Immune response - Alternative complement pathway

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Alternative complement pathway

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

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

In most cases, the smaller fragment resulting from cleavage of a component is designated 'a' and the larger fragment designated 'b' (e.g., C3a, C3b; note that C2 is an exception: Complement component 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) [2], [3], [4]. 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 [2].

Complement fragments interact with each another to form functional complexes.

Alternative complement pathway is independent of antibodies and other molecules that bind to Complement component 1 q subcomponent (C1q). It is activated by molecules, such as bacterial lipopolysaccharides [5].

Complement component C3b present on the surface of foreign cells can bind another serum protein called Complement factor B (Factor B) to form a complex. C3b binding exposes a site on Factor B that serves as a substrate for enzymatically active serum protein called Complement factor D (Factor D). Factor D cleaves Factor B, releasing a small fragment Factor Ba and the larger fragment Factor Bb. Complement component C3b and Factor Bb form the enzymatically active complex C5 convertase (C3bBb). Subsequently, Complement factor Properdin (also called Factor P) binds to C5 convertase (C3bBb) and stabilizes it. The C5 convertase (C3bBb) complex has C3 convertase activity and thus is analogous to the C3 convertase (C2aC4b) complex in the classical pathway. C5 convertase (C3bBb) make a complex with C3b, which exhibits C5 convertase activity, analogous to the C5 convertase (C2aC4bC3b) complex in the classical pathway [6], [7].

Regulatory molecule of the alternative pathway is a Factor I. Factor I cleaves C3b. CD46 molecule, complement regulatory protein (MCP) is a cofactor for Factor I-mediated degradation of C3b. Complement factor H (Factor H) accelerates the destructive action of Factor I [8]. CD55 molecule decay accelerating factor for complement (DAF) also regulates the complement system activity by accelerating the decay of the C3/C5-convertase activity of the alternative pathway [9].

Smaller fragments resulting from complement cleavage, Complement components C3a and C5a, called anaphylatoxins, bind to 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 [2].

The terminal sequence of complement activation involves 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 [10].

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 [11], [12]. Plasma complement regulatory protein Clusterin can also interfere with formation of the Membrane attack complex pore [13].

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. Gasque P
    Complement: a unique innate immune sensor for danger signals. Molecular immunology 2004 Nov;41(11):1089-98
  3. Villiers MB, Perrin-Cocon L, Marche PN, Villiers CL
    Complement receptors and B lymphocytes. Critical reviews in immunology 2004;24(6):465-78
  4. 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
  5. Kohl J
    The role of complement in danger sensing and transmission. Immunologic research 2006;34(2):157-76
  6. Xu Y, Narayana SV, Volanakis JE
    Structural biology of the alternative pathway convertase. Immunological reviews 2001 Apr;180:123-35
  7. Pangburn MK, Rawal N
    Structure and function of complement C5 convertase enzymes. Biochemical Society transactions 2002 Nov;30(Pt 6):1006-10
  8. Seya T, Hirano A, Matsumoto M, Nomura M, Ueda S
    Human membrane cofactor protein (MCP, CD46): multiple isoforms and functions. The international journal of biochemistry & cell biology 1999 Nov;31(11):1255-60
  9. Mikesch JH, Buerger H, Simon R, Brandt B
    Decay-accelerating factor (CD55): a versatile acting molecule in human malignancies. Biochimica et biophysica acta 2006 Aug;1766(1):42-52
  10. Peitsch MC, Tschopp J
    Assembly of macromolecular pores by immune defense systems. Current opinion in cell biology 1991 Aug;3(4):710-6
  11. Smith GP, Smith RA
    Membrane-targeted complement inhibitors. Molecular immunology 2001 Aug;38(2-3):249-55
  12. Kim DD, Song WC
    Membrane complement regulatory proteins. Clinical immunology (Orlando, Fla.) 2006 Feb-Mar;118(2-3):127-36
  13. 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. Gasque P
    Complement: a unique innate immune sensor for danger signals. Molecular immunology 2004 Nov;41(11):1089-98
  3. Villiers MB, Perrin-Cocon L, Marche PN, Villiers CL
    Complement receptors and B lymphocytes. Critical reviews in immunology 2004;24(6):465-78
  4. 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
  5. Kohl J
    The role of complement in danger sensing and transmission. Immunologic research 2006;34(2):157-76
  6. Xu Y, Narayana SV, Volanakis JE
    Structural biology of the alternative pathway convertase. Immunological reviews 2001 Apr;180:123-35
  7. Pangburn MK, Rawal N
    Structure and function of complement C5 convertase enzymes. Biochemical Society transactions 2002 Nov;30(Pt 6):1006-10
  8. Seya T, Hirano A, Matsumoto M, Nomura M, Ueda S
    Human membrane cofactor protein (MCP, CD46): multiple isoforms and functions. The international journal of biochemistry & cell biology 1999 Nov;31(11):1255-60
  9. Mikesch JH, Buerger H, Simon R, Brandt B
    Decay-accelerating factor (CD55): a versatile acting molecule in human malignancies. Biochimica et biophysica acta 2006 Aug;1766(1):42-52
  10. Peitsch MC, Tschopp J
    Assembly of macromolecular pores by immune defense systems. Current opinion in cell biology 1991 Aug;3(4):710-6
  11. Smith GP, Smith RA
    Membrane-targeted complement inhibitors. Molecular immunology 2001 Aug;38(2-3):249-55
  12. Kim DD, Song WC
    Membrane complement regulatory proteins. Clinical immunology (Orlando, Fla.) 2006 Feb-Mar;118(2-3):127-36
  13. Tschopp J, French LE
    Clusterin: modulation of complement function. Clinical and experimental immunology 1994 Aug;97 Suppl 2:11-4

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