Immune response - Lectin induced complement pathway

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Lectin induced complement pathway

The complement system is the major effector of the humoral branch of the immune system, acting to protect the host from microorganisms such as bacteria.

Complement components are designated by numerals (C1-C9), by letter symbols (e.g., Complement factor I (Factor I)), or by trivial names. Peptide fragments formed by activation of a component are denoted by small letters [1], [2].

In most cases, the smaller fragment resulting from cleavage of a Complement component is designated 'a' and the larger fragment designated 'b' (e.g., C3a, C3b; note that C2 is an exception: C2a is the larger cleavage fragment) [1].

Larger fragments bind to targets near activation sites, while smaller fragments, called anaphylatoxins, diffuse from the site and may initiate localized inflammatory responses by binding to specific receptors, such as Complement component 3a receptor 1 (CR3aR) and Complement component 5a receptor 1 (CR5aR) [3], [4], [5]. Complement fragments named opsonins, i.e., C3b, C3dg, and iC3b, interact with the cell surface receptors, such as Complement component receptor 1 (CR1), Complement component receptor 2 (CD21), Integrins alpha-M/beta-2 integrin and alpha-X/beta-2 integrin, to promote phagocytosis [3].

Complement fragments interact with one another to form functional complexes.

Lectins such as Ficolin 3 (H-Ficolin), Ficolin 2 (L-Ficolin) and Mannose-binding lectin 2 soluble (MBL2) are proteins that recognize and bind to specific carbohydrate targets [6]. The lectin pathway, like the alternative pathway, does not depend on antibodies for its activation. The lectin pathway is activated by the binding of MBL2 to mannose residues on glycoproteins or carbohydrates on the surface of microorganisms [7], [8]. MBL2 is an acute phase protein produced in inflammatory responses. Its function in the complement pathway is similar to that of Complement component 1 q subcomponent (C1q), which it resembles in structure [9]. After MBL2 binds to the surface of a cell or pathogen, Mannan-binding lectin serine peptidase 1 and 2 (MASP1 and MASP2), bind to MBL2 [10]. The active complex formed by this association causes cleavage and activation of C4 and C2. The MASP1 and MASP2 proteins have structural similarity to Complement component 1 r subcomponent (C1r) and Complement component 1 s subcomponent (C1s) and mimic their activities. C3 convertase (C2aC4b) and C5 convertase (C2aC4bC3b) are formed via assembly of C4b, C2a and additional C3b molecules without specific antibody binding. This mechanism represents an important innate defense mechanism comparable to the alternative complement pathway [7], [8], [11], [12].

Smaller fragments resulting from complement cleavage, C3a and C5a, called anaphylatoxins, bind to receptors CR3aR and CR5aR on the surface of mast cells and blood basophils. These complement components induce degranulation, with release of histamine and other biologically active mediators [3].

Factor I is a major regulator of complement. As a protease it has very restricted specificity, cleaving only C3b or C4b in the presence of a cofactor such as Complement factor H (Factor H). Cleavage of C3b by Factor I yields iC3b, a major opsonin [13].

The classical, alternative, or lectin complement pathways lead to the production of an active C5 convertase (C2aC4bC3b) [12]. The terminal sequence of complement activation involves Complement components C5b, C6, C7, C8, and C9, which interact sequentially to form a macromolecular structure called Membrane attack complex. This complex creates pores in the cell membrane and induces cell lysis. C5b initiates assembly of Membrane attack complex by binding of C6 and C7 resulting in C5b/C6/C7 hydrophobic complex. It inserts into the lipid bilayer of cell membranes, where it becomes a high-affinity receptor for C8 molecules (C8alpha, C8beta, C8gamma). C5b/C6/C7/C8 complex has a limited ability to lyse cells. The formation of fully active Membrane attack complex is accomplished by binding of C9 to C5b/C6/C7/C8 complex. This fully active Membrane attack complex forms a large channel through the membrane of the target cell, enabling ions and small molecules to diffuse freely across the membrane [14].

The latest step of complement activation is also controlled by the membrane-associated complement regulatory protein CD59 that prevents the formation of the Membrane attack complex at the terminal step of complement activation cascade [15], [16]. Plasma complement regulatory protein Clusterin can also interfere with formation of the Membrane attack complex pore [17].

References:

  1. Mastellos D, Morikis D, Isaacs SN, Holland MC, Strey CW, Lambris JD
    Complement: structure, functions, evolution, and viral molecular mimicry. Immunologic research 2003;27(2-3):367-86
  2. Sahu A, Lambris JD
    Structure and biology of complement protein C3, a connecting link between innate and acquired immunity. Immunological reviews 2001 Apr;180:35-48
  3. Gasque P
    Complement: a unique innate immune sensor for danger signals. Molecular immunology 2004 Nov;41(11):1089-98
  4. Villiers MB, Perrin-Cocon L, Marche PN, Villiers CL
    Complement receptors and B lymphocytes. Critical reviews in immunology 2004;24(6):465-78
  5. Wagner C, Hansch GM
    Receptors for complement C3 on T-lymphocytes: relics of evolution or functional molecules? Molecular immunology 2006 Jan;43(1-2):22-30
  6. Fujita T, Matsushita M, Endo Y
    The lectin-complement pathway--its role in innate immunity and evolution. Immunological reviews 2004 Apr;198:185-202
  7. Holmskov U, Thiel S, Jensenius JC
    Collections and ficolins: humoral lectins of the innate immune defense. Annual review of immunology 2003;21:547-78
  8. Fujita T
    Evolution of the lectin-complement pathway and its role in innate immunity. Nature reviews. Immunology 2002 May;2(5):346-53
  9. Sim RB, Tsiftsoglou SA
    Proteases of the complement system. Biochemical Society transactions 2004 Feb;32(Pt 1):21-7
  10. S?rensen R, Thiel S, Jensenius JC
    Mannan-binding-lectin-associated serine proteases, characteristics and disease associations. Springer seminars in immunopathology 2005 Nov;27(3):299-319
  11. Matsushita M, Endo Y, Hamasaki N, Fujita T
    Activation of the lectin complement pathway by ficolins. International immunopharmacology 2001 Mar;1(3):359-63
  12. Pangburn MK, Rawal N
    Structure and function of complement C5 convertase enzymes. Biochemical Society transactions 2002 Nov;30(Pt 6):1006-10
  13. Tsiftsoglou SA, Willis AC, Li P, Chen X, Mitchell DA, Rao Z, Sim RB
    The catalytically active serine protease domain of human complement factor I. Biochemistry 2005 Apr 26;44(16):6239-49
  14. Peitsch MC, Tschopp J
    Assembly of macromolecular pores by immune defense systems. Current opinion in cell biology 1991 Aug;3(4):710-6
  15. Smith GP, Smith RA
    Membrane-targeted complement inhibitors. Molecular immunology 2001 Aug;38(2-3):249-55
  16. Kim DD, Song WC
    Membrane complement regulatory proteins. Clinical immunology (Orlando, Fla.) 2006 Feb-Mar;118(2-3):127-36
  17. Tschopp J, French LE
    Clusterin: modulation of complement function. Clinical and experimental immunology 1994 Aug;97 Suppl 2:11-4

  1. Mastellos D, Morikis D, Isaacs SN, Holland MC, Strey CW, Lambris JD
    Complement: structure, functions, evolution, and viral molecular mimicry. Immunologic research 2003;27(2-3):367-86
  2. Sahu A, Lambris JD
    Structure and biology of complement protein C3, a connecting link between innate and acquired immunity. Immunological reviews 2001 Apr;180:35-48
  3. Gasque P
    Complement: a unique innate immune sensor for danger signals. Molecular immunology 2004 Nov;41(11):1089-98
  4. Villiers MB, Perrin-Cocon L, Marche PN, Villiers CL
    Complement receptors and B lymphocytes. Critical reviews in immunology 2004;24(6):465-78
  5. Wagner C, Hansch GM
    Receptors for complement C3 on T-lymphocytes: relics of evolution or functional molecules? Molecular immunology 2006 Jan;43(1-2):22-30
  6. Fujita T, Matsushita M, Endo Y
    The lectin-complement pathway--its role in innate immunity and evolution. Immunological reviews 2004 Apr;198:185-202
  7. Holmskov U, Thiel S, Jensenius JC
    Collections and ficolins: humoral lectins of the innate immune defense. Annual review of immunology 2003;21:547-78
  8. Fujita T
    Evolution of the lectin-complement pathway and its role in innate immunity. Nature reviews. Immunology 2002 May;2(5):346-53
  9. Sim RB, Tsiftsoglou SA
    Proteases of the complement system. Biochemical Society transactions 2004 Feb;32(Pt 1):21-7
  10. S?rensen R, Thiel S, Jensenius JC
    Mannan-binding-lectin-associated serine proteases, characteristics and disease associations. Springer seminars in immunopathology 2005 Nov;27(3):299-319
  11. Matsushita M, Endo Y, Hamasaki N, Fujita T
    Activation of the lectin complement pathway by ficolins. International immunopharmacology 2001 Mar;1(3):359-63
  12. Pangburn MK, Rawal N
    Structure and function of complement C5 convertase enzymes. Biochemical Society transactions 2002 Nov;30(Pt 6):1006-10
  13. Tsiftsoglou SA, Willis AC, Li P, Chen X, Mitchell DA, Rao Z, Sim RB
    The catalytically active serine protease domain of human complement factor I. Biochemistry 2005 Apr 26;44(16):6239-49
  14. Peitsch MC, Tschopp J
    Assembly of macromolecular pores by immune defense systems. Current opinion in cell biology 1991 Aug;3(4):710-6
  15. Smith GP, Smith RA
    Membrane-targeted complement inhibitors. Molecular immunology 2001 Aug;38(2-3):249-55
  16. Kim DD, Song WC
    Membrane complement regulatory proteins. Clinical immunology (Orlando, Fla.) 2006 Feb-Mar;118(2-3):127-36
  17. Tschopp J, French LE
    Clusterin: modulation of complement function. Clinical and experimental immunology 1994 Aug;97 Suppl 2:11-4

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