TAMI-67. INVESTIGATION OF THE COMPLEMENT SYSTEM IN THE IRRADIATED BRAIN TUMOR MICROENVIRONMENT

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi212-vi212
Author(s):  
Rebecca Rosberg ◽  
Karolina Smolag ◽  
Vasiliki Pantazopoulou ◽  
Anna Blom ◽  
Alexander Pietras
Keyword(s):  
Brain Tumor ◽  
Tumor Microenvironment ◽  
Complement System ◽  
Neurological Diseases ◽  
Glioma Cells ◽  
Reactive Astrocytes ◽  
Complement Protein ◽  
Survival Prognosis ◽  
Complement Proteins ◽  
The Complement System

Abstract Glioblastoma is the most common and aggressive primary brain tumor in adults. Despite treatment through surgery, irradiation and chemotherapy all patients suffer recurrence of treatment-resistant tumors and the survival prognosis remains poor. The recurrence of tumors is driven by the invasive nature of the tumor and appears to be related to cells with stem like characteristics that are present in perivascular and hypoxic niches. Previous studies from our lab showed that astrocytes grown in hypoxic or irradiated conditions increase the stemness of glioma cells. The altered behavior of the astrocytes leads to increased cell size and a change in secreted cytokines. Reactive astrocytes are important in other central nervous system (CNS) diseases involved in tissue repair such as traumatic brain injury and Alzheimer’s disease. Interestingly, in several neurological diseases, reactive astrocytes upregulate complement proteins, especially complement component 3 (C3). However, it remains relatively unexplored how these complement proteins in stromal astrocytes are expressed in glioblastoma. Tissue sections from our glioma mouse model shows presence of C3 around hypoxic areas where there is an abundance of astrocytes. We have also shown that astrocytes grown at 21%, 1% and 0.1% oxygen upregulate complement protein C3 as well as other proteins associated with a more extensive infiltrative phenotype of glioblastoma. Datasets with human patients showed that C3 expression was correlated with higher grade tumors and that patients with tumors expressing C3 had more risk to get new tumors after primary treatment (including but not limited to radiotherapy). In this ongoing project, we are investigating whether activation of the complement system in the tumor microenvironment contributes to tumor progression. The upregulation of C3 in astrocytes in hypoxic conditions could therefore through local complement activation possibly led to tumor promoting signaling leading to beneficial survival of therapies of nearby glioma cells.

Serine proteases of the complement system

2000 ◽  
Vol 28 (5) ◽  
pp. 545-550 ◽  
Author(s):  
R. B. Sim ◽  
A. Laich
Keyword(s):  
Complement System ◽  
Serine Proteases ◽  
Enzymic Activity ◽  
Host Cells ◽  
Complement Protein ◽  
Factor B ◽  
Complement Proteins ◽  
Protein Protein Interaction ◽  
The Complement System ◽  
Natural Inhibitors

The complement system in blood plasma is a major mediator of innate immune defence. The function of complement is to recognize, then opsonize or lyse, particulate materials, including bacteria, yeasts and other microrganisms, host cell debris and altered host cells. Recognition occurs by binding of complement proteins to charge or saccharide arrays. After recognition, a series of serine proteases is activated, culminating in the assembly of complex unstable proteases called C3/C5 convertases. These activate the complement protein C3, which acts as an opsonin. The complement serine proteases include the closely related Clr, Cls, MASPs 1–3 (80–90 kDa), C2 and Factor B (100 kDa), Factor D (25 kDa) and Factor 1 (85 kDa). Each of these has unusually restricted specificity and low enzymic activity. The C1r, C1s and MASP group occur as proenzymes. When activated, they are regulated, like many plasma serine proteases, by a serpin, C1-inhibitor. C2 and Factor B, however, have complex multiple regulation by a group of complement proteins called the Regulation of Complement Activation (or RCA) proteins, whereas Factors I and D appear to have no natural inhibitors. Advances in structure determination and protein-protein interaction properties are leading to a more detailed understanding of the complement-system proteases, and are indicating possible new routes for potential therapeutic control of complement.

scholarly journals Semi-Quantitative Multiplex Profiling of the Complement System Identifies Associations of Complement Proteins with Genetic Variants and Metabolites in Age-Related Macular Degeneration

2021 ◽  
Vol 11 (12) ◽  
pp. 1256
Author(s):  
I. Erkin Acar ◽  
Esther Willems ◽  
Eveline Kersten ◽  
Jenneke Keizer-Garritsen ◽  
Else Kragt ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Complement System ◽  
Genetic Variants ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Complement Protein ◽  
Complement Proteins ◽  
New Associations ◽  
Age Related ◽  
The Complement System

Age-related macular degeneration (AMD) is a major cause of vision loss among the elderly in the Western world. The complement system has been identified as one of the main AMD disease pathways. We performed a comprehensive expression analysis of 32 complement proteins in plasma samples of 255 AMD patients and 221 control individuals using mass spectrometry-based semi-quantitative multiplex profiling. We detected significant associations of complement protein levels with age, sex and body-mass index (BMI), and potential associations of C-reactive protein, factor H related-2 (FHR-2) and collectin-11 with AMD. In addition, we confirmed previously described associations and identified new associations of AMD variants with complement levels. New associations include increased C4 levels for rs181705462 at the C2/CFB locus, decreased vitronectin (VTN) levels for rs11080055 at the TMEM97/VTN locus and decreased factor I levels for rs10033900 at the CFI locus. Finally, we detected significant associations between AMD-associated metabolites and complement proteins in plasma. The most significant complement-metabolite associations included increased high density lipoprotein (HDL) subparticle levels with decreased C3, factor H (FH) and VTN levels. The results of our study indicate that demographic factors, genetic variants and circulating metabolites are associated with complement protein components. We suggest that these factors should be considered to design personalized treatment approaches and to increase the success of clinical trials targeting the complement system.

scholarly journals Differential Interactions of Serum and Bronchoalveolar Lavage Fluid Complement Proteins with Conidia of Airborne Fungal Pathogen Aspergillus fumigatus

2020 ◽  
Vol 88 (9) ◽  
Author(s):  
Sarah Sze Wah Wong ◽  
Irene Daniel ◽  
Jean-Pierre Gangneux ◽  
Jeya Maheshwari Jayapal ◽  
Hélène Guegan ◽  
...  
Keyword(s):  
Bronchoalveolar Lavage ◽  
Complement System ◽  
Fungal Pathogen ◽  
Bronchoalveolar Lavage Fluid ◽  
Alternative Pathway ◽  
Lavage Fluid ◽  
Complement Protein ◽  
Content Type ◽  
Complement Proteins ◽  
The Complement System

ABSTRACT Even though both cellular and humoral immunities contribute to host defense, the role played by humoral immunity against the airborne opportunistic fungal pathogen Aspergillus fumigatus has been underexplored. In this study, we aimed at deciphering the role of the complement system, the major humoral immune component, against A. fumigatus. Mass spectrometry analysis of the proteins extracted from A. fumigatus conidial (asexual spores and infective propagules) surfaces opsonized with human serum indicated that C3 is the major complement protein involved. Flow cytometry and immunolabeling assays further confirmed C3b (activated C3) deposition on the conidial surfaces. Assays using cell wall components of conidia indicated that the hydrophobin RodAp, β-(1,3)-glucan (BG) and galactomannan (GM) could efficiently activate C3. Using complement component-depleted sera, we showed that while RodAp activates C3 by the alternative pathway, BG and GM partially follow the classical and lectin pathways, respectively. Opsonization facilitated conidial aggregation and phagocytosis, and complement receptor (CR3 and CR4) blockage on phagocytes significantly inhibited phagocytosis, indicating that the complement system exerts a protective role against conidia by opsonizing them and facilitating their phagocytosis mainly through complement receptors. Conidial opsonization with human bronchoalveolar lavage fluid (BALF) confirmed C3 to be the major complement protein interacting with conidia. Nevertheless, complement C2 and mannose-binding lectin (MBL), the classical and lectin pathway components, respectively, were not identified, indicating that BALF activates the alternative pathway on the conidial surface. Moreover, the cytokine profiles were different upon stimulation of phagocytes with serum- and BALF-opsonized conidia, highlighting the importance of studying interaction of conidia with complement proteins in their biological niche.

scholarly journals Halting targeted and collateral damage to red blood cells by the complement system

2021 ◽  
Author(s):  
M. Jalink ◽  
E. C. W. de Boer ◽  
D. Evers ◽  
M. Q. Havinga ◽  
J. M. I. Vos ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Complement System ◽  
Blood Cells ◽  
Defense Mechanism ◽  
Standard Of Care ◽  
Complement Protein ◽  
Complement Inhibition ◽  
Complement Inhibitors ◽  
The Complement System ◽  
Patient Burden

AbstractThe complement system is an important defense mechanism against pathogens; however, in certain pathologies, the system also attacks human cells, such as red blood cells (RBCs). In paroxysmal nocturnal hemoglobinuria (PNH), RBCs lack certain complement regulators which sensitize them to complement-mediated lysis, while in autoimmune hemolytic anemia (AIHA), antibodies against RBCs may initiate complement-mediated hemolysis. In recent years, complement inhibition has improved treatment prospects for these patients, with eculizumab now the standard of care for PNH patients. Current complement inhibitors are however not sufficient for all patients, and they come with high costs, patient burden, and increased infection risk. This review gives an overview of the underlying pathophysiology of complement-mediated hemolysis in PNH and AIHA, the role of therapeutic complement inhibition nowadays, and the high number of complement inhibitors currently under investigation, as for almost every complement protein, an inhibitor is being developed. The focus lies with novel therapeutics that inhibit complement activity specifically in the pathway that causes pathology or those that reduce costs or patient burden through novel administration routes.

scholarly journals Complement protein levels and MBL2 polymorphisms are associated with dengue and disease severity

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ngo Truong Giang ◽  
Hoang van Tong ◽  
Do Quyet ◽  
Nghiem Xuan Hoan ◽  
Trinh Huu Nghia ◽  
...  
Keyword(s):  
Warning Signs ◽  
Severe Dengue ◽  
Healthy Controls ◽  
Complement Protein ◽  
Complement Proteins ◽  
Protein Levels ◽  
Study Population ◽  
Dengue With Warning Signs ◽  
The Complement System

Abstract The complement system may be crucial during dengue virus infection and progression to severe dengue. This study investigates the role of MBL2 genetic variants and levels of MBL in serum and complement proteins in Vietnamese dengue patients. MBL2 genotypes (− 550L/H, MBL2 codon 54), MBL2 diplotypes (XA/XO, YA/XO) and MBL2 haplotypes (LXPB, HXPA, XO) were associated with dengue in the study population. The levels of complement factors C2, C5, and C5a were higher in dengue and dengue with warning signs (DWS) patients compared to those in healthy controls, while factor D levels were decreased in dengue and DWS patients compared to the levels determined in healthy controls. C2 and C5a levels were associated with the levels of AST and ALT and with WBC counts. C9 levels were negatively correlated with ALT levels and WBC counts, and factor D levels were associated with AST and ALT levels and with platelet counts. In conclusions, MBL2 polymorphisms are associated with dengue in the Vietnamese study population. The levels of the complement proteins C2, C4b, C5, C5a, C9, factor D and factor I are modulated in dengue patients during the clinical course of dengue.

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.

scholarly journals Viral-derived complement inhibitors: current status and potential role in immunomodulation

2016 ◽  
Vol 242 (4) ◽  
pp. 397-410 ◽  
Author(s):  
Hadi Abou-El-Hassan ◽  
Hassan Zaraket
Keyword(s):  
Complement System ◽  
Defense Mechanisms ◽  
Inflammatory Diseases ◽  
Immune Defense ◽  
Current Status ◽  
Viral Origin ◽  
Complement Proteins ◽  
Complement Inhibitors ◽  
Autoimmune And Inflammatory Diseases ◽  
The Complement System

The complement system is one of the body’s major innate immune defense mechanisms in vertebrates. Its function is to detect foreign bodies and promote their elimination through opsonisation or lysis. Complement proteins play an important role in the immunopathogenesis of several disorders. However, excessive complement activation does not confer more protection but instead leads to several autoimmune and inflammatory diseases. With inappropriate activation of the complement system, activated complement proteins and glycoproteins may damage both healthy and diseased tissues. Development of complement inhibitors represents an effective approach in controlling dysregulated complement activity and reducing disease severity, yet few studies have investigated the nature and role of novel complement inhibitory proteins of viral origin. Viral complement inhibitors have important implications in understanding the importance of complement inhibition and their role as a promising novel therapeutic approach in diseases caused by dysregulated complement function. In this review, we discuss the role and importance of complement inhibitors derived from several viruses in the scope of human inflammatory and autoimmune diseases.

Complement System in Healthy Term Newborns: Reference Values in Umbilical Cord Blood

1998 ◽  
Vol 1 (2) ◽  
pp. 131-135 ◽  
Author(s):  
J. Sonntag ◽  
U. Brandenburg ◽  
D. Polzehl ◽  
E. Strauss ◽  
M. Vogel ◽  
...  
Keyword(s):  
Cord Blood ◽  
Reference Values ◽  
Complement System ◽  
Alternative Pathway ◽  
Factor H ◽  
Reference Ranges ◽  
Complement Proteins ◽  
Factor I ◽  
Term Newborns ◽  
The Complement System

Activation of the complement system occurs in several diseases. For reliable identification of complement activation in neonates, we establish reference ranges of several components in cord blood of healthy term newborns. For this study cord blood samples were taken from 125 healthy term newborns. Concentrations of C1r, C2, C5, C7, Properdin, and factors D, H, and I were determined by single radial immunodiffusion. C3a and C5a were measured by specific EIA and complement function was measured by hemolytic assays. The results were expressed as 5th percentile, median, and 95th percentile. The following respective concentrations were found: C1r: 27, 47, 65 mg/l; C2: 12.0, 18.0, 24.0 mg/l; C5: 64, 92, 127 mg/l; C7: 32, 60, 89 mg/l; Properdin: 5.6, 9.7, 14.2 mg/l; factor D: 3.6, 5.2, 7.3 mg/l; factor H: 178, 234, 296 mg/l; and factor I: 15, 24, 32 mg/l. The functional activity of the whole complement system was 24%, 43%, 97% and for the alternative pathway 39%, 58%, 76%. The concentration of the activated split products C3a was 4, 65, 255 μg/l and of C5a, 0.11, 0.26, 1.19 μg/l. These reference values may be important for the detection of deficiencies of native complement proteins or perinatal processes leading to an activation of the complement system.

scholarly journals Targeting the Complement Pathway in Malignant Glioma Microenvironments

2021 ◽  
Vol 9 ◽  
Author(s):  
Hongtao Zhu ◽  
Xingjiang Yu ◽  
Suojun Zhang ◽  
Kai Shu
Keyword(s):  
Malignant Glioma ◽  
Complement System ◽  
Immune Surveillance ◽  
Glioma Cells ◽  
Multiple Tumor ◽  
Tumor Microenvironments ◽  
Malignant Glioma Cells ◽  
And Function ◽  
Tumor Types ◽  
The Complement System

Malignant glioma is a highly fatal type of brain tumor, and its reoccurrence is largely due to the ordered interactions among the components present in the complex microenvironment. Besides its role in immune surveillance and clearance under physiological conditions, the complement system is expressed in a variety of tumor types and mediates the interactions within the tumor microenvironments. Recent studies have uncovered the broad expression spectrum of complement signaling molecules in the tumor microenvironment and various tumor cells, in particular, malignant glioma cells. Involvement of the complement system in tumor growth, immunosuppression and phenotype transition have also been elucidated. In this review, we enumerate the expression and function of complement molecules in multiple tumor types reported. Moreover, we elaborate the complement pathways in glioma cells and various components of malignant glioma microenvironments. Finally, we summarize the possibility of the complement molecules as prognostic factors and therapeutic targets in the treatment of malignant glioma. Specific targeting of the complement system maybe of great significance and value in the future treatment of multi-type tumors including malignant glioma.

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