scholarly journals Regulation of complement functional efficiency by histidine-rich glycoprotein

Blood ◽  
1992 ◽  
Vol 79 (11) ◽  
pp. 2973-2980 ◽  
Author(s):  
NS Chang ◽  
RW Leu ◽  
JA Rummage ◽  
JK Anderson ◽  
JE Mole
Keyword(s):  
Divalent Cations ◽  
Alternative Pathway ◽  
Normal Serum ◽  
Peptide Sequence ◽  
Poly I:C ◽  
Complement Alternative Pathway ◽  
Nylon Membrane ◽  
Complement Components ◽  
S Protein ◽  
Functional Efficiency

The modulation of complement functional efficiency by serum histidine- rich glycoprotein (HRG) was investigated. Addition of exogenous HRG to prewarmed diluted serum, followed immediately by sensitized sheep erythrocytes (EA), resulted in enhanced hemolysis. However, when HRG was incubated with diluted serum for 10 minutes at 37 degrees C, inhibition of hemolysis occurred. The biphasic modulation of complement function was also obtained with the complement alternative pathway when HRG was added to diluted serum for hemolysis of rabbit erythrocytes. Partial reduction of complement functional activity was shown when serum was absorbed by an HRG-Sepharose 6MB column. Western blot analysis showed that complement C8, C9, factor D, and S-protein in diluted serum were bound by nylon membrane-immobilized HRG. However, by immunoprecipitation of relatively undiluted serum with anti-HRG IgG beads, HRG was found to coprecipitate with S-protein and plasminogen, which suggested that HRG may complex with these proteins in serum. In functional tests, HRG inhibited C8 hemolytic activity, probably by preventing C8 binding to EAC1–7 cells. HRG also enhanced polymerization of purified C9 as well as the generation of a 45-Kd C9 fragment. Such an effect was even more pronounced in the presence of divalent cations with the reaction mixtures of C9 and HRG. Partial dimerization of C9 was shown when exogenous HRG was added to normal serum. In contrast, polymerization of serum C9 was inhibited by exogenous HRG during poly I:C activation of serum or incubation under low ionic strength conditions. HRG was further shown to inhibit factor D-mediated cleavage of factor B when bound by cobra venom factor. The molecular basis by which HRG regulates serum complement function is not clear. Hypothetically, the tandem repetitions of a consensus histidine-rich penta-peptide sequence in HRG may provide a highly charged area that interacts with complement components.

scholarly journals Regulation of complement functional efficiency by histidine-rich glycoprotein

Blood ◽  
1992 ◽  
Vol 79 (11) ◽  
pp. 2973-2980 ◽  
Author(s):  
NS Chang ◽  
RW Leu ◽  
JA Rummage ◽  
JK Anderson ◽  
JE Mole
Keyword(s):  
Divalent Cations ◽  
Alternative Pathway ◽  
Normal Serum ◽  
Peptide Sequence ◽  
Poly I:C ◽  
Complement Alternative Pathway ◽  
Nylon Membrane ◽  
Complement Components ◽  
S Protein ◽  
Functional Efficiency

Abstract The modulation of complement functional efficiency by serum histidine- rich glycoprotein (HRG) was investigated. Addition of exogenous HRG to prewarmed diluted serum, followed immediately by sensitized sheep erythrocytes (EA), resulted in enhanced hemolysis. However, when HRG was incubated with diluted serum for 10 minutes at 37 degrees C, inhibition of hemolysis occurred. The biphasic modulation of complement function was also obtained with the complement alternative pathway when HRG was added to diluted serum for hemolysis of rabbit erythrocytes. Partial reduction of complement functional activity was shown when serum was absorbed by an HRG-Sepharose 6MB column. Western blot analysis showed that complement C8, C9, factor D, and S-protein in diluted serum were bound by nylon membrane-immobilized HRG. However, by immunoprecipitation of relatively undiluted serum with anti-HRG IgG beads, HRG was found to coprecipitate with S-protein and plasminogen, which suggested that HRG may complex with these proteins in serum. In functional tests, HRG inhibited C8 hemolytic activity, probably by preventing C8 binding to EAC1–7 cells. HRG also enhanced polymerization of purified C9 as well as the generation of a 45-Kd C9 fragment. Such an effect was even more pronounced in the presence of divalent cations with the reaction mixtures of C9 and HRG. Partial dimerization of C9 was shown when exogenous HRG was added to normal serum. In contrast, polymerization of serum C9 was inhibited by exogenous HRG during poly I:C activation of serum or incubation under low ionic strength conditions. HRG was further shown to inhibit factor D-mediated cleavage of factor B when bound by cobra venom factor. The molecular basis by which HRG regulates serum complement function is not clear. Hypothetically, the tandem repetitions of a consensus histidine-rich penta-peptide sequence in HRG may provide a highly charged area that interacts with complement components.

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.

Association between thrombotic microangiopathy and activated alternative complement pathway in malignant nephrosclerosis

2020 ◽  
Author(s):  
Ying Zhang ◽  
Chaona Yang ◽  
Xinjin Zhou ◽  
Ruimin Hu ◽  
Songxia Quan ◽  
...  
Keyword(s):  
Thrombotic Microangiopathy ◽  
Alternative Pathway ◽  
Factor H ◽  
Complement Factor ◽  
Complement Alternative Pathway ◽  
Complement Components ◽  
Atypical Haemolytic Uraemic Syndrome ◽  
Urinary Levels ◽  
Normal Controls ◽  
Malignant Nephrosclerosis

Abstract Background Malignant nephrosclerosis, defined as renal microangiopathy in the setting of severe hypertension, remains a critical renal emergency leading to end-stage renal disease despite aggressive anti-hypertensive treatment. Recently, activation of the complement alternative pathway (AP) has been reported to play a prominent role in the pathogenesis of malignant nephrosclerosis. However, subsequent study failed to recapitulate the findings of genetic complement abnormalities in the disease. This study aimed to determine the presence of AP activation and genetic complement defects and establish their correlations to renal microangiopathy lesions, clinical features and prognosis in patients with malignant nephrosclerosis. Methods Fifty patients with malignant hypertension and concomitant thrombotic microangiopathy (TMA) proven by renal biopsy were investigated; 25 cases of kidney donors who received zero-hour allograft biopsies were used as normal controls. Various renal TMA lesions in patients with malignant nephrosclerosis were reviewed and evaluated using a semi-quantitative scoring system. Deposition of C5b-9, C3a, C5a, C4d and mannose-binding lectin was assessed by immunohistochemistry. Co-localization of C5b-9 and CD34 was detected by confocal microscopy. Complement factor B (FB), factor P (FP; properdin), factor D (FD), factor H (FH), C3a and C5a levels were quantified by enzyme-linked immonosorbent assay in plasma and urine samples of patients with malignant nephrosclerosis and controls. Genetic abnormalities of complement components were analysed by whole-exome sequencing. Results Renal biopsies of malignant nephrosclerosis showed identical histopathological and ultrastructural features to atypical haemolytic uraemic syndrome. C5b-9, C3a and C5a deposits were found along the walls of arteries/arterioles and glomerular capillaries and localized in the endothelial cells. Elevated plasma and urinary levels of FB, FP, FD, C3a and C5a as well as decreased FH levels were observed in patients with malignant nephrosclerosis compared with normal controls. The urinary levels of complement AP components, but not the plasma levels, were correlated with renal functions, prognosis and active TMA lesions except for arteriolar thrombi. Finally, mutations of the MCP, CFB, CFH and CFHR5 genes were identified in 8 of 20 patients with malignant nephrosclerosis. Conclusions Aberrant complement AP dysregulation was demonstrated and associated with the activity, severity and renal outcomes of malignant nephrosclerosis. This observation warrants screening for complement defects in patients with malignant nephrosclerosis for the potential use of complement regulators and also highlights the need for further investigation of the precise role of AP in the pathogenesis of the disease.

scholarly journals Clinicopathological Characteristics and Outcomes of Chinese Patients with Scanty Immune Deposits Lupus Nephritis: A Large Cohort Study from a Single Center

2014 ◽  
Vol 2014 ◽  
pp. 1-11
Author(s):  
Qiuyu Li ◽  
Di Song ◽  
Fengmei Wang ◽  
Ying Tan ◽  
Feng Yu ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Immune Complex ◽  
Alternative Pathway ◽  
Clinicopathological Characteristics ◽  
Factor H ◽  
Chinese Patients ◽  
Complement Alternative Pathway ◽  
Complement Components ◽  
Immune Deposits ◽  
Large Cohort Study

Objective. To assess clinicopathological characteristics of lupus nephritis patients with scanty immune deposits.Methods. The data of patients with scanty immune deposits lupus nephritis were retrospectively analyzed. Plasma ANCA and complement components were detected.Results. Among 316 cases with renal biopsy-proven lupus nephritis, 40 cases were diagnosed as scanty immune deposits. There were significantly higher value of serum creatinine (P=0.002) and lower hemoglobin level (P=0.009) and higher score of cellular crescents (P=0.015) in scanty immune deposits group compared with immune complex deposits group. The frequency of positive plasma ANCA was significantly higher in scanty immune deposits group than that in immune complex deposits group (52.5% versus 10.1%,P<0.001). As for comparisons of plasma complement components, there were significantly higher levels of C1q (P=0.005) and Bb (P=0.02) and lower level of factor H (P=0.003) in scanty immune deposits group. The ratio of treatment failure was significantly higher in scanty immune deposits group than that in immune deposits group (42.5% versus 19.20%,P=0.001). The renal outcomes were similar between the two groups.Conclusions. Patients with scanty immune deposits lupus nephritis had more severe kidney damage. ANCA and activation of complement alternative pathway might be involved in the pathogenesis of the disease.

scholarly journals Activation of the alternative pathway of complement by monoclonal lambda light chains in membranoproliferative glomerulonephritis.

1992 ◽  
Vol 175 (4) ◽  
pp. 939-950 ◽  
Author(s):  
S Meri ◽  
V Koistinen ◽  
A Miettinen ◽  
T Törnroth ◽  
I J Seppälä
Keyword(s):  
Membranoproliferative Glomerulonephritis ◽  
Alternative Pathway ◽  
Immunoglobulin A ◽  
Fluid Phase ◽  
Normal Serum ◽  
Factor H ◽  
Control Factor ◽  
Dependent Manner ◽  
Complement Components ◽  
Alternative Pathway Of Complement

Immunopathological evidence suggests that activation of the alternative pathway of complement (AP) is involved in membranoproliferative glomerulonephritis (MPGN) and in immunoglobulin A nephropathy. In this report we describe an AP dysfunction-associated factor that was isolated from the serum and urine of a patient with hypocomplementemic MPGN. Extensive glomerular deposits of C3, properdin, and of the terminal complement components were observed in the kidney of the patient. In her serum the AP hemolytic activity was virtually absent. When mixed with fresh normal serum, the patient's serum induced a 96% C3 conversion during a 30-min incubation at +37 degrees C. This activity was found to be due to a circulating factor that by immunochemical characterization proved to be a 46-kD monoclonal immunoglobulin lambda light (L) chain dimer (lambda L). Purified lambda L, but not control lambda or kappa L chains from patients with L chain disease, activated the AP in a dose- and ionic strength-dependent manner. Functionally, lambda L was differentiated from C3 nephritic factor (an autoantibody against the AP C3 convertase, C3bBb) by its inability to bind to and stabilize the C3bBb enzyme. Instead, lambda L was observed to interact directly with the AP control factor H. Thus, lambda L represents a novel type of immunoglobulin-related AP-activating factor with the capacity to initiate alternative complement pathway activation in the fluid phase.

scholarly journals New functional and structural insights from updated mutational databases for complement factor H, Factor I, membrane cofactor protein and C3

2014 ◽  
Vol 34 (5) ◽  
Author(s):  
Elizabeth Rodriguez ◽  
Pavithra M. Rallapalli ◽  
Amy J. Osborne ◽  
Stephen J. Perkins
Keyword(s):  
Alternative Pathway ◽  
Factor H ◽  
Complement Factor H ◽  
Complement C3 ◽  
Complement Factor ◽  
Membrane Cofactor Protein ◽  
Complement Alternative Pathway ◽  
Factor I ◽  
Mutational Hotspots ◽  
Structural Insights

A new compilation of 324 mutations in four major proteins from the complement alternative pathway reveals mutational hotspots in factor H and complement C3, and less so in factor I and membrane cofactor protein. Their associations with function are discussed.

Acute post-streptococcal glomerulonephritis associated with prolonged hypocomplementaemia

2008 ◽  
Vol 61 (10) ◽  
pp. 1133-1135 ◽  
Author(s):  
D Payne ◽  
P Houtman ◽  
M Browning
Keyword(s):  
Renal Disease ◽  
Alternative Pathway ◽  
Complement Alternative Pathway ◽  
Pathway Activity ◽  
Post Streptococcal Glomerulonephritis

The case of a 6-year-old boy who presented with acute post-streptococcal glomerulonephritis is reported. C3 levels and complement alternative pathway activity remained low for at least 10 months after presentation, before returning to normal. There was no evidence of other renal disease. This case highlights that hypocomplementaemia in acute post-streptococcal glomerulonephritis may persist for several months, and that prolonged hypocomplementaemia does not exclude this diagnosis.

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