mannose binding lectin complement pathway

Summary

Summary: Complement activation triggered by the interaction of microbial POLYSACCHARIDES with serum MANNOSE-BINDING LECTIN resulting in the activation of MANNOSE-BINDING PROTEIN-ASSOCIATED SERINE PROTEASES. As in the classical pathway, MASPs cleave COMPLEMENT C4 and COMPLEMENT C2 to form C3 CONVERTASE (C4B2A) and the subsequent C5 CONVERTASE (C4B2A3B) leading to cleavage of COMPLEMENT C5 and assembly of COMPLEMENT MEMBRANE ATTACK COMPLEX.

Top Publications

  1. Hajela K, Kojima M, Ambrus G, Wong K, Moffatt B, Ferluga J, et al. The biological functions of MBL-associated serine proteases (MASPs). Immunobiology. 2002;205:467-75 pubmed
    ..These reactions are also relevant to defence against microorganisms, and may represent a biologically significant action of MASP1. ..
  2. Seelen M, Roos A, Wieslander J, Mollnes T, Sjoholm A, Wurzner R, et al. Functional analysis of the classical, alternative, and MBL pathways of the complement system: standardization and validation of a simple ELISA. J Immunol Methods. 2005;296:187-98 pubmed
    ..The results demonstrate the value of these ELISA-based procedures for the functional assessment of complement deficiencies in clinical practice. The assay is now available commercially in kit form. ..
  3. Hart M, Ceonzo K, Shaffer L, Takahashi K, Rother R, Reenstra W, et al. Gastrointestinal ischemia-reperfusion injury is lectin complement pathway dependent without involving C1q. J Immunol. 2005;174:6373-80 pubmed
    ..These data demonstrate that C2 and MBL, but not C1q, are necessary for gut injury after GI/R. Lung injury in mice after GI/R is MBL and C1q independent, but C2 dependent, suggesting a potential role for ficolins in this model. ..
  4. Brown K, Keogh M, Tagiuri N, Grainge M, Presanis J, Ryder S, et al. Severe fibrosis in hepatitis C virus-infected patients is associated with increased activity of the mannan-binding lectin (MBL)/MBL-associated serine protease 1 (MASP-1) complex. Clin Exp Immunol. 2007;147:90-8 pubmed
    ..The potential role of MBL/MASP-1 complex activity in disease progression is worthy of further study to investigate possible mechanistic links. ..
  5. Thiel S, Møller Kristensen M, Jensen L, Jensenius J. Assays for the functional activity of the mannan-binding lectin pathway of complement activation. Immunobiology. 2002;205:446-54 pubmed
    ..In parallel we determine the MBL concentration in the sample. As predicted a very high correlation is observed between the results of the two assays. ..
  6. Takahashi M, Iwaki D, Kanno K, Ishida Y, Xiong J, Matsushita M, et al. Mannose-binding lectin (MBL)-associated serine protease (MASP)-1 contributes to activation of the lectin complement pathway. J Immunol. 2008;180:6132-8 pubmed
    ..From these results, we propose that MASP-1 contributes to the activation of the lectin pathway, probably through the activation of MASP-2. ..
  7. Stengaard Pedersen K, Thiel S, Gadjeva M, Møller Kristensen M, Sørensen R, Jensen L, et al. Inherited deficiency of mannan-binding lectin-associated serine protease 2. N Engl J Med. 2003;349:554-60 pubmed
  8. Ng P, Le Saux A, Lee C, Tan N, Lu J, Thiel S, et al. C-reactive protein collaborates with plasma lectins to boost immune response against bacteria. EMBO J. 2007;26:3431-40 pubmed
    ..We propose that CRP does not act alone but collaborates with other plasma PRRs to form stable pathogen recognition complexes when targeting a wide range of bacteria for destruction...
  9. Ma Y, Cho M, Zhao M, Park J, Matsushita M, Fujita T, et al. Human mannose-binding lectin and L-ficolin function as specific pattern recognition proteins in the lectin activation pathway of complement. J Biol Chem. 2004;279:25307-12 pubmed
    ..These results indicate that human PGN and 1,3-beta-D-glucan recognition proteins function as complement-activating lectins. ..

More Information

Publications62

  1. Fujita T, Matsushita M, Endo Y. The lectin-complement pathway--its role in innate immunity and evolution. Immunol Rev. 2004;198:185-202 pubmed
    ..Based on these findings, it seems likely that the complement system played a pivotal role in innate immunity before the evolution of an acquired immune system in jawed vertebrates. ..
  2. Iwaki D, Kanno K, Takahashi M, Endo Y, Lynch N, Schwaeble W, et al. Small mannose-binding lectin-associated protein plays a regulatory role in the lectin complement pathway. J Immunol. 2006;177:8626-32 pubmed
    ..Therefore, MASP-2 is essential for the activation of C4 and sMAP plays a regulatory role in the activation of the lectin pathway. ..
  3. Kocsis A, Kekesi K, Szasz R, Végh B, Balczer J, Dobó J, et al. Selective inhibition of the lectin pathway of complement with phage display selected peptides against mannose-binding lectin-associated serine protease (MASP)-1 and -2: significant contribution of MASP-1 to lectin pathway activation. J Immunol. 2010;185:4169-78 pubmed publisher
    ..Because the lectin pathway has been implicated in several life-threatening pathological states, these inhibitors should be considered as lead compounds toward developing lectin pathway blocking therapeutics. ..
  4. Manuel O, Tarr P, Venetz J, Trendelenburg M, Meylan P, Pascual M. Meningococcal disease in a kidney transplant recipient with mannose-binding lectin deficiency. Transpl Infect Dis. 2007;9:214-8 pubmed
    ..To our knowledge, this is the first report of meningococcal disease after organ transplantation in a patient with MBL deficiency. ..
  5. Tacx A, Groeneveld A, Hart M, Aarden L, Hack C. Mannan binding lectin in febrile adults: no correlation with microbial infection and complement activation. J Clin Pathol. 2003;56:956-9 pubmed
    ..The results argue against a predominant role for the MBL pathway of complement activation and a deficiency of MBL predisposing to serious and invasive microbial infection in non-selected adults. ..
  6. Walsh M, Shaffer L, Guikema B, Body S, Shernan S, Fox A, et al. Fluorochrome-linked immunoassay for functional analysis of the mannose binding lectin complement pathway to the level of C3 cleavage. J Immunol Methods. 2007;323:147-59 pubmed
    ..The FLISA can be used potentially to identify specific human disease correlations between these components and clinical outcomes in already established databases. ..
  7. Presanis J, Kojima M, Sim R. Biochemistry and genetics of mannan-binding lectin (MBL). Biochem Soc Trans. 2003;31:748-52 pubmed
    ..Many studies demonstrate that MBL deficiency is associated with susceptibility to a range of infectious and inflammatory diseases. ..
  8. Ma B, Nakamura N, Dlabac V, Naito H, Yamaguchi S, Ishikawa M, et al. Isolation, cloning, and characterization of a novel phosphomannan-binding lectin from porcine serum. J Biol Chem. 2007;282:12963-75 pubmed
  9. Linton N, Wessels J, Cnossen S, Croy B, Tayade C. Immunological mechanisms affecting angiogenesis and their relation to porcine pregnancy success. Immunol Invest. 2008;37:611-29 pubmed publisher
    ..Together, these components of the immune system could regulate lymphocyte- and non-lymphocyte-promoted endometrial angiogenesis to determine conceptus survival. ..
  10. Hamad I, Hunter A, Szebeni J, Moghimi S. Poly(ethylene glycol)s generate complement activation products in human serum through increased alternative pathway turnover and a MASP-2-dependent process. Mol Immunol. 2008;46:225-32 pubmed publisher
  11. Dumestre Pérard C, Lamy B, Aldebert D, Lemaire Vieille C, Grillot R, Brion J, et al. Aspergillus conidia activate the complement by the mannan-binding lectin C2 bypass mechanism. J Immunol. 2008;181:7100-5 pubmed
    ..Finally, a stronger activation of the alternative pathway was observed for the clinical strains isolated from patients with invasive aspergillosis, compared with the environmental strains. ..
  12. Hisano S, Matsushita M, Fujita T, Iwasaki H. Activation of the lectin complement pathway in Henoch-Schönlein purpura nephritis. Am J Kidney Dis. 2005;45:295-302 pubmed
    ..Complement activation through the lectin pathway may contribute to the development of advanced glomerular injuries and prolonged urinary abnormalities in patients with HSPN. ..
  13. Kerr F, Thomas A, Wijeyewickrema L, Whisstock J, Boyd S, Kaiserman D, et al. Elucidation of the substrate specificity of the MASP-2 protease of the lectin complement pathway and identification of the enzyme as a major physiological target of the serpin, C1-inhibitor. Mol Immunol. 2008;45:670-7 pubmed
    ..C1-inhibitor inhibited MASP-2 50-fold faster than C1s and much faster than any other protease tested to date, implying that MASP-2 is a major physiological target of C1-inhibitor. ..
  14. Kuipers S, Aerts P, Cluysenaer O, Bartelink A, Ezekowitz R, Bax W, et al. A case of familial meningococcal disease due to deficiency in mannose-binding lectin (MBL). Adv Exp Med Biol. 2003;531:351-5 pubmed
  15. Cedzynski M, Madalinski K, Gregorek H, Swierzko A, Nowicka E, Obtułowicz K, et al. Possible disease-modifying factors: the mannan-binding lectin pathway and infections in hereditary angioedema of children and adults. Arch Immunol Ther Exp (Warsz). 2008;56:69-75 pubmed publisher
    ..These results suggest that the MBL complement activation pathway itself does not contribute to the frequency of angioedema attacks. Infections with H. pylori and HBV may slightly influence the disease score (not significant). ..
  16. Varga L, Széplaki G, Laki J, Kocsis A, Kristof K, Gal P, et al. Depressed activation of the lectin pathway of complement in hereditary angioedema. Clin Exp Immunol. 2008;153:68-74 pubmed publisher
    ..0001) in healthy controls, but there was no significant correlation in the HAE patients. We conclude that the activation of LP might also occur in subjects with C1INH deficiency, which is reflected by the low MASP-2 and C4 levels. ..
  17. Chan R, Ibrahim S, Takahashi K, Kwon E, McCormack M, Ezekowitz A, et al. The differing roles of the classical and mannose-binding lectin complement pathways in the events following skeletal muscle ischemia-reperfusion. J Immunol. 2006;177:8080-5 pubmed
    ..Thus, the activation of both pathways is likely responsible for the full spectrum of injuries observed after skeletal muscle reperfusion injury. ..
  18. Zhang M, Takahashi K, Alicot E, Vorup Jensen T, Kessler B, Thiel S, et al. Activation of the lectin pathway by natural IgM in a model of ischemia/reperfusion injury. J Immunol. 2006;177:4727-34 pubmed
    ..The results reveal that IgM binds initially to ischemic Ag providing a binding site for mannan-binding lectin which subsequently leads to activation of complement and injury. ..
  19. Brouwer N, Dolman K, van Zwieten R, Nieuwenhuys E, Hart M, Aarden L, et al. Mannan-binding lectin (MBL)-mediated opsonization is enhanced by the alternative pathway amplification loop. Mol Immunol. 2006;43:2051-60 pubmed
    ..In conclusion, our data demonstrate that the MBL-mediated route of complement activation depends on the alternative pathway amplification loop for optimal opsonization of zymosan. ..
  20. Petersen T, Møller Larsen A, Thiel S, Brudek T, Hansen T, Christensen T. Effects of interferon-beta therapy on innate and adaptive immune responses to the human endogenous retroviruses HERV-H and HERV-W, cytokine production, and the lectin complement activation pathway in multiple sclerosis. J Neuroimmunol. 2009;215:108-16 pubmed publisher
    ..We found no overall changes in Th1/Th2 ratios. Our results support that HERV-H/HERV-W and the antiviral immune response may play a role in MS development, and that these HERVs have potential as biomarkers for disease activity. ..
  21. Evans Osses I, Ansa Addo E, Inal J, Ramirez M. Involvement of lectin pathway activation in the complement killing of Giardia intestinalis. Biochem Biophys Res Commun. 2010;395:382-6 pubmed publisher
    ..Our finding provides insight into the role of lectin pathway in the control of G. intestinalis and about the nature of surface components of parasite. ..
  22. Zhang J, Koh J, Lu J, Thiel S, Leong B, Sethi S, et al. Local inflammation induces complement crosstalk which amplifies the antimicrobial response. PLoS Pathog. 2009;5:e1000282 pubmed publisher
    ..Our findings provide new insights into the host immune response to P. aeruginosa infection under pathological conditions and the potential development of new therapeutic strategies against bacterial infection. ..
  23. Li J, Qi H, Tuzun E, Allman W, Yilmaz V, Saini S, et al. Mannose-binding lectin pathway is not involved in myasthenia gravis pathogenesis. J Neuroimmunol. 2009;208:40-5 pubmed publisher
    ..Moreover, no significant difference was observed between the serum MBL levels of 77 anti-AChR antibody positive generalized MG patients and 105 healthy controls. Therefore, MBL pathway does not play a role in EAMG/MG pathogenesis. ..
  24. Mayilyan K, Weinberger D, Sim R. The complement system in schizophrenia. Drug News Perspect. 2008;21:200-10 pubmed publisher
  25. Endo Y, Nakazawa N, Iwaki D, Takahashi M, Matsushita M, Fujita T. Interactions of ficolin and mannose-binding lectin with fibrinogen/fibrin augment the lectin complement pathway. J Innate Immun. 2010;2:33-42 pubmed publisher
    ..Therefore, it is suggested that the lectin pathway collaborates with the coagulation system in the first-line host defense against pathogens under conditions such as injury and inflammation. ..
  26. Roos A, Daha M, van Pelt J, Berger S. Mannose-binding lectin and the kidney. Nephrol Dial Transplant. 2007;22:3370-7 pubmed
  27. Norup L, Juul Madsen H. An assay for measuring the mannan-binding lectin pathway of complement activation in chickens. Poult Sci. 2007;86:2322-6 pubmed
    ..8549, P < 0.0001). There was no difference in C4 deposition among sera from the chicken lines when calculated as C4 deposition relative to the cMBL concentration. ..
  28. Garred P, Honore C, Ma Y, Munthe Fog L, Hummelshøj T. MBL2, FCN1, FCN2 and FCN3-The genes behind the initiation of the lectin pathway of complement. Mol Immunol. 2009;46:2737-44 pubmed publisher
    ..This overview will summarize the current molecular knowledge of the human MBL2, FCN1, FCN2 and FCN3 genes. ..
  29. Pertyńska Marczewska M, Cedzynski M, Swierzko A, Szala A, Sobczak M, Cypryk K, et al. Evaluation of lectin pathway activity and mannan-binding lectin levels in the course of pregnancy complicated by diabetes type 1, based on the genetic background. Arch Immunol Ther Exp (Warsz). 2009;57:221-8 pubmed publisher
    ..Therefore, determination of MBL status might be beneficial in identifying type 1 diabetic patients who are at increased risk of developing both vascular complications and poor pregnancy outcomes. ..
  30. Wang X, Saito J, Tanino Y, Ishida T, Fujita T, Munakata M. Mannose binding lectin gene polymorphisms and asthma. Clin Exp Allergy. 2007;37:1334-9 pubmed
    ..Although plasma MBL levels depend on the MBL2 polymorphisms, these polymorphisms and plasma MBL levels are not associated with the asthma phenotype. ..
  31. Juul Madsen H, Norup L, Handberg K, Jørgensen P. Mannan-binding lectin (MBL) serum concentration in relation to propagation of infectious bronchitis virus (IBV) in chickens. Viral Immunol. 2007;20:562-70 pubmed
    ..Results suggested that MBL plays a role in the innate immunity against IBV in the way that it performs an acute phase response, is able to activate complement, and inhibits the propagation of the virus in the trachea. ..
  32. Granell M, Urbano Ispizua A, Suarez B, Rovira M, Fernandez Aviles F, Martinez C, et al. Mannan-binding lectin pathway deficiencies and invasive fungal infections following allogeneic stem cell transplantation. Exp Hematol. 2006;34:1435-41 pubmed
    ..8, p = 0.02) retained independent prognostic value. These results show for the first time that polymorphisms responsible for not only MBL but also MASP-2 deficiency are independent predictive factors for IFI after allo-SCT. ..
  33. Harboe M, Garred P, Borgen M, Stahl G, Roos A, Mollnes T. Design of a complement mannose-binding lectin pathway-specific activation system applicable at low serum dilutions. Clin Exp Immunol. 2006;144:512-20 pubmed
    ..Thus, this assay is unique in being LP-specific at low serum dilution and thus particularly suitable to study LP activation mechanisms and the role of AP amplification under physiological conditions. ..
  34. Weber R. A Christmas 'complement' Carol. Dermatol Nurs. 2005;17:468 pubmed
  35. Wallis R, Lynch N, Roscher S, Reid K, Schwaeble W. Decoupling of carbohydrate binding and MASP-2 autoactivation in variant mannose-binding lectins associated with immunodeficiency. J Immunol. 2005;175:6846-51 pubmed
    ..Analogous molecular defects in human MBL probably combine to create the mutant phenotypes of immunodeficient individuals. ..
  36. Lozano F, Suarez B, Munoz A, Jensenius J, Mensa J, Vives J, et al. Novel MASP2 variants detected among North African and Sub-Saharan individuals. Tissue Antigens. 2005;66:131-5 pubmed
    ..5%). As reported for MBL2, the marked geographic distribution of the new MASP2 variants may represent an evolutionary adaptation to different environments. ..
  37. Rawal N, Rajagopalan R, Salvi V. Activation of complement component C5: comparison of C5 convertases of the lectin pathway and the classical pathway of complement. J Biol Chem. 2008;283:7853-63 pubmed publisher
  38. Bugla Płoskońska G, Cisowska A, Karpinska K, Jankowski S, Doroszkiewicz W. The mechanisms of activation of normal human serum complement by Escherichia coli strains with K1 surface antigen. Folia Microbiol (Praha). 2006;51:627-32 pubmed
    ..Important role of alternative pathway activation in the bactericidal action of NHS against E. coli K1 strains independent of the classical and lectin pathways was not established. ..
  39. Lynch N, Khan S, Stover C, Sandrini S, Marston D, Presanis J, et al. Composition of the lectin pathway of complement in Gallus gallus: absence of mannan-binding lectin-associated serine protease-1 in birds. J Immunol. 2005;174:4998-5006 pubmed
    ..Despite the lack of MASP-1-like enzymatic activity in sera of chicken and other birds, avian lectin pathway complexes efficiently activate C4. ..
  40. Eisen D, Stubbs J, Spilsbury D, Carnie J, Leydon J, Howden B. Low mannose-binding lectin complement activation function is associated with predisposition to Legionnaires' disease. Clin Exp Immunol. 2007;149:97-102 pubmed
    ..There was no significant interval change in MBL function or level after a mean of 46 days. MBL complement activation functional deficiency appears to predispose to Legionnaires' disease. ..
  41. Walsh M, Bourcier T, Takahashi K, Shi L, Busche M, Rother R, et al. Mannose-binding lectin is a regulator of inflammation that accompanies myocardial ischemia and reperfusion injury. J Immunol. 2005;175:541-6 pubmed
    ..MBL is an example of a pattern recognition molecule that plays a dual role in modifying inflammatory responses to sterile and infectious injury. ..
  42. Ip W, Lau Y. Role of mannose-binding lectin in the innate defense against Candida albicans: enhancement of complement activation, but lack of opsonic function, in phagocytosis by human dendritic cells. J Infect Dis. 2004;190:632-40 pubmed
    ..albicans without the need for opsonophagocytosis by DCs, in which a direct interaction of MBL with C. albicans results in agglutination and accelerated complement activation via the lectin pathway, leading to inhibition of growth. ..
  43. Banda N, Levitt B, Wood A, Takahashi K, Stahl G, Holers V, et al. Complement activation pathways in murine immune complex-induced arthritis and in C3a and C5a generation in vitro. Clin Exp Immunol. 2010;159:100-8 pubmed publisher
    ..We conclude that neither the CP nor LP alone is capable of mediating CAIA in vivo and that mouse sera exhibits a high level of IgG-induced C5a generation in vitro through either the CP or AP. ..
  44. Møller Kristensen M, Thiel S, Hansen A, Jensenius J. On the site of C4 deposition upon complement activation via the mannan-binding lectin pathway or the classical pathway. Scand J Immunol. 2003;57:556-61 pubmed
    ..More than 99% of deposited C4b was bound directly to the solid phase rather than to the initiator complex. Our approach cannot answer the question of the whereabouts of the C2 when it is cleaved. ..
  45. Hummelshoj T, Fog L, Madsen H, Sim R, Garred P. Comparative study of the human ficolins reveals unique features of Ficolin-3 (Hakata antigen). Mol Immunol. 2008;45:1623-32 pubmed
    ..Moreover, Ficolin-3 has a high complement activating potential and is the only collagenase proteolytic resistant molecule among the lectin complement pathway initiators. ..
  46. Matsushita M. Ficolins: complement-activating lectins involved in innate immunity. J Innate Immun. 2010;2:24-32 pubmed publisher
    ..Thus, serum ficolins play an important role in innate immunity. ..
  47. Avirutnan P, Fuchs A, Hauhart R, Somnuke P, Youn S, Diamond M, et al. Antagonism of the complement component C4 by flavivirus nonstructural protein NS1. J Exp Med. 2010;207:793-806 pubmed publisher
    ..Through this mechanism, NS1 protects DENV from complement-dependent neutralization in solution. These studies define a novel immune evasion mechanism for restricting complement control of microbial infection...
  48. Mayilyan K, Arnold J, Presanis J, Soghoyan A, Sim R. Increased complement classical and mannan-binding lectin pathway activities in schizophrenia. Neurosci Lett. 2006;404:336-41 pubmed
    ..01). The increase was accompanied by increased CH50 (P<0.02) and C4 CH50 (P<0.02). Our results support the idea that complement system alterations may be involved in schizophrenia. ..
  49. Garcia Laorden M, Garcia Saavedra A, de Castro F, Violán J, Rajas O, Blanquer J, et al. Low clinical penetrance of mannose-binding lectin-associated serine protease 2 deficiency. J Allergy Clin Immunol. 2006;118:1383-6 pubmed
  50. Sagedal S, Thiel S, Hansen T, Mollnes T, Rollag H, Hartmann A. Impact of the complement lectin pathway on cytomegalovirus disease early after kidney transplantation. Nephrol Dial Transplant. 2008;23:4054-60 pubmed publisher
    ..However, low MASP-2 levels may play a role in the development of symptomatic CMV disease. ..
  51. Gadjeva M, Thiel S, Jensenius J. Assays for the mannan-binding lectin pathway. Curr Protoc Immunol. 2004;Chapter 13:Unit 13.6 pubmed publisher
    ..The unit also includes an MBL/MASP complex activity assay to evaluate MBL activity in serum or plasma samples, which allows for the measurement of the specific activity of the MBL pathway. ..
  52. Popadiak K, Potempa J, Riesbeck K, Blom A. Biphasic effect of gingipains from Porphyromonas gingivalis on the human complement system. J Immunol. 2007;178:7242-50 pubmed
    ..At later stages of infection the concentration of proteases is high enough to destroy complement factors and thus render the bacteria resistant to the bactericidal activity of complement. ..
  53. Lee H, Green D, Lai L, Hou Y, Jensenius J, Liu D, et al. Early complement factors in the local tissue immunocomplex generated during intestinal ischemia/reperfusion injury. Mol Immunol. 2010;47:972-81 pubmed publisher
    ..Furthermore, the classical complement pathway also appears to interact with the of nIgM-ischemic antigen immunocomplex. Finally, the alternative complement pathway is not involved in I/R injury induction in the current intestinal model. ..