CCL19 and CCR7 Expression, Signaling Pathways, and Adjuvant Functions in Viral Infection and Prevention.

Chemokine (C-C motif) ligand 19 (CCL19) is a critical regulator of the induction of T cell activation, immune tolerance, and inflammatory responses during continuous immune surveillance, homeostasis, and development. Migration of CC-chemokine receptor 7 (CCR7)-expressing cells to secondary lymphoid organs is a crucial step in the onset of adaptive immunity, which is initiated by a complex interaction between CCR7 and its cognate ligands. Recent advances in knowledge regarding the response of the CCL19-CCR7 axis to viral infections have elucidated the complex network of interplay among the invading virus, target cells and host immune responses. Viruses use various strategies to evade or delay the cytokine response, gaining additional time to replicate in the host. In this review, we summarize the impacts of CCL19 and CCR7 expression on the regulation of viral pathogenesis with an emphasis on the corresponding signaling pathways and adjuvant mechanisms. We present and discuss the expression, signaling adaptor proteins and effects of CCL19 and CCR7 as these molecules differentially impact different viral infections and viral life cycles in host homeostatic strategies. The underlying mechanisms discussed in this review may assist in the design of novel agents to modulate chemokine activity for viral prevention

RANTES/CCL5 and Risk for Coronary Events: Results from the MONICA/KORA Augsburg Case-Cohort, Athero-Express and CARDIoGRAM Studies

BACKGROUND: The chemokine RANTES (regulated on activation, normal T-cell expressed and secreted)/CCL5 is involved in the pathogenesis of cardiovascular disease in mice, whereas less is known in humans. We hypothesised that its relevance for atherosclerosis should be reflected by associations between CCL5 gene variants, RANTES serum concentrations and protein levels in atherosclerotic plaques and risk for coronary events. METHODS AND FINDINGS: We conducted a case-cohort study within the population-based MONICA/KORA Augsburg studies. Baseline RANTES serum levels were measured in 363 individuals with incident coronary events and 1,908 non-cases (mean follow-up: 10.2±4.8 years). Cox proportional hazard models adjusting for age, sex, body mass index, metabolic factors and lifestyle factors revealed no significant association between RANTES and incident coronary events (HR [95% CI] for increasing RANTES tertiles 1.0, 1.03 [0.75-1.42] and 1.11 [0.81-1.54]). None of six CCL5 single nucleotide polymorphisms and no common haplotype showed significant associations with coronary events. Also in the CARDIoGRAM study (>22,000 cases, >60,000 controls), none of these CCL5 SNPs was significantly associated with coronary artery disease. In the prospective Athero-Express biobank study, RANTES plaque levels were measured in 606 atherosclerotic lesions from patients who underwent carotid endarterectomy. RANTES content in atherosclerotic plaques was positively associated with macrophage infiltration and inversely associated with plaque calcification. However, there was no significant association between RANTES content in plaques and risk for coronary events (mean follow-up 2.8±0.8 years). CONCLUSIONS: High RANTES plaque levels were associated with an unstable plaque phenotype. However, the absence of associations between (i) RANTES serum levels, (ii) CCL5 genotypes and (iii) RANTES content in carotid plaques and either coronary artery disease or incident coronary events in our cohorts suggests that RANTES may not be a novel coronary risk biomarker. However, the potential relevance of RANTES levels in platelet-poor plasma needs to be investigated in further studies

RANTES/CCL5 and risk for coronary events: Results from the MONICA/KORA Augsburg case-cohort, Athero-express and CARDIoGRAM studies

Background: The chemokine RANTES (regulated on activation, normal T-cell expressed and secreted)/CCL5 is involved in the pathogenesis of cardiovascular disease in mice, whereas less is known in humans. We hypothesised that its relevance for atherosclerosis should be reflected by associations between CCL5 gene variants, RANTES serum concentrations and protein levels in atherosclerotic plaques and risk for coronary events. Methods and Findings: We conducted a case-cohort study within the population-based MONICA/KORA Augsburg studies. Baseline RANTES serum levels were measured in 363 individuals with incident coronary events and 1,908 non-cases (mean follow-up: 10.2±

Observations, knowledge, and attitude towards treatment options in patients with dry mouth: a survey among German dentists

Objectives The aim of this study was to investigate the attitude, observations, and knowledge of German dentists regarding the management of dry mouth. Materials and methods A questionnaire including queries about attitudes, observations, and treatment options in patients with dry mouth was developed and sent to all 1251 dentist members of a regional German dental association. Results An overall total of 284 returned questionnaires were included in the analyses, which relates to a response rate of 22.7%. Dentists infrequently encountered dry mouth in their clinical routine, yet were well aware that patients suffer from the symptoms of dry mouth; for affected patients, the majority of participating dentists provided specific dental prophylaxis measures. Drug side effects, neoplasia, and psychological disorders were regarded as the primary etiological factors for dry mouth, and caries, increased plaque formation, and rhagades as the most frequently observed clinical symptoms. While the majority of participating dentists was of the opinion that saliva substitutes are useful treatment options in patients with dry mouth, only few frequently recommended their use. Mechanical and gustatory stimulation of salivary flow as well as the advice to rinse with water were the most frequently pursued treatment options. Conclusions Despite the high prevalence of dry mouth identified in epidemiological studies, it appears to be an infrequent observation in clinical routine

Discovery of Multifold Modified Sialosides as <i>Human</i> CD22/Siglec‑2 Ligands with Nanomolar Activity on B‑Cells

Sialic acids are abundant in higher domains of life and lectins recognizing sialosaccharides are heavily involved in the regulation of the human immune system. Modified sialosides are useful tools to explore the functions of those lectins, especially members of the Siglec (sialic acid binding immunoglobulin like lectin) family. Here we report design, synthesis, and affinity evaluation of novel sialoside classes with combined modification at positions 2, 4, and 9 or 2, 3, 4, and 9 of the sialic acid scaffold as <i>human</i> CD22 (<i>human</i> Siglec-2) ligands. They display up to 7.5 × 10⁵-fold increased affinity over αMe Neu5Ac (the minimal Siglec ligand). CD22 is a negative regulating coreceptor of the B-cell receptor (BCR). <i>In vitro</i> experiments with a human B-lymphocyte cell line showed functional blocking of CD22 upon B-cell receptor (BCR) stimulation in the presence of nanomolar concentrations of the novel ligands. The observed increased Ca²⁺ response corresponds to enhanced cell activation, providing an opportunity to therapeutically modulate B-lymphocyte responses, e.g., in immune deficiencies and infections

Data on the test-retest reproducibility of streamline counts as a measure of structural connectivity

These data provide estimations of test-retest reproducibility of streamline counts based on diffusion weighted imaging (DWI) data using a global tractography algorithm in a sample of young healthy adults. Data on descriptive statistics and factorial analyses of within-session and between-session reproducibility in terms of intra-class correlation coefficients for the absolute agreement between measurements are provided. The effect of several exemplary methodological parameters pertaining to different steps along the tractography processing pipeline on reproducibility are considered. These data are related to the research article entitled ‘Probing the reproducibility of quantitative estimates of structural connectivity derived from global tractography’ (Schumacher et al., Neuroimage, 175 (2018) 215–229)

Design, Synthesis, and Biological Evaluation of Small, High-Affinity Siglec‑7 Ligands: Toward Novel Inhibitors of Cancer Immune Evasion

Natural killer cells are able to directly lyse tumor cells, thereby participating in the immune surveillance against cancer. Unfortunately, many cancer cells use immune evasion strategies to avoid their eradication by the immune system. A prominent escape strategy of malignant cells is to camouflage themselves with Siglec-7 ligands, thereby recruiting the inhibitory receptor Siglec-7 expressed on the NK cell surface which subsequently inhibits NK-cell-mediated lysis. Here we describe the synthesis and evaluation of the first, high-affinity low molecular weight Siglec-7 ligands to interfere with cancer cell immune evasion. The compounds are Sialic acid derivatives and bind with low micromolar <i>K</i>_d values to Siglec-7. They display up to a 5000-fold enhanced affinity over the unmodified sialic acid scaffold αMe Neu5Ac, the smallest known natural Siglec-7 ligand. Our results provide a novel immuno-oncology strategy employing natural immunity in the fight against cancers, in particular blocking Siglec-7 with low molecular weight compounds

Design, Synthesis, and Biological Evaluation of Small, High-Affinity Siglec‑7 Ligands: Toward Novel Inhibitors of Cancer Immune Evasion

Natural killer cells are able to directly lyse tumor cells, thereby participating in the immune surveillance against cancer. Unfortunately, many cancer cells use immune evasion strategies to avoid their eradication by the immune system. A prominent escape strategy of malignant cells is to camouflage themselves with Siglec-7 ligands, thereby recruiting the inhibitory receptor Siglec-7 expressed on the NK cell surface which subsequently inhibits NK-cell-mediated lysis. Here we describe the synthesis and evaluation of the first, high-affinity low molecular weight Siglec-7 ligands to interfere with cancer cell immune evasion. The compounds are Sialic acid derivatives and bind with low micromolar <i>K</i>_d values to Siglec-7. They display up to a 5000-fold enhanced affinity over the unmodified sialic acid scaffold αMe Neu5Ac, the smallest known natural Siglec-7 ligand. Our results provide a novel immuno-oncology strategy employing natural immunity in the fight against cancers, in particular blocking Siglec-7 with low molecular weight compounds