIDO on Immunocompetence: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study

Background: Consumption of Lactobacillus plantarum HOKKAIDO (HOKKAIDO strain) reportedly increases immunocompetence. However, the concentration of viable bacteria and the type of food they can be incorporated into limits their consumption. The study aims to demonstrate the effect of daily intake of the heat-killed L. plantarum HOKKAIDO strain (HK-HOKKAIDO strain; 5 × 1010 colony-forming units/day) by healthy subjects with low natural killer (NK) cell activity for 8 weeks.Method: In this randomized, double-blind, placebo-controlled, parallel-group study, 70 healthy Japanese subjects who showed relatively low NK cell activity were recruited and randomly assigned to the HK-HOKKAIDO strain or placebo group. All subjects ingested one capsule per day for 8 weeks. We conducted medical interviews and performed body composition measurements, vital sign examinations, and blood sampling at weeks 0 (baseline), 4, and 8, and we collected salivary samples at weeks 0 and 8. In addition, the frequency and severity of cold symptoms in the subjects were recorded daily during the intake period.Results: Intake of the HK-HOKKAIDO strain did not increase the NK cell activity or immunity marker levels, including those of immunoglobulin, leukocyte fraction, and salivary secretory immunoglobulin A. However, the frequency and severity of the common cold symptoms were significantly reduced after the daily consumption of the HK-HOKKAIDO strain.Conclusions: The results showed that HK-HOKKAIDO strain administration can decrease the frequency and severity of common cold symptoms in healthy subjects. Our findings support the use of the HK-HOKKAIDO strain as a functional food with health benefits.Clinical trial registration: UMIN000034822