Red Cell Distribution Width and Absolute Lymphocyte Count Associate With Biomarkers of Inflammation and Subsequent Mortality in Rheumatoid Arthritis.

OBJECTIVE: Morbidity and mortality in rheumatoid arthritis (RA) is partly mitigated by maintaining immune and hematologic homeostasis. Identification of those at risk is challenging. Red cell distribution width (RDW) and absolute lymphocyte count (ALC) associate with cardiovascular disease (CVD) and mortality in the general population, and with disease activity in RA. How these variables relate to inflammation and mortality in RA was investigated. METHODS: In a retrospective single Veterans Affairs (VA) Rheumatology Clinic cohort of 327 patients with RA treated with methotrexate (MTX)+/- a tumor necrosis factor (TNF) inhibitor (TNFi), we evaluated RDW and ALC before and during therapy and in relation to subsequent mortality. Findings were validated in a national VA cohort (n = 13,914). In a subset of patients and controls, we evaluated inflammatory markers. RESULTS: In the local cohort, high RDW and low ALC prior to MTX treatment was associated with subsequent mortality over 10 years (both P < 0.001). The highest mortality was observed in those with both high RDW and low ALC. This remained after adjusting for age and comorbidities and was validated in the national RA cohort. In the immunology cohort, soluble and cellular inflammatory markers were higher in patients with RA than in controls. ALC correlated with age, plasma TNF receptor II, natural killer HLA-DR mean fluorescence intensity, and CD4CM/CD8CM HLA-DR/CD38%, whereas RDW associated with age and ALC. MTX initiation was followed by an increase in RDW and a decrease in ALC. TNFi therapy added to MTX resulted in an increase in ALC. CONCLUSION: RDW and ALC before disease-modifying antirheumatic drug therapy are associated with biomarkers of monocyte/macrophage inflammation and subsequent mortality. The mechanistic linkage between TNF signaling and lymphopenia found here warrants further investigation.

Mission, Organization, and Future Direction of the Serological Sciences Network for COVID-19 (SeroNet) Epidemiologic Cohort Studies.

Background: Global efforts are needed to elucidate the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the underlying cause of coronavirus disease 2019 (COVID-19), including seroprevalence, risk factors, and long-term sequelae, as well as immune responses after vaccination across populations and the social dimensions of prevention and treatment strategies. Methods: In the United States, the National Cancer Institute in partnership with the National Institute of Allergy and Infectious Diseases, established the SARS-CoV-2 Serological Sciences Network (SeroNet) as the nation's largest coordinated effort to study coronavirus disease 2019. The network comprises multidisciplinary researchers bridging gaps and fostering collaborations among immunologists, epidemiologists, virologists, clinicians and clinical laboratories, social and behavioral scientists, policymakers, data scientists, and community members. In total, 49 institutions form the SeroNet consortium to study individuals with cancer, autoimmune disease, inflammatory bowel diseases, cardiovascular diseases, human immunodeficiency virus, transplant recipients, as well as otherwise healthy pregnant women, children, college students, and high-risk occupational workers (including healthcare workers and first responders). Results: Several studies focus on underrepresented populations, including ethnic minorities and rural communities. To support integrative data analyses across SeroNet studies, efforts are underway to define common data elements for standardized serology measurements, cellular and molecular assays, self-reported data, treatment, and clinical outcomes. Conclusions: In this paper, we discuss the overarching framework for SeroNet epidemiology studies, critical research questions under investigation, and data accessibility for the worldwide scientific community. Lessons learned will help inform preparedness and responsiveness to future emerging diseases.

High Red Cell Distribution Width and Low Absolute Lymphocyte Count Associate With Subsequent Mortality in HCV Infection.

BACKGROUND: Hepatitis-C virus (HCV) chronic infection can lead to cirrhosis, hepatocellular carcinoma (HCC), end-stage liver disease, cardiovascular disease (CVD), and mortality. Transient Elastography (TE) is used to non-invasively assess fibrosis. Whether immune monitoring provides additive prognostic value is not established. Increased red-cell distribution width (RDW) and decreased absolute lymphocyte count (ALC) predict mortality in those without liver disease. Whether these relationships remain during HCV infection is unknown. MATERIALS AND METHODS: A retrospective cohort of 1,715 single-site VA Liver Clinic patients receiving Transient Elastography (TE) 2014-2019 to evaluate HCV-associated liver damage were evaluated for RDW and ALC in relation to traditional parameters of cardiovascular risk, liver health, development of HCC, and mortality. RESULTS: The cohort was 97% male, 55% African American, 26% with diabetes mellitus, 67% with hypertension, and 66% with tobacco use. After TE, 3% were subsequently diagnosed with HCC, and 12% (n=208) died. Most deaths (n=189) were due to non-liver causes. The TE score associated with prevalent CVD, positively correlated with atherosclerotic cardiovascular disease (ASCVD) 10-Year Risk Score, age, RDW, and negatively correlated with ALC. Patients with anisocytosis (RDW above 14%) or lymphopenia (ALC level under 1.2×109/L) had greater subsequent all-cause mortality, even after adjusting for age, TE score, and comorbidities. TE score, and to a modest degree RDW, were associated with subsequent liver-associated mortality, while TE score, RDW, and ALC were each independently associated with non-liver cause of death. CONCLUSION: Widely available mortality calculators generally require multiple pieces of clinical information. RDW and ALC, parameters collected on a single laboratory test that is commonly performed, prior to HCV therapy may be pragmatic markers of long-term risk of mortality.

Soluble Tumor Necrosis Factor Receptor 1 is Associated With Cardiovascular Risk in Persons With Coronary Artery Calcium Score of Zero.

BACKGROUND: A coronary artery calcium (CAC) score of zero confers a low but nonzero risk of atherosclerotic cardiovascular events (CVD) in asymptomatic patient populations, and additional risk stratification is needed to guide preventive interventions. Soluble tumor necrosis factor receptors (sTNFR-1 and sTNFR-2) are shed in the context of TNF-alpha signaling and systemic inflammation, which play a role in atherosclerosis and plaque instability. We hypothesized that serum sTNFR-1 concentrations may aid in cardiovascular risk stratification among asymptomatic patients with a CAC score of zero. METHODS: We included all participants with CAC=0 and baseline sTNFR-1 measurements from the prospective cohort Multi-Ethnic Study of Atherosclerosis (MESA). The primary outcome was a composite CVD event (myocardial infarction, stroke, coronary revascularization, cardiovascular death). RESULTS: The study included 1471 participants (mean age 57.6 years, 64% female), with measured baseline sTNFR-1 ranging from 603 pg/mL to 5544 pg/mL (mean 1294 pg/mL ±378.8 pg/mL). Over a median follow-up of 8.5 years, 37 participants (2.5%) experienced a CVD event. In multivariable analyses adjusted for Framingham Score, doubling of sTNFR-1 was associated with a 3-fold increase in the hazards of CVD (HR 3.0, 95% CI: 1.48-6.09, P = 0.002), which remained significant after adjusting for traditional CVD risk factors individually (HR 2.29; 95% CI: 1.04-5.06, P=0.04). Doubling of sTNFR-1 was also associated with progression of CAC >100, adjusted for age (OR 2.84, 95% CI: 1.33-6.03, P=0.007). CONCLUSIONS: sTNFR-1 concentrations are associated with more CVD events in participants with a CAC score of zero. Utilizing sTNFR-1 measurements may improve cardiovascular risk stratification and guide primary prevention in otherwise low-risk individuals.

Macrophage maturation from blood monocytes is altered in people with HIV, and is linked to serum lipid profiles and activation indices: A model for studying atherogenic mechanisms.

People with HIV (PWH) are at increased risk for atherosclerotic cardiovascular disease (ASCVD). Proportions of vascular homing monocytes are enriched in PWH; however, little is known regarding monocyte-derived macrophages (MDMs) that may drive atherosclerosis in this population. We isolated PBMCs from people with and without HIV, and cultured these cells for 5 days in medium containing autologous serum to generate MDMs. Differential gene expression (DGE) analysis of MDMs from PWH identified broad alterations in innate immune signaling (IL-1ß, TLR expression, PPAR ßδ) and lipid processing (LXR/RXR, ACPP, SREBP1). Transcriptional changes aligned with the functional capabilities of these cells. Expression of activation markers and innate immune receptors (CD163, TLR4, and CD300e) was altered on MDMs from PWH, and these cells produced more TNFα, reactive oxygen species (ROS), and matrix metalloproteinases (MMPs) than did cells from people without HIV. MDMs from PWH also had greater lipid accumulation and uptake of oxidized LDL. PWH had increased serum levels of free fatty acids (FFAs) and ceramides, with enrichment of saturated FAs and a reduction in polyunsaturated FAs. Levels of lipid classes and species that are associated with CVD correlated with unique DGE signatures and altered metabolic pathway activation in MDMs from PWH. Here, we show that MDMs from PWH display a pro-atherogenic phenotype; they readily form foam cells, have altered transcriptional profiles, and produce mediators that likely contribute to accelerated ASCVD.

Cytomegalovirus Coinfection Is Associated with Increased Vascular-Homing CD57+ CD4 T Cells in HIV Infection.

Cytotoxic CD4 T cells are linked to cardiovascular morbidities and accumulate in both HIV and CMV infections, both of which are associated with increased risk of cardiovascular disease (CVD). In this study, we identify CMV coinfection as a major driver of the cytotoxic phenotype, characterized by elevated CD57 expression and reduced CD28 expression, in circulating CD4 T cells from people living with HIV infection, and investigate potential mechanisms linking this cell population to CVD. We find that human CD57+ CD4 T cells express high levels of the costimulatory receptor CD2 and that CD2/LFA-3 costimulation results in a more robust and polyfunctional effector response to TCR signals, compared with CD28-mediated costimulation. CD57+ CD4 T cells also express the vascular endothelium-homing receptor CX3CR1 and migrate toward CX3CL1-expressing endothelial cells in vitro. IL-15 promotes the cytotoxic phenotype, elevates CX3CR1 expression, and enhances the trafficking of CD57+ CD4 T cells to endothelium and may therefore be important in linking these cells to cardiovascular complications. Finally, we demonstrate the presence of activated CD57+ CD4 T cells and expression of CX3CL1 and LFA-3 in atherosclerotic plaque tissues from HIV-uninfected donors. Our findings are consistent with a model in which cytotoxic CD4 T cells contribute to CVD in HIV/CMV coinfection and in atherosclerosis via CX3CR1-mediated trafficking and CD2/LFA-3-mediated costimulation. This study identifies several targets for therapeutic interventions and may help bridge the gap in understanding how CMV infection and immunity are linked to increased cardiovascular risk in people living with HIV infection.

Elevated neutrophil-lymphocyte ratio predicts mortality following elective endovascular aneurysm repair.

OBJECTIVE: The neutrophil-lymphocyte ratio (NLR) is an inexpensive and useful inflammatory marker that incorporates the balance of the innate (neutrophil) and adaptive (lymphocyte) immune responses. Data exist on the association between NLR and mortality in various coronary diseases and in cancer surgery, but there is a paucity of data on the impact of preoperative NLR on vascular surgical outcomes. The aim of this study was to evaluate the relationship between preoperative NLR and elective endovascular aortic aneurysm repair (EVAR) outcome. METHODS: A retrospective review of all patients who underwent elective EVAR at a single institution between 2010 and 2018 was conducted (n = 373). Only patients who had a preoperative complete blood count with differential within 30 days of their operation were included. The NLR was computed by dividing the absolute neutrophil count by the absolute lymphocyte count. A receiver operating characteristic curve was used to determine the optimal cutoff value of NLR with the strongest association with mortality. NLR was dichotomized so that patients with NLR above the threshold were at increased risk of mortality compared with those below it. Continuous variables were analyzed using Wilcoxon nonparametric signed-rank test and categorical variables with the Fisher exact test. A comparison of NLR and mortality was completed using Kaplan-Meier survival analysis. Cox regression analysis was used to evaluate factors associated with mortality through 5-year follow-up. RESULTS: Overall, 108 patients were included in this study. An NLR ≥ 4.0 was found to be associated with mortality (P < .0001). Thirty-two patients composed the High-NLR (NLR ≥ 4.0) group and the remaining 76 patients formed the Low-NLR (NLR < 4.0) group. Baseline characteristics were similar between groups, except that the High-NLR group was older (77.9 vs 74.4; P = .047). At a mean of 36.4 months follow-up, the overall mortality rate was 32.4%. Although there were no differences in the perioperative period, the Kaplan-Meier estimates of mortality were significantly greater in the High-NLR group at 1, 2, and 5 years postoperatively (P < .0001). The mean preoperative NLR of the deceased was higher (5.94 ± 5.20; median, 4.75; interquartile range, 3.17-7.83) than those who survived (2.87 ± 1.61; median, 2.53; interquartile range, 1.97-3.49) (P < .0001). Secondary interventions and sac enlargement rates were similar between groups. On univariable analysis, NLR (hazard ratio [HR], 1.17; 95% confidence interval [CI], 1.10-1.23; P < .0001), age (HR, 1.06; 95% CI, 1.02-1.11; P = .004), and aneurysm diameter (HR, 1.04; 95% CI, 1.01-1.07; P = .003) were associated with mortality. On multivariable analysis, NLR (HR, 1.19; 95% CI, 1.12-1.27; P < .0001), age (HR, 1.06; 95% CI, 1.01-1.11; P = .026), and aneurysm diameter (HR, 1.04; 95% CI, 1.02-1.07; P = .003) were associated with mortality. CONCLUSIONS: Patients with an elevated preoperative NLR, irrespective of other comorbidities, may represent a previously unrecognized subset of patients who are at heightened risk of mortality after elective EVAR. A complete blood count with differential is an inexpensive test that may be used as a prognostic indicator for outcome after EVAR. Further research is warranted to identify clinical, pathological, or anatomical factors associated with an elevated NLR and to determine modifiable factors, which may help improve long-term survival.

Association of Lymphopenia With Risk of Mortality Among Adults in the US General Population.

Importance: Immune dysregulation can increase the risk of infection, malignant neoplasms, and cardiovascular disease, but improved methods are needed to identify and quantify immunologic hazard in the general population. Objective: To determine whether lymphopenia is associated with reduced survival in outpatients. Design, Setting, and Participants: This retrospective cohort study of the National Health and Nutrition Examination Survey (NHANES) included participants enrolled from January 1, 1999, to December 31, 2010, a large outpatient sample representative of the US adult population. Associations were evaluated between lymphopenia and other immunohematologic (IH) markers, clinical features, and survival during 12 years of follow-up, completed on December 31, 2011. Spearman correlations, Cox proportional hazards regression models, and Kaplan-Meier curves were used in univariable and multivariable models, allowing for nonlinear associations with bivariate cubic polynomials. Data were analyzed from September 1, 2018, through July 24, 2019. Exposures: Absolute lymphocyte counts (ALC), red blood cell distribution width (RDW), and C-reactive protein (CRP) level. Main Outcomes and Measures: All-cause survival. Results: Among the 31 178 participants, the median (interquartile range) age at baseline was 45 (30-63) years, 16 093 (51.6%) were women, 16 260 (52.2%) were nonwhite, and overall 12-year rate of survival was 82.8%. Relative lymphopenia (≤1500/µL) and severe lymphopenia (≤1000/µL) were observed in 20.1% and 3.0%, respectively, of this general population and were associated with increased risk of mortality (age- and sex-adjusted hazard ratios [HRs], 1.3 [95% CI, 1.2-1.4] and 1.8 [95% CI, 1.6-2.1], respectively) due to cardiovascular and noncardiovascular causes. Lymphopenia was also associated with worse survival in multivariable models, including traditional clinical risk factors, and this risk intensified when accompanied by bone marrow dysregulation (elevated RDW) and/or inflammation (elevated CRP level). Ten-year mortality ranged from 3.8% to 62.1% based on lymphopenia status, tertile of CRP level, and tertile of RDW. A high-risk IH profile was nearly twice as common as type 2 diabetes (19.3% and 10.0% of participants, respectively) and associated with a 3-fold risk of mortality (HR, 3.2; 95% CI, 2.6-4.0). Individuals aged 70 to 79 years with low IH risk had a better 10-year survival (74.1%) than those who were a decade younger with a high-risk IH profile (68.9%). Conclusions and Relevance: These findings suggest that lymphopenia is associated with reduced survival independently of and additive to traditional risk factors, especially when accompanied by altered erythropoiesis and/or heightened inflammation. Immune risk may be analyzed as a multidimensional entity derived from routine tests, facilitating precision medicine and population health interventions.

CD8+ T-Cell-Derived Tumor Necrosis Factor Can Induce Tissue Factor Expression on Monocytes.

Circulating CD8+ T cells and monocytes are activated during human immunodeficiency virus (HIV) infection and colocalize in the aortas of simian immunodeficiency virus-infected nonhuman primates. We hypothesized that CD8+ T cells could exert a proatherosclerotic effect via paracrine actions on monocytes. We found that T-cell receptor-stimulated CD8+ T cells induce monocytes to express tissue factor, a potent activator of coagulation. Tumor necrosis factor was both necessary and sufficient for this effect.

Outcomes Among Patients With Heart Failure With Reduced Ejection Fraction Undergoing Transcatheter Aortic Valve Replacement: Minimally Invasive Strategy Versus Conventional Strategy.

OBJECTIVES: To investigate the effect of TAVR technique on in-hospital and 30-day outcomes in patients with aortic stenosis (AS) and reduced ejection fraction (EF). BACKGROUND: Patients with AS and concomitant low EF may be at risk for adverse hemodynamic effects from general anesthesia utilized in transcatheter aortic valve replacement (TAVR) via the conventional strategy (CS). These patients may be better suited for the minimally invasive strategy (MIS), which employs conscious sedation. However, data are lacking that compare MIS to CS in patients with AS and concomitant low EF. METHODS: In this retrospective study, we identified all patients with low EF (<50%) undergoing transfemoral MIS-TAVR vs CS-TAVR between March 2011 and May 2018. Our primary endpoint was defined as the composite of in-hospital mortality and major periprocedural bleeding or vascular complications. RESULTS: Two hundred and seventy patients had EF <50%, while 154 patients had EF ≤35%. Overall, a total of 236 patients were in the MIS group and 34 were in the CS group. Baseline characteristics between the two groups were similar except for Society of Thoracic Surgeons (STS) score (MIS 8.4 ± 5.1 vs CS 11.7 ± 6.8; P<.01). There were no differences between the two groups in incidence of the primary endpoint (MIS 5.5% vs CS 8.8%; odds ratio for MIS, 0.60; 95% confidence interval, 0.16-2.23; P=.45). CONCLUSIONS: In patients with severe AS and reduced EF, MIS was not associated with adverse in-hospital or 30-day clinical outcomes compared with CS. In these patients, MIS may be a suitable alternative to CS without compromising clinical outcomes.

Red Cell Distribution Width Is Positively Correlated with Atherosclerotic Cardiovascular Disease 10-Year Risk Score, Age, and CRP in Spondyloarthritis with Axial or Peripheral Disease.

BACKGROUND: Red blood cell distribution width (RDW) is a routine hematologic parameter that is a predictor of cardiovascular disease (CVD) events and is independent of combined traditional risk factor scoring systems. The RDW has also been associated with rheumatic disease activity. Whether RDW is associated with traditional CVD risk factors or Atherosclerotic Cardiovascular Disease (ASCVD) 10-year CVD risk score in patients with seronegative spondyloarthritis with axial or peripheral disease has not been previously determined. METHODS: We performed a retrospective, chart review study evaluating the relationship between RDW, albumin, hemoglobin, C-reactive protein (CRP), absolute lymphocyte count (ALC), and ASCVD scoring parameters [age, hypertension status, diabetes mellitus (DM) status, lipid profile, and smoking status] in a cohort of spondyloarthritis patients, taking into consideration their HLA-B27 status, race, and treatment status. RESULTS: RDW was found to positively correlate with ASCVD 10-year score and age, and ASCVD score did not change over time after patients were treated for spondyloarthritis. Albumin was found to negatively correlate with ASCVD 10-year risk score. Both RDW and albumin correlated with CRP. ALC failed to correlate with ASCVD 10-year score but did show a tendency to be associated with CVD, CVD events, and cardiac conduction abnormalities. CONCLUSIONS: These data indicate that further study is warranted to evaluate RDW, albumin level, and ALC as potential predictors of CVD in the spondyloarthritis patient population.

The effects of HIV and smoking on aortic and splenic inflammation.

OBJECTIVE: To determine the association of smoking and HIV status with tissue-specific inflammation measured by flurodeoxyglucose positron emission tomography (PET). DESIGN: A cross-sectional study. METHODS: We prospectively enrolled 55 HIV study participants on stable antiretroviral therapy and 19 age-matched HIV-uninfected controls without known cardiovascular disease. We measured aortic target-to-background ratio (TBR) and spleen standardized uptake values (SUV) 3-h post-FDG, and used regression models to examine the independent association of HIV and smoking status with PET variables. RESULTS: Overall, median (interquartile range) age was 50 (42-55) years; 81% were men and 54% were current smokers (median 0.5 packs/day, 25 pack-years]. Median CD4 of HIV study participants was 690 cells/ml and 88% had HIV-1 RNA less than 20 c/ml; 43% were on a protease inhibitor. In fully adjusted models, HIV was associated with 0.16 (95% confidence interval 0.04-0.27; P = 0.009) higher aortic TBR, whereas current smoking was marginally associated with a lower TBR [-0.11 (95% confidence interval -0.23 to 0.01); P = 0.07]. Spleen SUVmean was not associated with HIV or smoking, and there was no evidence for an HIVsmoking interaction for aortic or spleen models (all P > 0.1). Spleen SUVmean was positively associated with biomarkers of inflammation and coronary artery calcium, but adjustment for traditional cardiovascular disease risk factors attenuated these relationships. CONCLUSION: The FDG-PET study of HIV study participants suggests that HIV is associated with increased aortic inflammation independent of traditional risk factors, but smoking is not. Future studies should continue to explore the mechanistic roles of smoking and inflammation at various stages of clinical and subclinical atherosclerotic vascular disease in HIV.

Practice Variation Among Hospitals in Revascularization Therapy and Its Association With Procedure-related Mortality.

BACKGROUND: While substantial practice variation in coronary revascularization has been described and deviation from clinical practice guidelines has been associated with worse outcomes, the degree to which this is driven by flawed decision making and/or appropriate deviation associated with comorbid conditions is unknown. We evaluated heterogeneity in procedure use, and the extent to which hospital-level practice variation is related to surgical mortality. METHODS: We analyzed data on 554,563 inpatients undergoing either percutaneous coronary intervention or coronary artery bypass grafting at 391 centers in 6 states. Procedure-specific risk models were developed based on demographics and comorbidities, allowing for differential effects of comorbidities for each sex. For each patient, the revascularization procedure that minimized predicted probability of inhospital mortality was designated as the model-preferred procedure.Hospital-level discordance rates-the proportion of cases in each hospital for which the opposite from the model-preferred procedure was performed-were calculated. Hierarchical linear models were used to analyze the relationship between HDRs and hospital-level risk-standardized mortality ratios (RSMRs). RESULTS: Comorbidities and demographics alone explained between 68% and 86% of overall variation in inhospital mortality (corresponding C-statistics of 0.84-0.93). The mean (SD) HDR was 26.3% (9.6%). There was a positive independent association between HDRs and inhospital mortality, with a 10% increase in HDR associated with an 11% increase in RSMR (P<0.001). CONCLUSIONS: Variance in procedure use according to model preference was strongly associated with worse outcomes. A systematic approach to incorporating comorbidity as part of the decision-making process for coronary revascularization is needed.

Role of Natural Autoantibodies in Ugandans With Rheumatic Heart Disease and HIV.

BACKGROUND: Rheumatic heart disease (RHD) and HIV are prevalent diseases in sub-Saharan Africa, but little is known about their potential interrelationships. The objective of this study was to assess the prevalence of protective natural autoantibodies among patients with RHD in Uganda, and to determine whether the levels of these autoantibodies are affected by HIV status. METHODS: Participants were grouped according to RHD and HIV status. The three control groups (RHD - HIV -, RHD - HIV +, RHD + HIV -) were age-matched to the RHD + HIV + participants. All participants underwent HIV testing and echocardiography to evaluate for RHD. Natural autoantibody levels reactive with phosphorylcholine (PC) and malondialdehyde (MDA) were measured. FINDINGS: We enrolled 220 participants; 21 with both RHD and HIV. Ages ranged from 10 to 60 years, with female predominance (144/220, 65%). After adjusting for age and gender, HIV infection and RHD were each associated with low IgM anti-PC (HIV: p < 0.0001 and RHD: p = 0.01). A distinct HIV ∗ RHD interaction was identified (p = 0.045) with increased IgG anti-MDA levels in HIV infected subjects without RHD, whereas IgG anti-MDA levels were decreased in HIV infected subjects with RHD. INTERPRETATION: We found that HIV and RHD are associated with alterations in natural autoantibody responses previously linked to an increased risk for atherosclerosis and autoimmune inflammatory disease.

Altered Monocyte and Endothelial Cell Adhesion Molecule Expression Is Linked to Vascular Inflammation in Human Immunodeficiency Virus Infection.

BACKGROUND: Human immunodeficiency virus (HIV)-infected individuals have increased risk for vascular thrombosis, potentially driven by interactions between activated leukocytes and the endothelium. METHODS: Monocyte subsets (CD14+CD16-, CD14+CD16+, CD14DimCD16+) from HIV negative (HIV-) and antiretroviral therapy-treated HIV positive (HIV+) participants (N = 19 and 49) were analyzed by flow cytometry for adhesion molecule expression (lymphocyte function-associated antigen 1 [LFA-1], macrophage-1 antigen [Mac-1], CD11c/CD18, very late antigen [VLA]-4) and the fractalkine receptor (CX3CR1); these receptors recognize ligands (intercellular adhesion molecules [ICAMs], vascular cell adhesion molecule [VCAM]-1, fractalkine) on activated endothelial cells (ECs) and promote vascular migration. Plasma markers of monocyte (soluble [s]CD14, sCD163) and EC (VCAM-1, ICAM-1,2, fractalkine) activation and systemic (tumor necrosis factor receptor [TNFR-I], TNFR-II) and vascular (lipoprotein-associated phospholipase A2 [Lp-PLA2]) inflammation were measured by enzyme-linked immunosorbent assay. RESULTS: Proportions of CD16+ monocyte subsets were increased in HIV+ participants. Among all monocyte subsets, levels of LFA-1 were increased and CX3CR1 levels were decreased in HIV+ participants (P < .01). Levels of sCD163, sCD14, fractalkine, ICAM-1, VCAM-1, TNFR-II, and Lp-PLA2 were also increased in HIV+ participants (P < .05), and levels of sCD14, TNFR-I, and TNFR-II were directly related to ICAM-1 and VCAM-1 levels in HIV+ participants. Expression of CX3CR1 on monocyte subsets was inversely related to plasma Lp-PLA2 (P < .05 for all). CONCLUSIONS: Increased proportions of CD16+ monocytes, cells with altered adhesion molecule expression, combined with elevated levels of their ligands, may promote vascular inflammation in HIV infection.

Shared monocyte subset phenotypes in HIV-1 infection and in uninfected subjects with acute coronary syndrome.

The mechanisms responsible for increased cardiovascular risk associated with HIV-1 infection are incompletely defined. Using flow cytometry, in the present study, we examined activation phenotypes of monocyte subpopulations in patients with HIV-1 infection or acute coronary syndrome to find common cellular profiles. Nonclassic (CD14(+)CD16(++)) and intermediate (CD14(++)CD16(+)) monocytes are proportionally increased and express high levels of tissue factor and CD62P in HIV-1 infection. These proportions are related to viremia, T-cell activation, and plasma levels of IL-6. In vitro exposure of whole blood samples from uninfected control donors to lipopolysaccharide increased surface tissue factor expression on all monocyte subsets, but exposure to HIV-1 resulted in activation only of nonclassic monocytes. Remarkably, the profile of monocyte activation in uncontrolled HIV-1 disease mirrors that of acute coronary syndrome in uninfected persons. Therefore, drivers of immune activation and inflammation in HIV-1 disease may alter monocyte subpopulations and activation phenotype, contributing to a pro-atherothrombotic state that may drive cardiovascular risk in HIV-1 infection.

Beta-arrestin 2 is required for complement C1q expression in macrophages and constrains factor-independent survival.

The beta-arrestins (ARRB1 and ARRB2) regulate G-protein coupled receptor (GPCR) dependent- and independent-signaling pathways and are ubiquitously expressed. Here we show that ARRB2 mRNA and protein expression is enriched in macrophages, and that it regulates complement C1q expression and cell survival. Basal and Toll-like receptor (TLR) inducible expression of mRNAs encoding the complement subcomponents C1qa, C1qb and C1qc was greatly reduced in bone marrow-derived macrophages (BMM) from ARRB2-deficient, but not ARRB1-deficient mice, while factor-independent survival of ARRB2(-/-) BMM was enhanced compared to wildtype BMM. TatARRB2(23), a cell-permeable peptide that contains the MAPK JNK-binding motif from within the ARRB2 C-domain, impaired ARRB2 interaction with JNK3, down-regulated C1q expression and permitted factor-independent survival in BMM, thus suggesting that this peptide antagonises ARRB2 function in macrophages. In addition, TatARRB2(23) transiently activated the phosphorylation of JNK and ERK, but not p38 in BMM. These data imply that ARRB2 acts to limit JNK/ERK activation and survival in macrophages, but is required for basal and TLR-inducible complement C1q expression. Given that loss of C1q function is strongly associated with the development of systemic lupus erythematosus, ARRB2 may act to limit the development of autoimmune disease.

G-protein-coupled receptor expression, function, and signaling in macrophages.

G-protein-coupled receptors (GPCRs) are widely targeted in drug discovery. As macrophages are key cellular mediators of acute and chronic inflammation, we review here the role of GPCRs in regulating macrophage function, with a focus on contribution to disease pathology and potential therapeutic applications. Within this analysis, we highlight novel GPCRs with a macrophage-restricted expression profile, which provide avenues for further exploration. We also review an emerging literature, which documents novel roles for GPCR signaling components in GPCR-independent signaling in macrophages. In particular, we examine the crosstalk between GPCR and TLR signaling pathways and highlight GPCR signaling molecules which are likely to have uncharacterized functions in this cell lineage.