scholarly journals 313: Quantitative functional alterations in complement alternative pathway and related genetic analysis in severe phenotype preeclampsia and HELLP syndrome

2018 ◽  
Vol 218 (1) ◽  
pp. S197-S198
Author(s):  
Layan Alrahmani ◽  
Wendy White ◽  
Margot A. Cousin ◽  
Maria Willrich ◽  
Pavan Parikh ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Hellp Syndrome ◽  
Alternative Pathway ◽  
Severe Phenotype ◽  
Complement Alternative Pathway

scholarly journals Quantitative alterations in complement alternative pathway and related genetic analysis in severe phenotype preeclampsia

Kidney360 ◽  
2021 ◽  
pp. 10.34067/KID.0000992021
Author(s):  
Layan Alrahmani ◽  
Maria L. Gonzalez Suarez ◽  
Margot A Cousin ◽  
Ann M Moyer ◽  
Maria Alice V Willrich ◽  
...  
Keyword(s):  
Alternative Pathway ◽  
Genetic Alterations ◽  
Sequence Variant ◽  
Therapeutic Approaches ◽  
Severe Phenotype ◽  
Complement Alternative Pathway ◽  
Elevated Liver Enzymes ◽  
Genes Encoding ◽  
Gestational Age At Delivery ◽  
Serological Studies

Background: Preeclampsia and HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome share many clinical and biologic features with thrombotic microangiopathy syndromes caused by complement abnormalities. Our hypothesis was that similar functional and genetic alterations in the complement alternative pathway (CAP) are present in these disorders of pregnancy. Methods: Quantitative analysis of proteins involved in CAP using ELISA and nephelometry was conducted on prospectively collected blood samples from cases of severe phenotype preeclampsia (defined as delivery <34 weeks due to preeclampsia), HELLP syndrome or eclampsia, and matched normotensive controls (n=25 in each arm) between 2011 and 2016. Sequencing was performed to interrogate 14 genes encoding CAP components. Results: Both groups were similar in age, gravidity, parity, marital status and race; the study group had a higher BMI (mean ± SD; 32±8 vs 25±4 kg/m2; p=0.002) and earlier gestational age at delivery (32.5±3.6 vs 40.3±1 weeks; p<0.001). Serological studies demonstrated elevated Bb subunit (median [range]; 1.2 [0.5-4.3] vs 0.6 [0.5-1] mcg/mL; p<0.001), complement C5 concentration (28 [18-33] vs 24 [15-34] mg/dL; p=0.03) and sMAC (371 [167-761] vs 184 [112-249] ng/mL; p<0.001) concentrations in patients with preeclampsia. Two-thirds had at least 1 non-synonymous sequence variant in CAP genes. Conclusion: Patients with severe phenotype preeclampsia manifest functional alterations in CAP activation. Genetic variants in the CAP genes were detected in several patients, a larger population study is necessary to fully evaluate genetic risk. Genetic screening and complement-targeted treatment may be useful in risk stratification and novel therapeutic approaches.

Factor H, membrane cofactor protein, and factor I mutations in patients with hemolysis, elevated liver enzymes, and low platelet count syndrome

Blood ◽  
2008 ◽  
Vol 112 (12) ◽  
pp. 4542-4545 ◽  
Author(s):  
Fadi Fakhouri ◽  
Mathieu Jablonski ◽  
Jacques Lepercq ◽  
Jacques Blouin ◽  
Alexandra Benachi ◽  
...  
Keyword(s):  
Platelet Count ◽  
Hellp Syndrome ◽  
Liver Enzymes ◽  
Alternative Pathway ◽  
Renal Involvement ◽  
Factor H ◽  
Complement Alternative Pathway ◽  
Elevated Liver Enzymes ◽  
Low Platelet Count ◽  
Alternative Pathway Of Complement

Abstract The HELLP syndrome, defined by the existence of hemolysis, elevated liver enzymes, and low platelet count, is a serious complication of pregnancy-related hypertensive disorders and shares several clinical and biologic features with thrombotic microangiopathy (TMA). Several recent studies have clearly shown that an abnormal control of the complement alternative pathway is a major risk for the occurrence of a peculiar type of TMA involving mainly the kidney. The aim of this study was to screen for complement abnormalities in 11 patients with HELLP syndrome and renal involvement. We identified 4 patients with a mutation in one of the genes coding for proteins involved in the regulation of the alternative pathway of complement. Our results suggest that an abnormal control of the complement alternative pathway is a risk factor for the occurrence of HELLP syndrome.

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 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.

Sign in / Sign up

Export Citation Format

Share Document