Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Evolution of the lectin–complement pathway and its role in innate immunity

Nature Reviews Immunology volume 2, pages 346–353 (2002)Cite this article

Key Points

  • Lectins, which are carbohydrate-binding proteins, are important in innate immunity because they are able to recognize a wide range of pathogens. Two classes of collagenous lectin — mannose-binding lectin (MBL) and ficolins — can activate the complement system, which was identified originally as an antibody-dependent effector system.

  • The complement system, which consists of more than 30 plasma and cell-surface proteins, is activated by three pathways — the classical, lectin and alternative pathways — which lead to the generation of opsonins and pathogen destruction.

  • The classical pathway is activated by binding of the first complement component — which consists of C1q and two serine proteases (C1r and C1s) — to immune complexes, whereas the lectin pathway is activated by the recognition of carbohydrates on pathogens through MBL and ficolins, which are associated with novel serine proteases.

  • MBL-associated serine proteases (MASPs), which share domain structure and several functions with the classical-pathway proteases C1r and C1s, are the proteolytic enzymes that are responsible for activation of the lectin pathway.

  • The ascidian complement system — which consists of MBL-like lectin, ficolins, two MASPs, C3 and C3 receptor — functions in an opsonic manner, and it constitutes a primordial complement system that corresponds to the mammalian lectin pathway.

  • Structural and functional similarities between the lectin–protease complex in the lectin pathway and the first component of the classical complement pathway indicate that the primitive lectin pathway in innate immunity might have evolved into the classical pathway to serve as an effector system of acquired immunity.

Abstract

Discrimination between self and non-self by lectins (carbohydrate-binding proteins) is a strategy of innate immunity that is found in both vertebrates and invertebrates. In vertebrates, immune recognition mediated by ficolins (lectins that consist of a fibrinogen-like and a collagen-like domain), as well as by mannose-binding lectins, triggers the activation of the complement system, which results in the activation of novel serine proteases. The presence of a similar lectin-based complement system in ascidians, our closest invertebrate relatives, indicates that the complement system probably had a pivotal role in innate immunity before the evolution of an adaptive immune system in jawed vertebrates.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Activation of the classical, lectin and alternative pathways.
Figure 2: Domain and oligomeric structure of mannose-binding lectin and ficolins.
Figure 3: The complement system from an evolutionary perspective.
Figure 4: Domain structure of the MASP family.
Figure 5: Gene organization of the MASP family.
Figure 6: Putative model of an ancient lectin-based complement system and its evolution.

Similar content being viewed by others

References

  1. Hoffmann, J. A., Kafatos, F. C., Janeway, C. A. & Ezekowitz, R. A. Phylogenetic perspectives in innate immunity. Science 284, 1313–1318 (1999).

    CAS  PubMed  Google Scholar 

  2. Medzhitov, R. & Janeway, C. Jr. Innate immune recognition: mechanisms and pathways. Immunol. Rev. 173, 89–97 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Walport, M. J. Complement. First of two parts. N. Engl. J. Med. 344, 1058–1066 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Walport, M. J. Complement. Second of two parts. N. Engl. J. Med. 344, 1140–1144 (2001).References 3 and 4 provide an excellent review of the complement system. They focus on recent advances in the role of complement in disease, and the interaction between innate and adaptive immunity.

    Article  CAS  PubMed  Google Scholar 

  5. Kishore, U. & Reid, K. B. C1q: structure, function and receptors. Immunopharmacology 49, 159–170 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Mizuno, Y., Kozutsumi, Y., Kawasaki, T. & Yamashina, I. Isolation and characterization of a mannan-binding protein from rat liver. J. Biol. Chem. 256, 4247–4252 (1981).

    CAS  PubMed  Google Scholar 

  7. Drickamer, K., Dordal, M. S. & Reynolds, L. Mannose-binding proteins isolated from rat liver contain carbohydrate-recognition domains linked to collagenous tails. Complete primary structures and homology with pulmonary surfactant apoprotein. J. Biol. Chem. 261, 6878–6887 (1986).

    CAS  PubMed  Google Scholar 

  8. Ezekowitz, R. A., Day, L. E. & Herman, G. A. A human mannose-binding protein is an acute-phase reactant that shares sequence homology with other vertebrate lectins. J. Exp. Med. 167, 1034–1046 (1988).

    Article  CAS  PubMed  Google Scholar 

  9. Turner, M. W. Mannose-binding lectin: the pluripotent molecule of the innate immune system. Immunol. Today 17, 532–540 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Super, M., Thiel, S., Lu, J., Levinsky, R. J. & Turner, M. W. Association of low levels of mannan-binding protein with a common defect of opsonisation. Lancet 2, 1236–1239 (1989).

    Article  CAS  PubMed  Google Scholar 

  11. Summerfield, J. A. et al. Mannose-binding protein gene mutations associated with unusual and severe infections in adults. Lancet 345, 886–889 (1995).

    Article  CAS  PubMed  Google Scholar 

  12. Neth, O. et al. Mannose-binding lectin binds to a range of clinically relevant microorganisms and promotes complement deposition. Infect. Immun. 68, 688–693 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jack, D. L., Klein, N. J. & Turner, M. W. Mannose-binding lectin: targeting the microbial world for complement attack and opsonophagocytosis. Immunol. Rev. 180, 86–99 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Holmskov, U., Malhotra, R., Sim, R. B. & Jensenius, J. C. Collectins: collagenous C-type lectins of the innate immune defense system. Immunol. Today 15, 67–74 (1994).

    Article  CAS  PubMed  Google Scholar 

  15. Dahl, M. R. et al. MASP-3 and its association with distinct complexes of the mannan-binding lectin complement-activation pathway. Immunity 15, 127–315 (2001).This study shows that human MBL is associated with a third serine protease termed MASP3, which is generated through alternative splicing of the MASP1/3 gene. Another important finding is that different MBL oligomers have distinct MASP composition and biological activities, as shown by the association of MASP1, sMAP and C3 activation with smaller MBL oligomers.

    Article  CAS  PubMed  Google Scholar 

  16. Weis, W. I., Drickamer, K. & Hendrickson, W. A. Structure of a C-type mannose-binding protein complexed with an oligosaccharide. Nature 360, 127–134 (1992).

    Article  CAS  PubMed  Google Scholar 

  17. Drickamer, K. Engineering galactose-binding activity into a C-type mannose-binding protein. Nature 360, 183–186 (1992).

    Article  CAS  PubMed  Google Scholar 

  18. Sheriff, S., Chang, C. Y. & Ezekowitz, R. A. Human mannose-binding protein carbohydrate-recognition domain trimerizes through a triple α-helical coiled-coil. Nature Struct. Biol. 1, 789–794 (1994).

    Article  CAS  PubMed  Google Scholar 

  19. Laursen, S. B. & Nielsen, O. L. Mannan-binding lectin (MBL) in chickens: molecular and functional aspects. Dev. Comp. Immunol. 24, 85–101 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Vitved, L. et al. The homologue of mannose-binding lectin in the carp family Cyprinidae is expressed at high level in spleen, and the deduced primary structure predicts affinity for galactose. Immunogenetics 51, 955–964 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Matsushita, M. & Fujita, T. Ficolins and the lectin complement pathway. Immunol. Rev. 180, 78–85 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Ichijo, H. et al. Molecular cloning and characterization of ficolin, a multimeric protein with fibrinogen- and collagen-like domains. J. Biol. Chem. 268, 14505–14513 (1993).

    CAS  PubMed  Google Scholar 

  23. Edgar, P. F. Hucolin, a new corticosteroid-binding protein from human plasma with structural similarities to ficolins, transforming growth factor-β-1-binding proteins. FEBS Lett. 375, 159–161 (1995).

    Article  CAS  PubMed  Google Scholar 

  24. Matsushita, M. et al. A novel human serum lectin with collagen- and fibrinogen-like domains that functions as an opsonin. J. Biol. Chem. 271, 2448–2454 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. Lu, J., Tay, P. N., Kon, O. L. & Reid, K. B. Human ficolin: cDNA cloning, demonstration of peripheral-blood leucocytes as the major site of synthesis and assignment of the gene to chromosome 9. Biochem. J. 313, 473–478 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Endo, Y., Sato, Y., Matsushita, M. & Fujita, T. Cloning and characterization of the human lectin P35 gene and its related gene. Genomics 36, 515–521 (1996).

    Article  CAS  PubMed  Google Scholar 

  27. Harumiya, S. et al. Characterization of ficolins as novel elastin-binding proteins and molecular cloning of human ficolin-1. J. Biochem. (Tokyo) 120, 745–751 (1996).

    Article  CAS  Google Scholar 

  28. Sugimoto, R. et al. Cloning and characterization of the Hakata antigen, a member of the ficolin/opsonin p35 lectin family. J. Biol. Chem. 273, 20721–20727 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Fujimori, Y. et al. Molecular cloning and characterization of mouse ficolin-A. Biochem. Biophys. Res. Commun. 244, 796–800 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Ohashi, T. & Erickson, H. P. Two oligomeric forms of plasma ficolin have differential lectin activity. J. Biol. Chem. 272, 14220–14226 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Omori-Satoh, T., Yamakawa, Y. & Mebs, D. The antihemorrhagic factor, erinacin, from the European hedgehog (Erinaceus europaeus), a metalloprotease inhibitor of large molecular size possessing ficolin/opsonin P35 lectin domains. Toxicon 38, 1561–1580 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Kenjo, A. et al. Cloning and characterization of novel ficolins from the solitary ascidian, Halocynthia roretzi. J. Biol. Chem. 276, 19959–19965 (2001).The first description of ficolins in invertebrates as GlcNAc-binding lectins, which are homologues of mammalian ficolins. The presence of ficolins in invertebrates indicates their crucial role in innate immunity.

    Article  CAS  PubMed  Google Scholar 

  33. Akaiwa, M. et al. Hakata antigen, a new member of the ficolin/opsonin p35 family, is a novel human lectin secreted into bronchus/alveolus and bile. J. Histochem. Cytochem. 47, 777–786 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Teh, C., Le, Y., Lee, S. H. & Lu, J. M-ficolin is expressed on monocytes and is a lectin binding to N-acetyl-d-glucosamine and mediates monocyte adhesion and phagocytosis of Escherichia coli. Immunology 101, 225–232 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Matsushita, M., Endo, Y. & Fujita, T. Cutting edge: complement-activating complex of ficolin and mannose-binding-lectin-associated serine protease. J. Immunol. 164, 2281–2284 (2000).This paper describes L-ficolin/P35 as another lectin that is able to mediate complement activation through association with MASPs.

    Article  CAS  PubMed  Google Scholar 

  36. Gokudan, S. et al. Horseshoe crab acetyl-group-recognizing lectins involved in innate immunity are structurally related to fibrinogen. Proc. Natl Acad. Sci. USA 96, 10086–10091 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kairies, N. et al. The 2.0 Å crystal structure of tachylectin 5A provides evidence for the common origin of the innate immunity and the blood coagulation systems. Proc. Natl Acad. Sci. USA 98, 13519–13524 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Matsushita, M. & Fujita, T. Activation of the classical complement pathway by mannose-binding protein in association with a novel C1s-like serine protease. J. Exp. Med. 176, 1497–1502 (1992).

    Article  CAS  PubMed  Google Scholar 

  39. Sato, T., Endo, Y., Matsushita, M. & Fujita, T. Molecular characterization of a novel serine protease involved in activation of the complement system by mannose-binding protein. Int. Immunol. 6, 665–669 (1994).

    Article  CAS  PubMed  Google Scholar 

  40. Takada, F., Takayama, Y., Hatsuse, H. & Kawakami, M. A new member of the C1s family of complement proteins found in a bactericidal factor, Ra-reactive factor, in human serum. Biochem. Biophys. Res. Commun. 196, 1003–1009 (1993).

    Article  CAS  PubMed  Google Scholar 

  41. Thiel, S. et al. A second serine protease associated with mannan-binding lectin that activates complement. Nature 386, 506–510 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. Ji, Y. H. et al. Activation of the C4 and C2 components of complement by a proteinase in serum bactericidal factor, Ra-reactive factor. J. Immunol. 150, 571–578 (1993).

    CAS  PubMed  Google Scholar 

  43. Matsushita, M., Takahashi, A., Hatsuse, H., Kawakami, M. & Fujita, T. Human mannose-binding protein is identical to a component of Ra-reactive factor. Biochem. Biophys. Res. Commun. 183, 645–651 (1992).

    Article  CAS  PubMed  Google Scholar 

  44. Takahashi, M., Endo, Y., Fujita, T. & Matsushita, M. A truncated form of mannose-binding lectin-associated serine protease (MASP)-2 expressed by alternative polyadenylation is a component of the lectin complement pathway. Int. Immunol. 11, 859–863 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Stover, C. M., Schwaeble, W. J., Lynch, N. J., Thiel, S. & Speicher, M. R. Assignment of the gene encoding mannan-binding-lectin-associated serine protease 2 (MASP2) to human chromosome 1p36.3→p36.2 by in situ hybridization and somatic-cell hybrid analysis. Cytogenet. Cell Genet. 84, 148–149 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Thiel, S. et al. Interaction of C1q and mannan-binding lectin (MBL) with C1r, C1s, MBL-associated serine proteases 1 and 2, and the MBL-associated protein MAp19. J. Immunol. 165, 878–887 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Gadjeva, M., Thiel, S. & Jensenius, J. C. The mannan-binding-lectin pathway of the innate immune response. Curr. Opin. Immunol. 13, 74–78 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Matsushita, M., Thiel, S., Jensenius, J. C., Terai, I. & Fujita, T. Proteolytic activities of two types of mannose-binding-lectin-associated serine protease. J. Immunol. 165, 2637–2642 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Vorup-Jensen, T. et al. Distinct pathways of mannan-binding lectin (MBL)- and C1-complex autoactivation revealed by reconstitution of MBL with recombinant MBL-associated serine protease 2. J. Immunol. 165, 2093–2100 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Wallis, R. & Dodd, R. B. Interaction of mannose-binding protein with associated serine proteases: effects of naturally occurring mutations. J. Biol. Chem. 275, 30962–30969 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Chen, C. B. & Wallis, R. Stoichiometry of complexes between mannose-binding protein and its associated serine proteases. Defining functional units for complement activation. J. Biol. Chem. 276, 25894–25902 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Thielens, N. M. et al. Interaction properties of human mannan-binding lectin (MBL)-associated serine proteases 1 and 2, MBL-associated protein 19 and MBL. J. Immunol. 166, 5068–5077 (2001).References 49–52 describe the molecular interactions between MASP1, MASP2 and sMAP/MAp19 in association with MBL.

    Article  CAS  PubMed  Google Scholar 

  53. Matsushita, M. & Fujita, T. Cleavage of the third component of complement (C3) by mannose-binding-protein-associated serine protease (MASP) with subsequent complement activation. Immunobiology 194, 443–448 (1995).

    Article  CAS  PubMed  Google Scholar 

  54. Rossi, V. et al. Substrate specificities of recombinant mannan-binding-lectin-associated serine proteases 1 and 2. J. Biol. Chem. 276, 40880–40887 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Endo, Y., Sato, T., Matsushita, M. & Fujita, T. Exon structure of the gene encoding the human mannose-binding-protein-associated serine protease light chain: comparison with complement C1r and C1s genes. Int. Immunol. 8, 1355–1358 (1996).

    Article  CAS  PubMed  Google Scholar 

  56. Endo, Y. et al. Two lineages of mannose-binding-lectin-associated serine protease (MASP) in vertebrates. J. Immunol. 161, 4924–4930 (1998).

    CAS  PubMed  Google Scholar 

  57. Matsushita, M., Endo, Y., Nonaka, M. & Fujita, T. Complement-related serine proteases in tunicates and vertebrates. Curr. Opin. Immunol. 10, 29–35 (1998).

    Article  CAS  PubMed  Google Scholar 

  58. Smith, L. C., Chang, L., Britten, R. J. & Davidson, E. H. Sea urchin genes expressed in activated coelomocytes are identified by expressed sequence tags. Complement homologues and other putative immune response genes suggest immune system homology within the deuterostomes. J. Immunol. 156, 593–602 (1996).

    CAS  PubMed  Google Scholar 

  59. Smith, L. C., Shih, C. S. & Dachenhausen, S. G. Coelomocytes express SpBf, a homologue of factor B, the second component in the sea urchin complement system. J. Immunol. 161, 6784–6793 (1998).

    CAS  PubMed  Google Scholar 

  60. Smith, L. C., Clow, L. A. & Terwilliger, D. P. The ancestral complement system in sea urchins. Immunol. Rev. 180, 16–34 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Nonaka, M. Evolution of the complement system. Curr. Opin. Immunol. 13, 69–73 (2001).An excellent, recent review of the molecular evolution of the complement system.

    Article  CAS  PubMed  Google Scholar 

  62. Sekine, H. et al. An ancient lectin-dependent complement system in an ascidian: novel lectin isolated from the plasma of the solitary ascidian, Halocynthia roretzi. J. Immunol. 167, 4504–4510 (2001).This study describes the presence of glucose-binding lectin (GBL) in the plasma of the solitary ascidian, which has a carbohydrate-recognition domain but lacks a collagen-like domain. The important finding is that the GBL–MASPs complex activates C3, leading to C3-dependent phagocytosis, which indicates that the primitive complement system consists of the lectin–proteases complex and C3.

    Article  CAS  PubMed  Google Scholar 

  63. Ji, X., Azumi, K., Sasaki, M. & Nonaka, M. Ancient origin of the complement lectin pathway revealed by molecular cloning of mannan-binding-protein-associated serine protease from a urochordate, the Japanese ascidian, Halocynthia roretzi. Proc. Natl Acad. Sci. USA 94, 6340–6345 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Nonaka, M. et al. Opsonic complement component C3 in the solitary ascidian, Halocynthia roretzi. J. Immunol. 162, 387–391 (1999).

    CAS  PubMed  Google Scholar 

  65. Miyazawa, S., Azumi, K. & Nonaka, M. Cloning and characterization of integrin α-subunits from the solitary ascidian, Halocynthia roretzi. J. Immunol. 166, 1710–1715 (2001).This study describes the presence of C3 receptor in the ascidian — which is homologous to human C3 receptor, CR3 or CR4 — and that this receptor is involved in the phagocytosis of yeast by ascidian haemocytes.

    Article  CAS  PubMed  Google Scholar 

  66. Nair, S. V. et al. A collectin-like protein from tunicates. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 125, 279–289 (2000).

    Article  CAS  PubMed  Google Scholar 

  67. Vasta, G. R., Quesenberry, M., Ahmed, H. & O'Leary, N. C-type lectins and galectins mediate innate and adaptive immune functions: their roles in the complement activation pathway. Dev. Comp. Immunol. 23, 401–420 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. Bulgakov, A. A. et al. Isolation and properties of a mannan-binding lectin from the coelomic fluid of the holothurian Cucumaria japonica. Biochemistry (Moscow) 65, 933–939 (2000).

    CAS  Google Scholar 

  69. Horstmann, R. D., Pangburn, M. K. & Muller-Eberhard, H. J. Species specificity of recognition by the alternative pathway of complement. J. Immunol. 134, 1101–1104 (1985).

    CAS  PubMed  Google Scholar 

  70. Kuhlman, M., Joiner, K. & Ezekowitz, R. A. The human mannose-binding protein functions as an opsonin. J. Exp. Med. 169, 1733–1745 (1989).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Ministry of Education, Culture, Sport, Science and Technology, and the Japanese Society for the Promotion of Science. I thank Y. Endo, M. Matsushita and M. Takahashi for helpful discussions and sharing of unpublished data.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Fukushima Medical University School of Medicine, 1 Hikarigao-ka, Fukushima, 960-1295, Japan

    Teizo Fujita

Authors
  1. Teizo Fujita
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

DATABASES

InterPro

CUB domain

CRD

EGF-like domain

fibrinogen-like domain

serine-protease domain

LocusLink

C1q

C1r

C1s

C2

C3

C4

factor B

factor D

fibrinogen-β

fibrinogen-γ

ficolins

H-ficolin

L-ficolin/P35

M-ficolin

MAC

MASP1

MASP2

MBL

TGF-β1

Glossary

C-TYPE LECTIN

A calcium-dependent animal lectin that is a carbohydrate-binding protein. The binding activity of a C-type lectin is based on the structure of the carbohydrate-recognition domain, which is highly conserved among this family. Calcium is essential not only for the carbohydrate binding itself, but also for the structural maintenance of this domain.

COLLECTIN

A C-type lectin that has a collagen-like domain. One group, the secreted lectins, consists of mannose-binding lectin, bovine conglutinin and collectin 43 in blood, and the two mucosal-associated proteins surfactant proteins A and D. The other group consists of the newly discovered, non-secreted-type collectin liver-1 and membrane-type collectin placenta-1.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fujita, T. Evolution of the lectin–complement pathway and its role in innate immunity. Nat Rev Immunol 2, 346–353 (2002). https://doi.org/10.1038/nri800

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri800

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing