scholarly journals Adjuvant Lineage-Negative Cell Therapy as a Potential Silencer of the Complement-Mediated Immune System in ALS Patients

2021 ◽  
Vol 10 (22) ◽  
pp. 5251
Author(s):  
Anna Sobuś ◽  
Bartłomiej Baumert ◽  
Monika Gołąb-Janowska ◽  
Piotr Kulig ◽  
Edyta Paczkowska ◽  
...  
Keyword(s):  
Immune System ◽  
Cell Therapy ◽  
Complement System ◽  
Autologous Bone Marrow ◽  
Medical Intervention ◽  
Complement Components ◽  
Inflammatory Reactions ◽  
Sporadic Als ◽  
Als Patients ◽  
The Complement System

ALS remains a fatal, neurodegenerative motor neuron disease. Numerous studies seem to confirm that innate immune system is involved in the pathophysiology of ALS. Hence, the assessment of the complement system and attempts to modify its activity remain the target of medical intervention in ALS. In the present study, three intrathecal administrations of autologous bone marrow-derived lineage-negative (Lin–) cells were performed every 6 weeks in 20 sporadic ALS patients. The concentrations of various complement components in the cerebrospinal fluid and plasma at different time points after cell injection were quantified using a Luminex multiplex. The results of the complement system were correlated with the level of leukocytes, neutrophils, lymphocytes, fibrinogen and CRP in the peripheral blood and the functional status of ALS patients using Norris and ALS-FRSr scales. The study showed a statistically significant decrease in plasma C3b concentration in all 7th days after cell application. In parallel, a peak decrease in neutrophil count and CRP level was observed on days 5–7, with a simultaneous maximum clinical improvement on days 7–28 of each Lin– cell administration. Adjuvant Lin– cell therapy appears to have the silencing potential on the complement-mediated immune system and thus suppress pro-inflammatory reactions responsible for neurodegeneration. However, further in-depth studies are necessary to address this issue.

scholarly journals Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway

2020 ◽  
Vol 11 ◽  
Author(s):  
Marion Ort ◽  
Jasper Dingemanse ◽  
John van den Anker ◽  
Priska Kaufmann
Keyword(s):  
Immune System ◽  
Complement System ◽  
Kidney Diseases ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Complement Pathway ◽  
Complement Components ◽  
C5a Receptor ◽  
Surface Patterns ◽  
The Complement System ◽  
Terminal Complement

The complement system comprises the frontline of the innate immune system. Triggered by pathogenic surface patterns in different pathways, the cascade concludes with the formation of a membrane attack complex (MAC; complement components C5b to C9) and C5a, a potent anaphylatoxin that elicits various inflammatory signals through binding to C5a receptor 1 (C5aR1). Despite its important role in pathogen elimination, priming and recruitment of myeloid cells from the immune system, as well as crosstalk with other physiological systems, inadvertent activation of the complement system can result in self-attack and overreaction in autoinflammatory diseases. Consequently, it constitutes an interesting target for specialized therapies. The paradigm of safe and efficacious terminal complement pathway inhibition has been demonstrated by the approval of eculizumab in paroxysmal nocturnal hematuria. In addition, complement contribution in rare kidney diseases, such as lupus nephritis, IgA nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, or antineutrophil cytoplasmic antibody-associated vasculitis has been demonstrated. This review summarizes the involvement of the terminal effector agents of the complement system in these diseases and provides an overview of inhibitors for complement components C5, C5a, C5aR1, and MAC that are currently in clinical development. Furthermore, a link between increased complement activity and lung damage in severe COVID-19 patients is discussed and the potential for use of complement inhibitors in COVID-19 is presented.

Complement Components, C3 and C4, and the Metabolic Syndrome

2018 ◽  
Vol 15 (1) ◽  
pp. 44-48 ◽  
Author(s):  
Melanie Copenhaver ◽  
Chack-Yung Yu ◽  
Robert P. Hoffman
Keyword(s):  
Metabolic Syndrome ◽  
Significant Role ◽  
Complement System ◽  
Gene Copy ◽  
Future Research ◽  
Obese Adults ◽  
Complement Components ◽  
Cardiometabolic Diseases ◽  
The Metabolic Syndrome ◽  
The Complement System

Introduction: Increased systemic inflammation plays a significant role in the development of adult cardiometabolic diseases such as insulin resistance, dyslipidemia, atherosclerosis, and hypertension. The complement system is a part of the innate immune system and plays a key role in the regulation of inflammation. Of particular importance is the activation of complement components C3 and C4. C3 is produced primarily by the liver but is also produced in adipocytes, macrophages and endothelial cells, all of which are present in adipose tissues. Dietary fat and chylomicrons stimulate C3 production. Adipocytes in addition to producing C3 also have receptors for activated C3 and other complement components and thus also respond to as well as produce a target for complement. C3adesArg, also known as acylation stimulation factor, increases adipocyte triglyceride synthesis and release. These physiological effects play a significant role in the development of metabolic syndrome. Epidemiologically, obese adults and non-obese adults with cardiometabolic disease who are not obese have been shown to have increased complement levels. C4 levels also correlate with body mass index. Genetically, specific C3 polymorphisms have been shown to predict future cardiovascular events and. D decreased C4 long gene copy number is associated with increased longevity. Conclusion: Future research is clearly needed to clarify the role of complement in the development of cardiovascular disease and mechanisms for its action. The complement system may provide a new area for intervention in the prevention of cardiometabolic diseases.

The complement system

2010 ◽  
pp. 213-224
Author(s):  
Marina Botto ◽  
Mark J. Walport
Keyword(s):  
Immune System ◽  
Complement System ◽  
Immune Complexes ◽  
Innate Immune System ◽  
Inflammatory Responses ◽  
Antibody Responses ◽  
Host Defence ◽  
System P ◽  
Dying Cells ◽  
The Complement System

The complement system consists of over 20 distinct proteins and is an essential component of the innate immune system. It is a major effector mechanism of host defence against infection and inflammatory responses, has an important role in the physiological removal of immune complexes and dying cells, and plays an accessory role in the induction of antibody responses....

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.

Introduction to the complement system

1984 ◽  
Vol 306 (1129) ◽  
pp. 279-281 ◽  
Keyword(s):  
Humoral Immunity ◽  
Complement System ◽  
Bacterial Infections ◽  
Cross Linking ◽  
Complement Components ◽  
The Third ◽  
Effector Mechanism ◽  
The Complement System

Complement is the essential effector mechanism in humoral immunity to infection. Combination of antibody with antigen causes cross-linking, leading to precipitation of soluble antigens and agglutination of particular antigens, but no more. Unless complement is also present, agglutinated microorganisms can, in appropriate media in vitro grow out and form as lethal a culture as if not reacted with antibody. That this is also true in vivo is apparent from experience with patients with inherited deficiencies in complement components. The pattern is complex because of the presence of two pathways of activation, but in the rare cases of deficiency of the third component, C3, which is central to both pathways, the individuals are susceptible to repeated bacterial infections similar to aggammaglobulinaemics who are unable to synthesize antibodies. Both antibodies and complement are essential for effective humoral immunity.

Solution structures of complement components by X-ray and neutron scattering and analytical ultracentrifugation

2002 ◽  
Vol 30 (6) ◽  
pp. 996-1001 ◽  
Author(s):  
S. J. Perkins ◽  
H. E. Gilbert ◽  
M. Aslam ◽  
J. Hannan ◽  
V. M. Holers ◽  
...  
Keyword(s):  
Neutron Scattering ◽  
Complement System ◽  
Analytical Ultracentrifugation ◽  
Factor H ◽  
Protein Domain ◽  
Complement Receptor ◽  
Complement Components ◽  
X Ray ◽  
Solution Studies ◽  
The Complement System

The short consensus/complement repeat (SCR) domain (also known as the complement control protein domain) is the most abundant domain type in the complement system. Crystal and NMR structures for proteins that contain single and multiple SCR domains have now been published. These contain inter-SCR linkers of between three and eight residues, and the structures show much variability in inter-SCR orientations. X-ray and neutron scattering, combined with analytical ultracentrifugation and constrained modelling based on known subunit structures will yield a medium-resolution structure for the protein of interest. The fewer parameters that are associated with the structure of interest, the more defined the structure of interest becomes. These solution studies have been applied to several SCR-containing proteins in the complement system, most notably Factor H with 20 SCR domains, a complement receptor type 2 fragment with two SCR domains, and rat complement receptor-related protein (Crry) which contains five SCR domains. The results show great conformational variability in the inter-SCR orientation, and these will be reviewed. Even though the rotational orientation cannot be modelled, it is nonetheless possible to measure the degree of extension of the multi-SCR proteins and, from this, to obtain functionally useful results.

scholarly journals Pathologies of the complement system

2020 ◽  
Vol 19 (1) ◽  
pp. 131-138
Author(s):  
A. A. Butilin ◽  
A. E. Filippova ◽  
S. S. Shakhidzhanov ◽  
F. I. Ataullakhanov
Keyword(s):  
Immune System ◽  
Complement System ◽  
The Complement System

Complement system is a part of the immune system that provides organism cells with protection against foreign pathogens. Various kinds of defects in the complement system can induce development of serious diseases. This review summarizes different malfunctions of the complement system and also shows how these defects can result in development of severe diseases.

scholarly journals COMPLEMENT SYSTEM AS A MARKER OF IMMUNE DYSFUNCTION IN CHILDREN AUTISM SPECTRUM DISORDERS

2019 ◽  
Vol 21 (4) ◽  
pp. 773-780
Author(s):  
E. G. Cheremnykh ◽  
P. A. Ivanov ◽  
M. I. Factor ◽  
E. Yu. Chikina ◽  
S. G. Nikitina ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Immune System ◽  
Complement System ◽  
Functional Activity ◽  
Autism Spectrum ◽  
Autistic Spectrum ◽  
Healthy Donors ◽  
Spectrum Disorders ◽  
The Difference ◽  
The Complement System

It is known that functional activity of complement system depends not only on balance and concentration of components participating in formation of the system end products, but also on levels of inhibitory activities. Numerous relations with hemostasis also substantially contribute to general level of complement system activity. Changes in complement system functioning are inevitable during chronic diseases accompanied with immune system dysregulation. All mental diseases tend to be chronic and are they aggravated by patients’ immune system changes. Autism spectrum disorders in children is a group of mental disorders. Immune system dysregulation is usually detected in such patients, manifesting as excessive susceptibility to viral and bacterial infections. Therefore, the level of its functional activity is diagnostically and prognostically significant in this pathology, since the complement system is a key element of immune system.We have evaluated functional activity of complement system in patients with autistic spectrum disorders, using the method which was developed earlier. It is based on the reaction of the protozoa (Tetrahymena pyriformis) which are both targets and activators for the complement system. The complement system capacity (cSC) was used as the main parameter of complement evaluation. The half-time of protozoa survival (T50) was defined using the BioLat device for each serum specimen added at four concentrations (1/20, 1/40, 1/80, 1/160 dilution). The complement capacity was calculated as the area enclosed by influence curve of the reciprocals of T50 and the serum dilution. According to Mann–Whitney U test, the difference between patients’ and healthy volunteers’ groups was established as Z = 4.43 (by T50 at 1/160 dilution), p < 0.001 and by cSCas Z = 5.8, p < 0.001. cSC was calculated from the results obtained at each serum concentration measured. The difference between the two groups according to Mann–Whitney U test appeared to be more significant than the difference according to T50. Therefore, cSC was taken as the main characteristic of complement system function.The contribution of hemostasis plasma components to complement system functional activity level was estimated by determination of complement capacity in plasma and serum of each blood sample from 6 patients with autism spectrum disorders and 5 healthy donors. All healthy donors showed small difference between plasma and serum complement capacity, and their complement activity was higher in plasma. In patients’ group, the complement capacity levels in plasma and serum differed significantly. The cSC levels of two patients were higher in serum than in plasma, and the cSC levels of three other patients were significantly higher in plasma than in serum. Differential involvement of coagulation into the complement system activation may be indicative for the immune system dysfunction which is observed in patients with autistic spectrum disorders of different etiology.

scholarly journals Complement System in Cutaneous Squamous Cell Carcinoma

2019 ◽  
Vol 20 (14) ◽  
pp. 3550 ◽  
Author(s):  
Pilvi Riihilä ◽  
Liisa Nissinen ◽  
Jaakko Knuutila ◽  
Pegah Rahmati Nezhad ◽  
Kristina Viiklepp ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Immune Responses ◽  
Cell Carcinoma ◽  
Cancer Progression ◽  
Squamous Cell ◽  
Complement System ◽  
Cutaneous Squamous Cell Carcinoma ◽  
Complement Components ◽  
The Complement System

Epidermal keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer with high mortality rates in the advanced stage. Chronic inflammation is a recognized risk factor for cSCC progression and the complement system, as a part of innate immunity, belongs to the microenvironment of tumors. The complement system is a double-edged sword in cancer, since complement activation is involved in anti-tumor cytotoxicity and immune responses, but it also promotes cancer progression directly and indirectly. Recently, the role of several complement components and inhibitors in the regulation of progression of cSCC has been shown. In this review, we will discuss the role of complement system components and inhibitors as biomarkers and potential new targets for therapeutic intervention in cSCC.

scholarly journals Influence of Lineage-Negative Stem Cell Therapy on Articulatory Functions in ALS Patients

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Wioletta Pawlukowska ◽  
Bartłomiej Baumert ◽  
Monika Gołąb-Janowska ◽  
Anna Sobuś ◽  
Agnieszka Wełnicka ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Trophic Factors ◽  
Group I ◽  
Sporadic Als ◽  
Group Ii ◽  
Als Patients ◽  
Proinflammatory Factors

Introduction. Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease, leading to loss of muscle strength and motor control. Impaired speech and swallowing lower the quality of life and consequently may induce acute respiratory failure. Bone marrow-derived stem and progenitor cells (SPCs) may be a valuable source of trophic factors. In this study, we assessed whether adjuvant cellular therapy could affect the levels of selected neurotrophins and proinflammatory factors in the cerebrospinal fluid (CSF) and subsequently prevent the deterioration of articulation. Materials and Methods. The study group consisted of 32 patients with sporadic ALS who underwent autologous lineage-negative (Lin−) stem cell intrathecal administration to the spinal canal. Lin− cells were aspirated from the bone marrow and isolated using immunomagnetic beads and a lineage cell depletion kit. Patients were examined for articulatory functions by means of the Voice Handicap Index (VHI) questionnaire and Frenchay Dysarthria Assessment (FDA). In parallel, we carried out the analysis of selected trophic and proinflammatory factors in CSF utilizing multiplex fluorescent bead-based immunoassays. Results. Of the 32 patients who received the Lin− progenitor cell therapy, 6 (group I) showed improvement in articulatory functions, 23 remained stable (group II), and 3 deteriorated (group III) on the 28th day. The improvement was particularly noticeable in a better cough reflex, laryngeal time, and dribble reflex. A statistically significant lower level of brain-derived neurotrophic factor (BDNF) was observed on day 0 in group I compared to group II. The CSF concentrations of C-reactive protein (CRP) in group I significantly decreased 7 days after Lin− SPC transplantation. On the contrary, a significant increase in the tumor necrosis factor receptor (TNF-R) level was confirmed among patients from group I with improvement of dribble and coughing reflex, tongue movements, and respiration on the 7th day, as well as on day 28 including dribble reflex solely. Conclusions. An application of Lin− stem cells could potentate the beneficial humoral effect. The prevention of deterioration of articulatory functions in ALS patients after applying adjuvant Lin− stem cell therapy seems to be promising. Although the procedure is safe and feasible, it requires further in-depth studies.

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