Genomes and Genes
complement membrane attack complex
Summary: A product of COMPLEMENT ACTIVATION cascade, regardless of the pathways, that forms transmembrane channels causing disruption of the target CELL MEMBRANE and cell lysis. It is formed by the sequential assembly of terminal complement components (COMPLEMENT C5B; COMPLEMENT C6; COMPLEMENT C7; COMPLEMENT C8; and COMPLEMENT C9) into the target membrane. The resultant C5b-8-poly-C9 is the "membrane attack complex" or MAC.
- De Bleecker J, Vervaet V, Van den Bergh P. Necrotizing myopathy with microvascular deposition of the complement membrane attack complex. Clin Neuropathol. 2004;23:76-9 pubmed..The link between the muscle fiber necrosis and the microangiopathy is unclear. Absence of prominent inflammatory changes in a diagnostic muscle biopsy does not exclude the diagnosis of a treatable autoimmune inflammatory myopathy. ..
- Klein R, Zeiss C, Chew E, Tsai J, Sackler R, Haynes C, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308:385-9 pubmed..This polymorphism is in a region of CFH that binds heparin and C-reactive protein. The CFH gene is located on chromosome 1 in a region repeatedly linked to AMD in family-based studies. ..
- Niculescu F, Niculescu T, Nguyen P, Puliaev R, Papadimitriou J, Gaspari A, et al. Both apoptosis and complement membrane attack complex deposition are major features of murine acute graft-vs.-host disease. Exp Mol Pathol. 2005;79:136-45 pubmed..These results indicate a role for both adaptive immunity and innate immunity in this model of GVHD and support its use in modeling human acute GVHD in the nonmyeloablative setting. ..
- Rus H, Cudrici C, Niculescu F. C5b-9 complement complex in autoimmune demyelination and multiple sclerosis: dual role in neuroinflammation and neuroprotection. Ann Med. 2005;37:97-104 pubmed..These findings indicate that activation of complement C5b-9 plays a pro-inflammatory role in the acute phase of the disease, but may also be neuroprotective during the chronic phase of the disease...
- Huang Y, Smith C, Song H, Morgan B, Abagyan R, Tomlinson S. Insights into the human CD59 complement binding interface toward engineering new therapeutics. J Biol Chem. 2005;280:34073-9 pubmed..Based on the enhanced activity of membrane-bound mutant CD59 molecules, clinically relevant soluble mutant CD59-based proteins were prepared and shown to have up to a 3-fold increase in complement inhibitory activity. ..
- Turnberg D, Botto M, Lewis M, Zhou W, Sacks S, Morgan B, et al. CD59a deficiency exacerbates ischemia-reperfusion injury in mice. Am J Pathol. 2004;165:825-32 pubmed
- Bora N, Kaliappan S, Jha P, Xu Q, Sivasankar B, Harris C, et al. CD59, a complement regulatory protein, controls choroidal neovascularization in a mouse model of wet-type age-related macular degeneration. J Immunol. 2007;178:1783-90 pubmed..Thus, our results suggest that the inhibition of complement by soluble CD59 may provide a novel therapeutic alternative to current treatment. ..
- Bjerre M, Kistorp C, Hansen T, Faber J, Lip G, Hildebrandt P, et al. Complement activation, endothelial dysfunction, insulin resistance and chronic heart failure. Scand Cardiovasc J. 2010;44:260-6 pubmed publisher..0001). Independent associations between sMAC, sEsel and IR were found in the CHF patients and we hypothesize that IR leading to endothelial activation results in activation of the complement system and thus damaging of the heart tissue. ..
- Speidl W, Kastl S, Huber K, Wojta J. Complement in atherosclerosis: friend or foe?. J Thromb Haemost. 2011;9:428-40 pubmed publisher..In addition, we summarize the role of complement components as biomarkers for cardiovascular disease. ..
- Cashman S, Ramo K, Kumar Singh R. A non membrane-targeted human soluble CD59 attenuates choroidal neovascularization in a model of age related macular degeneration. PLoS ONE. 2011;6:e19078 pubmed publisher..We propose that the above approaches warrant further exploration as potential approaches for alleviating complement mediated damage to ocular tissues in AMD. ..
- Hadders M, Beringer D, Gros P. Structure of C8alpha-MACPF reveals mechanism of membrane attack in complement immune defense. Science. 2007;317:1552-4 pubmed..Proteins of the complement membrane attack complex (MAC) and the protein perforin share a common MACPF domain that is responsible for membrane ..
- Slade D, Lovelace L, Chruszcz M, Minor W, Lebioda L, Sodetz J. Crystal structure of the MACPF domain of human complement protein C8 alpha in complex with the C8 gamma subunit. J Mol Biol. 2008;379:331-42 pubmed publisher..Also observed is structural conservation of the MACPF signature motif Y/W-G-T/S-H-F/Y-X(6)-G-G in alphaMACPF and Plu-MACPF, and conservation of several key glycine residues known to be important for refolding and pore formation by CDCs. ..
- Fondevila C, Shen X, Tsuchihashi S, Uchida Y, Freitas M, Ke B, et al. The membrane attack complex (C5b-9) in liver cold ischemia and reperfusion injury. Liver Transpl. 2008;14:1133-41 pubmed publisher..This is the first report using a clinically relevant liver cold ischemia model to show that local MAC inhibition attenuates IRI cascade in OLT recipients. ..
- Haahr Pedersen S, Bjerre M, Flyvbjerg A, Mogelvang R, Dominquez H, Hansen T, et al. Level of complement activity predicts cardiac dysfunction after acute myocardial infarction treated with primary percutaneous coronary intervention. J Invasive Cardiol. 2009;21:13-9 pubmed..The predictive value of low peripheral plasma sC5b-9 may be explained by an accumulation and activation of sC5b-9 in the infarcted myocardium. ..
- Siezenga M, Chandie Shaw P, van der Geest R, Mollnes T, Daha M, Rabelink T, et al. Enhanced complement activation is part of the unfavourable cardiovascular risk profile in South Asians. Clin Exp Immunol. 2009;157:98-103 pubmed publisher..4, 95% confidence interval 1.8-15.8). These results suggest that enhanced complement activation is part of the unfavourable cardiovascular risk profile in South Asians. ..
- Shagdarsuren E, Wellner M, Braesen J, Park J, Fiebeler A, Henke N, et al. Complement activation in angiotensin II-induced organ damage. Circ Res. 2005;97:716-24 pubmed..VSMC from dTGR are more sensitive for C3 activation. Our data show that, in this Ang II-induced model, complement activation is a major participant and suggest that TNF-alpha and CRP may play a role in its induction. ..
- Leung V, Yun S, Botto M, Mason J, Malik T, Song W, et al. Decay-accelerating factor suppresses complement C3 activation and retards atherosclerosis in low-density lipoprotein receptor-deficient mice. Am J Pathol. 2009;175:1757-67 pubmed publisher..Because upstream complement activation is potentially protective, this study underlines the importance of DAF in shielding the arterial wall from the atherogenic effects of complement...
- Happonen K, Fürst C, Saxne T, Heinegard D, Blom A. PRELP protein inhibits the formation of the complement membrane attack complex. J Biol Chem. 2012;287:8092-100 pubmed publisher..The net outcome of PRELP-mediated complement inhibition will highly depend on the local concentration of other complement modulating molecules as well as on the local concentration of available complement proteins. ..
- Triantafilou K, Hughes T, Triantafilou M, Morgan B. The complement membrane attack complex triggers intracellular Ca2+ fluxes leading to NLRP3 inflammasome activation. J Cell Sci. 2013;126:2903-13 pubmed publisher..This is the first study that links non-lethal effects of sublytic MAC attack with inflammasome activation and provides a mechanism by which sublytic MAC can drive inflammation and apoptosis. ..
- Bora P, Sohn J, Cruz J, Jha P, Nishihori H, Wang Y, et al. Role of complement and complement membrane attack complex in laser-induced choroidal neovascularization. J Immunol. 2005;174:491-7 pubmed..It is possible that a similar mechanism may be involved in the pathophysiology of other angiogenesis essential diseases. ..
- Bossi F, Fischetti F, Pellis V, Bulla R, Ferrero E, Mollnes T, et al. Platelet-activating factor and kinin-dependent vascular leakage as a novel functional activity of the soluble terminal complement complex. J Immunol. 2004;173:6921-7 pubmed..SC5b-9 induced opening of interendothelial junctions in mesenteric endothelium documented by transmission electron microscopy. ..
- Yamada K, Miwa T, Liu J, Nangaku M, Song W. Critical protection from renal ischemia reperfusion injury by CD55 and CD59. J Immunol. 2004;172:3869-75 pubmed..Our findings suggest a rationale for anti-complement therapies aimed at preventing microvascular injury during ischemia reperfusion, and the CD55(-/-)CD59(-/-) mouse provides a useful animal model in this regard. ..
- Niculescu T, Weerth S, Soane L, Niculescu F, Rus V, Raine C, et al. Effects of membrane attack complex of complement on apoptosis in experimental autoimmune encephalomyelitis. Ann N Y Acad Sci. 2003;1010:530-3 pubmed..These results indicate that C5 and possibly MAC may be required for the limitation of inflammatory response within the central nervous system. ..
- Näreaho A, Saari S, Meri S, Sukura A. Complement membrane attack complex formation and infectivity of Trichinella spiralis and T. nativa in rats. Vet Parasitol. 2009;159:263-7 pubmed publisher..nativa have efficient mechanisms to protect themselves against complement attack. The difference in infectivity for rats between the two species, however, is not due to a differential resistance to complement membrane attack complex.
- Ramo K, Cashman S, Kumar Singh R. Evaluation of adenovirus-delivered human CD59 as a potential therapy for AMD in a model of human membrane attack complex formation on murine RPE. Invest Ophthalmol Vis Sci. 2008;49:4126-36 pubmed publisher..The humanized model of MAC deposition on murine ocular tissues allows testing of human complement regulators that may have potential in the treatment of AMD or other diseases associated with complement activation. ..
- Qin X, Hu W, Song W, Grubissich L, Hu X, Wu G, et al. Generation and phenotyping of mCd59a and mCd59b double-knockout mice. Am J Hematol. 2009;84:65-70 pubmed publisher..We report here that total abrogation of mCd59 function in mCd59ab(-/-) mice results in complement-mediated hemolytic anemia that is rescued by the deficiency of C3 in compound mCd59ab(-/-)/C3(-/-) mice. ..
- Wu G, Hu W, Shahsafaei A, Song W, Dobarro M, Sukhova G, et al. Complement regulator CD59 protects against atherosclerosis by restricting the formation of complement membrane attack complex. Circ Res. 2009;104:550-8 pubmed publisher..CD59 is a key regulator of complement membrane attack complex (MAC) assembly...
- Rosado C, Buckle A, Law R, Butcher R, Kan W, Bird C, et al. A common fold mediates vertebrate defense and bacterial attack. Science. 2007;317:1548-51 pubmed..Sequence similarity between bacterial and vertebrate MACPF domains suggests that the fold of the CDCs, a family of proteins important for bacterial pathogenesis, is probably used by vertebrates for defense against infection. ..
- Lovelace L, Chiswell B, Slade D, Sodetz J, Lebioda L. Crystal structure of complement protein C8gamma in complex with a peptide containing the C8gamma binding site on C8alpha: implications for C8gamma ligand binding. Mol Immunol. 2008;45:750-6 pubmed..These results suggest a role for C8alpha in regulating access to the putative C8gamma ligand binding site. ..
- Brannen C, Sodetz J. Incorporation of human complement C8 into the membrane attack complex is mediated by a binding site located within the C8beta MACPF domain. Mol Immunol. 2007;44:960-5 pubmed..Furthermore, results indicate the principal binding sites for C8alpha and C5b-7 are located within this domain, and that C8beta binding specificity is not determined by the N- and C-terminal modules. ..
- Endo M, Fuke Y, Tamano M, Hidaka M, Ohsawa I, Fujita T, et al. Glomerular deposition and urinary excretion of complement factor H in idiopathic membranous nephropathy. Nephron Clin Pract. 2004;97:c147-53 pubmed..These findings suggest that factor H contributes to the control mechanism of in situ complement activation and prevents renal damage in idiopathic MN. ..
- Tramontini N, Huber C, Liu Bryan R, Terkeltaub R, Kilgore K. Central role of complement membrane attack complex in monosodium urate crystal-induced neutrophilic rabbit knee synovitis. Arthritis Rheum. 2004;50:2633-9 pubmed..C6 and MAC activation may represent novel therapeutic targets for suppression of neutrophil-mediated joint inflammation in gout. ..
- Qin X, Goldfine A, Krumrei N, Grubissich L, Acosta J, Chorev M, et al. Glycation inactivation of the complement regulatory protein CD59: a possible role in the pathogenesis of the vascular complications of human diabetes. Diabetes. 2004;53:2653-61 pubmed..We conclude that glycation inactivation of hCD59 that leads to increased MAC deposition may contribute to the extensive vascular pathology that complicates human diabetes. ..
- Nangaku M, Shankland S, Couser W. Cellular response to injury in membranous nephropathy. J Am Soc Nephrol. 2005;16:1195-204 pubmed..Improved understanding of the role of complement in the pathogenesis of MN and of the cellular response to C5b-9 attack creates several new opportunities for therapeutic intervention that may benefit patients with MN in the future...
- Harboe M, Garred P, Karlstrøm E, Lindstad J, Stahl G, Mollnes T. The down-stream effects of mannan-induced lectin complement pathway activation depend quantitatively on alternative pathway amplification. Mol Immunol. 2009;47:373-80 pubmed publisher..In conclusion, the down-stream effect of LP activation depends strongly on AP amplification in normal human serum and in the C2 bypass pathway. ..
- Gandhi J, Cashman S, Kumar Singh R. Soluble CD59 expressed from an adenovirus in vivo is a potent inhibitor of complement deposition on murine liver vascular endothelium. PLoS ONE. 2011;6:e21621 pubmed publisher..This result, unanticipated based on prior studies, suggests that the use of non membrane-targeted sCD59 as an anti-complement therapy be re-visited. ..
- Rangan G, Pippin J, Coombes J, Couser W. C5b-9 does not mediate chronic tubulointerstitial disease in the absence of proteinuria. Kidney Int. 2005;67:492-503 pubmed..These data suggest that, in contrast to proteinuric states, C5b-9 does not have a significant impact on the progression of tubulointerstitial damage in nonproteinuric chronic renal disease. ..
- Turnberg D, Botto M, Warren J, Morgan B, Walport M, Cook H. CD59a deficiency exacerbates accelerated nephrotoxic nephritis in mice. J Am Soc Nephrol. 2003;14:2271-9 pubmed..The lack of CD59a, by allowing unregulated MAC deposition, exacerbates the renal injury in this model of immune complex-mediated glomerulonephritis. ..
- Xiong Z, Qian W, Suzuki K, McNamara J. Formation of complement membrane attack complex in mammalian cerebral cortex evokes seizures and neurodegeneration. J Neurosci. 2003;23:955-60 pubmed..Deposition of the complement MAC in cortical gray matter may contribute to epileptic seizures and cell death in diverse diseases of the human brain. ..
- Musingarimi P, Plumb M, Sodetz J. Interaction between the C8 alpha-gamma and C8 beta subunits of human complement C8: role of the C8 beta N-terminal thrombospondin type 1 module and membrane attack complex/perforin domain. Biochemistry. 2002;41:11255-60 pubmed..Results from activity assays suggest that residues within this segment also mediate binding and incorporation of C8 into the MAC. ..
- Kraiczy P, Hunfeld K, Breitner Ruddock S, Wurzner R, Acker G, Brade V. Comparison of two laboratory methods for the determination of serum resistance in Borrelia burgdorferi isolates. Immunobiology. 2000;201:406-19 pubmed..The IFA, however, is regarded as superior to the GIA owing to the obvious ease of performance and its rapid capability for the classification of even very slow growing isolates. ..
- Nangaku M, Pippin J, Couser W. C6 mediates chronic progression of tubulointerstitial damage in rats with remnant kidneys. J Am Soc Nephrol. 2002;13:928-36 pubmed..Treatment to reduce C5b-9 attack in tubular cells may slow progression and facilitate recovery. ..
- Davies A, Simmons D, Hale G, Harrison R, Tighe H, Lachmann P, et al. CD59, an LY-6-like protein expressed in human lymphoid cells, regulates the action of the complement membrane attack complex on homologous cells. J Exp Med. 1989;170:637-54 pubmed
- Kissel J, Mendell J, Rammohan K. Microvascular deposition of complement membrane attack complex in dermatomyositis. N Engl J Med. 1986;314:329-34 pubmed..In addition to providing further evidence for the presence of vasculopathy in dermatomyositis, these findings suggest a primary role for complement in mediating vessel injury in the disease, particularly in its childhood form. ..
- Endo M, Ohi H, Ohsawa I, Matsushita M, Fujita T. Glomerular deposition of mannose-binding lectin (MBL) indicates a novel mechanism of complement activation in IgA nephropathy. Nephrol Dial Transplant. 1998;13:1984-90 pubmed..In addition, these findings will add insight to the pathogenesis of IgA-N, including its relation to infection, since MBL plays a crucial role in the host defense against various pathogens. ..
- Kraus S, Seger R, Fishelson Z. Involvement of the ERK mitogen-activated protein kinase in cell resistance to complement-mediated lysis. Clin Exp Immunol. 2001;123:366-74 pubmed..In conclusion, cell desensitization by sublytic doses of the complement membrane attack complex involves a signalling cascade that includes PKC-mediated ERK activation.
- Stahel P, Morganti Kossmann M, Perez D, Redaelli C, Gloor B, Trentz O, et al. Intrathecal levels of complement-derived soluble membrane attack complex (sC5b-9) correlate with blood-brain barrier dysfunction in patients with traumatic brain injury. J Neurotrauma. 2001;18:773-81 pubmed..998; p < 0.05). These data demonstrate for the first time that terminal pathway complement activation occurs after head injury and suggest a possible pathophysiological role of complement with regard to posttraumatic BBB dysfunction. ..
- Casarsa C, De Luigi A, Pausa M, De Simoni M, Tedesco F. Intracerebroventricular injection of the terminal complement complex causes inflammatory reaction in the rat brain. Eur J Immunol. 2003;33:1260-70 pubmed..Elevated concentration of IL-1 beta was also found in the cerebrospinal fluid and in periventricular areas of rats treated with TCC. ..
- Gerl V, Bohl J, Pitz S, Stoffelns B, Pfeiffer N, Bhakdi S. Extensive deposits of complement C3d and C5b-9 in the choriocapillaris of eyes of patients with diabetic retinopathy. Invest Ophthalmol Vis Sci. 2002;43:1104-8 pubmed..Complement activation at this site may evoke a spectrum of pathologic sequelae that could contribute to ocular tissue disease and visual impairment. ..
- Niculescu F, Niculescu T, Rus H. C5b-9 terminal complement complex assembly on apoptotic cells in human arterial wall with atherosclerosis. Exp Mol Pathol. 2004;76:17-23 pubmed..In conclusion, some apoptotic cells carry C5b-9 deposits, suggesting that complement might be activated by apoptotic cells and involved in the promotion of apoptosis, contributing to the progression of atherosclerotic lesions. ..
- Badea T, Park J, Soane L, Niculescu T, Niculescu F, Rus H, et al. Sublytic terminal complement attack induces c-fos transcriptional activation in myotubes. J Neuroimmunol. 2003;142:58-66 pubmed..We propose that c-fos gene transcription associated with myotube dedifferentiation is induced by C5b-9 through ERK1-mediated assembly of serum response factor-ternary complex. ..
- Zhang J, Gerhardinger C, Lorenzi M. Early complement activation and decreased levels of glycosylphosphatidylinositol-anchored complement inhibitors in human and experimental diabetic retinopathy. Diabetes. 2002;51:3499-504 pubmed..These are novel clues for probing how diabetes affects and damages vascular cells. ..
- Emslie Smith A, Engel A. Necrotizing myopathy with pipestem capillaries, microvascular deposition of the complement membrane attack complex (MAC), and minimal cellular infiltration. Neurology. 1991;41:936-9 pubmed..and a microangiopathy with thick "pipestem" vessels and microvascular deposits of complement membrane attack complex. Quantitative analysis revealed focal capillary depletion...