The frequency of interleukin-1ß-producing monocytes is significantly associated with varicella-zoster responses of nursing home residents.

Previous studies have demonstrated that the status of the T cell compartment and inflammation-related factors are associated with the immunogenicity of the varicella-zoster virus (VZV) vaccine in older adults; however, little is known about the roles of other immune cell subsets known to influence the generation and maintenance of immunological memory. Responses to a live-attenuated VZV vaccine were studied in relation to peripheral blood mononuclear cell (PBMC) composition and function in a sample of 30 nursing home residents (aged 80-99 years). Interferon-gamma enzyme-linked immunospot (ELISPOT) was used to measure VZV responses at baseline and 6 weeks following vaccination, and associations were sought with the frequencies of monocytes and T, B and natural killer (NK) cells and the production and secretion of cytokines following their ex-vivo stimulation with different agents. While only the frequency of interleukin (IL)-6+ CD14+ monocytes was inversely associated with post-vaccination VZV response, amounts of IL-1ß, IL-10, IL-17A and tumour necrosis factor (TNF) secreted by PBMCs and the frequency of IL-1ß+ CD14+ monocytes was positively correlated with pre-vaccination VZV response. Furthermore, both bivariate correlation and causal mediation analyses supported the notion that IL-1ß+ CD14+ monocytes were significant mediators of the associations between IL-1ß and TNF secretion by PBMCs and pre-vaccination VZV responses. Our findings implicate a strong cytokine response mediated by inflammatory IL-1ß+ monocytes in coordinating responses of long-lived VZV-reactive memory T cells, but with an opposing effect of IL-6+ CD14+ monocytes. Whether monocyte status promotes or inhibits the induction and/or maintenance of these memory T cells later in life has yet to be determined.

Monocyte activation is elevated in women with knee-osteoarthritis and associated with inflammation, BMI and pain.

OBJECTIVE: Monocytes contribute to synovitis and disease pathogenesis in osteoarthritis (OA). Low-grade inflammation occurs in OA and correlates with disease severity and progression. Since monocyte development and function is altered by systemic inflammation, we analyzed monocyte numbers and function between individuals with knee OA and healthy age- and sex-matched controls. DESIGN: We analyzed markers of soluble and cellular inflammation in peripheral blood of women with knee OA and compared them to healthy age- and sex-matched controls. Soluble inflammatory mediators (TNF, IL-6, IL-10 and CRP) in the serum were measured by high-sensitivity ELISA. Leukocyte numbers, surface expression of monocyte activation markers, and monocyte production of pro-inflammatory mediators (TNF and IL-1ß) following stimulation were measured by flow cytometry. RESULTS: Women with knee OA (n = 15) had elevated levels of serum c-reactive protein (CRP) and a lower proportion of circulating monocytes. Monocytes from OA participants had elevated expression of the activation markers CD16, CCR2, and HLA-DR and induced greater production of tumor necrosis factor (TNF) and IL-1ß compared to healthy controls. Higher serum TNF and BMI were correlated with increased monocyte expression of CCR2. Additionally monocyte CCR2 expression and serum TNF were correlated with worse pain on a validated questionnaire. CONCLUSIONS: Our findings suggest monocytes are activated prior to their entry into the synovium. Modulating systemic inflammation and monocyte recruitment to the synovium could be of therapeutic benefit.

Histone deacetylase activity and recurrent bacterial bronchitis in severe eosinophilic asthma.

An increase in P13 Kinase activity and an associated reduction in histone deacetylase activity may contribute to both relative steroid insensitivity in patients with severe eosinophilic asthma and impaired macrophage scavenger function and susceptibility to recurrent infective bronchitis that may, in turn, contribute to further steroid insensitivity.

G-protein-coupled receptor independent, immunomodulatory properties of chemokine CXCL9.

Certain chemokines possess anti-angiogenic and antibacterial activity, in addition to their ability to recruit leukocytes. Herein, we demonstrate that CXCL9/MIG induces the expression, by a monocytic cell line and peripheral blood mononuclear cells, of a variety of chemokines including CXCL8/IL-8, CCL3/MIP-1alpha, CCL4/MIP-1beta, CCL2/MCP-1 in a pertussis toxin insensitive manner. Similarly, another cationic chemokine CCL20/MIP-3alpha, but not the non-cationic chemokines CCL2 or CCL3, stimulated monocytic cells to produce substantial amounts of CXCL8 and CCL3. Microarray experiments demonstrated that CXCL9, but not CCL2, induced the expression of hundreds of genes, many of which have known or proposed immunomodulatory functions. Induction of CXCL8 required the p38 and ERK1/2 mitogen-activated protein kinases but not NFkappaB, JAK-STAT or JNK signaling pathways. These results collectively demonstrate that CXCL9 has immunomodulatory functions that are not mediated through a G-protein coupled receptor and may possess additional roles in host defenses against infection.

Proceedings of the Canadian Frailty Network Workshop: Identifying Biomarkers of Frailty to Support Frailty Risk Assessment, Diagnosis and Prognosis. Toronto, January 15, 2018.

The Canadian Frailty Network (CFN), a pan-Canadian not-for-profit organization funded by the Government of Canada through the Networks of Centres of Excellence Program, is dedicated to improving the care of older Canadians living with frailty. The CFN has partnered with the Canadian Longitudinal Study on Aging (CLSA) to measure potential frailty biomarkers in biological samples (whole blood, plasma, urine) collected in over 30,000 CLSA participants. CFN hosted a workshop in Toronto on January 15 2018, bringing together experts in the field of biomarkers, aging and frailty. The overall objectives of the workshop were to start building a consensus on potential frailty biomarker domains and identify specific frailty biomarkers to be measured in the CLSA biological samples. The workshop was structured with presentations in the morning to frame the discussions for the afternoon session, which was organized as a free-flowing discussion to benefit from the expertise of the participants. Participants and speakers were from Canada, Italy, Spain, United Kingdom and the United States. Herein we provide pertinent background information, a summary of all the presentations with key figures and tables, and the distillation of the discussions. In addition, moving forward, the principles CFN will use to approach frailty biomarker research and development are outlined. Findings from the workshop are helping CFN and CLSA plan and conduct the analysis of biomarkers in the CLSA samples and which will inform a follow-up data access competition.

Macrophage receptors implicated in the "adaptive" form of innate immunity.

The adaptive component of innate immunity occurs during the course of infection when antigen presenting cells alter expression of soluble or surface associated pattern recognition receptors. This results in increased recognition of a broad spectrum of pathogens, enhancement of effector functions and altered regulation of the inflammatory response.

Immunomodulatory properties of defensins and cathelicidins.

Host defence peptides are a conserved component of the innate immune response in all complex life forms. In humans, the major classes of host defence peptides include the alpha- and beta-defensins and the cathelicidin, hCAP-18/LL-37. These peptides are expressed in the granules of neutrophils and by a wide variety of tissue types. They have many roles in the immune response including both indirect and direct antimicrobial activity, the ability to act as chemokines as well as induce chemokine production leading to recruitment of leukocytes to the site of infection, the promotion of wound healing and an ability to modulate adaptive immunity. It appears that many of these properties are mediated though direct interaction of peptides with the cells of the innate immune response including monocytes, dendritic cells, T cells and epithelial cells. The importance of these peptides in immune responses has been demonstrated since animals defective in the expression of certain host defence peptides show greater susceptibility to bacterial infections. In the very few instances in which human patients have been demonstrated to have defective host defence peptide expression, these individuals suffer from frequent infections. Although studies of the immunomodulatory properties of these peptides are in their infancy, there is a growing body of evidence suggesting that the immunomodulatory properties of these small, naturally occurring molecules might be harnessed for development as novel therapeutic agents.

Endogenous pulmonary antibiotics.

The human lung produces a variety of peptides and proteins which have intrinsic antimicrobial activity. In general these molecules have broad spectra of antimicrobial activity, kill micro-organisms rapidly, and evade resistance generated by pathogens. In recent years it has become increasingly apparent that the antimicrobial peptides (AMPs) simultaneously possess immunomodulatory functions, suggesting complex roles for these molecules in regulating the clearance of, and immune response to, invading pathogens. These collective properties have stimulated considerable interest in the potential clinical application of endogenous AMPs. This article outlines the biology of AMPs, their pattern of expression in the lung, and their functions, with reference to both antimicrobial and immunomodulatory activity. We then consider the biological importance of AMPs, before concentrating on the potential to use AMPs to therapeutic effect. The principles discussed in the article apply to innate immune defence throughout the body, but particular emphasis is placed on AMPs in the lung and the potential application to pulmonary infection.

Interactions of chloroethylclonidine with rauwolscine- and prazosin-sensitive adrenoceptors in dog saphenous vein.

1. alpha 1-Adrenoceptors have been classified pharmacologically into four subtypes (alpha 1A, alpha 1B, alpha 1C and alpha 1D) on the basis of their differential affinity for novel antagonists such as chloroethylclonidine (CEC). While CEC is considered an alpha 1B-adrenoceptor antagonist, our earlier studies revealed that it also acted like an agonist in the dog saphenous vein (DSV). The present study characterized the contraction induced by CEC in endothelium-denuded rings from DSV. 2. Concentration-response curves for CEC were constructed in the absence (EC50 value of 11.13 +/- 3.6 microM, n = 8) and presence of propranolol (beta-adrenoceptor antagonist, 30 nM), rauwolscine (alpha 2-adrenoceptor antagonist, 30 nM), prazosin (alpha 1-adrenoceptor antagonist, 30 nM) or methysergide (5HT2 antagonist, 30 nM) or both prazosin and rauwolscine. Pretreatment with methysergide (9.83 +/- 5.14 microM, n = 4) or propranolol (23.78 +/- 12.32 microM, n = 4) had no consistent effect. In the presence of rauwolscine, the concentration-response curve for CEC was significantly shifted to the right with an EC50 value of 48.82 +/- 13.2 microM (n = 8). In the presence of prazosin, the CEC concentration-response curve had an EC50 value of 29.12 +/- 6.42 microM (n = 8). Pretreatment with both prazosin and rauwolscine shifted the concentration-response curve for CEC to the right with an EC50 value of 72.67 +/- 10.69 microM (n = 8, P < 0.05). Maximum responses were significantly reduced only in tissues that were treated with both prazosin and rauwolscine. 3. CEC (100 microM) pretreatment abolished prazosin binding sites and reduced the Bmax for rauwolscine by 50% without affecting the Kd value or the Hill slope.4. In Ca2+-free Krebs solution containing 50 microM EGTA, CEC produced a small transient contraction,suggesting that it can mobilize internally-stored Ca2+ . Pretreatment with rauwolscine abolished the CEC-induced contraction in Ca2+-free medium; prazosin pretreatment reduced but did not abolish CEC response in Ca2+-free medium.5. Restoring Ca2+ (0.5-2.5 mM) to the extracellular solution increased CEC contraction in a concentration-dependent manner, reaching a plateau at around 1.5mM Ca2 . The contraction was insensitive to nicardipine (1 microM), a voltage-operated Ca2+ channel blocker, but was blocked in a concentration-dependent manner by the putative receptor-operated Ca2+ channel blockers, SK&F 96365(1-1O microM) and genistein, also a tyrosine kinase inhibitor (10-100 microM).6. We conclude that CEC acts on rauwolscine- and, to a less extent, prazosin-sensitive adrenoceptors inDSV to release internally stored Ca2+ and to open receptor-operated Ca2+ channels. The inhibitory effect on CEC-induced contraction that depended on external Ca2+ by genistein suggests a role forty rosine kinase in the regulation of dihydropyridine-insensitive Ca2+ entry.