Human Leukocyte antigen-D Related Expression Research Articles

Decreased human leukocyte antigen-D–related expression on CD14+ monocytes in patients with out-of-hospital cardiac arrest provided target temperature management therapy: a prospective observational study

Decreased human leukocyte antigen-D–related expression on CD14+ monocytes in patients with out-of-hospital cardiac arrest provided target temperature management therapy: a prospective observational study

Application of Peak Glucose Range and Diabetes Status in Mortality Risk Stratification in Critically Ill Patients with Sepsis

The effects of diabetes and glucose on the outcomes of patients with sepsis are somewhat conflicting. This retrospective study enrolled 1214 consecutive patients with sepsis, including a subpopulation of 148 patients with immune profiles. The septic patients were stratified according to their Diabetes mellitus (DM) status or peak glucose level (three-group tool; P1: ≤140 mg/dL, P2: 141–220 mg/dL, P3: >220 mg/dL) on day 1. Although the DM group had a lower hazard ratio (HR) for 90-day mortality compared to non-DM patients, the adjusted HRs were insignificant. The modified sequential organ failure assessment-glucose (mSOFA-g) score can predict 90-day survival in patients with and without diabetes (β = 1.098, p < 0.001; β = 1.202, p < 0.001). The goodness of fit of the mSOFA-g score was 5% higher than the SOFA score of the subgroup without diabetes. The SOFA score and human leukocyte antigen-D-related (HLA-DR) expression were comparable between the groups. The P3 group had lower HLA-DR expression on days 1 and 3 and a higher 90-day mortality. The three-group tool was useful for predicting 90-day mortality in patients with separate Kaplan-Meier survival curves and mortality HRs in the construction and validation cohorts. The peak glucose level, instead of diabetes status, can be used as an easy adjunctive tool for mortality risk stratification in critically ill septic patients.

Prognosis-related classification and dynamic monitoring of immune status in patients with sepsis: A prospective observational study.

The dynamic monitoring of immune status is crucial to the precise and individualized treatment of sepsis. In this study, we aim to introduce a model to describe and monitor the immune status of sepsis and to explore its prognostic value. A prospective observational study was carried out in Zhongshan Hospital, Fudan University, enrolling septic patients admitted between July 2016 and December 2018. Blood samples were collected at days 1 and 3. Serum cytokine levels (e.g., tumor necrosis factor-α [TNF-α], interleukin-10 [IL-10]) and CD14+ monocyte human leukocyte antigen-D-related (HLA-DR) expression were measured to serve as immune markers. Classification of each immune status, namely systemic inflammatory response syndrome (SIRS), compensatory anti-inflammatory response syndrome (CARS), and mixed antagonistic response syndrome (MARS), was defined based on levels of immune markers. Changes of immune status were classified into four groups which were stabilization (SB), deterioration (DT), remission (RM), and non-remission (NR). A total of 174 septic patients were enrolled including 50 non-survivors. Multivariate analysis discovered that IL-10 and HLA-DR expression levels at day 3 were independent prognostic factors. Patients with MARS had the highest mortality rate. Immune status of 46.1% patients changed from day 1 to day 3. Among four groups of immune status changes, DT had the highest mortality rate, followed by NR, RM, and SB with mortality rates of 64.7%, 42.9%, and 11.2%, respectively. Severe immune disorder defined as MARS or deterioration of immune status defined as DT lead to the worst outcomes. The preliminary model of the classification and dynamic monitoring of immune status based on immune markers has prognostic values and is worthy of further investigation.

Risk factors and associated outcomes of ventilator-associated events developed in 28\xa0days among sepsis patients admitted to intensive care unit

We hypothesized that Ventilator-Associated Event (VAE) within 28 days upon admission to medical intensive care units (ICUs) can be a predictor for poor outcomes in sepsis patients. We aimed to determine the risk factors and associated outcomes of VAE. A total of 453 consecutive mechanically ventilated (MV) sepsis patients were enrolled. Of them, 136 patients had immune profile study. Early VAE (< 7-day MV, n = 33) was associated with a higher mortality (90 days: 81.8% vs. 23.0% [non-VAE], P < 0.01), while late VAE (developed between 7 and 28 days, n = 85) was associated with longer MV day (43.8 days vs. 23.3 days [non-VAE], P < 0.05). The 90-day Kaplan–Meier survival curves showed three lines that separate the groups (non-VAE, early VAE, and late VAE). Cox regression models with time-varying coefficient covariates (adjusted for the number of days from intubation to VAE development) confirmed that VAE which occurred within 28 days upon admission to the medical ICUs can be associated with higher 90-day mortality. The risk factors for VAE development include impaired immune response (lower human leukocyte antigen D-related expression, higher interleukin-10 expression) and sepsis progression with elevated SOFA score (especially in coagulation sub-score).

Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure

SummaryProper management of COVID-19 mandates better understanding of disease pathogenesis. The sudden clinical deterioration 7–8 days after initial symptom onset suggests that severe respiratory failure (SRF) in COVID-19 is driven by a unique pattern of immune dysfunction. We studied immune responses of 54 COVID-19 patients, 28 of whom had SRF. All patients with SRF displayed either macrophage activation syndrome (MAS) or very low human leukocyte antigen D related (HLA-DR) expression accompanied by profound depletion of CD4 lymphocytes, CD19 lymphocytes, and natural killer (NK) cells. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production by circulating monocytes was sustained, a pattern distinct from bacterial sepsis or influenza. SARS-CoV-2 patient plasma inhibited HLA-DR expression, and this was partially restored by the IL-6 blocker Tocilizumab; off-label Tocilizumab treatment of patients was accompanied by increase in circulating lymphocytes. Thus, the unique pattern of immune dysregulation in severe COVID-19 is characterized by IL-6-mediated low HLA-DR expression and lymphopenia, associated with sustained cytokine production and hyper-inflammation.

Clinical characteristics, risk factors, immune status and prognosis of secondary infection of sepsis: a retrospective observational study

BackgroundSecondary infection has a higher incidence in septic patients and affects clinical outcomes. This study aims to investigate the clinical characteristics, risk factors, immune status and prognosis of secondary infection of sepsis.MethodsA four-year retrospective study was carried out in Zhongshan Hospital, Fudan University, enrolling septic patients admitted between January, 2014 and January, 2018. Clinical data were acquired from medical records. CD14+ monocyte human leukocyte antigen-D related (HLA-DR) expression and serum cytokines levels were measured by flow cytometry and enzyme-linked immunosorbent assay (ELISA) respectively.ResultsA total of 297 septic patients were enrolled, 92 of whom developed 150 cases of secondary infections. Respiratory tract was the most common site of secondary infection (n = 84, 56%) and Acinetobacter baumanii the most commonly isolated pathogen (n = 40, 31%). Urinary and deep venous catheterization increased the risk of secondary infection. Lower HLA-DR expression and elevated IL-10 level were found in secondary infection group. The expected prolonged in-hospital stay owing to secondary infection was 4.63 ± 1.87 days. Secondary infection was also associated with higher in-hospital, 30-day and 90-day mortality. Kaplan-Meier survival analysis and Log-rank test revealed that secondary infection group had worse survival between day 15 and day 90.ConclusionsUrinary and deep venous catheterization increased the risk of secondary infection, in which underlying immunosuppression might also play a role. Secondary infection affected the prognosis of septic patients and prolonged in-hospital length of stay.

307 The Association Between Immune Dysfunction and Outcome of Septic Patients: A Prospective Observational Study

Sepsis is a dysregulated host response to an infection or injury which features as a multiple-system failure. Immune mechanism plays a vital role in the pathogenesis of sepsis. Some immune status might exist in septic patients, such as systemic inflammatory response syndrome (SIRS), compensatory anti-inflammatory response syndrome (CARS) and mixed antagonistic response syndrome (MARS), which is a severe imbalance of pro- and anti-inflammatory activities. The objective of this study is to explore the association between prognosis of sepsis and immune markers, namely pro-inflammatory markers such as tumor necrosis factor (TNF)-α, interleukin (IL)-2R, IL-6, IL-8, and anti-inflammatory markers such as IL-10, CD14+ monocyte human leukocyte antigen-D related (HLA-DR) expression. Also, the prognosis of each immune status was also targeted. A prospective observational study was carried out in Zhongshan Hospital, Fudan University, enrolling septic patients admitted between October 2016 and December 2018. Peripheral blood samples of patients were collected at day 1, day 3 and day 7 after admission. Medical records were screened for available clinical data. Plasma cytokines level were measured by enzyme-linked immunosorbent assay (ELISA) method and the flow cytometry was performed to measure the CD14+ monocyte HLA-DR expression. The median value of each immune marker was used as the cut-off point. Level of a pro-inflammatory marker higher than cut-point was marked as (+) , so was an anti-inflammatory marker lower than cut-point. Otherwise, it was marked as (-). Immune status of sepsis was classified according to levels of immune markers. SIRS was defined as 0-4 pro-inflammatory markers(+) and 0 anti-inflammatory markers(+). CARS was defined as 0-2 pro-inflammatory markers(+) and 1-2 anti-inflammatory marker(+). MARS was defined as 3-4 pro-inflammatory markers(+) and 1-2 anti-inflammatory marker(+). We analyzed the association between in-hospital mortality of septic patients and immune markers, as well as three immune status. Statistical analysis was conducted on SPSS 25.0 A total of 174 septic patients were enrolled in the study, among whom 124 survived and 50 did not. Immune markers were significantly associated with outcomes of sepsis (TNF-α: P<0.01 at day 1, P<0.001 at day 3; IL-2R: P=0.013 at day 1, P=0.029 at day 3; IL-6: P<0.001 at day 1 and day 3;IL-8:P<0.001 at day1 and day 3, P=0.023; IL-10: P<0.001 at day1 and day 3,P=0.006 at day 7; HLA-DR expression: P<0.001 at day1 and day 3). MARS caused higher in-hospital mortality than SIRS and CARS (P<0.001). Survival analysis also revealed that patients with MARS had poor 30-day survival than patients with SIRS and CARS (Log-rank test: P<0.001). Immune markers such as plasma cytokines level and CD14+ monocyte HLA-DR expression were associated with prognosis of septic patients. Patients with severe immune disorder, defined as MARS, could be predictive of poor outcome.

High-Performance Concurrent Chemo-Immuno-Radiotherapy for the Treatment of Hematologic Cancer through Selective High-Affinity Ligand Antibody Mimic-Functionalized Doxorubicin-Encapsulated Nanoparticles.

Non-Hodgkin lymphoma is one of the most common types of cancer. Relapsed and refractory diseases are still common and remain significant challenges as the majority of these patients eventually succumb to the disease. Herein, we report a translatable concurrent chemo-immuno-radiotherapy (CIRT) strategy that utilizes fully synthetic antibody mimic Selective High-Affinity Ligand (SHAL)-functionalized doxorubicin-encapsulated nanoparticles (Dox NPs) for the treatment of human leukocyte antigen-D related (HLA-DR) antigen-overexpressed tumors. We demonstrated that our tailor-made antibody mimic-functionalized NPs bound selectively to different HLA-DR-overexpressed human lymphoma cells, cross-linked the cell surface HLA-DR, and triggered the internalization of NPs. In addition to the direct cytotoxic effect by Dox, the internalized NPs then released the encapsulated Dox and upregulated the HLA-DR expression of the surviving cells, which further augmented immunogenic cell death (ICD). The released Dox not only promotes ICD but also sensitizes the cancer cells to irradiation by inducing cell cycle arrest and preventing the repair of DNA damage. In vivo biodistribution and toxicity studies confirm that the targeted NPs enhanced tumor uptake and reduced systemic toxicities of Dox. Our comprehensive in vivo anticancer efficacy studies using lymphoma xenograft tumor models show that the antibody-mimic functional NPs effectively inhibit tumor growth and sensitize the cancer cells for concurrent CIRT treatment without incurring significant side effects. With an appropriate treatment schedule, the SHAL-functionalized Dox NPs enhanced the cell killing efficiency of radiotherapy by more than 100% and eradicated more than 80% of the lymphoma tumors.

Immunopathological Features of Severe Chronic Atopic Keratoconjunctivitis and Effects of Topical Cyclosporine Treatment

ABSTRACTPurpose: To assess differential roles of inflammatory cells in pathophysiology of severe atopic keratoconjunctivitis (AKC) and evaluate immunomodulatory effects of topical cyclosporine A (CsA).Methods: A total of 10 patients with severe, steroid-dependent/resistant chronic active AKC were treated using frequent topical CsA 0.05% as monotherapy for 2 months. Conjunctival biopsy specimens before and after treatment were examined using immunohistochemistry. A total of 10 healthy age-matched adults served as the control group.Results: Baseline AKC samples revealed greater cluster of differentiation 4 (CD4), interferon gamma (IFNγ), human leukocyte antigen–D-related (HLA-DR) positive cell densities compared with healthy controls (P < 0.05), as well as interleukin (IL)-17 (P = 0.08). Topical CsA treatment induced a significant reduction in CD4 and IL-17 expressions (P < 0.05); post-treatment levels were same as normals (P > 0.05). Despite reduction after treatment (P = 0.06), HLA-DR expression remained higher than controls (P < 0.05).Conclusions: AKC-related conjunctival inflammation appears to be mediated by delayed hypersensitivity. In this short-term trial, frequent topical CsA improved conjunctival inflammation.

In vivo application of Granulocyte-Macrophage Colony-stimulating Factor enhances postoperative qualitative monocytic function.

BACKGROUND: Granulocyte macrophage colony-stimulating factor (GM-CSF) can be used as a potent stimulator for immune suppressed patients as defined by a decrease of human leukocyte antigen-D related expression on monocytes (mHLA-DR) after surgery. However, the exact role of GM-CSF on monocytic and T cell function is unclear. METHODS: In this retrospective randomized controlled trial (RCT) subgroup analysis, monocytic respectively T cell function and T cell subspecies of 20 immune suppressed (i.e. mHLA-DR levels below 10,000 monoclonal antibodies (mAb) per cell at the first day after surgery) patients after esophageal or pancreatic resection were analyzed. Each 10 patients received either GM-CSF (250 μg/m²/d) or placebo for a maximum of three consecutive days if mHLA-DR levels remained below 10,000 mAb per cell. mHLA-DR and further parameters of immune function were measured preoperatively (od) until day 5 after surgery (pod5). Statistical analyses were performed using nonparametric statistical procedures. RESULTS: In multivariate analysis, mHLA-DR significantly differed between the groups (p < 0.001). mHLA-DR was increased on pod2 (p < 0.001) and pod3 (p = 0.002) after GM-CSF application. Tumor necrosis factor-α (TNF-α) release of lipopolysaccharide (LPS) stimulated monocytes multivariately significantly differed between the groups (p < 0.008) and was increased in the GM-CSF group on pod2 (p < 0.001) and pod3 (p = 0.046). Th17/regulatory T (Treg) cell ratio was higher after GM-CSF treatment on pod2 (p = 0.041). No differences were seen in lymphocytes and T helper cell (Th)1/Th2 specific cytokine production after T cell stimulation with Concanavalin (Con) A between the groups. CONCLUSIONS: Postoperative application of GM-CSF significantly enhanced qualitative monocytic function by increased mHLA-DR and TNF-α release after LPS stimulation and apparently enhanced Th17/Treg ratio.Clinical trial registered with www.controlled-trials.com (ISRCTN27114642) 05 December 2008.

T cell activation profiles in different granulomatous interstitial lung diseases – a role for CD8+CD28null cells?

Lymphocytes play a crucial role in lung inflammation. Different interstitial lung diseases may show distinct lymphocyte activation profiles. The aim of this study was to examine the expression of a variety of activation markers on T lymphocyte subsets from blood and bronchoalveolar lavage fluid (BALF) of patients with different granulomatous interstitial lung diseases and healthy controls. Bronchoalveolar lavage cells and blood cells from 23 sarcoidosis patients, seven patients with hypersensitivity pneumonitis and 24 healthy controls were analysed. Lymphocyte activation status was determined by flow cytometry. Lymphocytes were stained with antibodies against CD3, CD4, CD8, CD25, CD28, CD69, very late antigen-1 (VLA)-1, VLA-4 and human leucocyte antigen D-related (HLA-DR). In general, CD28, CD69 and VLA-1 expression on BALF CD4+ lymphocytes and HLA-DR expression on BALF CD8+ lymphocytes was different in patients with hypersensitivity pneumonitis and sarcoidosis patients with parenchymal involvement. This BALF lymphocyte phenotype correlated with carbon monoxide diffusing lung capacity (Dlco) values across interstitial lung diseases (ILD) (r2 = 0.48, P = 0.0002). In sarcoidosis patients, CD8+CD28(null) blood lymphocytes correlated with lower Dlco values (r = -0.66, P = 0.004), chronic BALF lymphocyte activation phenotype (r2 = 0.65, P < 0.0001), radiographic staging (stage I versus stage II and higher, P = 0.006) and with the need for corticosteroid treatment (P = 0.001). Higher expression of CD69, VLA-1 and HLA-DR and lower expression of CD28 on BALF lymphocytes suggests prolonged stimulation and chronic lymphocyte activation in patients with ILD. In sarcoidosis, blood CD8+CD28(null) cells might be a new biomarker for disease severity but needs further investigation.

Statins Decrease the Aberrant HLA-DR Expression on Thyrocytes from Patients with Hashimoto's Thyroiditis

Statins have been found to exert anti-inflammatory and immune modulatory effects. It seems likely that these drugs may improve thyroid function in patients with Hashimoto's thyroiditis (HT). The objective of our study was to investigate the effect of statins on HLA-DR (human leukocyte antigen D-related) expression of thyrocytes from patients with HT hypothyroidism. Thyroid tissues were obtained from surgical specimens. Thyrocytes were cultured in the presence or absence of IFN-gamma (50 ng/ml) with or without statins (simvastatin 10 microM or atorvastatin 10 microM) for 72 hours. HLA-DR expression was detected by flow cytometry. Normal thyrocytes were used for controls. HLA-DR expression of HT thyrocytes was much higher than that of normal thyrocytes (41.2+/-4.5% vs. 2.7+/-2.1%, p<0.01), which could be further increased by IFN-gamma stimulation in both groups (p<0.01). However, simvastatin and atorvastatin could significantly inhibit the "aberrant" HLA-DR expression on HT thyrocytes and decrease IFN-gamma- induced HLA-DR expression in both HT and normal thyroid cells (p<0.01). Statins can repress HLA-DR expression of HT thyrocytes, which might inhibit the subsequent lymphocyte activation and ameliorate the immune disturbance of HT.

Th1 and Th2 Responses on the Ocular Surface in Uveitis Identified by CCR4 and CCR5 Conjunctival Expression

To investigate CC chemokine receptor 4 (CCR4) and CC chemokine receptor 5 (CCR5) expression, known to be related to the Th2 and Th1 inflammatory pathways, respectively, and human leukocyte antigen-D related (HLA-DR) antigens as hallmarks for ocular surface inflammation in patients with uveitis using conjunctival impression cytologic specimens. Case-controlled study. Conjunctival impression cytologic specimens were obtained from patients with anterior uveitis (n = 26), and their inflammatory profile was compared with those of patients with vernal keratoconjunctivitis (VKC; n = 24), keratoconjunctivitis sicca (KCS; n = 17), and normal subjects (n = 17). Expressions of CCR4, CCR5, and HLA-DR were analyzed using flow cytometry and were expressed by determining the percentage of cells expressing the markers in the conjunctival epithelium. CCR4 was overexpressed in the uveitis group (mean, 19.8% +/- 19.7% of positive cells) and in the VKC group (24.7% +/- 20.1%). CCR5 was expressed only weakly in uveitis patients (6.4% +/- 13.1%) and in the normal subjects (2.4% +/- 2.4%). HLA-DR expression by conjunctival cells was increased in the uveitis patients (57.4% +/- 21.1%) and in the KCS group (52.4% +/- 12.1%) compared with the VKC group (23.9% +/- 26.8%; P < .001) and normal subjects (22.1% +/- 19.1%; P < .001). CCR4, classically related to the Th2 system, and HLA-DR both were overexpressed by the conjunctival epithelium in uveitis patients, whereas CCR5, related to the Th1 system, was expressed weakly in uveitis patients. These preliminary results seem to suggest an involvement of the Th2 system on the ocular surface in uveitis. Exploration of the ocular surface in uveitis may represent a new way to understand better the immune pathways involved in this complex disease.

Immunohistochemical analysis of coeliac mucosa following ingestion of oats.

There is now considerable clinical evidence that oats do not activate coeliac disease. Nonetheless, a reluctance to include oats in the gluten-free diet remains. Because gluten-induced damage is accompanied by activation of the gastrointestinal immune system, the purpose of this study was to investigate if similar changes were induced by oats ingestion. Small intestinal histological sections from 10 patients who ingested 50 g of oats daily for 3 months were investigated for possible evidence of immune activation. Tissue obtained before and after oats challenge was stained with a series of antibodies directed against the following molecules: human leucocyte antigen D-related (HLA-DR), Ki-67, CD25, CD54 [intercellular adhesion molecule 1 (ICAM-1)] and mast cell tryptase. None of the patients developed clinical or laboratory evidence of adverse effects. The distribution of intestinal HLA-DR expression was not affected by oats ingestion and the crypt epithelium remained unstained. In the pre-oats biopsies, the percentage of Ki-67 positive enterocytes, 29.5 +/- 6.9 [95% confidence interval (CI) 13.9-45.0] did not differ significantly from that found in post-oats biopsies, 41.2 +/- 3.7 (95% CI, 32.8-49.6), P = 0.19, not significant. Furthermore, oats ingestion did not alter the number of CD25 positive and tryptase positive cells. Finally, the distribution and intensity of ICAM-1 staining was unchanged by dietary oats. In summary, detailed immunohistological studies of biopsies from patients ingesting oats for 3 months did not reveal evidence of immune activation. Together with other reported findings, this study strengthens the view that oats can be included safely in the diet of gluten sensitive patients.

Sex differences in cytokine production and surface antigen expression of peripheral blood mononuclear cells after surgery

Background Several clinical and epidemiological studies have observed a better outcome after sepsis in women than in men. The purpose of this study was to determine if these sex differences are observed in cytokine responses and the surface antigen expression of monocytes. In addition, the clinical courses of male and female patients after gastrointestinal surgery were compared. Methods A total of 25 patients with gastric carcinoma who underwent gastrectomy were enrolled in this study. Tumor necrosis factor-α (TNF-α), interleukin-10, and interferon-γ (IFN-γ) production by lipopolysaccharide-stimulated peripheral blood mononuclear cells (PBMCs) as well as the expression of Toll-like receptor-4 (TLR-4), TLR-2, human leukocyte antigen–D related (HLA-DR), and CD16 on monocytes in 16 men and 9 women on the day before surgery were compared with measurements on postoperative day (POD) 1. Furthermore, postoperative infectious complications, the development of systemic inflammatory response syndrome, and serum C-reactive protein levels on POD3 were compared. Results TNF-α production of PBMCs and TLR-2 and CD16 expression on monocytes were significantly higher in women than in men before surgery. IFN-γ production of PBMCs and HLA-DR expression on monocytes were significantly lower in men than in women on POD1. Furthermore, TNF-α production of PBMCs on POD1 was significantly increased, and both IFN-γ production and HLA-DR expression were significantly decreased compared with that observed before surgery in men, but no corresponding significant changes were observed in women. In addition, C-reactive protein levels on POD3 were significantly higher in men than in women. Conclusions Both TNF-α and interleukin-10 production of PBMCs and both TLR-2 and CD16 expression on monocytes were significantly higher in women than in men on the day before surgery. Excessive TNF-α and suppressive IFN-γ production of PBMCs, as well as a decrease in HLA-DR expression on monocytes, occurred more often in men than in women after surgery, suggesting that these factors all contribute to an increased susceptibility of men to develop systemic inflammatory response syndrome or postoperative infectious complications.