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.

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 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.

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.

Complement alternative pathway activation associated with pulmonary hypertension in lupus nephritis patients

Lupus ◽  
2019 ◽  
Vol 28 (9) ◽  
pp. 1051-1061
Author(s):  
Q Li ◽  
H Li ◽  
J Shi ◽  
B He ◽  
F Yu
Keyword(s):  
Pulmonary Hypertension ◽  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Alternative Pathway ◽  
Factor H ◽  
Renal Outcome ◽  
Complement Alternative Pathway ◽  
Complement Components ◽  
Pathway Activation ◽  
Excessive Activation

Pulmonary hypertension occurs in systemic lupus erythematosus (SLE) for several reasons, such as vasculopathy. Previous studies have indicated that the excessive activation of the complement alternative pathway might be involved in the pathogenesis of lupus nephritis, especially in the absence of factor H or its functional impairment. However, the clinical and pathological significance of the alternative complement activation in lupus nephritis patients with pulmonary hypertension remains elusive. The data on patients with pulmonary hypertension and non-pulmonary hypertension lupus nephritis were retrospectively analyzed in our centre. Major plasma levels of complement components were evaluated. The depositions of Bb, C3d and C5b-9 in the lung specimens of pulmonary hypertension combined with SLE patients were detected by immunofluorescence staining. Among 352 lupus nephritis cases, 24 were diagnosed with pulmonary hypertension and 328 with non-pulmonary hypertension. Higher levels of Bb and lower levels of factor H were detected in the pulmonary hypertension group in comparison with the negative group ( P = 0.049, P = 0.024, respectively). Pulmonary hypertension was a risk factor for renal outcome as deduced by the log-rank and Cox test for survival analysis. C3d, C5b-9 and Bb were found to be positive in lung specimens of lupus nephritis patients with pulmonary hypertension. We concluded that activation of the complement alternative pathway may be involved in the pathogenesis of pulmonary hypertension in lupus nephritis.

The interaction of complement components with Aeromonas species

1986 ◽  
Vol 32 (1) ◽  
pp. 1-3 ◽  
Author(s):  
R. A. Brenden ◽  
J. M. Janda
Keyword(s):  
Complement System ◽  
Alternative Pathway ◽  
Systemic Disease ◽  
Aeromonas Species ◽  
Classical Pathway ◽  
Bactericidal Action ◽  
Complement Components ◽  
Aeromonas Caviae ◽  
Human Sera ◽  
The Complement System

The interaction of seven serum-sensitive Aeromonas strains with the complement system was investigated using a 2-h quantitative assay. Of the strains tested, four isolates activated both the alternative and classical pathways, two activated only the alternative pathway, and one strain was sensitive to the bactericidal action of complement through the classical pathway only. Two of the four Aeromonas caviae strains were such efficient activators of the complement system that when challenged with human sera deficient in normal concentrations of C3 and C4, they were still subject to complement-mediated bacterial lysis. This phenomenon, in conjunction with previous studies on complement activation by Aeromonas spp., may help account for the decreased incidence observed of systemic disease caused by Aeromonas caviae.

Antiphospholipid antibodies and complement components levels in patients with systemic lupus erythematosus and antiphospholipid syndrome

2021 ◽  
Author(s):  
Ф.А. Чельдиева ◽  
А.А. Шумилова ◽  
А.М. Лила ◽  
Т.М. Решетняк
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Antiphospholipid Syndrome ◽  
Complement System ◽  
Lupus Erythematosus ◽  
Antiphospholipid Antibodies ◽  
Vascular Pathology ◽  
Systemic Lupus ◽  
Complement Components ◽  
History Of ◽  
The Complement System

Введение. Антифосфолипидный синдром (АФС) — аутоиммунная патология сосудов, клинически проявляющаяся рецидивирующими тромбозами сосудов любой локализации и калибра и акушерской патологией — рецидивирующими потерями плода. В последние 2 десятилетия в патогенетических аспектах АФС обсуждается роль системы комплемента. Цель исследования: определить связь между клинико-лабораторными проявлениями АФС и уровнем компонентов комплемента. Материалы и методы. Обследованы 111 пациентов: 87 (78%) женщин и 24 (22%) мужчины; 31 (28%) пациент был с первичным АФС (пАФС), 63 (57%) — с АФС в сочетании с системной красной волчанкой (СКВ) и 17 (15%) — с СКВ без АФС. У всех пациентов определяли антитела к кардиолипину (аКЛ) классов IgG и IgM и антитела к β2-гликопротеину 1 (аβ2-ГП1) классов IgG и IgM иммуноферментным анализом (ИФА), а также уровни С3 и С4 компонентов комплемента нефелометрическим методом. Результаты. У 72 пациентов в анамнезе были зарегистрированы тромбозы: у 23 пациентов с пАФС, у 44 с СКВ + АФС, у 5 с СКВ без АФС. Снижение уровня С3 было выявлено у 61 (55%) пациента из 111: у 14 (23%) пациентов с пАФС, у 35 (57%) с СКВ + АФС, у 12 (20%) с СКВ. Снижение С4 установлено у 37 (33%) из 111 пациентов: у 4 (11%) с пАФС, у 24 (65%) с СКВ + АФС, у 9 (24%) с СКВ. Снижение уровня С3 значимо чаще определено у пациентов c пАФС, позитивных по IgG-аКЛ и IgG-аβ2-ГП1 (р < 0,05). Снижение уровня С4 также ассоциировалось с позитивностью IgG-аКЛ и IgG-аβ2-ГП1 у пациентов с пАФС. У пациентов с СКВ + АФС гипокомплементемия С3 ассоциировалась с IgM-аКЛ и IgM-аβ2-ГП1, а снижение уровня С4 компонента комплемента существенно чаще зарегистрировано у пациентов с IgG-аКЛ (р = 0,002) и IgG-аβ2-ГП1 (р = 0,0001). Гипокомплементемия у пациентов с СКВ без антифосфолипидных антител имела место более чем в половине случаев: у 12 из 17 (71%) выявлено снижение С3 компонента комплемента и у 9 (53%) — снижение С4. Заключение. Зарегистрировано снижение С3 больше чем у половины (55%) и снижение С4 у трети (33%) обследованных пациентов, что свидетельствует об активации системы комплемента при АФС. Наличие IgG-аКЛ и IgG-аβ2-ГП1 ассоциировалось с гипокомплементемией, что свидетельствует о значимости этих антител в механизме активации комплемента и запуске гиперкоагуляции через систему комплемента. Background. Antiphospholipid syndrome (APS) is an autoimmune vascular pathology that is clinically manifested by recurrent vascular thrombosis and pregnancy loss. The role of complement system in the pathogenesis of APS is discussed in the last 2 decades. Objectives: to find out the relationships between the clinical and laboratory manifestations of APS and the level of complement components. Patients/Methods. We examined 111 patients: 87 (78%) women and 24 (22%) men; among them were 31 (28%) patients with primary APS (pAPS), 63 (57%) with APS and systemic lupus erythematosus (SLE) and 17 (15%) with SLE without APS. In all patients, antibodies to cardiolipin (aCL) of IgG and IgM classes and antibodies to β2-glycoprotein 1 (aβ2-GP1) components by the nephelometric method. Results. 72 patients had a history of thrombosis: 23 patients with pAPS, 44 with SLE + APS, 5 with SLE without APS. Decreased C3 level was detected in 61 (55%) of 111 patients: in 14 (23%) patients with pAPS, in 35 (57%) with SLE + APS, and in 12 (20%) with SLE. Decreased C4 level was observed in 37 (33%) of 111 patients: in 4 (11%) with pAPS, in 24 (65%) with SLE + APS, and in 9 (24%) with SLE. Decreased C3 level was significantly more often registered in pAPS-patients positive for IgG-aCL and IgG-aβ2-GP1 (p < 0.05). Decreased C4 level was also associated with positivity for IgG-aCL and IgG-aβ2-GP1 in pAPS-patients. In patients with SLE + APS, C3 hypocomplementemia was associated with IgM-аCL and IgM-аβ2-ГП1 and decreased C4 level was significantly more often registered in patients with IgG-aCL (p = 0.002) and IgG-аβ2-ГП1 (р = 0,0001). Hypocomplementemia in patients with SLE without antiphospholipid antibodies occurred in more than half of the cases: decreased C3 level was revealed in 12 of 17 (71%) patients, and decreased C4 level — in 9 (53%) patients. Conclusions. Decreased level of C3 was registered in more than half (55%) and a decreased level of C4 — in a third (33%) of examined patients, that indicated the complement system activation in APS. The presence of IgG-aCL and IgG-aβ2-GP1 was associated with hypocomplementemia that evidenced the significance of these antibodies in the mechanism of complement activation and the triggering of hypercoagulation through the complement system.

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....

Immune complexes: characteristics, clinical correlations, and interpretive approaches in the clinical laboratory.

1982 ◽  
Vol 28 (6) ◽  
pp. 1259-1271 ◽  
Author(s):  
S E Ritzmann ◽  
J C Daniels
Keyword(s):  
Immune Complex ◽  
Lupus Erythematosus ◽  
Immune Complexes ◽  
Complex Disease ◽  
Clinical Medicine ◽  
Clinical Laboratory ◽  
Therapeutic Monitoring ◽  
Serum Samples ◽  
Complement Components ◽  
Antigen Antibody

Abstract Immune-complex-mediated injury is thought to play a role in diseases such as rheumatoid arthritis, systemic lupus erythematosus, serum sickness, various infectious diseases, and malignancies. With increased appreciation of the biological and pathological significance of circulating immune complexes has come efforts to develop appropriate techniques for identifying and measuring them. Common approaches exploit such phenomena as the attachment of complement components to antigen-antibody complexes, the presence of specialized receptors for immune complexes at the surface of cells, and the ability of rheumatoid factor to bind with immune complexes. This variety of assay systems for immune complexes has yielded abstruse results in numerous human pathological conditions. Unfortunately, these results seldom correlate with one another in a given disease. Thus, use of a panel of immune complex assays has been recommended. Indirect consequences of immune complex disease may still be appraised and evaluated with some confidence in clinical medicine: measurements of C3 and C4, cryoglobulins, serum viscosity, and turbidity of serum samples. Measurement of immune complexes may be useful in diagnosis, prognosis, and therapeutic monitoring, but it is the characterization of immune complexes that holds the greatest potential for better understanding of disease mechanisms.

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