Alternative pathway activation due to low level of complement factor H in primary antiphospholipid syndrome

2018 ◽  
Vol 164 ◽  
pp. 63-68 ◽  
Author(s):  
Hiroyuki Nakamura ◽  
Kenji Oku ◽  
Yusuke Ogata ◽  
Kazumasa Ohmura ◽  
Yoko Yoshida ◽  
...  
Keyword(s):  
Antiphospholipid Syndrome ◽  
Alternative Pathway ◽  
Factor H ◽  
Complement Factor H ◽  
Complement Factor ◽  
Primary Antiphospholipid Syndrome ◽  
Low Level ◽  
Pathway Activation

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.

scholarly journals Upregulation of Complement Factor H by SOCS-1/3–STAT4 in Lung Cancer

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 471 ◽  
Author(s):  
Yeon-Hee Yoon ◽  
Hyeon-Ji Hwang ◽  
Hye-Jin Sung ◽  
Sun-Hee Heo ◽  
Dong-Sun Kim ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Transcription Factor ◽  
Cancer Cells ◽  
Expression Patterns ◽  
Factor H ◽  
Complement Factor H ◽  
Lung Cancer Cells ◽  
Luciferase Reporter ◽  
Complement Factor ◽  
Low Level

Complement factor H (CFH) is a fluid phase regulator of complement proteins and functions to prevent complement attack and immune surveillance. CFH is known to inactivate therapeutic antibody-dependent complement-mediated cellular cytotoxicity. We found that CFH was highly expressed in human lung cancer cells and tissues. To investigate mechanisms of CFH upregulation, we searched for a CFH transcription factor and its regulatory factors. First, signal transducer and activator of transcription 4 (STAT4) expression patterns coincided with CFH expression patterns in lung cancer tissues. Knockdown of STAT4 led to decreased CFH secretion from lung cancer cells. STAT4 bound directly to the CFH promoter, as demonstrated by luciferase reporter assay, electrophoretic mobility shift assay (EMSA), and chromatin immunoprecipitation (ChIP) assay, suggesting that STAT4 is a transcription factor for CFH. In addition, a low level of suppressors of cytokine signaling (SOCS)-1/3, a Janus kinase (JAK) inhibitor, was observed in lung cancer cells and its transfection decreased CFH protein levels and promoter activity. Unexpectedly, the low level of SOCS-1/3 was not due to epigenetic silencing. Instead, differential methylation was found on the regulatory region of STAT4 between normal and lung cancer cells. In conclusion, our results demonstrated that CFH is upregulated by constitutive activation of STAT4, which is accounted for by SOCS silencing in lung cancer cells.

Some Patients with Antiphospholipid Syndrome Express hitherto Undescribed Antibodies to Cardiolipin-binding Proteins

2001 ◽  
Vol 85 (01) ◽  
pp. 57-62 ◽  
Author(s):  
P. Rampazzo ◽  
A. Biasiolo ◽  
J. Garin ◽  
A. Rosato ◽  
C. Betterle ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Antiphospholipid Syndrome ◽  
Lupus Erythematosus ◽  
Binding Proteins ◽  
Anticardiolipin Antibodies ◽  
Factor H ◽  
Complement Factor H ◽  
Macromolecular Complex ◽  
Complement Factor ◽  
Close Relationship

SummaryContrary to infective anticardiolipin (aCL) antibodies, autoimmune aCL antibodies react with phospholipids (PL) mainly via binding to the plasma glycoprotein cofactor β2-Glycoprotein I (β2GPI). While there is a well-documented link between the risk of thrombosis and the presence of β2GPI-dependent anticardiolipin antibodies, the pathological impact of other antiphospholipid antibodies is less clear. By means of cardiolipin affinity-chromatography, we isolated and identified 3 CL-binding proteins, complement component C4, complement factor H and a kallikrein-sensitive glycoprotein, and tested for the presence of autoantibodies against these proteins in patients with antiphospholipid syndrome (APS), systemic lupus erythematosus (SLE) and other autoimmune diseases. High titers of autoantibodies to C4 as compared to age- and sex-matched healthy controls were present in 3 of 26 patients with APS, and weak titers were found in 2 of 26 patients with SLE and in none of 26 patients with other autoimmune diseases. Autoantibodies to complement factor H were found in 4 APS, 3 SLE and none of the other autoimmune patients. Autoantibodies to kallikrein-sensitive glycoprotein were detected in 6 APS patients, 1 SLE patient, and 1 patient with another autoimmune disease. A close relationship between these antibodies was found, suggesting their origin from a common macromolecular complex. However, no relationship with anti-β2GPI antibodies was found, with the three patients with higher levels of autoantibodies having a low titer of anti-β2GPI antibodies. In conclusion, some patients with APS harbor circulating antibodies to other CL-binding proteins which might be useful to further characterize these patients.

scholarly journals An Engineered Complement Factor H Construct for Treatment of C3 Glomerulopathy

2018 ◽  
Vol 29 (6) ◽  
pp. 1649-1661 ◽  
Author(s):  
Yi Yang ◽  
Harriet Denton ◽  
Owen R. Davies ◽  
Kate Smith-Jackson ◽  
Heather Kerr ◽  
...  
Keyword(s):  
Chinese Hamster Ovary Cells ◽  
Alternative Pathway ◽  
Treatment Options ◽  
Chinese Hamster ◽  
Factor H ◽  
Complement Factor H ◽  
Complement Factor ◽  
C3 Glomerulopathy

Background C3 glomerulopathy (C3G) is associated with dysregulation of the alternative pathway of complement activation, and treatment options for C3G remain limited. Complement factor H (FH) is a potent regulator of the alternative pathway and might offer a solution, but the mass and complexity of FH makes generation of full-length FH far from trivial. We previously generated a mini-FH construct, with FH short consensus repeats 1–5 linked to repeats 18–20 (FH1–5^18–20), that was effective in experimental C3G. However, the serum t1/2 of FH1–5^18–20 was significantly shorter than that of serum-purified FH.Methods We introduced the oligomerization domain of human FH-related protein 1 (denoted by R1–2) at the carboxy or amino terminus of human FH1–5^18–20 to generate two homodimeric mini-FH constructs (FHR1–2^1–5^18–20 and FH1–5^18–20^R1–2, respectively) in Chinese hamster ovary cells and tested these constructs using binding, fluid-phase, and erythrocyte lysis assays, followed by experiments in FH-deficient Cfh−/− mice.Results FHR1–2^1–5^18–20 and FH1–5^18–20^R1–2 homodimerized in solution and displayed avid binding profiles on clustered C3b surfaces, particularly FHR1–2^1–5^18–20. Each construct was >10-fold more effective than FH at inhibiting cell surface complement activity in vitro and restricted glomerular basement membrane C3 deposition in vivo significantly better than FH or FH1–5^18–20. FH1–5^18–20^R1–2 had a C3 breakdown fragment binding profile similar to that of FH, a >5-fold increase in serum t1/2 compared with that of FH1–5^18–20, and significantly better retention in the kidney than FH or FH1–5^18–20.Conclusions FH1–5^18–20^R1–2 may have utility as a treatment option for C3G or other complement-mediated diseases.

scholarly journals Mutations in Complement Factor H Impair Alternative Pathway Regulation on Mouse Glomerular Endothelial Cellsin Vitro

2016 ◽  
Vol 291 (10) ◽  
pp. 4974-4981 ◽  
Author(s):  
Markus A. Loeven ◽  
Angelique L. Rops ◽  
Markus J. Lehtinen ◽  
Toin H. van Kuppevelt ◽  
Mohamed R. Daha ◽  
...  
Keyword(s):  
Alternative Pathway ◽  
Factor H ◽  
Complement Factor H ◽  
Complement Factor ◽  
Pathway Regulation

scholarly journals Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients

Neurology ◽  
2017 ◽  
Vol 90 (4) ◽  
pp. e332-e341 ◽  
Author(s):  
Mark McCormack ◽  
Hongsheng Gui ◽  
Andrés Ingason ◽  
Doug Speed ◽  
Galen E.B. Wright ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Alternative Pathway ◽  
Han Chinese ◽  
Factor H ◽  
Complement Factor H ◽  
Chinese Patients ◽  
Complement Factor ◽  
Genetic Associations ◽  
Genetic Predictors ◽  
Maculopapular Exanthema

ObjectiveTo characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs.MethodsWe conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed.ResultsWe report an association between a rare variant in the complement factor H–related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 × 10–11; odds ratio [95% confidence interval] 7 [3.2–16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients.ConclusionsThe identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H–related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients.

scholarly journals Novel Complement Factor H mutation, a case report of atypical hemolytic uremic syndrome

2017 ◽  
Vol 4 (2) ◽  
pp. 13 ◽  
Author(s):  
Rodrigo Andrés Sepúlveda ◽  
Rodrigo Tagle ◽  
Aquiles Jara
Keyword(s):  
Renal Failure ◽  
Hemolytic Uremic Syndrome ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Complement Factor H ◽  
Complement Factor ◽  
Severe Renal Failure ◽  
Uremic Syndrome ◽  
I Factor

 Atypical hemolytic uremic syndrome (aHUS) is a rare but catastrophic disease. It is characterized by a triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. When the aHUS is primary, the cause is due to mutations in proteins that regulate the alternative pathway of complement, such as Factor H, Factor I, Factor B, C3, Membrane Co-Factor Protein and Thrombomodulin. Usually primary aHUS is associated with other amplifiers complement factors. We present a case of aHUS in a 25-year-old female patient; she presented with malignant hypertension and severe renal failure. After a widespread study, the etiology of the aHUS was a mutation in the complement factor H, not previously described in the literature (p.Tyr1177His). After treatment with Eculizumab (C5 inhibitor monoclonal antibody), she recovered renal function with not hemodialysis requirements. 

scholarly journals Limited tryptic cleavage of complement factor H abrogates recognition of sialic acid-containing surfaces by the alternative pathway of complement

1992 ◽  
Vol 283 (2) ◽  
pp. 317-319 ◽  
Author(s):  
V Koistinen
Keyword(s):  
Sialic Acid ◽  
Cleavage Site ◽  
Alternative Pathway ◽  
Factor H ◽  
Complement Factor H ◽  
Complement Factor ◽  
Complement Protein ◽  
Sheep Erythrocytes ◽  
Tryptic Cleavage ◽  
N Terminus

The potency of complement factor H (H) in accelerating the decay of the alternative pathway C3 convertase, C3b,Bb (decay-accelerating activity), was used as a measure of the affinity of native versus trypsin-treated H for the complement protein C3b bound to surfaces. When about 99% of H was cleaved at the primary tryptic cleavage site 34 kDa from the N-terminus, its decay-accelerating activity on C3b,Bb on sheep erythrocytes fell about 60-fold, whereas the trypsin-treated H was only 3-4 times less potent than native H in dissociating C3b,Bb on Sepharose 4B. The residual decay-accelerating activity, remaining after the primary cleavage, was not affected by secondary cleavage at a site 120 kDa from the N-terminus, as shown with H preparations cleaved to different degrees. Because cell surface sialic acid is known to be responsible for the high affinity of H for C3b bound on sheep erythrocytes, the results strongly suggest that the integrity of the primary tryptic cleavage site of H is essential for the recognition of sialic acid-containing surfaces by the C3b-H complex.

scholarly journals Insights into the effects of complement factor H on the assembly and decay of the alternative pathway C3 proconvertase and C3 convertase.

2017 ◽  
Vol 292 (15) ◽  
pp. 6094-6094
Author(s):  
Serena Bettoni ◽  
Elena Bresin ◽  
Giuseppe Remuzzi ◽  
Marina Noris ◽  
Roberta Donadelli
Keyword(s):  
Alternative Pathway ◽  
Factor H ◽  
Complement Factor H ◽  
Complement Factor

scholarly journals Complement factor H and susceptibility to major depressive disorder in Han Chinese

2016 ◽  
Vol 208 (5) ◽  
pp. 446-452 ◽  
Author(s):  
Chen Zhang ◽  
Deng-Feng Zhang ◽  
Zhi-Guo Wu ◽  
Dai-Hui Peng ◽  
Jun Chen ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Alternative Pathway ◽  
Age At Onset ◽  
Han Chinese ◽  
Factor H ◽  
Complement Factor H ◽  
Complement Factor ◽  
Mrna Levels ◽  
Major Depressive

BackgroundAccumulating evidence suggests that altered immunity contributes to the development of major depressive disorder (MDD).AimsTo examine whether complement factor H (CFH), a regulator of activation of the alternative pathway of the complement cascade, confers susceptibility to MDD.MethodExpression analyses were tested in 53 unmedicated people with MDD and 55 healthy controls. A two-stage genetic association analysis was performed in 3323 Han Chinese with or without MDD. Potential associations between CFH single nucleotide polymorphisms and age at MDD onset were evaluated.ResultsCFH levels were significantly lower in the MDD group at both protein and mRNA levels (P = 0.009 and P = 0.014 respectively). A regulatory variant in the CFH gene, rs1061170, showed statistically significant genotypic and allelic differences between the MDD and control groups (genotypic P = 0.0005, allelic P = 0.0001). Kaplan–Meier survival analysis showed that age at onset of MDD was significantly associated with the C allele of rs1061170 (log rank statistic χ2 = 6.82, P = 0.009). The C-allele carriers had a younger age at onset of MDD (22.2 years, s.d. = 4.0) than those without the C allele (23.6 years, s.d. = 4.3).ConclusionsCFH is likely to play an important role in the development of MDD. rs1061170 has an important effect on age at onset of MDD in Han Chinese and may therefore be related to early pathogenesis of MDD, although further study is needed.

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