Soluble CD14 Levels Research Articles

The significance of CD14 in clear cell renal cell carcinoma progression and survival prognosis

Purpose: CD14-positive tumour and immune cells have been implicated in cancer progression. This study evaluated the prognostic significance of CD14 immunostaining in clear cell renal cell carcinoma (ccRCC) compared to the adjacent non-cancer kidney, and serum soluble CD14 (sCD14) levels in patients versus controls. Methods: Immunohistochemistry was performed for CD14 on ccRCC and the corresponding adjacent non-cancer kidney tissue from 88 patients. Staining intensity was determined using Aperio ImageScope morphometry. Serum sCD14 was evaluated for 39 ccRCC patients and 38 non-cancer controls using ELISA. CD14 levels were compared with tumour characteristics and survival status. Results: CD14 overall and nuclear immunostaining was higher in ccRCC compared to the adjacent non-cancer kidney tissue. CD14 nuclear immunostaining in the adjacent non-cancer kidney was significantly associated with advanced stage and adverse RCC survival prognosis. Serum sCD14 concentration was elevated in ccRCC patients compared to non-cancer controls and was also significantly associated with tumour stage and worse survival prognosis. Higher CD14 expression, in particular CD14 positive immune cell infiltrates found in the adjacent non-RCC kidney tissue, were associated with tumour progression and poorer prognosis. Conclusion: The levels of CD14 in non-RCC adjacent kidney and serum could be potential prognostic indicators.

A preliminary study of soluble CD14 levels in the serum of patients with hidradenitis suppurativa as a marker of “leaky gut”

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurring inflammatory lesions resulting from the rupture of occluded hair follicles. The aetiology of this disease is poorly understood, but it is clear that numerous immunological pathways are dysregulated, both locally and systemically. It is also increasingly appreciated that the gut and skin microbiomes of HS patients are deleteriously altered. Several lines of evidence indicate that this may lead to a “leaky gut” in HS patients, including the strong prevalence of Crohn’s disease as a co-morbidity, resulting in excessive bacterial translocation and lipopolysaccharide (LPS) circulation. Methods: We sought to investigate whether soluble CD14, a proxy for circulating LPS and subsequent excessive monocyte activation, was elevated in the serum of HS patients. sCD14 levels in HS patients from a Dublin hospital were assessed using ELISA. Results: We found that there was no significant difference in sCD14 levels present in the plasma of 12 healthy controls and 17 HS patients. Conclusions: Our results indicate that sCD14 is not a useful marker of inflammation in HS patients and does not indicate a grossly compromised gut epithelial barrier.

Glycocalyx Disruption Triggers Human Monocyte Activation in Acute Heart Failure Syndromes.

Acute heart failure (AHF) syndromes manifest increased inflammation and vascular dysfunction; however, mechanisms that integrate the two in AHF remain largely unknown. The glycocalyx (GAC) is a sugar-based shell that envelops all mammalian cells. Much GAC research has focused on its role in vascular responses, with comparatively little known about how the GAC regulates immune cell function. In this study, we sought to determine if GAC degradation products are elevated in AHF patients, how these degradation products relate to circulating inflammatory mediators, and whether the monocyte GAC (mGAC) itself modulates monocyte activation. Inflammatory markers and GAC degradation products were profiled using ELISAs. Flow cytometry was used to assess the mGAC and RNA-seq was employed to understand the role of the mGAC in regulating inflammatory activation programs. In a cohort of hospitalized AHF patients (n = 17), we found that (1) the GAC degradation product heparan sulfate (HS) was elevated compared with age-matched controls (4396 and 2903ng/mL; p = 0.01) and that (2) HS and soluble CD14 (a marker of monocyte activation) levels were closely related (Pearson's r = 0.65; p = 0.002). Mechanistically, Toll-like receptor (TLR) activation of human monocytes results in GAC remodeling and a decrease in the mGAC (71% compared with no treatment; p = 0.0007). Additionally, we found that ex vivo enzymatic removal of HS and disruption of the mGAC triggers human monocyte activation and amplifies monocyte inflammatory responses. Specifically, using RNA-seq, we found that enzymatic degradation of the mGAC increases transcription of inflammatory (IL6, CCL3) and vascular (tissue factor/F3) mediators. These studies indicate that the mGAC is dynamically remodeled during monocyte activation and that mGAC remodeling itself may contribute to the heightened inflammation associated with AHF.

CD163 and CD206 expression define distinct macrophage subsets involved in active ANCA-associated glomerulonephritis

IntroductionMacrophages are key players in the immunopathology of anti-neutrophil cytoplasmic antibody (ANCA) mediated-vasculitis (AAV) with glomerulonephritis (ANCA GN). Different macrophage phenotypes are expected to play distinct roles in ANCA GN. Macrophages expressing CD163 and CD206 are found in lesions associated with ANCA GN. Hence, we aimed to investigate the clinicopathological significance of CD206 and CD163 in ANCA GN in a multicenter retrospective cohort study. Material and methodsPatients with ANCA-associated vasculitis, with clinical data, serum and urine samples were included from three cohorts. Serum soluble CD206 (ssCD206) and urinary soluble CD163 (usCD163) levels were measured. Human kidney tissue samples (n = 53) were stained for CD206 and CD163 using immunohistochemistry and immunofluorescence, and findings were correlated with clinical and pathological data. ResultsIn total, 210 patients were included (i.e., ANCA GN, n = 134; AAV without GN, n = 24; AAV in remission n = 52). Increased levels of both ssCD206 and usCD163 were seen in ANCA GN. High levels of ssCD206 declined after reaching remission, however, ssCD206 did not improve the accuracy of usCD163 to detect ANCA GN. Soluble markers correlated with histopathological findings. CD163+CD206- macrophages were found in the glomerulus and may play pivotal roles in glomerulonephritis, whereas CD206+CD163- and CD206+CD163+ macrophages were located tubulointerstitially and likely play a more prominent role in ANCA-associated tubulointerstitial inflammation. In ANCA GN patients increasing levels of ssCD206 increased the risk for end-stage renal disease and mortality. ConclusionsOur results confirm and extend the notion that CD206+ and CD163+ macrophages are prominent components of the cellular infiltrate in ANCA GN. We found distinct macrophage phenotypes that may play distinct roles in the immunopathology of ANCA GN and elaborate on a potential mechanism underlying the findings of this study. usCD163 remains an excellent marker to detect active ANCA GN, whereas ssCD206 seems a more prominent marker for risk prediction.

Modified DEP regimen as induction therapy for lymphoma-associated hemophagocytic lymphohistiocytosis: a prospective, multicenter study.

Hemophagocytic lymphohistiocytosis (HLH), especially lymphoma-associated HLH (LA-HLH), is a refractory immune disorder with high mortality. There is still no consensus regarding the ideal treatment for LA-HLH. We performed a prospective multicenter study (NCT04077905) to explore the efficacy of a modified DEP regimen as induction therapy for LA-HLH. Twenty-eight patients from 6 clinical centers in China were enrolled between September 2019 and July 2021. We evaluated the efficacy of the modified DEP induction therapy 4 weeks after the initiation of treatment. The results showed that the overall response rate was 89.3% (25/28 patients), whereby 28.6% (8/28 patients) achieved a complete response and 60.7% (17/28 patients) were in partial response. Ferritin and soluble CD25 levels were decreased significantly 4 weeks after the modified DEP induction therapy (P = 0.001 and P = 0.00016, respectively), while platelet count and total bilirubin improved significantly (P = 0.004 and P = 0.001, respectively). The 1-year overall survival rate of all patients was 34.5%, with a median survival of 6.5months (range 0.5-19months). Patients with LA-HLH who underwent a stem cell transplantation had a significantly better prognosis than those not achieving complete response 4 weeks after modified DEP induction therapy (P = 0.034). Our study suggests that the modified DEP regimen is a safe and effective induction therapy for LA-HLH. Timely stem cell transplantation can improve the prognosis of patients with LA-HLH. NCT04077905. URL: https://clinicaltrials.gov/ct2/show/NCT04077905?id=NCT04077905&draw=2&rank=1 .

Abstract 685: Circulating immune markers and risks of non-Hodgkin lymphoma subtypes: A pooled analysis

Abstract Background: Peripheral blood levels of soluble CD27 (sCD27), sCD30 and chemokine ligand-13 (CXCL13) are proposed markers of immune activation, the effects of which may influence the development of non-Hodgkin lymphoma (NHL). Pre-diagnostic circulating levels of sCD27, sCD30 and CXCL13 have been associated with NHL, although individual studies have typically been underpowered to assess associations for individual NHL subtypes. We pooled data from eight case-control studies nested within general-population cohorts to investigate subtype-specific relationships with these immune markers. Methods: After pooling, immune marker data for 2,455 cases diagnosed >2 years after blood collection and 3,310 controls were available for analysis. Using polytomous regression models, we calculated odds ratios (ORs) with 95% confidence intervals (CIs) relating study-specific tertiles of each immune marker to the following subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n=623), diffuse large B-cell lymphoma (DLBCL; n=621), follicular lymphoma (FL; n=398), marginal zone lymphoma (MZL; n=138), mantle cell lymphoma (MCL; n=82) and T-cell lymphoma (TCL; n=92). Results: We observed associations with DLBCL for elevated levels of sCD27 [OR for 3rd vs. 1st tertile (ORT3) = 2.2, 95% CI = 1.6-3.1; Ptrend = 9.3x10-6), sCD30 (ORT3 = 2.0, 95% CI 1.6-2.5; Ptrend = 6.5 x10-10) and CXCL-13 (ORT3 = 2.3, 95% CI 1.8-3.0; Ptrend = 3.9 x10-12). These associations remained in a model simultaneously adjusting for all three markers. We also observed associations with sCD27 for CLL/SLL (ORT3 = 3.3, 95% CI = 2.4-4.6; Ptrend = 1.6x10-13), MZL (ORT3 =7.7, 95% CI 3.0-20.1; Ptrend = 2.3x10-6) and TCL (ORT3 = 3.4, 95% CI 1.5-7.7; Ptrend = 0.003), and between sCD30 and FL (ORT3 = 2.7, 95% CI 2.0-3.5; Ptrend = 1.7x10-12), all of which remained after adjustment for the other immune markers. In analyses stratified by follow-up time from blood collection to case diagnosis, the sCD27-TCL association and all three DLBCL associations were equivalent across both follow-up periods (>2-<7.5, ≥7.5 years). The sCD27-CLL/SLL, sCD27-MZL and sCD30-FL associations were weaker for cases diagnosed ≥7.5 years post-phlebotomy compared to the earlier follow-up period but remained statistically significant. Conclusions: In this pooled analysis, to our knowledge the first of its kind, we found robust evidence of an association between the three immune markers and DLBCL, consistent with hypotheses that mechanisms related to immune activation are important in the etiology of this malignancy. Other findings are notable, particularly the strong associations with sCD27 for the rare subtypes MZL and TCL, but require further investigation before causal inferences can be drawn. Citation Format: Jongeun Rhee, Brenda M. Birmann, Anneclaire J. De Roos, Mara M. Epstein, Otoniel Martinez-Maza, Elizabeth C. Breen, Lynn I. Levin, Kala Visvanathan, H Dean Hosgood, Thomas Rohan, Lihong Qi, Qing Lan, Nathaniel Rothman, Mark P. Purdue. Circulating immune markers and risks of non-Hodgkin lymphoma subtypes: A pooled analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 685.

Serum soluble CD23 levels are an independent predictor of time to first treatment in chronic lymphocytic leukemia.

Serum soluble CD23 (sCD23) levels have been acknowledged as a prognostic factor in patients with chronic lymphocytic leukemia (CLL), but their potential relevance has not been analyzed in recent times. We retrospectively studied 338 CLL, small lymphocytic lymphoma, or CLL-type monoclonal B-cell lymphocytosis patients from a single institution, with available sCD23 levels at diagnosis. Baseline features and outcomes were compared between patients with sCD23 ≤/>1000UI/L. The 140 patients (41%) who had sCD23>1000 UI/L showed adverse-risk clinical and biological characteristics. High sCD23 levels were predictive of a shorter time to first treatment (5-year probability of requiring treatment: 60 vs. 20%, p<0.0001; hazard ratio (HR)=1.72, p=0.003 in a multivariable model also including the CLL International Prognostic Index and the absolute lymphocyte count), and a poorer 5-year overall survival (70 vs. 82%, p=0.0009). These data suggest the potential of sCD23 to predict treatment-free survival and to shed light on mechanisms of activity and resistance to CD23-directed therapies.

Intestinal barrier dysfunction mediates Whipple's disease immune reconstitution inflammatory syndrome (IRIS).

Background & AimsClassical Whipple's disease (CWD) affects the gastrointestinal tract and causes chronic diarrhea, malabsorption, and barrier dysfunction with microbial translocation (MT). Immune reconstitution inflammatory syndrome (IRIS) is a serious complication during antimicrobial treatment of CWD. The pathomechanisms of IRIS have not been identified and mucosal barrier integrity has not been studied in patients with IRIS CWD.MethodsIn 96 CWD patients (n = 23 IRIS, n = 73 non‐IRIS) and 30 control subjects, we analysed duodenal morphology by histology, measured serum markers of MT, and proinflammatory cytokines in biopsy supernatants, and correlated microbial translocation with T cell reconstitution and activation.ResultsBefore treatment, duodenal specimens from patients who later developed IRIS exhibited a more pronounced morphological transformation that suggested a disturbed barrier integrity when compared with the non‐IRIS group. Villous atrophy was mediated by increased apoptosis of epithelial cells, which was insufficiently counterbalanced by regenerative proliferation of crypt cells. Pretreatment deficiencies in the mucosal secretion of proinflammatory cytokines and chemokines (e.g., IL‐6, CCL2) in these patients markedly resolved after therapy induction. High serum levels of lipopolysaccharides (LPS), soluble CD14 (sCD14), and LPS‐binding protein (LBP) combined with low endotoxin core antibody (EndoCAb) titres suggested systemic MT in CWD patients developing IRIS. CD4+ T cell count and activation in IRIS CWD patients correlated positively with sCD14 levels and negatively with EndoCAb titres. Furthermore, the degree of intestinal barrier dysfunction and MT was predictive for the onset of IRIS.ConclusionProlonged MT across a dysfunctional intestinal mucosal barrier due to severe tissue damage favors dysbalanced immune reconstitution and systemic immune activation in IRIS CWD. Therefore, the monitoring of inflammatory and MT markers in CWD patients might be helpful in identifying patients who are at risk of developing IRIS. Therapeutic strategies to reconstitute the mucosal barrier and control inflammation could assist in the prevention of IRIS.

Immune Activation in Primary Human Immunodeficiency Virus: Influence of Duration of Infection, Treatment, and Substance Use.

BackgroundPrimary human immunodeficiency virus (HIV) is characterized by dynamic changes in viral load and innate and adaptive immune responses; it is unclear the extent to which time from acquisition to antiretroviral therapy (ART) initiation and substance use impact these immunologic changes.MethodsWe studied plasma immune activation biomarkers, viral load, and CD4+ and CD8+ cell counts in participants from the Sabes primary infection study in Peru, who had been randomized to begin ART immediately after diagnosis vs 24 weeks later. We modeled influence of substance use and duration of HIV infection on biomarkers at baseline and over 24 weeks.ResultsCompared to participants enrolled >30 days after HIV acquisition, participants enrolled during acute infection (≤30 days) had higher mean interferon (IFN)–γ and IFN-α2a (1.7-fold and 3.8-fold interquartile range [IQR] higher, respectively). Participants enrolled >30 days after HIV acquisition had higher mean baseline CD8+ cell count (2.7 times the IQR). Alcohol use (positive phosphatidylethanol level) was associated with elevated IFN-γ, tumor necrosis factor alpha (TNF-α), and interleukin 12p70 (IL-12p70), and smoking was associated with higher macrophage inflammatory protein 1α, TNF-α, and IL-12p70. Most biomarkers declined more quickly in participants who initiated ART immediately; however, substance use and duration of HIV infection at enrollment had little influence on rate of decline.ConclusionsIFN-γ and other biomarkers are elevated during early primary infection, when exposure to HIV antigens is high. Immune activation decreased most quickly in those who started ART during acute/early primary infection. Higher CD8+ cell counts and a trend toward higher soluble CD163 levels during the 30 days after acquisition suggest the onset of compensatory responses and immune exhaustion.

Up-regulated serum levels of soluble CD25 and soluble CD163 in pediatric patients with SARS-CoV-2

Similar to hemophagocytic lymphohistiocytosis (HLH), some patients with SARS-CoV-2 have cytokine storm. Serum soluble interleukin-2 receptor (sCD25) and soluble CD163 (sCD163) are potential diagnostic biomarkers for HLH that help in guiding its treatment. This study was the first to investigate serum sCD25 and sCD163 levels in SARS-CoV-2. Serum sCD25 and sCD163 were measured by ELISA in 29 patients with SARS-CoV-2, aged between 2 months and 16 years (13 had COVID-19 and 16 had multisystem inflammatory syndrome in children (MIS-C)), in comparison to 30 age- and sex-matched healthy control children and 10 patients with HLH. Levels of these markers were re-measured in 21 patients with SARS-CoV-2 who were followed up 3 months after recovery. Patients with SARS-CoV-2 had significantly higher serum sCD25 and sCD163 than healthy control children (P < 0.001). SARS-CoV-2 patients had significantly higher sCD25 than patients with HLH (P < 0.05). Serum sCD25 was a good differentiating marker between patients with SARS-CoV-2 and HLH. Although there was a significant decrease of serum sCD25 and sCD163 of the 21 SARS-CoV-2 patients who were followed up, these levels were still significantly higher than the healthy controls levels (P < 0.001). Conclusion: Serum sCD25 and sCD163 levels were up-regulated in SARS-CoV-2 patients. Serum sCD25 was a good differentiating marker between SARS-CoV-2 and HLH. This initial report requires further studies, on large scales, to investigate the relationship between SARS-CoV-2 and both sCD25 and sCD163, including the disease severity and outcome. The therapeutic role of sCD25 and sCD163 antagonists should also be studied in SARS-CoV-2 patients.What is Known:• Similar to hemophagocytic lymphohistiocytosis (HLH), some patients with COVID-19 have cytokine storm due to excessive pro-inflammatory host response.• Serum soluble interleukin-2 receptor (sCD25) and soluble CD163 (sCD163) are potential diagnostic biomarkers for HLH. Monitoring of serum sCD25 and sCD163 levels can also help in guiding the treatment.What is New:• Serum sCD25 and sCD163 levels are up-regulated in patients with COVID-19, including patients presenting with multisystem inflammatory syndrome in children (MIS-C).• Serum sCD25 is a good differentiating marker between SARS-CoV-2 and HLH.

Fever, Rash, Cytopenia, and Disseminated Intravascular Coagulation in a 6-year-old.

Fever, Rash, Cytopenia, and Disseminated Intravascular Coagulation in a 6-year-old.

Soluble CD163 and CD163 Expression on Monocytes Associated with Chronic Hepatitis B Inflammation and HBsAg Loss.

Monocyte/macrophage-associated CD163 is an indicator of the severity of liver inflammation and cirrhosis, but the difference of soluble CD163 (sCD163) levels in chronic hepatitis B (CHB) patients and hepatitis B surface antigen (HBsAg)-loss patients is unclear. Herein, we aimed to compare the sCD163 levels in CHB patients and HBsAg-loss patients with or without antiviral treatment. sCD163 and CD163 expression on monocytes were compared among four groups, healthy subjects, treatment-naïve CHB patients, spontaneous HBsAg-loss patients, and treatment-related HBsAg-loss patients. The correlation between sCD163 levels and clinical parameters in CHB patients was analyzed. A group of 80 patients with hepatitis B virus (HBV) infection and liver biopsy were recruited. sCD163 levels were higher in the CHB group than in the other three groups. sCD163 levels were higher in treatment-related HBsAg-loss patients than in spontaneous HBsAg-loss patients. sCD163 levels were negatively correlated with hepatitis B e-antigen (HBeAg) and HBsAg levels in HBeAg-positive patients. Liver biopsy results further demonstrated that sCD163 levels were elevated in CHB patients with substantial inflammation (A≥2) or fibrosis (F≥2). The sCD163 model was more sensitive in predicting inflammation than other noninvasive models. Its levels were higher in patients with normal alanine aminotransferase levels and significant inflammation (A≥2) than in patients with no or mild inflammation. sCD163 and CD163 expression on monocytes were associated with CHB inflammation and HBsAg loss, and may be used as markers to predict HBV-specific immune activation.

CD30-targeted therapy induces apoptosis of inflammatory cytokine-stimulated synovial fibroblasts and ameliorates collagen antibody-induced arthritis in mice.

It has been reported that levels of soluble CD30 in serum and joint fluid are significantly elevated in patients with rheumatoid arthritis (RA). This study aimed to investigate whether CD30 could be a therapeutic target for RA. The expression and localization of CD30 were examined by immunohistochemical and double immunofluorescence staining on synovial tissue samples obtained from patients with RA or osteoarthritis (OA) during surgery. Changes in CD30 expression of fibroblast-like synoviocytes (FLS) from RA patients with or without TNFα and IL-1β stimulation were examined by the polymerase chain reaction (PCR) and flow cytometry. Collagen antibody-induced arthritis (CAIA) was created in DBA/1 mice, and the therapeutic effect of brentuximab vedotin (BV) was examined by clinical score, histological findings and measurement of serum levels of SAA, IL-6, and TNFα. CD30 expression was significantly higher in samples from patients with RA than from those with OA. Double immunofluorescence showed a low rate of co-localization of CD30 with CD20 or CD90, but a high rate of co-localization of CD30 and CD138. CD30 mRNA expression was upregulated 11.7-fold in FLS following stimulation by inflammatory cytokines. The clinical scores of CAIA mice were significantly lower following both BV treatments, however, the histological scores of CAIA mice were significantly lower only following treatment with high dose BV (70mg/kg). CD30 was expressed on immunocompetent cells in synovial tissue from RA patients and in cytokine-stimulated FLS in vitro. High dose BV (70mg/kg) showed significant therapeutic effects in ameliorating inflammation and joint destruction in CAIA mice, but low dose BV (30mg/kg) was insufficient.

Monitoring Circulating Immune Checkpoint Proteins as Predictors of Non-AIDS Morbid Events in People With HIV Initiating Antiretroviral Therapy.

BackgroundAlthough cell surface immune checkpoint proteins (ICPs) such as PD-1 expressed on T cells are associated with T-cell exhaustion, HIV disease progression, and AIDS events, they have shown limited utility in predicting non-AIDS morbidity. Given that ICPs also exist in soluble forms and are elevated in ART-treated HIV infection, we tested the hypothesis that soluble ICPs may be predictive of non-AIDS events in adults initiating ART.MethodsUtilizing a nested case–control study from the AIDS Clinical Trials Group ALLRT cohort, we measured plasma levels of 15 soluble inhibitory and activating ICPs by Luminex. Participants (134 cases, 292 matched controls) were evaluated pre-ART, a year post-ART, and immediately preceding a non-AIDS event, which included myocardial infarction (MI)/stroke, malignancy, serious bacterial infection, and nonaccidental death.ResultsConditional logistic regression analysis determined that higher levels of soluble CD27 were associated with increased risk of non-AIDS events at all time points. Higher levels of CD40 at baseline and pre-event and CD80 at pre-event were associated with increased risk of non-AIDS events. Examining specific non-AIDS events, multiple ICPs were associated with malignancy at baseline and pre-event, whereas only higher CD27 levels were associated with increased risk of MI/stroke at year 1 and pre-event.ConclusionsWhile select soluble ICPs were associated with non-AIDS events, CD27 emerged as a consistent marker irrespective of ART. Our data may offer guidance on new targets for early clinical monitoring in people with HIV who remain at greater risk of specific non-AIDS events.

Philadelphia-negative myeloproliferative neoplasms display alterations in monocyte subpopulations frequency and immunophenotype.

Philadelphia-negative myeloproliferative neoplasms (MPN) are clonal hematological diseases associated with driver mutations in JAK2, CALR, and MPL genes. Moreover, several evidence suggests that chronic inflammation and alterations in stromal and immune cells may contribute to MPN’s pathophysiology. We evaluated the frequency and the immunophenotype of peripheral blood monocyte subpopulations in patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (MF). Peripheral blood monocytes from PV (n = 16), ET (n = 16), and MF (n = 15) patients and healthy donors (n = 10) were isolated and submitted to immunophenotyping to determine the frequency of monocyte subpopulations and surface markers expression density. Plasma samples were used to measure the levels of soluble CD163, a biomarker of monocyte activity. PV, ET, and MF patients presented increased frequency of intermediate and non-classical monocytes and reduced frequency of classical monocytes compared to controls. Positivity for JAK2 mutation was significantly associated with the percentage of intermediate monocytes. PV, ET, and MF patients presented high-activated monocytes, evidenced by higher HLA-DR expression and increased soluble CD163 levels. The three MPN categories presented increased frequency of CD56+ aberrant monocytes, and PV and ET patients presented reduced frequency of CD80/86+ monocytes. Therefore, alterations in monocyte subpopulations frequency and surface markers expression pattern may contribute to oncoinflammation and may be associated with the pathophysiology of MPN.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12032-022-01825-6.

Dysregulation of the CD163-Haptoglobin Axis in the Airways of COPD Patients.

Pulmonary iron levels are increased in chronic obstructive pulmonary disease (COPD) patients. Iron causes oxidative stress and is a nutrient for pathogenic bacteria. Iron may therefore play an important role in the pathophysiology of COPD. The CD163-haptglobin axis plays a central role in the regulation of iron bioavailability. The aim of this study was to examine dysregulation of the CD163-haptglobin axis in COPD. We measured soluble CD163 (sCD163) and haptoglobin levels in sputum supernatants by enzyme-linked immunosorbent assay (ELISA) and sputum macrophage CD163 and haptoglobin expression by flow cytometry in COPD patients and controls. SCD163 levels were lower in COPD patients compared to controls (p = 0.02), with a significant correlation to forced expiratory volume in 1 s (FEV1)% predicted (rho = 0.5, p = 0.0007). Sputum macrophage CD163 expression was similar between COPD patients and controls. SCD163 levels and macrophage CD163 expression were lower in COPD current smokers compared to COPD ex-smokers. Haptoglobin levels were not altered in COPD patients but were regulated by genotype. Macrophage CD163 and haptolgobin expression were significantly correlated, supporting the role of CD163 in the cellular uptake of haptoglobin. Our data implicates a dysfunctional CD163-haptoglobin axis in COPD, which may contribute to disease pathophysiology, presumably due to reduced clearance of extracellular iron.

Reduced CCR5 Expression and Immune Quiescence in Black South African HIV-1 Controllers.

Unique Individuals who exhibit either suppressive HIV-1 control, or the ability to maintain low viral load set-points and preserve their CD4+ T cell counts for extended time periods in the absence of antiretroviral therapy, are broadly termed HIV-1 controllers. We assessed the extent to which black South African controllers (n=9), differ from uninfected healthy controls (HCs, n=22) in terms of lymphocyte and monocyte CCR5 expression (density and frequency of CCR5-expressing cells), immune activation as well as peripheral blood mononuclear cell (PBMC) mitogen-induced chemokine/cytokine production. In addition, relative CD4+ T cell CCR5 mRNA expression was assessed in a larger group of controllers (n=20) compared to HCs (n=10) and HIV-1 progressors (n=12). Despite controllers having significantly higher frequencies of activated CD4+ and CD8+ T cells (HLA-DR+) compared to HCs, CCR5 density was significantly lower in these T cell populations (P=0.039 and P=0.064, respectively). This lower CCR5 density was largely attributable to controllers with higher VLs (>400 RNA copies/ml). Significantly lower CD4+ T cell CCR5 density in controllers was maintained (P=0.036) when HCs (n=12) and controllers (n=9) were matched for age. CD4+ T cell CCR5 mRNA expression was significantly less in controllers compared to HCs (P=0.007) and progressors (P=0.002), whereas HCs and progressors were similar (P=0.223). The levels of soluble CD14 in plasma did not differ between controllers and HCs, suggesting no demonstrable monocyte activation. While controllers had lower monocyte CCR5 density compared to the HCs (P=0.02), significance was lost when groups were age-matched (P=0.804). However, when groups were matched for both CCR5 promoter haplotype and age (n=6 for both) reduced CCR5 density on monocytes in controllers relative to HCs was highly significant (P=0.009). Phytohemagglutinin-stimulated PBMCs from the controllers produced significantly less CCL3 (P=0.029), CCL4 (P=0.008) and IL-10 (P=0.028) compared to the HCs, which was largely attributable to the controllers with lower VLs (<400 RNA copies/ml). Our findings support a hypothesis of an inherent (genetic) predisposition to lower CCR5 expression in individuals who naturally control HIV-1, as has been suggested for Caucasian controllers, and thus, likely involves a mechanism shared between ethnically divergent population groups.

Decreased Levels of Soluble CD44 in a High-Risk Population following a Smoking Cessation Program.

Tobacco is a risk factor of head and neck cancer (HNC) and smoking cessation alone may reduce HNC risk by 70%. Soluble CD44 (solCD44), a cell surface receptor linked to cell proliferation and migration, and total protein (TP) levels can detect early HNC. This study aims to determine whether salivary solCD44 and TP levels in oral rinses change following a smoking cessation program. 150 smokers provided oral rinse samples at baseline and at a 12-month follow-up after participation in a smoking cessation program. Assays to measure levels of solCD44, TP, and cotinine, a metabolite used as a biomarker of tobacco exposure, were completed. A paired-samples t-test was used to determine whether there was a statistically significant (p < 0.05) mean difference in biomarker levels before and after the program. Baseline and at 12-month follow-up data were available for 88 subjects, 21 of whom quit smoking entirely. Mean levels of solCD44 significantly decreased by 0.412 ng/mL from baseline to the 12-month follow-up, p = 0.010. There was no significant difference in mean TP levels, p = 0.975. Mean cotinine levels decreased significantly by 74.7 ng/mL, p = 0.035. This is the first work demonstrating an association between smoking cessation and decreased solCD44 levels in oral rinses. Decreased expression of the tumorigenic CD44 may be one mechanism by which smoking cessation lowers cancer risk.

Plasma Soluble CD14 Subtype Levels Are Associated With Clinical Outcomes in Critically Ill Subjects With Coronavirus Disease 2019.

In bacterial sepsis, CD14 and its N-terminal fragment (soluble CD14 subtype, "Presepsin") have been characterized as markers of innate immune responses and emerging evidence has linked both to coronavirus disease 2019 pathophysiology. Our aim was to determine the relationship between the soluble form of CD14 and soluble CD14 subtype plasma levels, coronavirus disease 2019 status, and coronavirus disease 2019-related outcomes. A prospective cohort study. ICUs in three tertiary hospitals in Seattle, WA. Two-hundred four critically ill patients under investigation for coronavirus disease 2019. We measured plasma soluble CD14 and soluble CD14 subtype levels in samples collected upon admission. We tested for associations between biomarker levels and coronavirus disease 2019 status. We stratified by coronavirus disease 2019 status and tested for associations between biomarker levels and outcomes. Among 204 patients, 102 patients had coronavirus disease 2019 and 102 patients did not. In both groups, the most common ICU admission diagnosis was respiratory failure or pneumonia and proportions receiving respiratory support at admission were similar. In regression analyses adjusting for age, sex, race/ethnicity, steroid therapy, comorbidities, and severity of illness, soluble CD14 subtype was 54% lower in coronavirus disease 2019 than noncoronavirus disease 2019 patients (fold difference, 0.46; 95% CI, 0.28-0.77; p = 0.003). In contrast to soluble CD14 subtype, soluble CD14 levels did not differ between coronavirus disease 2019 and noncoronavirus disease 2019 patients. In both coronavirus disease 2019 and noncoronavirus disease 2019, in analyses adjusting for age, sex, race/ethnicity, steroid therapy, and comorbidities, higher soluble CD14 subtype levels were associated with death (coronavirus disease 2019: adjusted relative risk, 1.21; 95% CI, 1.06-1.39; p = 0.006 and noncoronavirus disease 2019: adjusted relative risk, 1.19; 95% CI, 1.03-1.38; p = 0.017), shock, and fewer ventilator-free days. In coronavirus disease 2019 only, an increase in soluble CD14 subtype was associated with severe acute kidney injury (adjusted relative risk, 1.23; 95% CI, 1.05-1.44; p = 0.013). Higher plasma soluble CD14 subtype is associated with worse clinical outcomes in critically ill patients irrespective of coronavirus disease 2019 status though soluble CD14 subtype levels were lower in coronavirus disease 2019 patients than noncoronavirus disease 2019 patients. Soluble CD14 subtype levels may have prognostic utility in coronavirus disease 2019.

A Randomized, Placebo-Controlled Trial Assessing the Effect of VISBIOME ES Probiotic in People With HIV on Antiretroviral Therapy.

BackgroundA5350, a phase II, randomized, double-blind study, evaluated the safety and tolerability of the probiotic Visbiome Extra Strength (ES) over 24 weeks and measured effects on inflammation and intestinal barrier function.MethodsThe primary outcome was change in soluble CD14 (sCD14) levels; secondary outcomes included safety and tolerability, markers of inflammation and cellular activation, and microbiome. In a substudy, gut permeability was assessed by paired colonic biopsies measuring the area of lamina propria occupied by CD4+ cells, interleukin (IL)-17+ cells, and myeloperoxidase (MPO). Changes between arms were compared with the 2-sample t test with equal variance or the Wilcoxon rank-sum test. For safety, the highest graded adverse events (AEs) were compared between arms using the Fisher exact test.ResultsOverall, 93 participants enrolled: 86% male, median age 51 years, median CD4 count 712 cells/mm3. Visbiome ES was safe and well tolerated. There was no difference in mean change in sCD14 from baseline to week 25/26 between placebo (mean change, 92.3 µg/L; 95% CI, –48.5 to 233 µg/L) and Visbiome ES (mean change, 41.0 µg/L; 95% CI, –94.1 to 176.2 µg/L; P=.60). Similarly, no statistically significant differences between arms in inflammatory marker changes were identified. In substudy participants, no statistical differences between arms for change in cellular marker expression or gut permeability were observed (P>.05 for all). The microbiome demonstrated increased probiotic species and a significant decrease in Gammaproteobacteria (P=.044) in the Visbiome ES arm.ConclusionsVisbiome ES was safe and altered the microbiome but demonstrated no effect on systemic inflammatory markers, pathology, or gut permeability in antiretroviral therapy–treated people with HIV.