Target Pattern Recognition by Complement Proteins of the Classical and Alternative Pathways

Kang, Young-Nam; Tan, Lee Aun; Carroll, Maria V.; Gentle, Madeleine E.; Sim, Robert B.

doi:10.1007/978-1-4419-0901-5_8

Cited by 41 publications

(26 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…More than 30 proteins, both in serum and on cell surfaces are part of this system (Kang et al, 2009). Complement recognizes a wide range of targets including microorganisms, altered host cells and synthetic particles.…”

Section: Introductionmentioning

confidence: 99%

Complement activation by phospholipids: the interplay of factor H and C1q

Tan

Sim

et al. 2010

Protein Cell

Self Cite

View full text Add to dashboard Cite

Complement proteins in blood recognize charged particles. The anionic phospholipid (aPL) cardiolipin binds both complement proteins C1q and factor H. C1q is an activator of the complement classical pathway, while factor H is an inhibitor of the alternative pathway. To examine opposing effects of C1q and factor H on complement activation by aPL, we surveyed C1q and factor H binding, and complement activation by aPL, either coated on microtitre plates or in liposomes. Both C1q and factor H bound to all aPL tested, and competed directly with each other for binding. All the aPL activated the complement classical pathway, but negligibly the alternative pathway, consistent with accepted roles of C1q and factor H. However, in this system, factor H, by competing directly with C1q for binding to aPL, acts as a direct regulator of the complement classical pathway. This regulatory mechanism is distinct from its action on the alternative pathway. Regulation of classical pathway activation by factor H was confirmed by measuring C4 activation by aPL in human sera in which the C1q:factor H molar ratio was adjusted over a wide range. Thus factor H, which is regarded as a down-regulator only of the alternative pathway, has a distinct role in downregulating activation of the classical complement pathway by aPL. A factor H homologue, β2-glycoprotein-1, also strongly inhibits C1q binding to cardiolipin. Recombinant globular domains of C1q A, B and C chains bound aPL similarly to native C1q, confirming that C1q binds aPL via its globular heads.

show abstract

Section: Introductionmentioning

confidence: 99%

Complement activation by phospholipids: the interplay of factor H and C1q

Tan

Sim

et al. 2010

Protein Cell

Self Cite

View full text Add to dashboard Cite

show abstract

“…In addition, C1q can also bind directly to repeat structures of non-immunoglobulin activators of the CP, such as nucleic acids, chromatin, cytoplasm intermediate filaments, mitochondrial proteins, cardiolipin, ligand-bound C-reactive protein, protein aggregates (e.g., amyloids), bacterial polysaccharides, and artificial surfaces (carbon nanotubes and polymers) [14]. These activators represent important potential mediators of glomerular damage.…”

Section: The Classical Pathwaymentioning

confidence: 99%

Complement-Mediated Glomerular Injury in Children

Prohászka

Vivarelli

Reusz

2014

Pediatric Nephrology

View full text Add to dashboard Cite

“…82 This activation may occur not only via the alternative pathway but also (as observed in ischemia reperfusion injury) by the classical and lectin pathways via exposure of novel epitopes recognized by these pathways. 83 In aHUS, the alternative pathway is likely to be responsible for the damage, because the disease is associated with dysregulation of this pathway in particular. 8 The damage-induced enhancement of complement activation can lead to further damage of nearby cells, both the cells residing in the immediate area and those passing by in the vicinity.…”

Section: Cell Damage-induced Complement Activation In Husmentioning

confidence: 99%

HUS and atypical HUS

Jokiranta

2017

Blood

239

260

View full text Add to dashboard Cite

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by intravascular hemolysis, thrombocytopenia, and acute kidney failure. HUS is usually categorized as typical, caused by Shiga toxin–producing Escherichia coli (STEC) infection, as atypical HUS (aHUS), usually caused by uncontrolled complement activation, or as secondary HUS with a coexisting disease. In recent years, a general understanding of the pathogenetic mechanisms driving HUS has increased. Typical HUS (ie, STEC-HUS) follows a gastrointestinal infection with STEC, whereas aHUS is associated primarily with mutations or autoantibodies leading to dysregulated complement activation. Among the 30% to 50% of patients with HUS who have no detectable complement defect, some have either impaired diacylglycerol kinase ε (DGKε) activity, cobalamin C deficiency, or plasminogen deficiency. Some have secondary HUS with a coexisting disease or trigger such as autoimmunity, transplantation, cancer, infection, certain cytotoxic drugs, or pregnancy. The common pathogenetic features in STEC-HUS, aHUS, and secondary HUS are simultaneous damage to endothelial cells, intravascular hemolysis, and activation of platelets leading to a procoagulative state, formation of microthrombi, and tissue damage. In this review, the differences and similarities in the pathogenesis of STEC-HUS, aHUS, and secondary HUS are discussed. Common for the pathogenesis seems to be the vicious cycle of complement activation, endothelial cell damage, platelet activation, and thrombosis. This process can be stopped by therapeutic complement inhibition in most patients with aHUS, but usually not those with a DGKε mutation, and some patients with STEC-HUS or secondary HUS. Therefore, understanding the pathogenesis of the different forms of HUS may prove helpful in clinical practice.

show abstract

Target Pattern Recognition by Complement Proteins of the Classical and Alternative Pathways

Cited by 41 publications

References 84 publications

Complement activation by phospholipids: the interplay of factor H and C1q

Complement activation by phospholipids: the interplay of factor H and C1q

Complement-Mediated Glomerular Injury in Children

HUS and atypical HUS

Contact Info

Product

Resources

About