Restricted accessResearch articleFirst published online 2017-09
Association of Lectin Pathway Protein Levels and Genetic Variants Early after Injury with Outcomes after Severe Traumatic Brain Injury: A Prospective Cohort Study
The lectin pathway of the complement system has been implicated in secondary ischemic/inflammatory injury after traumatic brain injury (TBI). However, previous experimental studies have yielded conflicting results, and human studies are scarce. In this exploratory study, we investigated associations of several lectin pathway proteins early after injury and single-nucleotide polymorphisms (SNP) with outcomes after severe TBI (mortality at 14 days [primary outcome] and consciousness assessed with the Glasgow Coma Scale [GCS] at 14 days, disability assessed with the Glasgow Outcome Scale Extended [GOSE] at 90 days). Forty-four patients with severe TBI were included. Plasma levels of lectin pathway proteins were sampled at 6, 12, 24, and 48 h after injury and eight mannose-binding lectin (MBL) and ficolin (FCN)2 SNPs were analyzed by enzyme-linked immunosorbent assay (ELISA) and genotyping, respectively. Plasma protein levels were stable with only a slight increase in mannose-binding protein-associated serine protease (MASP)-2 and FCN2 levels after 48 h (p < 0.05), respectively. Neither lectin protein plasma levels (6 h or mean levels) nor MBL2 genotypes or FCN2 variant alleles were associated with 14 day mortality or 14 day consciousness. However, FCN2, FCN3, and MASP-2 levels were higher in patients with an unfavorable outcome (GOSE 1–4) at 90 days (p < 0.05), whereas there was no difference in MBL2 genotypes or FCN2 variant alleles. In particular, higher mean MASP-2 levels over 48 h were independently associated with a GOSE score < 4 at 90 days after adjustment (odds ratio 3.46 [95% confidence interval 1.12–10.68] per 100 ng/mL increase, p = 0.03). No association was observed between the lectin pathway of the complement system and 14 day mortality or 14 day consciousness. However, higher plasma FCN2, FCN3, and, in particular, MASP-2 levels early after injury were associated with an unfavorable outcome at 90 days (death, vegetative state, and severe disability) which may be related to an increased activation of the lectin pathway.
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References
1.
van VelzenJ.M., van BennekomC.A., EdelaarM.J., SluiterJ.K., and Frings-DresenM.H. (2009). How many people return to work after acquired brain injury?. A systematic review. Brain Inj., 23, 473–488.
2.
AndriessenT.M., HornJ., FranschmanG., van der NaaltJ., HaitsmaI., JacobsB., SteyerbergE.W., and VosP.E. (2011). Epidemiology, severity classification, and outcome of moderate and severe traumatic brain injury: a prospective multicenter study. J. Neurotrauma, 28, 2019–2031.
3.
MaasA.I., StocchettiN., and BullockR. (2008). Moderate and severe traumatic brain injury in adults. Lancet Neurol. 7, 728–741.
4.
WalderB., HallerG., RebetezM.M., DelhumeauC., BottequinE., SchoettkerP., RavussinP., Brodmann MaederM., StoverJ.F., ZurcherM., HallerA., WackelinA., HaberthurC., FandinoJ., HallerC.S., and OsterwalderJ. (2013). Severe traumatic brain injury in a high-income country: an epidemiological study. J. Neurotrauma, 30, 1934–1942.
5.
SahuquilloJ., PocaM.A., and AmorosS. (2001). Current aspects of pathophysiology and cell dysfunction after severe head injury. Curr. Pharm. Des., 7, 1475–1503.
6.
BrennanF.H., AndersonA.J., TaylorS.M., WoodruffT.M., and RuitenbergM.J. (2012). Complement activation in the injured central nervous system: another dual-edged sword?. J. Neuroinflammation, 9, 137.
7.
VeenithT.V., CarterE.L., GeeraertsT., GrossacJ., NewcombeV.F., OuttrimJ., GeeG.S., LupsonV., SmithR., AigbirhioF.I., FryerT.D., HongY.T., MenonD.K., and ColesJ.P. (2016). Pathophysiologic mechanisms of cerebral ischemia and diffusion hypoxia in traumatic brain injury. JAMA Neurol. 73, 542–550.
8.
BellanderB.M., SinghraoS.K., OhlssonM., MattssonP., and SvenssonM. (2001). Complement activation in the human brain after traumatic head injury. J. Neurotrauma, 18, 1295–1311.
9.
KossmannT., StahelP.F., Morganti–KossmannM.C., JonesJ.L., and BarnumS.R. (1997). Elevated levels of the complement components C3 and factor B in ventricular cerebrospinal fluid of patients with traumatic brain injury. J. Neuroimmunol., 73, 63–69.
10.
StahelP.F., Morganti–KossmannM.C., PerezD., RedaelliC., GloorB., TrentzO., and KossmannT. (2001). 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, 18, 773–781.
11.
EisenD.P., and OsthoffM. (2014). If there is an evolutionary selection pressure for the high frequency of MBL2 polymorphisms, what is it?. Clin. Exp. Immunol., 176, 165–171.
12.
KjaerT.R., ThielS, and AndersenG.R. (2013). Toward a structure-based comprehension of the lectin pathway of complement. Mol. Immunol., 56, 413–422.
13.
SallenbachS., ThielS., AebiC., OtthM., BiglerS., JenseniusJ.C., SchlapbachL.J., and AmmannR.A. (2011). Serum concentrations of lectin-pathway components in healthy neonates, children and adults: mannan-binding lectin (MBL), M-, L-, and H-ficolin, and MBL-associated serine protease-2 (MASP-2). Pediatr. Allergy Immunol., 22, 424–430.
14.
GarredP., LarsenF., SeyfarthJ., FujitaR., and MadsenH.O. (2006). Mannose-binding lectin and its genetic variants. Genes Immun. 7, 85–94.
GarredP., HonoreC., MaY.J., RorvigS., CowlandJ., BorregaardN., and HummelshojT. (2010). The genetics of ficolins. J. Innate Immun., 2, 3–16.
17.
KilpatrickD.C., St SwierzkoA., MatsushitaM., Domzalska–PopadiukI., Borkowska–KlosM., SzczapaJ., and CedzynskiM. (2013). The relationship between FCN2 genotypes and serum ficolin-2 (L-ficolin) protein concentrations from a large cohort of neonates. Hum. Immunol., 74, 867–871.
18.
DegnS.E., JenseniusJ.C., and ThielS. (2011). Disease-causing mutations in genes of the complement system. Am. J. Hum. Genet., 88, 689–705.
19.
KurayaM., MingZ., LiuX., MatsushitaM., and FujitaT. (2005). Specific binding of L-ficolin and H-ficolin to apoptotic cells leads to complement activation. Immunobiology, 209, 689–697.
20.
OgdenC.A., deCathelineauA., HoffmannP.R., BrattonD., GhebrehiwetB., FadokV.A., and HensonP.M. (2001). C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J. Exp. Med., 194, 781–795.
21.
LonghiL., OrsiniF., De BlasioD., FumagalliS., OrtolanoF., LocatelliM., StocchettiN., and De SimoniM.G. (2014). Mannose-binding lectin is expressed after clinical and experimental traumatic brain injury and its deletion is protective. Crit. Care Med., 42, 1910–1918.
22.
YagerP.H., YouZ., QinT., KimH.H., TakahashiK., EzekowitzA.B., StahlG.L., CarrollM.C., and WhalenM.J. (2008). Mannose binding lectin gene deficiency increases susceptibility to traumatic brain injury in mice. J. Cereb. Blood Flow Metab., 28, 1030–1039.
23.
OrsiniF., VillaP., ParrellaS., ZangariR., ZanierE.R., GesueteR., StravalaciM., FumagalliS., OttriaR., ReinaJ.J., PaladiniA., MicottiE., Ribeiro–VianaR., RojoJ., PavlovV.I., StahlG.L., BernardiA., GobbiM., and De SimoniM.G. (2012). Targeting mannose-binding lectin confers long-lasting protection with a surprisingly wide therapeutic window in cerebral ischemia. Circulation, 126, 1484–1494.
24.
van der PolP., SchlagweinN., van GijlswijkD.J., BergerS.P., RoosA., BajemaI.M., de BoerH.C., de FijterJ.W., StahlG.L., DahaM.R., and van KootenC. (2012). Mannan-binding lectin mediates renal ischemia/reperfusion injury independent of complement activation. Am. J. Transplant., 12, 877–887.
25.
La BonteL.R., PavlovV.I., TanY.S., TakahashiK., TakahashiM., BandaN.K., ZouC., FujitaT., and StahlG.L. (2012). Mannose-binding lectin-associated serine protease-1 is a significant contributor to coagulation in a murine model of occlusive thrombosis. J. Immunol., 188, 885–891.
26.
PanJ.W., GaoX.W., JiangH., LiY.F., XiaoF., and ZhanR.Y. (2015). Low serum ficolin-3 levels are associated with severity and poor outcome in traumatic brain injury. J. Neuroinflammation, 12, 226.
27.
YuW., LeH.W., LuY.G., HuJ.A., YuJ.B., WangM., and ShenW. (2015). High levels of serum mannose-binding lectins are associated with the severity and clinical outcomes of severe traumatic brain injury. Clin. Chim. Acta, 451, 111–116.
28.
WalderB., RobinX., RebetezM.M., CopinJ.C., GascheY., SanchezJ.C., and TurckN. (2013). The prognostic significance of the serum biomarker heart-fatty acidic binding protein in comparison with s100b in severe traumatic brain injury. J. Neurotrauma, 30, 1631–1637.
29.
WilsonJ.T., EdwardsP., FiddesH., StewartE., and TeasdaleG.M. (2002). Reliability of postal questionnaires for the Glasgow Outcome Scale. J. Neurotrauma, 19, 999–1005.
30.
WrightD.W., YeattsS.D., SilbergleitR., PaleschY.Y., HertzbergV.S., FrankelM., GoldsteinF.C., CaveneyA.F., Howlett–SmithH., BengelinkE.M., ManleyG.T., MerckL.H., JanisL.S., BarsanW.G., and InvestigatorsN. (2014). Very early administration of progesterone for acute traumatic brain injury. N. Engl. J. Med., 371, 2457–2466.
31.
EisenD.P., DeanM.M., ThomasP., MarshallP., GernsN., HeatleyS., QuinnJ., MinchintonR.M., and LipmanJ. (2006). Low mannose-binding lectin function is associated with sepsis in adult patients. FEMS Immunol. Med. Microbiol., 48, 274–282.
32.
MinchintonR.M., DeanM.M., ClarkT.R., HeatleyS., and MullighanC.G. (2002). Analysis of the relationship between mannose-binding lectin (MBL) genotype, MBL levels and function in an Australian blood donor population. Scand. J. Immunol., 56, 630–641.
33.
EisenD.P., DeanM.M., BoermeesterM.A., FidlerK.J., GordonA.C., KronborgG., KunJ.F., LauY.L., PayerasA., ValdimarssonH., BrettS.J., IpW.K., MilaJ., PetersM.J., SaevarsdottirS., van TillJ.W., HindsC.J., and McBrydeE.S. (2008). Low serum mannose-binding lectin level increases the risk of death due to pneumococcal infection. Clin. Infect. Dis., 47, 510–516.
34.
OsthoffM., DeanM.M., BairdP.N., RichardsonA.J., DaniellM., GuymerR.H., and EisenD.P. (2015). Association study of mannose-binding lectin levels and genetic variants in lectin pathway proteins with susceptibility to age-related macular degeneration: a case-control study. PLoS One, 10, e0134107.
35.
OsthoffM., KatanM., FluriF., SchuetzP., BingisserR., KapposL., SteckA.J., EngelterS.T., MuellerB., Christ-CrainM., and TrendelenburgM. (2011). Mannose-binding lectin deficiency is associated with smaller infarction size and favorable outcome in ischemic stroke patients. PLoS One, 6, e21338.
36.
TrendelenburgM., TherouxP., StebbinsA., GrangerC., ArmstrongP., and PfistererM. (2010). Influence of functional deficiency of complement mannose-binding lectin on outcome of patients with acute ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Eur. Heart J., 31, 1181–1187.
37.
CerveraA., PlanasA.M., JusticiaC., UrraX., JenseniusJ.C., TorresF., LozanoF., and ChamorroA. (2010). Genetically-defined deficiency of mannose-binding lectin is associated with protection after experimental stroke in mice and outcome in human stroke. PLoS One, 5, e8433.
38.
WalshM.C., BourcierT., TakahashiK., ShiL., BuscheM.N., RotherR.P., SolomonS.D., EzekowitzR.A., and StahlG.L. (2005). Mannose-binding lectin is a regulator of inflammation that accompanies myocardial ischemia and reperfusion injury. J. Immunol., 175, 541–546.
39.
RahpeymaiY., HietalaM.A., WilhelmssonU., FotheringhamA., DaviesI., NilssonA.K., ZwirnerJ., WetselR.A., GerardC., PeknyM., and PeknaM. (2006). Complement: a novel factor in basal and ischemia-induced neurogenesis. EMBO J. 25, 1364–1374.
40.
OsthoffM., Au YongH.M., DeanM.M., and EisenD.P. (2013). Significance of mannose-binding lectin deficiency and nucleotide-binding oligomerization domain 2 polymorphisms in Staphylococcus aureus bloodstream infections: a case-control study. PLoS One, 8, e76218.
41.
OsthoffM., NgianG.S., DeanM.M., NikpourM., StevensW., ProudmanS., EisenD.P., and SahharJ. (2014). Potential role of the lectin pathway of complement in the pathogenesis and disease manifestations of systemic sclerosis: a case-control and cohort study. Arthritis Res. Ther., 16, 480.
42.
ZangariR., ZanierE.R., TorganoG., BersanoA., BerettaS., BeghiE., CasollaB., CheccarelliN., LanfranconiS., MainoA., MandelliC., MicieliG., OrziF., PicettiE., SilvestriniM., StocchettiN., ZeccaB., GarredP., De SimoniM.G., LEPAS group. (2016). Early ficolin-1 is a sensitive prognostic marker for functional outcome in ischemic stroke. J. Neuroinflammation, 13, 16.
43.
FustG., Munthe–FogL., IllesZ., SzeplakiG., MolnarT., PuschG., HirschbergK., SzegediR., SzeplakiZ., ProhaszkaZ., SkjoedtM.O., and GarredP. (2011). Low ficolin-3 levels in early follow-up serum samples are associated with the severity and unfavorable outcome of acute ischemic stroke. J. Neuroinflammation, 8, 185.
44.
FrauenknechtV., ThielS., StormL., MeierN., ArnoldM., SchmidJ.P., SanerH., and SchroederV. (2013). Plasma levels of mannan-binding lectin (MBL)-associated serine proteases (MASPs) and MBL-associated protein in cardio- and cerebrovascular diseases. Clin. Exp. Immunol., 173, 112–120.
45.
ZanierE.R., ZangariR., Munthe–FogL., HeinE., ZoerleT., ConteV., OrsiniF., TettamantiM., StocchettiN., GarredP., and De SimoniM.G. (2014). Ficolin-3-mediated lectin complement pathway activation in patients with subarachnoid hemorrhage. Neurology, 82, 126–134.
46.
KozarcaninH., LoodC., Munthe–FogL., SandholmK., HamadO.A., BengtssonA.A., SkjoedtM.O., Huber–LangM., GarredP., EkdahlK.N., and NilssonB. (2016). The lectin complement pathway serine proteases (MASPs) represent a possible crossroad between the coagulation and complement systems in thromboinflammation. J. Thromb. Haemost., 14, 531–545.
47.
De BlasioD., FumagalliS., LonghiL., OrsiniF., PalmioliA., StravalaciM., VeglianteG., ZanierE.R., BernardiA., GobbiM., and De SimoniM.G. (2016). Pharmacological inhibition of mannose-binding lectin ameliorates neurobehavioral dysfunction following experimental traumatic brain injury. J Cereb Blood Flow Metab. 37, 938–950.
48.
LonghiL., PeregoC., OrtolanoF., ZanierE.R., BianchiP., StocchettiN., McIntoshT.K., and De SimoniM.G. (2009). C1-inhibitor attenuates neurobehavioral deficits and reduces contusion volume after controlled cortical impact brain injury in mice. Crit. Care Med., 37, 659–665.
49.
AmbrusG., GalP., KojimaM., SzilagyiK., BalczerJ., AntalJ., GrafL., LaichA., MoffattB.E., SchwaebleW., SimR.B., and ZavodszkyP. (2003). Natural substrates and inhibitors of mannan-binding lectin-associated serine protease-1 and -2: a study on recombinant catalytic fragments. J. Immunol., 170, 1374–1382.
50.
BeinrohrL., DoboJ., ZavodszkyP., and GalP. (2008). C1, MBL-MASPs and C1-inhibitor: novel approaches for targeting complement-mediated inflammation. Trends Mol. Med., 14, 511–521.
51.
GesueteR., StoriniC., FantinA., StravalaciM., ZanierE.R., OrsiniF., VietschH., MannesseM.L., ZiereB., GobbiM., and De SimoniM.G. (2009). Recombinant C1 inhibitor in brain ischemic injury. Ann. Neurol., 66, 332–342.
52.
FadenA.I., and StoicaB. (2007). Neuroprotection: challenges and opportunities. Arch. Neurol., 64, 794–800.
53.
CaiS., DoleV.S., BergmeierW., ScafidiJ., FengH., WagnerD.D., and DavisA.E., 3rd (2005). A direct role for C1 inhibitor in regulation of leukocyte adhesion. J. Immunol. 174, 6462–6466.
