The present review is focused on the main achievements realized in the lysozyme research field since the meeting held in 1972 to commemorate the fiftieth anniversary of the discovery of this enzyme. Despite of extensive structural, physico-chemical, crystallographic, genetic, immunological and evolutionary studies devoted to lysozymes, their biological role is still not exactly known.

What's new in lysozyme research? Always a model system, today as yesterday.

The chronic toxicity of aluminium, cadmium, mercury, and lead in birds: a review.

We recently identified dectin-1 (betaGR) as a major beta-glucan receptor on leukocytes and demonstrated that it played a significant role in the non-opsonic recognition of soluble and particulate beta-glucans. Using a novel mAb (2A11) raised against betaGR, we show here that the receptor is not dendritic cell-restricted as first reported, but is broadly expressed, with highest surface expression on populations of myeloid cells (monocyte/macrophage (Mphi) and neutrophil lineages). Dendritic cells and a subpopulation of T cells also expressed the betaGR, but at lower levels. Alveolar Mphi, like inflammatory Mphi, exhibited the highest surface expression of betaGR, indicative of a role for this receptor in immune surveillance. In contrast, resident peritoneal Mphi expressed much lower levels of betaGR on the cell surface. Characterization of the nonopsonic recognition of zymosan by resident peritoneal Mphi suggested the existence of an additional beta-glucan-independent mechanism of zymosan binding that was not observed on elicited or bone marrow-derived Mphi. Although this recognition could be inhibited by mannan, we were able to exclude involvement of the Mphi mannose receptor and complement receptor 3 in this process. These observations imply the existence of an additional mannan-dependent receptor involved in the recognition of zymosan by resident peritoneal Mphi.

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The beta-glucan receptor, dectin-1, is predominantly expressed on the surface of cells of the monocyte/macrophage and neutrophil lineages.

When phagocyte CR3 binds to iC3b on bacteria or yeast, phagocytosis and degranulation are triggered because of simultaneous recognition of iC3b via a CD11b I-domain binding site and specific microbial polysaccharides via a lectin site located COOH-terminal to the I-domain. By contrast, when phagocyte or natural killer (NK) cell CR3 adheres to iC3b on erythrocytes or tumor cells that lack CR3-binding membrane polysaccharides, neither lysis nor cytotoxicity are stimulated. This investigation showed that soluble CR3-specific polysaccharides such as beta-glucan induced a primed state of CR3 that could trigger killing of iC3b-target cells that were otherwise resistant to cytotoxicity. Anti-CR3 added before sugars prevented priming, whereas anti-CR3 added after sugars blocked primed CR3 attachment to iC3b-targets. Polysaccharide priming required tyrosine kinase(s) and a magnesium-dependent conformational change of the I-domain that exposed the CBRM1/5 activation epitope. Unlike LPS or cytokines, polysaccharides did not up-regulate neutrophil CR3 expression nor expose the mAb 24 reporter epitope representing the high affinity ICAM-1-binding state. The current data apparently explain the mechanism of tumoricidal beta-glucans used for immunotherapy. These polysaccharides function through binding to phagocyte or NK cell CR3, priming the receptor for cytotoxicity of neoplastic tissues that are frequently targeted with iC3b and sparing normal tissues that lack iC3b.

/pdf/soluble-beta-glucan-polysaccharide-binding-to-the-lectin-2vhx1m7rem.pdf

Soluble beta-glucan polysaccharide binding to the lectin site of neutrophil or natural killer cell complement receptor type 3 (CD11b/CD18) generates a primed state of the receptor capable of mediating cytotoxicity of iC3b-opsonized target cells.

https://www.jbc.org/content/276/47/43818.full.pdf

Characterization of the Human Beta -Glucan Receptor and Its Alternatively Spliced Isoforms

Glucan is a potent reticuloendothelial stimulant whose immunobiological activity is mediated, in part, by an increase in the number and function of macrophages. In studying the role of glucan as a mediator of antibacterial activity, we attempted to ascertain the ability of glucan to modify the mortality of mice with experimentally induced Gram-positive bacteremia, and to enhance antibacterial defenses in rats as denoted by serum lysozyme and phagocytic activity. After intravenous administration of glucan, serum lysozyme concentrations were increased approximately sevenfold over control concentrations. The increase in serum lysozyme appeared to parallel the glucan-induced increase in phagocytosis and induced hyperplasia of macrophages. Prior treatment of mice with glucan significantly enhanced their survival when they were challenged systemically with Staphylococcus aureus. These studies indicate that glucan confers an enhanced state of host defense against bacterial infections.

https://science.sciencemag.org/content/sci/199/4335/1340.full.pdf

Increased resistance to Staphylococcus aureus infection and enhancement in serum lysozyme activity by glucan

Intravenous administration of an acute dose of lead acetate or cadmium acetate enhanced the susceptibility of rats to intravenous challenge with E. coli by approximately 1000-fold. Since equivalent vulnerability of lead- or cadmium-treated rats to killed E. coli was observed, toxicity is probably due to the endotoxin content of the bacteria. This postulate is further supported by the observation that equal doses of the Gram-positive bacteria, Staphylococci epidermidis, failed to elicit lethality in the acute lead-intoxicated rats. The synthetic glucocorticoid, methylprednisolone, prevented lethality induced by the Gram-negative bacteria in lead-treated rats. It did not, however, afford significant protection in cadmium-treated rats in the presence of E. coli. Marked alterations in hepatic morphology were apparent in both lead- and cadmium-treated rats challenged with E. coli.

J.A. Cook

Papers

Increased resistance to Staphylococcus aureus infection and enhancement in serum lysozyme activity by glucan

Influence of lead and cadmium on the susceptibility of rats to bacterial challenge.

Lead, cadmium, endotoxin interaction: Effect on mortality and hepatic function

The employment of glucan and glucan activated macrophages in the enhancement of host resistance to malignancies in experimental animals

Protective effect of cysteine and methylprednisolone in lead acetate-endotoxin induced shock