scholarly journals Cytokine and Complement Response in the Glaucomatous βB1-CTGF Mouse Model

2021 ◽  
Vol 15 ◽  
Author(s):  
Sabrina Reinehr ◽  
Johanna D. Doerner ◽  
Ana M. Mueller-Buehl ◽  
Dennis Koch ◽  
Rudolf Fuchshofer ◽  
...  
Keyword(s):  
Complement System ◽  
Ganglion Cells ◽  
Membrane Attack Complex ◽  
Cell Loss ◽  
Interferon Γ ◽  
Cytokine Response ◽  
Classical Pathway ◽  
Mrna Levels ◽  
C5a Receptor ◽  
The Complement System

Glaucoma is a complex neurodegenerative disease leading to a loss of retinal ganglion cells (RGCs) and optic nerve axons. An activation of the complement system seems to contribute to cell loss in this disease. Hence, we investigated a possible initiation of the complement system and the cytokine response in the βB1-CTGF glaucoma model. In these mice, intraocular pressure is elevated, which is the main glaucoma risk factor in patients, and RGC loss occurs at 15 weeks of age. Therefore, quantitative real-time PCR and immunohistological experiments were performed in 5-, 10-, and 15-week-old βB1-CTGF animals and their corresponding wildtypes (WT) to analyze the expression of several complement system factors. We could show that mRNA levels of the terminal complement pathway components C3 and C5 (Hc) were upregulated at 10 weeks. In accordance, more C3+ and membrane attack complex+ cells were observed in transgenic retinae. Further, the C5a receptor anaphylatoxin receptor (C5ar) and the complement component C5a receptor 1 (C5ar1; CD88) mRNA levels were upregulated in 10- and 15-week-old βB1-CTGF mice. Interestingly, all three activation routes of the complement system were elevated in βB1-CTGF mice at some age. Especially C1q, as a marker of the classical pathway, was significantly increased at all investigated ages. Furthermore, mRNA expression levels of interferon-γ (Infg) were upregulated at 5 weeks, while Cxcl1 and Cxcl2 mRNA levels were upregulated at 10 and 15 weeks. The mRNA levels of the chemokines Cxcl10 were increased at all ages in βB1-CTGF mice. These results lead to the assumption that in these transgenic mice, a complement activation mainly through the classical pathway as well as a cytokine response plays a major role in cell death.

The Role of C5a in the Mobilization of Hematopoietic Stem/Progenitor Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3472-3472
Author(s):  
Ali Jalili ◽  
Neeta Shirvaikar ◽  
Chris Korol ◽  
Anna Janowska-Wieczorek
Keyword(s):  
Steady State ◽  
Progenitor Cells ◽  
Complement System ◽  
Cxcr4 Expression ◽  
Classical Pathway ◽  
Dependent Manner ◽  
C5a Receptor ◽  
Hematopoietic Stem ◽  
The Complement System ◽  
Deficient Mice

Abstract The complement system, a vital component of the immune system, has been shown to play a role in hematopoietic stem/progenitor cell (HSPC) trafficking. C3a is known to be important in the retention of HSPC in the bone marrow (BM) as C3a-deficient mice are good mobilizers, and C5a is important in the mobilization of HSPC because C5a-deficient mice are poor mobilizers (Stem Cells2007; 25: 3093). Further, granulocyte-colony stimulating factor (G-CSF) activates the complement system via the classical pathway, down-regulates stromal-derived factor (SDF)-1 in BM stromal cells and decreases expression of its receptor, CXCR4, in myeloid cells. In this work investigated the mechanism of C5a involvement in HSPC mobilization. Using RT-PCR and FACS we examined the expression of the C5a receptor (CD88) on mobilized peripheral blood (PB) and steady-state PB HSPC and mature white blood cells, and in vitro-expanded myeloid, erythroid, and megakaryocytic progenitor cells. We found that CD88, like the G-CSF receptor, is not expressed on BM, PB or cord blood HSPC (CD34+ cells); during CD34+ cell differentiation the expression of CD88 increases in myelocytic and megakaryocytic progenitors; and the percentage of monocytes and polymorphonuclear (PMN) cells expressing CD88 is significantly higher in mobilized than in steady-state PB. Examing the function of C5a (using flow cytometry) we found that, unlike C3a, C5a decreases CXCR4 expression in a dose-dependent manner in monocytes and PMN, but not in lymphocytes; and this effect was not seen when anti-C5a antibody was added. Interestingly, we found that G-CSF down-regulation of CXCR4 expression on PMN was partially restored by anti-C5a antibody, suggesting that the mobilizing effects of G-CSF are at least in part due to the action of C5a. Moreover, chemotaxis of PMN towards SDF-1 (chemotaxis assay) increased when these cells were stimulated with C3a but decreased with both C5a and G-CSF, reflecting the CXCR4 expression status of these cells after stimulation. We also examined the effect of C5a on matrix metalloproteinase (MMP) secretion in BM leukocytes and found that, like G-CSF, C5a increased MMP-9 and MMP-2 secretion into media (zymography). Since the SDF-1/CXCR4 axis plays an integral role in the retention of HSPC in the BM, we conclude that C5a promotes mobilization by disrupting this axis, as well as increasing MMP-9 and MMP-2 secretion by BM leukocytes, thereby allowing egress of HSPC into the PB.

scholarly journals Hypoxic Processes Induce Complement Activation via Classical Pathway in Porcine Neuroretinas

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3575
Author(s):  
Ana M. Mueller-Buehl ◽  
Torsten Buehner ◽  
Christiane Pfarrer ◽  
Leonie Deppe ◽  
Laura Peters ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Immune System ◽  
Complement System ◽  
Ganglion Cells ◽  
Age Related Macular Degeneration ◽  
Classical Pathway ◽  
Retinal Diseases ◽  
Multifactorial Diseases ◽  
Age Related ◽  
The Complement System

Considering the fact that many retinal diseases are yet to be cured, the pathomechanisms of these multifactorial diseases need to be investigated in more detail. Among others, oxidative stress and hypoxia are pathomechanisms that take place in retinal diseases, such as glaucoma, age-related macular degeneration, or diabetic retinopathy. In consideration of these diseases, it is also evidenced that the immune system, including the complement system and its activation, plays an important role. Suitable models to investigate neuroretinal diseases are organ cultures of porcine retina. Based on an established model, the role of the complement system was studied after the induction of oxidative stress or hypoxia. Both stressors led to a loss of retinal ganglion cells (RGCs) accompanied by apoptosis. Hypoxia activated the complement system as noted by higher C3+ and MAC+ cell numbers. In this model, activation of the complement cascade occurred via the classical pathway and the number of C1q+ microglia was increased. In oxidative stressed retinas, the complement system had no consideration, but strong inflammation took place, with elevated TNF, IL6, and IL8 mRNA expression levels. Together, this study shows that hypoxia and oxidative stress induce different mechanisms in the porcine retina inducing either the immune response or an inflammation. Our findings support the thesis that the immune system is involved in the development of retinal diseases. Furthermore, this study is evidence that both approaches seem suitable models to investigate undergoing pathomechanisms of several neuroretinal diseases.

scholarly journals Chronic complement dysregulation drives neuroinflammation after traumatic brain injury: a transcriptomic study

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Amer Toutonji ◽  
Mamatha Mandava ◽  
Silvia Guglietta ◽  
Stephen Tomlinson
Keyword(s):  
Gene Expression ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Complement System ◽  
Classical Pathway ◽  
Post Injury ◽  
Complement Inhibition ◽  
Time Points ◽  
Complement Gene ◽  
The Complement System

AbstractActivation of the complement system propagates neuroinflammation and brain damage early and chronically after traumatic brain injury (TBI). The complement system is complex and comprises more than 50 components, many of which remain to be characterized in the normal and injured brain. Moreover, complement therapeutic studies have focused on a limited number of histopathological outcomes, which while informative, do not assess the effect of complement inhibition on neuroprotection and inflammation in a comprehensive manner. Using high throughput gene expression technology (NanoString), we simultaneously analyzed complement gene expression profiles with other neuroinflammatory pathway genes at different time points after TBI. We additionally assessed the effects of complement inhibition on neuropathological processes. Analyses of neuroinflammatory genes were performed at days 3, 7, and 28 post injury in male C57BL/6 mice following a controlled cortical impact injury. We also characterized the expression of 59 complement genes at similar time points, and also at 1- and 2-years post injury. Overall, TBI upregulated the expression of markers of astrogliosis, immune cell activation, and cellular stress, and downregulated the expression of neuronal and synaptic markers from day 3 through 28 post injury. Moreover, TBI upregulated gene expression across most complement activation and effector pathways, with an early emphasis on classical pathway genes and with continued upregulation of C2, C3 and C4 expression 2 years post injury. Treatment using the targeted complement inhibitor, CR2-Crry, significantly ameliorated TBI-induced transcriptomic changes at all time points. Nevertheless, some immune and synaptic genes remained dysregulated with CR2-Crry treatment, suggesting adjuvant anti-inflammatory and neurotropic therapy may confer additional neuroprotection. In addition to characterizing complement gene expression in the normal and aging brain, our results demonstrate broad and chronic dysregulation of the complement system after TBI, and strengthen the view that the complement system is an attractive target for TBI therapy.

Schistosoma mansoni: complement activation in human and rodent sera by living parasites of various developmental stages

Parasitology ◽  
1983 ◽  
Vol 87 (1) ◽  
pp. 75-86 ◽  
Author(s):  
A. Ruppel ◽  
U. Rother ◽  
H. Vongerichten ◽  
H. J. Diesfeld
Keyword(s):  
Schistosoma Mansoni ◽  
Complement System ◽  
Developmental Stages ◽  
Alternative Pathway ◽  
Classical Pathway ◽  
Factor B ◽  
The Complement System ◽  
Dose Dependent ◽  
Living Adult

SUMMARYLiving Schistosoma mansoni of various developmental stages were studied with respect to their ability to activate the complement system in sera of humans, mice and rats. Immunofluorescence assays demonstrated that binding of human C3 occurred on fresh schistosomula as well as on schistosomula prepared from mouse lymph-nodes or lungs and on adult schistosomes. However, rodent C3 was deposited only on fresh schistosomula. Deposition of human C3 on the worms' surface required activation of the complement system. The alternative pathway was shown to be involved in deposition of human C3 on schistosomes of all ages, whereas activation of the classical pathway was demonstrable only with fresh schistosomula. Immunoelectrophoretic studies demonstrated a dose-dependent cleavage of human C3 and conversion of factor B by living adult schistosomes. The results demonstrate that the ability of living schistosomes to activate complement in vitro is dependent not only on their developmental stage but also on the species of the serum.

scholarly journals Development of a Novel Cytomedical Treatment that can Protect Entrapped Cells from Host Humoral Immunity

2002 ◽  
Vol 11 (8) ◽  
pp. 787-797 ◽  
Author(s):  
Ryo Suzuki ◽  
Yasuo Yoshioka ◽  
Etsuko Kitano ◽  
Tatsunobu Yoshioka ◽  
Hiroaki Oka ◽  
...  
Keyword(s):  
Humoral Immunity ◽  
Complement System ◽  
Alternative Pathway ◽  
Classical Pathway ◽  
Dependent Manner ◽  
Complement Components ◽  
Alternative Pathways ◽  
Low Cytotoxicity ◽  
The Complement System

Cell therapy is expected to relieve the shortage of donors needed for organ transplantation. When patients are treated with allogeneic or xenogeneic cells, it is necessary to develop a means by which to isolate administered cells from an immune attack by the host. We have developed “cytomedicine, ” which consists of functional cells entrapped in semipermeable polymer, and previously reported that alginate-poly-l-lysine-alginate microcapsules and agarose microbeads could protect the entrapped cells from injury by cellular immunity. However, their ability to isolate from humoral immunity was insufficient. It is well known that the complement system plays an essential role in rejection of transplanted cells by host humoral immunity. Therefore, the goal of the present study was to develop a novel cytomedical device containing a polymer capable of inactivating complement. In the screening of various polymers, polyvinyl sulfate (PVS) exhibited high anticomplement activity and low cytotoxicity. Murine pancreatic β-cell line (MIN6 cell) entrapped in agarose microbeads containing PVS maintained viability and physiological insulin secretion, replying in response to glucose concentration, and resisted rabbit antisera in vitro. PVS inhibited hemolysis of sensitized sheep erythrocytes (EAs) and rabbit erythrocytes by the complement system. This result suggests that PVS inhibits both the classical and alternative complement pathways of the complement system. Next, the manner in which PVS exerts its effects on complement components was examined. PVS was found to inhibit generation of C4a and Ba generation in activation of the classical and alternative pathways, respectively. Moreover, when the EAC1 cells, which were carrying C1 on the EAs, treated with PVS were exposed to C1-deficient serum, hemolysis decreased in a PVS dose-dependent manner. These results suggest that PVS inhibits C1 in the classical pathway and C3 convertase formation in the alternative pathway. Therefore, PVS may be a useful polymer for developing an anticomplement device for cytomedical therapy.

Modulation of CD11b/CD18 on Monocytes and Granulocytes following Hemodialysis Membrane Interaction in vitro

1996 ◽  
Vol 19 (3) ◽  
pp. 156-163 ◽  
Author(s):  
P. Thylén ◽  
E. Fernvik ◽  
J. Lundahl ◽  
J. Hed ◽  
S.H. Jacobson
Keyword(s):  
Complement System ◽  
Blood Donors ◽  
Alternative Pathway ◽  
Classical Pathway ◽  
Dialysis Membrane ◽  
Serum Factors ◽  
Relative Contribution ◽  
Normal Human ◽  
The Complement System

We studied the generation of CD11b/CD18 mobilizing factors in serum after incubation with dialysis membrane fragments of different chemical composition. We also evaluated the relative importance of the alternative and classical pathways of the complement system in the generation of such factors. Monocytes and granulocytes from healthy blood donors were incubated in normal human serum (NHS) and in NHS that had been preincubated with Cuprophan (CU) membrane (NHS-CU), Hemophan (HE) (NHS-HE) or polysulfone (PS) (NHS-PS). NHS-CU caused the highest up-regulation of the CD11b/CD18 receptor on monocytes and granulocytes. The rank in capacity to mobilize CD11b/CD18 on granulocytes was CU>HE>PS (p<0.001), CU>HE (p<0.05) and HE>PS (p<0.001). The rank in capacity to mobilize CD11b/CD18 on monocytes was CU>HE>PS (p<0.001), CU>HE (p<0.05) and HE>PS (p<0.01). NHS-PS induced a lower up-regulation of CD11b/CD18 compared to NHS which indicates that serum factors with the ability to mobilize the CD11b/CD18 receptor on monocytes and granulocytes are deposited on or adsorbed by PS. In order to study the relative contribution of the alternative and classical pathways of the complement system in the generation of CD11b/CD18 mobilizing factors in serum, three different serum preparations (1. both pathways intact. 2. only the alternative intact and 3. only the classical pathway intact) were used. The CU membrane activated the classical pathway to a larger extent than the PS membrane (p<0.01). When only the alternative pathway was intact no difference in the generation of CD11b/CD18 mobilizing factors between the CU and PS membranes was observed. These studies show that CD11b/CD18 mobilizing serum factors are generated after incubation with CU membranes and that such factors are probably adsorbed by PS. The classical pathway of complement activation seems to contribute to the generation of CD11b/CD18 mobilizing factors in serum.

Inherited complement deficiencies

1984 ◽  
Vol 306 (1129) ◽  
pp. 419-430 ◽  
Keyword(s):  
Immune Complex ◽  
Complement System ◽  
Lupus Erythematosus ◽  
Alternative Pathway ◽  
Strong Association ◽  
Factor H ◽  
Complement Deficiency ◽  
Classical Pathway ◽  
The Complement System

Isolated genetic deficiencies of individual components of the complement system have been described in man for all the components of the classical pathway and the membrane attack complex as well as for Factor I, Factor H and properdin. It is only for Factor B and Factor D of the alternative pathway that homozygous deficiency states are not so far known. Complement deficiency states provide the most direct way of looking at the role of the complement system in vivo and emphasize the importance of complement in resistance to bacterial infection and in particular to infection with Neisseria . This association is not unexpected since in vitro studies have shown complement to be an efficient enhancer of phagocytosis and inflammation. The particularly frequent occurrence of neisserial infection may be ascribed to the ability of these organisms to survive in phagocytic cells so that the plasma cytolytic activity provided by complement is needed to kill them. On the other hand the strong association between complement deficiencies and immune-complex diseases - especially systemic lupus erythematosus — was unexpected and seems paradoxical in view of the large part played by complement in the pathogenesis of immune complex mediated tissue damage. The paradox can be explained in part by the necessity for an intact complement system in the solubilization and the proper handling of immune complexes. It is also likely that complement deficiency can allow the persistence of low virulence organisms that produce disease solely by an immune complex mechanism. Recently described deficiencies of complement receptors and their effects in vivo are described.

Dynamic Expression of the Membrane Attack Complex (MAC) of the Complement System in Failing Human Myocardium

2006 ◽  
Vol 97 (11) ◽  
pp. 1626-1629 ◽  
Author(s):  
Guilherme H.M. Oliveira ◽  
Corinne N. Brann ◽  
Katy Becker ◽  
Vinay Thohan ◽  
Michael M. Koerner ◽  
...  
Keyword(s):  
Complement System ◽  
Membrane Attack Complex ◽  
Human Myocardium ◽  
Dynamic Expression ◽  
The Complement System

scholarly journals Immunity against the Obligate Intracellular Bacterial PathogenRickettsia australisRequires a Functional Complement System

2018 ◽  
Vol 86 (6) ◽  
Author(s):  
Sean P. Riley ◽  
Abigail I. Fish ◽  
Fabio Del Piero ◽  
Juan J. Martinez
Keyword(s):  
Complement System ◽  
Membrane Attack Complex ◽  
Immune Functions ◽  
Complement Protein ◽  
Membrane Pore ◽  
Content Type ◽  
Genetic Ablation ◽  
Obligate Intracellular ◽  
Susceptibility To Infection ◽  
The Complement System

ABSTRACTThe complement system has a well-defined role in deterring blood-borne infections. However, complement is not entirely efficacious, as several bacterial pathogens, including some obligate intracellular pathogens, have evolved mechanisms for resistance. It is presumed that obligate intracellular bacteria evade complement attack by residing within a host cell; however, recent studies have challenged this presumption. Here, we demonstrate that the complement system is activated during infection with the obligate intracellular bacteriumRickettsia australisand that genetic ablation of complement increases susceptibility to infection. Interaction ofRickettsia australiswith serum-borne complement leads to activation of the complement cascade, producing three effector mechanisms that could negatively influenceR. australis.The C9-dependent membrane attack complex can lead to deposition of a bacteriolytic membrane pore on the bacteria, but this system does not contribute to control of rickettsial infection. Similarly, complement receptor (CR1/2)-dependent opsonophagocytosis may lead to engulfment and killing of the bacteria, but this system is also dispensable for immunity. Nevertheless, intact complement is essential for naturally acquired and antibody-mediated immunity toRickettsiainfection. Comparison of infection in mice lacking the central complement protein C3 with infection in their wild-type counterparts demonstrated decreases in gamma interferon (IFN-γ) production, IgG secretion, and spleen hyperplasia in animals lacking complement. The correlation between loss of secondary immune functions and loss of complement indicates that the proinflammatory signaling components of the complement system, and not membrane attack complex or opsonophagocytosis, contribute to the immune response to this pathogen.

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