Immune response - Classical complement pathway

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:

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