Immune response - Classical complement pathway

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Classical complement pathway

Complement system is a 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 Complement component 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., C1q, C3b, C3dg, and iC3b, interact with the cell surface receptors, such as CD93 molecule (C1qRp), 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], [6].

Complement fragments interact with each another to form functional complexes.

Complement activation by the classical pathway commonly begins with the formation of soluble antigen-antibody complexes (immune complexes) or with the binding of antibody (Immunoglobulins such as IgG1 and IgM) to antigen on a suitable target, such as a bacterial cell.

Initial stage of activation involves Complement components C1, C2, C3 and C4, which are present in plasma in functionally inactive forms.

Formation of an antigen-antibody complex induces conformational changes in the Fc part of the IgM molecule that expose a binding site for the Complement component C1. C1 in serum is represented by a macromolecular complex (also called C1qr2s2). It consists of three protein subunits Complement component 1 q subcomponent (C1q), Complement component 1 r subcomponent (C1r) and Complement component 1 s subcomponent (C1s). Components of complex are stabilized by Ca(2+) ions [7], [8].

Serpin peptidase inhibitor clade G member 1 (C1 inhibitor) inhibits activated C1r and C1s and thus regulates complement activation [9].

C1r cleaves and activates C1s, which translates the activation of the Complement component C1 complex into complement activation via cleavage of C4 and C2 to form a C3 convertase (C2aC4b). C3 convertase (C2aC4b) cleaves C3.

C5 convertase (C2aC4bC3b) involved in classical pathway is assembled of two proteins, C4b and C2a, and additional C3b molecules. CD55 molecule decay accelerating factor for complement (DAF) inhibits the assembly of the complement system C3/C5 convertases by complex formation with C4b and C3b [10], [11].

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 [12]. CD46 molecule, complement regulatory protein (MCP) is a cofactor for the Factor I -mediated degradation of C3b and C4b deposited on host cells [13].

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

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. Ghebrehiwet B, Peerschke EI
    cC1q-R (calreticulin) and gC1q-R/p33: ubiquitously expressed multi-ligand binding cellular proteins involved in inflammation and infection. Molecular immunology 2004 Jun;41(2-3):173-83
  7. Gaboriaud C, Thielens NM, Gregory LA, Rossi V, Fontecilla-Camps JC, Arlaud GJ
    Structure and activation of the C1 complex of complement: unraveling the puzzle. Trends in immunology 2004 Jul;25(7):368-73
  8. Tarr J, Eggleton P
    Immune function of C1q and its modulators CD91 and CD93. Critical reviews in immunology 2005;25(4):305-30
  9. Chesne S, Villiers CL, Arlaud GJ, Lacroix MB, Colomb MG
    Fluid-phase interaction of C1 inhibitor (C1 Inh) and the subcomponents C1r and C1s of the first component of complement, C1. The Biochemical journal 1982 Jan 1;201(1):61-70
  10. Kinoshita T, Medof ME, Nussenzweig V
    Endogenous association of decay-accelerating factor (DAF) with C4b and C3b on cell membranes. Journal of immunology (Baltimore, Md. : 1950) 1986 May 1;136(9):3390-5
  11. Pangburn MK, Rawal N
    Structure and function of complement C5 convertase enzymes. Biochemical Society transactions 2002 Nov;30(Pt 6):1006-10
  12. 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
  13. Cho SW, Oglesby TJ, Hsi BL, Adams EM, Atkinson JP
    Characterization of three monoclonal antibodies to membrane co-factor protein (MCP) of the complement system and quantification of MCP by radioassay. Clinical and experimental immunology 1991 Feb;83(2):257-61
  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. Ghebrehiwet B, Peerschke EI
    cC1q-R (calreticulin) and gC1q-R/p33: ubiquitously expressed multi-ligand binding cellular proteins involved in inflammation and infection. Molecular immunology 2004 Jun;41(2-3):173-83
  7. Gaboriaud C, Thielens NM, Gregory LA, Rossi V, Fontecilla-Camps JC, Arlaud GJ
    Structure and activation of the C1 complex of complement: unraveling the puzzle. Trends in immunology 2004 Jul;25(7):368-73
  8. Tarr J, Eggleton P
    Immune function of C1q and its modulators CD91 and CD93. Critical reviews in immunology 2005;25(4):305-30
  9. Chesne S, Villiers CL, Arlaud GJ, Lacroix MB, Colomb MG
    Fluid-phase interaction of C1 inhibitor (C1 Inh) and the subcomponents C1r and C1s of the first component of complement, C1. The Biochemical journal 1982 Jan 1;201(1):61-70
  10. Kinoshita T, Medof ME, Nussenzweig V
    Endogenous association of decay-accelerating factor (DAF) with C4b and C3b on cell membranes. Journal of immunology (Baltimore, Md. : 1950) 1986 May 1;136(9):3390-5
  11. Pangburn MK, Rawal N
    Structure and function of complement C5 convertase enzymes. Biochemical Society transactions 2002 Nov;30(Pt 6):1006-10
  12. 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
  13. Cho SW, Oglesby TJ, Hsi BL, Adams EM, Atkinson JP
    Characterization of three monoclonal antibodies to membrane co-factor protein (MCP) of the complement system and quantification of MCP by radioassay. Clinical and experimental immunology 1991 Feb;83(2):257-61
  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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