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.

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.

scholarly journals Distinct and Separable Roles of the Complement System in Factor H-Deficient Bone Marrow Chimeric Mice with Immune Complex Disease

2006 ◽  
Vol 17 (5) ◽  
pp. 1354-1361 ◽  
Author(s):  
Jessy J. Alexander ◽  
O.G.B. Aneziokoro ◽  
Anthony Chang ◽  
Bradley K. Hack ◽  
Adam Markaryan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Complex ◽  
Complement System ◽  
Complex Disease ◽  
Factor H ◽  
Immune Complex Disease ◽  
Chimeric Mice ◽  
The Complement System

Response of gene expression to LPS challenge manifests the ontogeny and maturation of the complement system in zebrafish larvae

2013 ◽  
Vol 93 (7) ◽  
pp. 1965-1971
Author(s):  
Zhiping Wang ◽  
Yanjun Han
Keyword(s):  
Complement System ◽  
Alternative Pathway ◽  
Experimental Period ◽  
Lectin Pathway ◽  
Classical Pathway ◽  
Adult Fish ◽  
Zebrafish Larvae ◽  
Lps Challenge ◽  
The Complement System ◽  
Ontogenic Expression

Information on the ontogeny of complement system might help us better understand the anti-infection mechanism in the early fish life. The ontogenic expression of the representative complement genes and their response to lipopolysaccharides (LPS) challenge in zebrafish larvae are reported here. The expression of C1r/s, C3, C4, C6 and MBL steadily increased before 21 days post-fertilization (dpf) and a decrease was detected thereafter. MASP expression elevated and peaked on 14 dpf and a decline followed. Bf expression fluctuated during the experimental period. Moreover, Bf (involved in alternative pathway, AP) expressed at higher levels than C1r/s (involved in classical pathway, CP), MASP (involved in lectin pathway, LP) and C4 (involved in both CP and LP) in the normal adult fish and larvae, suggesting the more significance of AP than CP and LP during the development of zebrafish. LPS challenge induced up-regulation of all the genes at 12 h in the adult fish. For the larvae, Bf, C3 (key complement component) and C6 (involved in lytic pathway) responded to LPS challenge at earlier stages than the other complement genes, with the up-regulation detected since 14, 14 and 7 dpf, respectively. In the larvae at 28 dpf, all the above three genes responded to LPS challenge by up-regulating their expression in a fashion similar to that of the adult fish, hinting that complement operating via AP develops earlier and plays a key role in protecting the larvae; it showed effective responses to LPS challenge from 14 dpf and might mature before 28 dpf.

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.

C3 glomerulonephritis and systemic lupus erythematosus: A report of a patient treated with eculizumab and review of the literature

Lupus ◽  
2021 ◽  
pp. 096120332110279
Author(s):  
Ruth Fernandez-Ruiz ◽  
Rebecca B Blank ◽  
Ming Wu ◽  
H Michael Belmont
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Nephritis ◽  
Complement System ◽  
Lupus Erythematosus ◽  
Alternative Pathway ◽  
Renal Diseases ◽  
C3 Glomerulonephritis ◽  
Complement Pathway ◽  
Systemic Lupus ◽  
The Complement System

Introduction Activation of the complement pathway by immune complexes is a key feature of systemic lupus erythematosus (SLE) and SLE glomerulonephritis, which translates into low levels of C3 and C4 during active disease. C3 glomerulonephritis (C3GN) is part of a broader group of rare renal diseases, the C3 glomerulopathies, characterized by prominent C3 accumulation in the glomeruli with minimal to no immunoglobulin (Ig) deposition secondary to dysregulation of the alternative pathway of the complement system. Distinguishing lupus nephritis from other complement-mediated kidney disorders, including C3GN, represents a diagnostic challenge with potential therapeutic implications. Methods We report an unusual case of a 55-year-old woman with SLE and previous biopsy-proven class IV lupus nephritis, subsequently diagnosed with C3GN. Furthermore, we review the available literature published from January 2010—March 2021 on the clinical features and management of C3GN in the setting of SLE. Results In addition to our case, very few reports exist in the literature regarding C3GN in association with SLE. The underlying pathogenic mechanism of C3GN consists of dysregulation of the alternative pathway of the complement system, either due to genetic variation in complement-related genes or to acquired autoantibodies targeting C3 or C5 convertases; the latter mechanism could explain the occurrence of C3GN in the setting of autoimmune diseases, although it was not definitively identified in our patient or others with SLE. Similar to some of the previous reports, after suboptimal renal response on mycophenolate mofetil and rituximab, our patient has been successfully treated with eculizumab, thus far with >50% improvement in proteinuria. Conclusions C3GN represents an additional mechanism of renal injury in SLE mediated by alternative complement pathway dysregulation. Although rare, patients with SLE and persistent proteinuria with very low C3 would benefit from expedited renal biopsy to evaluate for C3GN as well as genetic testing, since this entity could require a different therapeutic approach.

scholarly journals Expanding the Role of Complement Therapies: The Case for Lupus Nephritis

2021 ◽  
Vol 10 (4) ◽  
pp. 626
Author(s):  
Nicholas L. Li ◽  
Daniel J. Birmingham ◽  
Brad H. Rovin
Keyword(s):  
Lupus Nephritis ◽  
Complement System ◽  
Lupus Erythematosus ◽  
Immune Complexes ◽  
Alternative Pathway ◽  
Immune Surveillance ◽  
Surveillance Network ◽  
Complement Components ◽  
Autoantibody Production ◽  
The Complement System

The complement system is an innate immune surveillance network that provides defense against microorganisms and clearance of immune complexes and cellular debris and bridges innate and adaptive immunity. In the context of autoimmune disease, activation and dysregulation of complement can lead to uncontrolled inflammation and organ damage, especially to the kidney. Systemic lupus erythematosus (SLE) is characterized by loss of tolerance, autoantibody production, and immune complex deposition in tissues including the kidney, with inflammatory consequences. Effective clearance of immune complexes and cellular waste by early complement components protects against the development of lupus nephritis, while uncontrolled activation of complement, especially the alternative pathway, promotes kidney damage in SLE. Therefore, complement plays a dual role in the pathogenesis of lupus nephritis. Improved understanding of the contribution of the various complement pathways to the development of kidney disease in SLE has created an opportunity to target the complement system with novel therapies to improve outcomes in lupus nephritis. In this review, we explore the interactions between complement and the kidney in SLE and their implications for the treatment of lupus nephritis.

scholarly journals Functional Activity of the Complement System in Hospitalized COVID-19 Patients: A Prospective Cohort Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Panteleimon Charitos ◽  
Ingmar A. F. M. Heijnen ◽  
Adrian Egli ◽  
Stefano Bassetti ◽  
Marten Trendelenburg ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Disease Severity ◽  
Complement System ◽  
Alternative Pathway ◽  
Lectin Pathway ◽  
Hospital Death ◽  
Classical Pathway ◽  
Phase Reaction ◽  
Significant Difference ◽  
The Complement System

AimsAlthough the exact factors promoting disease progression in COVID-19 are not fully elucidated, unregulated activation of the complement system (CS) seems to play a crucial role in the pathogenesis of acute lung injury (ALI) induced by SARS-CoV-2. In particular, the lectin pathway (LP) has been implicated in previous autopsy studies. The primary purpose of our study is to investigate the role of the CS in hospitalized COVID-19 patients with varying degrees of disease severity.MethodsIn a single-center prospective observational study, 154 hospitalized patients with PCR-confirmed SARS-CoV-2 infection were included. Serum samples on admission to the COVID-19 ward were collected for analysis of CS pathway activities and concentrations of LP proteins [mannose-binding lectin (MBL) and ficolin-3 (FCN-3)] &amp; C1 esterase inhibitor (C1IHN). The primary outcome was mechanical ventilation or in-hospital death.ResultsThe patients were predominately male and had multiple comorbidities. ICU admission was required in 16% of the patients and death (3%) or mechanical ventilation occurred in 23 patients (15%). There was no significant difference in LP activity, MBL and FCN-3 concentrations according to different peak disease severities. The median alternative pathway (AP) activity was significantly lower (65%, IQR 50-94) in patients with death/invasive ventilation compared to patients without (87%, IQR 68-102, p=0.026). An optimal threshold of &lt;65.5% for AP activity was derived from a ROC curve resulting in increased odds for death or mechanical ventilation (OR 4,93; 95% CI 1.70-14.33, p=0.003) even after adjustment for confounding factors. Classical pathway (CP) activity was slightly lower in patients with more severe disease (median 101% for death/mechanical ventilation vs 109%, p=0.014). C1INH concentration correlated positively with length of stay, inflammatory markers and disease severity on admission but not during follow-up.ConclusionOur results point to an overactivated AP in critically ill COVID-19 patients in vivo leading to complement consumption and consequently to a significantly reduced AP activity in vitro. The LP does not seem to play a role in the progression to severe COVID-19. Apart from its acute phase reaction the significance of C1INH in COVID-19 requires further studies.

scholarly journals Hijacking Factor H for Complement Immune Evasion

2021 ◽  
Vol 12 ◽  
Author(s):  
Sara R. Moore ◽  
Smrithi S. Menon ◽  
Claudio Cortes ◽  
Viviana P. Ferreira
Keyword(s):  
Host Cell ◽  
Complement System ◽  
Alternative Pathway ◽  
Expression Patterns ◽  
Fluid Phase ◽  
Factor H ◽  
Host Cells ◽  
Complement C3 ◽  
Complement Regulators ◽  
The Complement System

The complement system is an essential player in innate and adaptive immunity. It consists of three pathways (alternative, classical, and lectin) that initiate either spontaneously (alternative) or in response to danger (all pathways). Complement leads to numerous outcomes detrimental to invaders, including direct killing by formation of the pore-forming membrane attack complex, recruitment of immune cells to sites of invasion, facilitation of phagocytosis, and enhancement of cellular immune responses. Pathogens must overcome the complement system to survive in the host. A common strategy used by pathogens to evade complement is hijacking host complement regulators. Complement regulators prevent attack of host cells and include a collection of membrane-bound and fluid phase proteins. Factor H (FH), a fluid phase complement regulatory protein, controls the alternative pathway (AP) both in the fluid phase of the human body and on cell surfaces. In order to prevent complement activation and amplification on host cells and tissues, FH recognizes host cell-specific polyanionic markers in combination with complement C3 fragments. FH suppresses AP complement-mediated attack by accelerating decay of convertases and by helping to inactivate C3 fragments on host cells. Pathogens, most of which do not have polyanionic markers, are not recognized by FH. Numerous pathogens, including certain bacteria, viruses, protozoa, helminths, and fungi, can recruit FH to protect themselves against host-mediated complement attack, using either specific receptors and/or molecular mimicry to appear more like a host cell. This review will explore pathogen complement evasion mechanisms involving FH recruitment with an emphasis on: (a) characterizing the structural properties and expression patterns of pathogen FH binding proteins, as well as other strategies used by pathogens to capture FH; (b) classifying domains of FH important in pathogen interaction; and (c) discussing existing and potential treatment strategies that target FH interactions with pathogens. Overall, many pathogens use FH to avoid complement attack and appreciating the commonalities across these diverse microorganisms deepens the understanding of complement in microbiology.

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