Nonspecific Lines of Defense Again (original) (raw)
Cell triggering by activated complement components
Immunology Letters, 1985
Activation of the complement system includes protein interactions, conversion of proteins from a zymogen form to active serine proteinases and proteolytic cleavages. Six of the twenty complement components which are known today bear catalytic sites and act specifically on other proteins of the complement system. This leads to generation of cleavage products which express many biological activities and are the subjects of this review. Since detailed reviews on the molecular dynamics of complement activation and regulation have been recently published [1-6], this subject is hereby only briefly discussed. Complement activation may proceed via the classical and/or the alternative pathway depending on the activating substance. Thus, for example, antigenbound antibodies of the IgG and IgM classes set the classical pathway (CP) into motion whereas polysaccharides in particulate form activate primarily the alternative pathway (AP). The components which comprise each pathway and their location in the complement cascade are depicted in Fig. 1. Clq, Clr, Cls, C4, C2, C3, calcium and magnesium ions participate in CP activation whereas Factor B, Factor D, C3, properdin and magnesium ions in AP activation. Both pathways are highly regulated by the serum proteins C1 inhibitor (CP), C4 binding protein
Complement System and Its Role in Immune Responses
eLS, 2012
Based in part on the previous version of this eLS article 'Complement' (2005) by M Claire H Holland and John D Lambris. The complement system is a network of more than 50 plasma proteins and receptors, which have the role of mediating innate and adaptive host defence mechanisms, whereas they also participate in various (patho)physiological processes. The primary functions mediated by complement proteins include phagocytosis of foreign elements (bacteria, viruses, particles etc.), cell lysis, inflammation, solubilisation of immune complexes, apoptotic cell clearance and enhancement of humoral immune responses. Dysregulation of complement activity has, therefore, been connected to various diseases, including autoimmune conditions, thrombotic pathologies and infections. Protein Structure Concentration (mg/mL) Cellular sources Key function Alternative pathway Factor B 93 kDa 210 Hepatocyte, mononuclear phagocytes, epithelial and endothelial cells, adipocytes, fibroblasts Catalytic subunit of AP C3 convertase, forms part of the C5 convertase
Complement System Part II: Role in Immunity
Frontiers in Immunology, 2015
The complement system has been considered for a long time as a simple lytic cascade, aimed to kill bacteria infecting the host organism. Nowadays, this vision has changed and it is well accepted that complement is a complex innate immune surveillance system, playing a key role in host homeostasis, inflammation, and in the defense against pathogens. This review discusses recent advances in the understanding of the role of complement in physiology and pathology. It starts with a description of complement contribution to the normal physiology (homeostasis) of a healthy organism, including the silent clearance of apoptotic cells and maintenance of cell survival. In pathology, complement can be a friend or a foe. It acts as a friend in the defense against pathogens, by inducing opsonization and a direct killing by C5b-9 membrane attack complex and by triggering inflammatory responses with the anaphylatoxins C3a and C5a. Opsonization plays also a major role in the mounting of an adaptive immune response, involving antigen presenting cells, T-, and B-lymphocytes. Nevertheless, it can be also an enemy, when pathogens hijack complement regulators to protect themselves from the immune system. Inadequate complement activation becomes a disease cause, as in atypical hemolytic uremic syndrome, C3 glomerulopathies, and systemic lupus erythematosus. Age-related macular degeneration and cancer will be described as examples showing that complement contributes to a large variety of conditions, far exceeding the classical examples of diseases associated with complement deficiencies. Finally, we discuss complement as a therapeutic target. Keywords: complement system, adaptive immunity, crosstalk TLR-complement, pathogen strategies for immune evasion, complement in cancer, complement and innate immunity, complement-related diseases, anaphylatoxins
An in vitro model mimicking the complement system to favor directed phagocytosis of unwanted cells
Electronic Journal of Biotechnology, 2021
Background: Opsonization, is the molecular mechanism by which target molecules promote interactions with phagocyte cell surface receptors to remove unwanted cells by induced phagocytosis. We designed an in vitro system to demonstrate that this procedure could be driven to eliminate adipocytes, using peptides mimicking regions of the complement protein C3b to promote opsonization and enhance phagocytosis. Two cell lines were used: (1) THP-1 monocytes differentiated to macrophages, expressing the C3b opsonin receptor CR1 in charge of the removal of unwanted coated complexes; (2) 3T3-L1 fibroblasts differentiated to adipocytes, expressing AQP7, to evaluate the potential of peptides to stimulate opsonization. (3) A co-culture of the two cell lines to demonstrate that phagocytosis could be driven to cell withdrawal with high efficiency and specificity. Results: An array of peptides were designed and chemically synthesized p3691 and p3931 joined bound to the CR1 receptor activating phagocytosis (p < 0.033) while p3727 joined the AQP7 protein (p < 0.001) suggesting that opsonization of adipocytes could occur. In the co-culture system p3980 and p3981 increased lipid uptake to 91.2% and 89.0%, respectively, as an indicator of potential adipocyte phagocytosis. Conclusions: This in vitro model could help understand the receptor-ligand interaction in the withdrawal of unwanted macromolecules in vivo. The adipocyte-phagocytosis discussed may help to control obesity, since peptides of C3b stimulated the CR1 receptor, promoting opsonisation and phagocytosis of lipidcontaining structures, and recognition of AQP7 in the differentiated adipocytes, favored the phagocytic activity of macrophages, robustly supported by the co-culture strategy. How to cite: Bartsch IM, Perelmuter K, Bollati-Fogolin M, et al. An in vitro model mimicking the complement system to favor directed phagocytosis of unwanted cells.
Alternative pathway of complement activation by stimulated T lymphocytes I. Binding of C3 fragments
European Journal of Immunology, 1987
Human blood lymphocytes cultured for 3 days with concanavalin A (Con A), phytohemagglutinin or pokeweed mitogen, in mixed lymphocyte culture with added interleukin 2 and stimulated by a lymphoblastoid cell line were found to activate and bind C3 molecules when exposed to human serum. The split products of C3 were detected in the supernatants and on the surface of the activated cells. The surfaceattached C3 fragment on the Con A blast was identified as C3b by immune adherence i.e. binding of CR1 carrying human erythrocytes. In the Con A-stimulated population the majority of cells that activated and bound C3 were CD3 and Fcy receptor (CD16)positive but complement receptor-negative blasts. In this cell subset both CD4 and CD8-positive cells were detected but their frequency suggested that a proportion of them carried both markers. Abbreviations: C3: The third component of complement ADCC: Antibody-dependent cellular cytotoxicity NK: Natural killer (cells) Con A: Concanavalin A PHA: Phytohemagglutinin PWM: Pokeweed mitogen TPA: 12-0-Tetradecanoylphorbol 13-acetate MLC: Mixed lymphocyte culture FcR: Receptors specific for Fcy FACS: Fluorescence-activated cell sorter IA: Immune adherence FITC: Fluorescein isothiocyanate IL 2: Interleukin 2 PBS: Phosphatebuffered saline CRl, CR2, CR3: Receptors specific for the split products of C3 VBS: Isotonic Veronal-buffered saline 0 VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1987
American Journal of Reproductive Immunology, 1999
Munksganrd. Copenhrrgen PROBLEM: To determine whether any blood plasma factor may play a regulatory role in trophoblast phagocytosis in rodent early pregnancy. METHOD O F STUDY: The effects of alloplasma on the phagocytosis of cultured mouse trophoblast cells (TCs) were evaluated using erythrocytes as target cells, in the presence of 10% fresh, normal plasma; 10% heat-inactivated plasma; lo'%, component 3 (C3)-depleted plasma; or medium alone. The possible activation of C3 complement, the phagocytosis of zymosan bound or unbound to C3b. and immunoreactivity to C3b receptor were also estimated. Phagocytic activity was expressed as the percentage of phagocytic TCs, and as the number of phagosomes/TCs. RESULTS: The use of complement sufficient plasma significantly enhanced the phagocytosis of the TCs while the use of heat-inactivated plasma eliminated the erythrophagocytosis. Very low levels of phagocytic activity were seen when the plasma was C3-complement deficient. Phagocytosis of C3b-bound zymosan was remarkable in comparison to zymosan alone, and immunoreactivity to C3b-receptors was seen on the TCs. CONCLUSION: These results indicate the participation of thermosensitive molecules mediating the phagocytosis of TCs and suggest, as in macrophages, a role for C3-C3b in this process.