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Background and Objectives: Whether chronic autoimmune inflammatory diseases causally affect the risk of Alzheimer disease (AD) is controversial. We characterized the relationship between inflammatory diseases and risk of AD and explored the role of circulating inflammatory biomarkers in the relationships between inflammatory diseases and AD., Methods: We performed observational analyses for chronic autoimmune inflammatory diseases and risk of AD using data from 2,047,513 participants identified in the UK Clinical Practice Research Datalink (CPRD). Using data of a total of more than 1,100,000 individuals from 15 large-scale genome-wide association study data sets, we performed 2-sample Mendelian randomizations (MRs) to investigate the relationships between chronic autoimmune inflammatory diseases, circulating inflammatory biomarker levels, and risk of AD., Results: Cox regression models using CPRD data showed that the overall incidence of AD was higher among patients with inflammatory bowel disease (hazard ratio [HR] 1.17; 95% CI 1.15-1.19; p = 2.1 × 10 -4 ), other inflammatory polyarthropathies and systematic connective tissue disorders (HR 1.13; 95% CI 1.12-1.14; p = 8.6 × 10 -5 ), psoriasis (HR 1.13; 95% CI 1.10-1.16; p = 2.6 × 10 -4 ), rheumatoid arthritis (HR 1.08; 95% CI 1.06-1.11; p = 4.0 × 10 -4 ), and multiple sclerosis (HR 1.06; 95% CI 1.04-1.07; p = 2.8 × 10 -4 ) compared with the age (±5 years) and sex-matched comparison groups free from all inflammatory diseases under investigation. Bidirectional MR analysis identified relationships between chronic autoimmune inflammatory diseases and circulating inflammatory biomarkers. Particularly, circulating monokine induced by gamma interferon (MIG) level was suggestively associated with a higher risk of AD (odds ratio from inverse variance weighted [OR IVW ] 1.23; 95% CI 1.06-1.42; p IVW = 0.007) and lower risk of Crohn disease (OR IVW 0.73; 95% CI -0.62 to 0.86; p IVW = 1.3 × 10 -4 ). Colocalization supported a common causal single nucleotide polymorphism for MIG and Crohn disease (posterior probability = 0.74), but not AD (posterior probability = 0.03). Using a 2-sample MR approach, genetically predicted risks of inflammatory diseases were not associated with higher AD risk., Discussion: Our data suggest that the association between inflammatory diseases and risk of AD is unlikely to be causal and may be a result of confounding. In support, although inflammatory biomarkers showed evidence for causal associations with inflammatory diseases, evidence was weak that they affected both inflammatory disease and AD., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: New biomarkers are needed to better predict the severity of acute pancreatitis. CD73/ecto-5'-nucleotidase is an enzyme that generates adenosine, which dampens inflammation and improves vascular barrier function in several disease models. CD73 also circulates in a soluble form in the blood. We studied whether levels of soluble form of CD73 predict the development of organ failure in acute pancreatitis., Design: A prospective cohort study of patients with acute pancreatitis from 2003 to 2007., Setting: Admissions to the biggest tertiary care hospital in Finland., Patients: One hundred sixty-one patients with acute pancreatitis, of which 107 were subclassified according to the revised Atlanta criteria into mild, 29 into moderately severe and 25 into severe., Interventions: None., Measurements and Main Results: Serum and blood cell samples were collected at admission. Protein levels of soluble form of CD73 in serum were determined using a novel enzyme-linked immunosorbent assay, activity of soluble form of CD73 using radioactive enzyme assays, and CD73 messenger RNA levels from leukocytes using quantitative polymerase chain reaction. Activity and protein concentration of soluble form of CD73, and messenger RNA level of CD73 all decreased along with the disease severity (p ≤ 0.01 for all). The activity of soluble form of CD73 at admission predicted the development of the severe pancreatitis in different groups of the patients. The area under the receiver-operating characteristic curve value for activity of soluble form of CD73 was 0.65 (95% CI, 0.51-0.80) among a subgroup of patients comprising moderately severe and severe disease, 0.79 (95% CI, 0.69-0.88) among all patients including mild pancreatitis, and 0.75 (95% CI, 0.60-0.89) among patients who had no signs of organ failure (modified Marshall score < 2) at admission. Especially, in the last-mentioned group, activity of soluble form of CD73 was better than C-reactive protein or creatinine in predicting the severe pancreat, Conclusions: : Activity of soluble form of CD73 at admission to hospital has prognostic value in predicting the development of the severe form of acute pancreatitis.

Background: Vascular adhesion protein-1 (VAP-1) associates to subclinical atherosclerotic manifestations in young people, but its association to incident major adverse cardiovascular events (MACEs) and cardiovascular mortality in a general population is not known., Methods and Results: We used a newly developed ELISA to measure soluble VAP-1 (sVAP-1) levels in 2775 participants (mean age, 60 years) from a prospective cohort study (the FINRISK 2002). During a mean follow-up of 9 years, 265 participants underwent a MACE, and these participants had higher levels of sVAP-1 than those without MACE (868 ng/mL and 824 ng/mL, respectively, P<0.001). In multivariate-adjusted Cox proportional hazard model including traditional Framingham risk factors (age, sex, systolic blood pressure, cholesterol, high-density lipoprotein cholesterol, smoking, prevalent diabetes mellitus, and antihypertensive treatment), sVAP-1 independently predicted incident MACE (P=0.0046) and MACE mortality (P=0.026). The impact of sVAP-1 in predicting the 9-year absolute risk of MACE was analyzed using integrated discrimination improvement and net reclassification improvement with 10-fold cross-validation. Inclusion of sVAP-1 in the Framingham model improved integrated discrimination improvement (P=0.042), and the clinical net reclassification improvement by correctly reclassifying 9% (P=0.0019) of people in the intermediate risk (5%-20%) group., Conclusions: sVAP-1 associated with increased risk of MACE and MACE mortality in people aged >50 years without prior MACE, and inclusion of sVAP-1 in the risk prediction model improved the clinical net reclassification improvement of incident MACE. Thus, sVAP-1 may be a potential new biomarker for cardiovascular diseases., (© 2014 American Heart Association, Inc.)

Rationale: Macrophage mannose receptor (MRC) is one of the few molecules known to be involved in lymphocyte trafficking via the lymphatic vessels. In endothelial cells of efferent lymphatics, it binds L-selectin on lymphocytes. In afferent lymphatics, MRC mediates trafficking of both normal and malignant L-selectin-negative cells to the draining lymph nodes., Objective: This work was designed to search for additional lymphocyte ligands of MRC to elucidate how lymphocytes migrate into the draining lymph nodes., Methods and Results: Using immunoprecipitation and binding studies with natural and recombinant proteins, we show that MRC and CD44 can interact with each other. Fine mapping revealed that the cysteine-rich domain of MRC binds to the chondroitin sulfate side chains of CD44. In vivo homing experiments with MRC- and CD44-deficient mice verified that MRC and CD44 function as a receptor-ligand pair in supporting lymphocyte migration via the afferent lymphatics into the draining lymph nodes., Conclusions: These data identify a new counter-receptor for MRC and reveal CD44 as a new molecule involved in the poorly understood process of lymphocyte transit via the lymphatic vasculature.

Objective: Vascular adhesion protein-1 is an endothelial enzyme that regulates leukocyte traffic and contributes to vascular damage in animal models. The relations of soluble vascular adhesion protein-1 (sVAP-1) with cardiovascular risk factors and markers of subclinical atherosclerosis at a population level have not been studied., Methods and Results: We developed a new high-throughput method and measured sVAP-1 activities in serum of 2183 persons (The Cardiovascular Risk in Young Finns Study). In women, sVAP-1 activity correlated indirectly with body mass index (r=-0.15, P<0.0001), triglycerides (r=-0.13, P<0.0001), C-reactive protein (r=-0.23; P<0.0001), and brachial artery flow-mediated vasodilatation (r=-0.076, P=0.0089) and directly with carotid plaques (r=0.066, P=0.023). None of these correlations was significant in men. In women, all these univariate correlations remained significant after adjustment for body mass index, and direct correlations with LDL-cholesterol (r=0.094, P=0.0014) and carotid intima-media thickness (r=0.075, P=0.010) became evident. In men, sVAP-1 activity associated directly with glucose (r=0.074, P=0.020), intima-media thickness (r=0.072, P=0.025), metabolic syndrome (P=0.016), and type 1 (P=0.0002) and type 2 (P<0.0001) diabetes. In multivariable analyses, sVAP-1 activity was an independent determinant of carotid intima-media thickness (P=0.0072) and plaques [odds ratio 1.71 (95% confidence interval 1.07-2.72, P=0.025] in women, but not in men., Conclusions: sVAP-1 activity correlates directly with intima-media thickness and carotid plaques in general population and may play a role in the pathophysiology of preclinical atherosclerosis.

Leukocyte extravasation from the blood into tissues is crucial for normal immune surveillance and in inflammation. Traditionally molecules belonging to selectin, chemokine, integrin, and immunoglobulin super families are thought to mediate the multiple adhesive and activation events needed for a successful emigration cascade. Recently, emerging evidence suggests that enzymes expressed on the surface of endothelial cells and leukocytes also contribute to the leukocyte extravasation cascade. Here we briefly review the role of vascular adhesion protein-1 (VAP-1) and CD73, 2 cell surface enzymes, in leukocyte migration form the blood into the tissues. Importantly, specific enzyme inhibitors, gene-deficient mice, and recombinant enzymes have recently unambiguously shown that the catalytic activity of these enzymes regulates the leukocyte traffic. The concept of enzymatic regulation of leukocyte extravasation provides new insight into the multi-step adhesion cascade and opens new possibilities for inhibiting inappropriate inflammatory reaction through the use of small molecule enzyme inhibitors.

Lymphocyte binding to vascular endothelium is a prerequisite for the movement of immune cells from the blood into lymphoid tissues and into sites of inflammation. Human vascular adhesion protein-1 (VAP-1) is an endothelial glycoprotein involved in this interaction. It also displays an enzymatic (monoamine oxidase) activity. Here we examined how recombinant human VAP-1 mediates lymphocyte binding using rotatory and flow chamber binding assays. VAP-1 cDNA transfected into an endothelial cell line, which does not bind lymphocytes, renders the cell line capable of binding lymphocytes in a shear-dependent manner. VAP-1 transfectants bound lymphocytes 5 times better than monocytes with a preference for T killer cells, and no specific granulocyte adherence was detectable. The binding is partially inhibited by anti-VAP-1 monoclonal antibodies or by blocking lymphocyte L-selectin and CD18 integrins, but not by inhibition of several other homing-associated molecules. In contrast, CD44 ligation on lymphocytes markedly upregulates their VAP-1-dependent adhesion, suggesting that the VAP-1 counterreceptor can be activated via CD44. The transfectant model also allowed us to perform detailed structure-function analyses of VAP-1. We show that the exposed integrin-binding motif RGD or the enzymatic activity is not indispensable for VAP-1-dependent adhesion. Together, these data show that VAP-1 can reconstitute the lymphocyte-endothelial adhesion cascade under shear and propose a critical role for VAP-1 in lymphocyte emigration from the blood.