Translational Mini-Review Series on Complement Factor H: Structural and functional correlations for factor H

Schmidt, Christoph Q.; Herbert, Andrew P.; Hocking, Henry G.; Uhrı́n, Dušan; Barlow, Paul N.

doi:10.1111/j.1365-2249.2007.03553.x

Cited by 126 publications

(121 citation statements)

References 78 publications

Supporting

Mentioning

120

Contrasting

Order By: Relevance

“…The finding here that the C3bB complexes formed in the same amounts in the presence or in the absence of FH would suggest that FH does not compete enough with FB for binding to C3b to prevent C3bB assembly. A plausible explanation of our results derives from biophysical studies in the literature, showing that the binding affinity between C3b and FH molecules is lower compared with the affinity between C3b and FB (K d C3b-FH, 1 M, versus K d C3b-FB, 73 nM) (29,33,56), which would indicate that C3b-FB interaction is favored toward that between C3b and FH. Finding that FH band was detected before C3bB(Mn 2ϩ ) complex formation would indicate that the interaction between C3b and FH might have faster kinetics than that between C3b and FB.…”

Section: Discussionmentioning

confidence: 62%

Insights into the Effects of Complement Factor H on the Assembly and Decay of the Alternative Pathway C3 Proconvertase and C3 Convertase

Bettoni

Bresin

Noris

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

The activated fragment of C3 (C3b) and factor B form the C3 proconvertase (C3bB), which is cleaved by factor D to C3 convertase ( Immunol. 122, 75-81) indicated that the complement alternative pathway regulator factor H (FH) competes with factor B for C3b binding; however, the capability of FH to prevent C3bB assembly has not been formally investigated. Moreover, in the few published studies FH did not favor C3bB dissociation. Whether FH may affect C3bBb formation from C3bB is unknown. We set up user-friendly assays based on combined microplate/Western blotting techniques that specifically detect either C3bB or C3bBb, with the aim of investigating the effect of FH on C3bB assembly and decay and C3bBb formation and decay. We document that FH does not affect C3bB assembly, indicating that FH does not efficiently compete with factor B for C3b binding. We also found that FH does not dissociate C3bB. FH showed a strong C3bBb decay-accelerating activity, as reported previously, and also exerted an apparent inhibitory effect on C3bBb formation. The latter effect was not fully attributable to a rapid FH-mediated dissociation of C3bBb complexes, because blocking decay with properdin and C3 nephritic factor did not restore C3bBb formation. FH almost completely prevented release of the smaller cleavage subunit of FB (Ba), without modifying the amount of C3bB complexes, suggesting that FH inhibits the conversion of C3bB to C3bBb. Thus, the inhibitory effect of FH on C3bBb formation is likely the sum of inhibition of C3bB conversion to C3bBb and of C3bBb decay acceleration. Further studies are required to confirm these findings in physiological cell-based settings.The complement system is a complex network of plasma proteins that cooperate in the defense against foreign microorganisms and in the maintenance of tissue homeostasis (1-3). Interest in the complement system was rekindled in the past decade by accumulating evidence that genetically determined complement dysregulation is involved in two rare devastating disorders of the kidney, atypical hemolytic uremic syndrome (aHUS) 3 and C3 glomerulopathy (C3G) (4 -8), as well as in age-related macular degeneration, the leading cause of blindness for older people (9). Finding that treatment with eculizumab (10), a monoclonal antibody that blocks the formation of terminal complement complex C5b-9, efficiently cured aHUS (11, 12) and C3G (13-15) further corroborated the role of complement in human disease (16).Complement can be triggered by three activation pathways, the classical, the lectin, and the alternative (AP) pathways, all leading to the formation of unstable protease complexes, named C3 convertases, that cleave the inactive central component C3 into C3a and C3b fragments. C3b molecules deposited on pathogens or damaged self-cells provide a molecular platform for the formation of an active AP C3 convertase, C3bBb, which enzymatically generates many more C3b molecules, resulting in a positive feedback loop. Notably, the AP C3 convertase is crucial within the complement ca...

show abstract

Section: Discussionmentioning

confidence: 62%

Insights into the Effects of Complement Factor H on the Assembly and Decay of the Alternative Pathway C3 Proconvertase and C3 Convertase

Bettoni

Bresin

Noris

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Two sites are involved in C3b binding (SCR 1-4 and SCR [19][20]. The SCR 7, 19-20 bind to the protein molecules on the cell surface [57] . Factor H has different effects on the complement cascade.…”

Section: C3bmentioning

confidence: 99%

Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations

Salvadori

Bertoni²

2013

WJN

116

111

View full text Add to dashboard Cite

Hemolytic uremic syndrome (HUS) is a rare disease. In this work the authors review the recent findings on HUS, considering the different etiologic and pathogenetic classifications. New findings in genetics and, in particular, mutations of genes that encode the complement-regulatory proteins have improved our understanding of atypical HUS. Similarly, the complement proteins are clearly involved in all types of thrombotic microangiopathy: typical HUS, atypical HUS and thrombotic thrombocytopenic purpura (TTP). Furthermore, several secondary HUS appear to be related to abnormalities in complement genes in predisposed patients. The authors highlight the therapeutic aspects of this rare disease, examining both "traditional therapy" (including plasma therapy, kidney and kidneyliver transplantation) and "new therapies". The latter include anti-Shiga-toxin antibodies and anti-C5 monoclonal antibody "eculizumab". Eculizumab has been recently launched for the treatment of the atypical HUS, but it appears to be effective in the treatment of typical HUS and in TTP. Future therapies are in phases Ⅰ and Ⅱ. They include anti-C5 antibodies, which are more purified, less immunogenic and absorbed orally and, anti-C3 antibodies, which are more powerful, but potentially less safe. Additionally, infusions of recombinant complement-regulatory proteins are a potential future therapy.

show abstract

“…Additionally, fH serves as a cofactor for the factor I (fI)-mediated proteolytic cleavage of active C3b into inactive C3b. 24 fH is composed of 20 short consensus repeat (SCR) domains, each composed of approximately 60 amino acid residues with 3-8 amino acid spacers between the individual SCR. 25 Distinct functional regions have been identified within the full-length molecule.…”

Section: Introductionmentioning

confidence: 99%

Complement factor H-derived short consensus repeat 18-20 enhanced complement-dependent cytotoxicity of ofatumumab on chronic lymphocytic leukemia cells

et al. 2013

View full text Add to dashboard Cite

The antitumor activity of monoclonal antibodies in the treatment of chronic lymphocytic leukemia is mediated mainly by antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Unfortunately, the efficacy of complement-dependent cytotoxicity is strongly restricted due to the expression and acquisition of regulators of complement activation by lymphocytic leukemia cells. Whereas the role of membrane regulators of complement activation, such as CD55 and CD59, has been investigated in detail in chronic lymphocytic leukemia, the involvement of soluble regulators of complement activation, such as complement factor H, has not yet been reported. Propidium iodide staining was performed to investigate the efficacy of ofatumumab and factor H-derived shortconsensus-repeat 18-20 in the induction of complement-dependent cytotoxicity on primary chronic lymphocytic leukemia cells from 20 patients. Deposition of complement C3 fragments was monitored by western blot analysis. Expression of CD20, CD55 or CD59 was determined by FACS analysis. Replacement of factor H with short consensus repeat 18-20 significantly increased the susceptibility of primary chronic lymphocytic leukemia cells to ofatumumab-induced complement-dependent cytotoxicity. More importantly, addition of short-consensus-repeat 18-20 was able to overcome complement-resistance occurring during treatment with ofatumumab alone. Use of short consensus repeat 18-20 is likely to prolong the turnover time of active C3b fragments generated on the target cells following ofatumumab-induced complement activation, thereby improving specific killing of chronic lymphocytic leukemia cells by complement-dependent cytotoxicity. The relative contribution of factor H to the protection of chronic lymphocytic leukemia cells against complement-dependent cytotoxicity was comparable to that of CD55. Our data suggest that, by abrogating factor H function, short consensus repeat 18-20 may provide a novel approach that improves the complement-dependent efficacy of therapeutic monoclonal antibodies.

show abstract

Translational Mini-Review Series on Complement Factor H: Structural and functional correlations for factor H

Cited by 126 publications

References 78 publications

Insights into the Effects of Complement Factor H on the Assembly and Decay of the Alternative Pathway C3 Proconvertase and C3 Convertase

Insights into the Effects of Complement Factor H on the Assembly and Decay of the Alternative Pathway C3 Proconvertase and C3 Convertase

Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations

Complement factor H-derived short consensus repeat 18-20 enhanced complement-dependent cytotoxicity of ofatumumab on chronic lymphocytic leukemia cells

Contact Info

Product

Resources

About