Low levels of FD activate complement alternative pathway

2018 ◽  
Vol 102 ◽  
pp. 229
Author(s):  
Xiaobo Wu ◽  
Irina Hutson ◽  
Antonina Akk ◽  
Christine Pham ◽  
Dennis Hourcade ◽  
...  
Keyword(s):  
Alternative Pathway ◽  
Complement Alternative Pathway ◽  
Low Levels

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.

scholarly journals Functional Mapping of YadA- and Ail-Mediated Binding of Human Factor H to Yersinia enterocolitica Serotype O:3

2008 ◽  
Vol 76 (11) ◽  
pp. 5016-5027 ◽  
Author(s):  
Marta Biedzka-Sarek ◽  
Saara Salmenlinna ◽  
Markus Gruber ◽  
Andrei N. Lupas ◽  
Seppo Meri ◽  
...  
Keyword(s):  
Yersinia Enterocolitica ◽  
Alternative Pathway ◽  
Outer Membrane Proteins ◽  
Factor H ◽  
Complement Alternative Pathway ◽  
Human Host ◽  
Serotype O ◽  
Complement Resistance ◽  
Sense And Respond ◽  
Active Complement

ABSTRACT Yersinia enterocolitica is an enteric pathogen that exploits diverse means to survive in the human host. Upon Y. enterocolitica entry into the human host, bacteria sense and respond to variety of signals, one of which is the temperature. Temperature in particular has a profound impact on Y. enterocolitica gene expression, as most of its virulence factors are expressed exclusively at 37°C. These include two outer membrane proteins, YadA and Ail, that function as adhesins and complement resistance (CR) factors. Both YadA and Ail bind the functionally active complement alternative pathway regulator factor H (FH). In this study, we characterized regions on both proteins involved in CR and the interaction with FH. Twenty-eight mutants having short (7 to 41 amino acids) internal deletions within the neck and stalk of YadA and two complement-sensitive site-directed Ail mutants were constructed to map the CR and FH binding regions of YadA and Ail. Functional analysis of the YadA mutants revealed that the stalk of YadA is required for both CR and FH binding and that FH appears to target several conformational and discontinuous sites of the YadA stalk. On the other hand, the complement-sensitive Ail mutants were not affected in FH binding. Our results also suggested that Ail- and YadA-mediated CR does not depend solely on FH binding.

scholarly journals Clinical relevance of glomerular IgM deposition in patients with lupus nephritis

2021 ◽  
Author(s):  
Fengmei Wang ◽  
Jirong Yu ◽  
Lei zhang ◽  
Yan Zhang ◽  
Jie Zhang ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Lupus Nephritis ◽  
Serum Creatinine ◽  
Plasma Levels ◽  
Clinical Relevance ◽  
Alternative Pathway ◽  
Clinicopathological Parameters ◽  
Low Density ◽  
Lower Plasma ◽  
Low Levels

Abstract Background The aim of the study was to investigate the clinical relevance of IgM deposition in patients with LN in a large cohort. Results 217 patients with renal biopsy–proven lupus nephritis were enrolled. The associations between glomerular IgM deposition and clinicopathological parameters were further analyzed. IgM deposition was positively correlated with glomerular C1q and C3 deposition moderately (r = 0.436, P < 0.001; r = 0.408, P < 0.001, respectively), and inversely correlated with plasma levels of C3 and CFH mildly (r=-0.138, P = 0.043; r=-0.147, P = 0.037, respectively). By multivariate analysis, we found that glomerular IgM deposition independently contributes to glomerular C3 deposition in patients with lupus nephritis (OR = 2.002, 95% CI: 1.295–3.094, P = 0.002). In addition, we also found that patients with IgM 0+-2 + had similar plasma CFH levels, but in patients with IgM3+-4+, plasma CFH levels were significantly lower (300.4 ± 155.8µg/ml vs. 429.9 ± 187.5µg/ml, P < 0.001). Furthermore, patients with high density of glomerular IgM and low levels of CFH had heavier proteinuria, higher serum creatinine and lower plasma C3 levels (5.7 ± 3.1g/d vs. 4.7 ± 3.5g/d, P = 0.037;150.1 ± 121.0µmol/L vs. 105.6 ± 97.1µmol/L, P = 0.005; 0.3 ± 0.2µg/L vs. 0.4 ± 0.2µg/L, P = 0.04, respectively), comparing with those with low density of glomerular IgM and low levels of CFH. Conclusions Our results suggested IgM might bind to injury-associated epitopes and be involved in disease progression and provided a possible relevance of CFH and IgM in the process of alternative pathway (AP) activation.

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 Maternal and Fetal Outcomes of Pregnancies in Women with Atypical Hemolytic Uremic Syndrome

2017 ◽  
Vol 29 (3) ◽  
pp. 1020-1029 ◽  
Author(s):  
Martina Gaggl ◽  
Christof Aigner ◽  
Dorottya Csuka ◽  
Ágnes Szilágyi ◽  
Zoltán Prohászka ◽  
...  
Keyword(s):  
Thrombotic Microangiopathy ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Intrauterine Fetal Death ◽  
Renal Outcome ◽  
Close Monitoring ◽  
Complement Alternative Pathway ◽  
Ckd Stage ◽  
Life Threatening ◽  
Stage 1

Atypical HUS (aHUS) is a disorder most commonly caused by inherited defects of the alternative pathway of complement, or the proteins that regulate this pathway, and life-threatening episodes of aHUS can be provoked by pregnancy. We retrospectively and prospectively investigated 27 maternal and fetal pregnancy outcomes in 14 women with aHUS from the Vienna Thrombotic Microangiopathy Cohort. Seven pregnancies (26%) were complicated by pregnancy-associated aHUS (p-aHUS), of which three appeared to be provoked by infection, bleeding, and curettage, and three individuals were considered to have preeclampsia/HELLP syndrome before the definitive diagnosis of p-aHUS was made. Mutations in genes that encode the complement alternative pathway proteins or the molecules that regulate this pathway were detected in 71% of the women, with no relationship to pregnancy outcome. Twenty-one pregnancies (78%) resulted in a live birth, two preterm infants were stillborn, and four pregnancies resulted in early spontaneous abortions. Although short-term renal outcome was good in most women, long-term renal outcome was poor; among the 14 women, four had CKD stage 1–4, five had received a renal allograft, and three were dialysis-dependent at study end. We prospectively followed nine pregnancies of four women and treated six of these pregnancies with prophylactic plasma infusions (one pregnancy resulted in p-aHUS, one intrauterine fetal death occurred, and seven pregancies were uneventful). Our study emphasizes the frequency of successful pregnancies in women with aHUS. Close monitoring of such pregnancies for episodes of thrombotic microangiopathy is essential but, the best strategy to prevent these episodes remains unclear.

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