Natural Compounds as Target Biomolecules in Cellular Adhesion and Migration: From Biomolecular Stimulation to Label-Free Discovery and Bioactivity-Based Isolation.

Plants and fungi can be used for medical applications because of their accumulation of special bioactive metabolites. These substances might be beneficial to human health, exerting also anti-inflammatory and anticancer (antiproliferative) effects. We propose that they are mediated by influencing cellular adhesion and migration via various signaling pathways and by directly inactivating key cell adhesion surface receptor sites.

Biologia Futura: stories about the functions of β-integrins in human phagocytes.

Integrins are essential membrane proteins that provide a tightly regulated link between the extracellular matrix and the intracellular cytoskeletal network. These cell surface proteins are composed of a non-covalently bound α chain and β chain. The leukocyte-specific complement receptor 3 (CR3, αβ, CD11b/CD18) and complement receptor 4 (CR4, αβ, CD11c/CD18) belong to the family of β-integrins.

Scientific memory from the early nineties; a common project with professors late János Gergely and Anna Erdei.

Based on the findings of common project 29 years ago, the Scandinavian J. of Immunology accepted and published our paper entitled by "FcγR-Dependent Regulation of the Biosynthesis of Complement C3 by Murine Macrophages: the Modulatory Effect of IL-6" (Bajtay et al. in SJI 35:195-201, 1992).

Conserved and Distinct Elements of Phagocytosis in Human and .

Endocytosis provides the cellular nutrition and homeostasis of organisms, but pathogens often take advantage of this entry point to infect host cells. This is counteracted by phagocytosis that plays a key role in the protection against invading microbes both during the initial engulfment of pathogens and in the clearance of infected cells. Phagocytic cells balance two vital functions: preventing the accumulation of cell corpses to avoid pathological inflammation and autoimmunity, whilst maintaining host defence.

BCR activated CLL B cells use both CR3 (CD11b/CD18) and CR4 (CD11c/CD18) for adhesion while CR4 has a dominant role in migration towards SDF-1.

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the western world. In previous studies, various proportion of patients was found to carry CD11b+ or CD11c+ B cells whose presence was an unfavourable prognostic factor. The exact mechanism however, how these receptors contribute to the pathogenesis of CLL has not been revealed so far.

New aspects in the regulation of human B cell functions by complement receptors CR1, CR2, CR3 and CR4.

The involvement of complement in the regulation of antibody responses has been known for long. By now several additional B cell functions - including cytokine production and antigen presentation - have also been shown to be regulated by complement proteins. Most of these important activities are mediated by receptors interacting with activation fragments of the central component of the complement system C3, such as C3b, iC3b and C3d, which are covalently attached to antigens and immune complexes.

Revisiting the Coreceptor Function of Complement Receptor Type 2 (CR2, CD21); Coengagement With the B-Cell Receptor Inhibits the Activation, Proliferation, and Antibody Production of Human B Cells.

The positive coreceptor function of complement receptor type 2 [CR2 (CD21)] on B cells is generally accepted, although its role in the enhancement of antibody production had only been proven in mice. The importance of this phenomenon prompted reinvestigation of the functional consequences of coclustering CD21 and the B cell receptor (BCR) on primary human cells. We found that, at non-stimulatory concentrations of anti-IgG/A/M, coclustering the BCR and CR2 enhanced the Ca response, while activation marker expression, cytokine production, proliferation, and antibody production were all inhibited upon the coengagement of CR2 and BCR on human B cells.

Activated Human Memory B Lymphocytes Use CR4 (CD11c/CD18) for Adhesion, Migration, and Proliferation.

Complement receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18) of myeloid cells are known for long to participate in actin linked functions like phagocytosis, adhesion, and migration. The expression and role of these two β-integrins however, in human B lymphocytes have only scarcely been studied so far, although it has been shown recently that CD11c B cells are mainly memory cells. In our systematic study we investigated B cells isolated from tonsils and peripheral blood of healthy donors.

The differential role of CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in the adherence, migration and podosome formation of human macrophages and dendritic cells under inflammatory conditions.

CR3 and CR4, the leukocyte specific β2-integrins, involved in cellular adherence, migration and phagocytosis, are often assumed to have similar functions. Previously however, we proved that under physiological conditions CR4 is dominant in the adhesion to fibrinogen of human monocyte-derived macrophages (MDMs) and dendritic cells (MDDCs). Here, using inflammatory conditions, we provide further evidence that the expression and function of CR3 and CR4 are not identical in these cell types.

Utilization of complement receptors in immune cell-microbe interaction.

The complement system is a major humoral component of immunity and is essential for the fast elimination of pathogens invading the body. In addition to its indispensable role in innate immunity, the complement system is also involved in pathogen clearance during the effector phase of adaptive immunity. The fastest way of killing the invader is lysis by the membrane attack complex, which is formed by the terminal components of the complement cascade.

Functional Characterization of Secreted Aspartyl Proteases in Candida parapsilosis.

is an emerging non- species that largely affects low-birth-weight infants and immunocompromised patients. Fungal pathogenesis is promoted by the dynamic expression of diverse virulence factors, with secreted proteolytic enzymes being linked to the establishment and progression of disease. Although secreted aspartyl proteases (Sap) are critical for pathogenicity, their role in is poorly elucidated.

The nucleoside diphosphate kinase NDK-1/NME1 promotes phagocytosis in concert with DYN-1/Dynamin.

Phagocytosis of various targets, such as apoptotic cells or opsonized pathogens, by macrophages is coordinated by a complex signaling network initiated by distinct phagocytic receptors. Despite the different initial signaling pathways, each pathway ends up regulating the actin cytoskeletal network, phagosome formation and closure, and phagosome maturation leading to degradation of the engulfed particle. Herein, we describe a new phagocytic function for the nucleoside diphosphate kinase 1 (NDK-1), the nematode counterpart of the first identified metastasis inhibitor NM23-H1 (nonmetastatic clone number 23) nonmetastatic clone number 23 or nonmetastatic isoform 1 (NME1).

Non-identical twins: Different faces of CR3 and CR4 in myeloid and lymphoid cells of mice and men.

Integrins are cell membrane receptors that are involved in essential physiological and serious pathological processes. Their main role is to ensure a closely regulated link between the extracellular matrix and the intracellular cytoskeletal network enabling cells to react to environmental stimuli. Complement receptor type 3 (CR3, αMβ, CD11b/CD18) and type 4 (CR4, αXβ, CD11c/CD18) are members of the β-integrin family expressed on most white blood cells.

Functional studies of chronic lymphocytic leukemia B cells expressing β-integrin type complement receptors CR3 and CR4.

The expression and role of CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in B cells are not yet explored in contrast to myeloid cells, where these β-integrin type receptors are known to participate in various cellular functions, including phagocytosis, adherence and migration. Here we aimed to reveal the expression and role of CR3 and CR4 in human B cells. In B cells of healthy donors CR3 and CR4 are scarcely expressed.

The role of CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in complement-mediated phagocytosis and podosome formation by human phagocytes.

CR3 and CR4 belong to the family of β-integrins and play an important role in phagocytosis, cellular adherence and migration. CR3 and CR4 are generally expected to mediate similar functions due to their structural homology, overlapping ligand specificity and parallel expression on human phagocytes. Although the different signalling pathways of these receptors suggest distinct functions, possible differences are just being revealed.

The versatile functions of complement C3-derived ligands.

The complement system is a major component of immune defense. Activation of the complement cascade by foreign substances and altered self-structures may lead to the elimination of the activating agent, and during the enzymatic cascade, several biologically active fragments are generated. Most immune regulatory effects of complement are mediated by the activation products of C3, the central component.

CD11c/CD18 Dominates Adhesion of Human Monocytes, Macrophages and Dendritic Cells over CD11b/CD18.

Complement receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18) belong to the family of beta2 integrins and are expressed mainly by myeloid cell types in humans. Previously, we proved that CR3 rather than CR4 plays a key role in phagocytosis. Here we analysed how CD11b and CD11c participate in cell adhesion to fibrinogen, a common ligand of CR3 and CR4, employing human monocytes, monocyte-derived macrophages (MDMs) and monocyte-derived dendritic cells (MDDCs) highly expressing CD11b as well as CD11c.

Adhesion kinetics of human primary monocytes, dendritic cells, and macrophages: Dynamic cell adhesion measurements with a label-free optical biosensor and their comparison with end-point assays.

Monocytes, dendritic cells (DCs), and macrophages (MFs) are closely related immune cells that differ in their main functions. These specific functions are, to a considerable degree, determined by the differences in the adhesion behavior of the cells. To study the inherently and essentially dynamic aspects of the adhesion of monocytes, DCs, and MFs, dynamic cell adhesion assays were performed with a high-throughput label-free optical biosensor [Epic BenchTop (BT)] on surfaces coated with either fibrinogen (Fgn) or the biomimetic copolymer PLL-g-PEG-RGD.

Secreted aspartic protease 2 of Candida albicans inactivates factor H and the macrophage factor H-receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18).

The opportunistic pathogenic yeast Candida albicans employs several mechanisms to interfere with the human complement system. This includes the acquisition of host complement regulators, the release of molecules that scavenge complement proteins or block cellular receptors, and the secretion of proteases that inactivate complement components. Secreted aspartic protease 2 (Sap2) was previously shown to cleave C3b, C4b and C5.

Single cell adhesion assay using computer controlled micropipette.

Cell adhesion is a fundamental phenomenon vital for all multicellular organisms. Recognition of and adhesion to specific macromolecules is a crucial task of leukocytes to initiate the immune response. To gain statistically reliable information of cell adhesion, large numbers of cells should be measured.

In-situ and label-free optical monitoring of the adhesion and spreading of primary monocytes isolated from human blood: dependence on serum concentration levels.

Adhesion and spreading of primary monocytes isolated from human blood were monitored utilizing optical waveguide lightmode spectroscopy (OWLS); a highly sensitive label-free biosensor technique using evanescent optical waves generated at a biocompatible surface. Appropriate development on a custom built setup enabled the OWLS cuvette to be operated as a 1.5 ml mini-incubator, controlling both temperature and CO2 levels.

Application of fluorescent monocytes for probing immune complexes on antigen microarrays.

Microarrayed antigens are used for identifying serum antibodies with given specificities and for generating binding profiles. Antibodies bind to these arrayed antigens forming immune complexes and are conventionally identified by secondary labelled antibodies.In the body immune complexes are identified by bone marrow derived phagocytic cells, such as monocytes.

CR3 is the dominant phagocytotic complement receptor on human dendritic cells.

Dendritic cells (DCs) play a decisive role in immunity; they interact with various pathogens via several pattern recognition and different opsonophagocytotic receptors, including Fc- and complement-receptors. β2-integrins, including complement receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18) participate in many immunological processes, especially those involving cell migration, adherence, and phagocytosis. Human monocyte derived dendritic cells (MDCs) are known to express CR3 as well as CR4, however possible differences regarding the role of these receptors has not been addressed so far.

Human T cell derived, cell-bound complement iC3b is integrally involved in T cell activation.

Although the complement system is thought to be mainly involved in innate immunity and in the humoral arm of adaptive responses, evidence implicating that complement impacts T cell responses are accumulating recently. The role of the various activation products of the major complement component C3 were mainly studied so far in animal systems, and investigations regarding the effect of different C3-fragments on human T cells are sparse. Here we show that anti-CD3 activated human T lymphocytes derived from the blood and tonsil of healthy individuals produce C3, and the major cleavage fragment that appears on the T cell surface is iC3b.

Impact of molecular mimicry on the clinical course and outcome of sepsis syndrome.

We investigated the impact of molecular mimicry between pathogenic microbes and their antigenic surrounding on the clinical course and outcome of pneumonia induced sepsis. Using mathematical prediction, we estimated the mimicry tendency of the identified pathogenic flora of patients with the human proteome as well as intestinal microbes. Since gut bacteria become invasive and hostile in critical illness, mimicry between these organisms and the infectious flora is expected to be rather hyperinflammatory type, in contrast to the expectedly tolerogenic self versus pathogen cross-reactions.