To understand the physiological roles of properdin, complement system needs to be understood to a certain degree. As an innate immune system defense system, complement plays a very vital role in recognizing non-self or foreign cells or particles. This leads to either phagocytosis of invading bodies or cell lysis due to formation of membrane attack complex (MAC).
In this review, the different pathways by which complement system is activated are described and the function of their components and products are discussed. Furthermore, the regulators of the complement system are briefly explored. The newly discovered and suggested roles of properdin will be discussed and the validity of current research will be commented upon.
The Complement System – Recognizing and eliminating pathogens and inducing inflammation
The complement system is an essential part of the immune system activated as a result of infection in the host. There are three pathways which consist of different molecular recognition events that activate the complement system. These pathways are classified as: the classical pathway (CP), the mannose binding lectin pathway (MBLP), and the alternative pathway (AP).
The CP is activated by antibodies recognizing the specific antigens on the surface of the pathogens and forming antibody: antigen complexes. As a result, there complexes are recognized by C1 component of the complement system. This component is made up of several subunits: C1q subunit, two C1r subunits and two C1s subunits. This C1 component binds to the Fc regions of the antibodies bound to the surface of the pathogen via the C1q subunit. This results in the activation of the activation of the molecule by cross proteolysis by the C1r and C1s proteases. Another component C4, binds to the C1 component and the activated C1s subunit causes the cleavage of C4. This releases the small peptide fragment, C4a, into the environment, which acts as an anaphylatoxin. The larger peptide fragment, C4b, binds to the surface of the bacteria. This is followed by the attachment of C2 component to the C4b fragment. This C2 component is also cleaved by the activated C1s subunit in the C1 component, releasing another small peptide, C2b. Thus, the C4bC2a protease is formed, also known as the C3 convertase of the CP.
In case of the MBLP, the C3 convertase formation occurs when the mannose-binding lectin binds to the mannose on the surface of pathogens. This causes the activation of the system and cleavage of C4 by the MBL. This is followed by the recruitment and cleavage of C2 and ultimately the formation of C3 convertase, C4b2a. In case of AP, however, the formation of C3 convertase is initiated by the spontaneous cleave of C3 component into C3b. This large C3b fragment recruits and cleaves factor B, forming Bb peptide. This cleaving of factor B is catalysed by factor D. This results in the formation of C3bBb, the AP C3 convertase. It is important to note that this loop of AP causes the amplification of C3 convertase formation so that the amount of C3b is increased in the system and the infection can be cleared more quickly.
The function of C3 convertase from all three pathways is to cleave C3 component to C3a and C3b. This peptide fragment, C3b has three main functions: as already discussed, it activates the AP, forming the amplification loop, it can also bind to the surface of the pathogen as opsonins, and it can form membrane attack complexes (MACs) by forming C5 convertase. By binding to the surface of the pathogen, C3b causes the phagocytosis of the pathogen by phagocytes. The opsonized targets are readily recognized by complement receptors expressed on different cell populations.
The formation of MAC, however, also involved some of the other components of the complement system. If C3b bind to the C3 convertase, it forms C5 convertase, which cleaves the C5 component forming C5a and C5b fragments. While the C5a component is a powerful chemoattractant for most leukocytes, the C5b component associates with the C6 and C7 components resulting in C5b67 complex. This C5b67 complex inserts into the pathogen membrane and recruits the C8 component, which penetrates deeper into the pathogen membrane. This is followed by the recruitment of several C9 subunits that form a pore in the pathogen known as the membrane attack complex. This MAC causes membrane disruption and ultimately cell lysis.
Complement and the Adaptive Immune System
The adaptive immune response depends, largely on the ability of the innate immune system to differentiate between self and non-self cells or particles. From the oldest studies, mainly work done by Eden et al and Pepys, it is evident that C3 component of the complement plays an essential role in B cell activity. This was shown by using C3-defienct mice, where the B cells response to T cell-dependent antigens was impaired. Eden et al also showed that B cells bind the C3 fragments on their surface.
It was also shown in the studies done by Fearon et al that C3d binding receptor, CD21, was a key component in complement mediated modulation of B cell response. It has been shown that CD21, with CD19 and CD81, forms a functional receptor group on B cells. This co-receptor complex engages with the C3d, and related fragments that opsonize the antigens on pathogen surface. This occurs to stimulate the B cell receptor. The main function of this signal is to act as an adjuvant and lower the threshold for B cell activation and antibody production. The threshold is lowered from 10 to 10000-fold, promoting the antibody production from B cells. Furthermore, CD21 also facilitates the antigen localization to follicular dendritic cells (FDCs) within lymphoid follicles. It also contributes towards the promotion of an optimal B cell memory pool.
While complement influences the B cell function, it is also important for optimal T cell function. There are two mechanisms by which complement influences the T-cell function: either indirectly, the complement activation products affect antigen presenting cells (APCs), or they directly impact the T cell functions.
There is a wide range of complement receptors found on APCs. Hence, they can easily sense and respond to the complement activation in the environment. The association of C3 fragments with antigens influences the recognition and processing of antigens by APCs. This is evident as the deficiency of C3 causes a reduced antigen presentation and ultimately impaired T cell immunity. Furthermore, C3-defiecient mice also show a lack of maturation of dendritic cells upon antigen uptake.
From the different fragments produced during complement activation, the anaphylotoxins are very critical in modulation of APC functions. For example, C3a/C5a receptors are found on APCs and when bound to the particular fragments, these receptors regulate the production of cytokines (specifically IL-12). Hence they have a dramatic impact on Th1 or Th2 lineage development, allergy onset and development, and also pathogen clearance. Moreover, in C3a/C5a receptor deficient mice, or mice treated with peptide antagonists, and in animals that are deficient in complement regulators, it has been shown that CD4 and CD8 T cell responses are diminished. In addition, it has also been shown that C3a/C5a intracellular signaling pathways intersect with those of the Toll-like receptor (TLR) family.
Whilst complement impacts T-cell function indirectly via APCs, it also influences T cells directly. The immune reactions are suppressed by complement. Upon activation, the complement receptors located on T-cell surface has an impact on cell proliferation, cell viability, and IFN-γ production. The purpose of this immune response suppression by the complement may be vital to prevent tissue damage and autoimmunity.
Word List
Adaptive Immunity
Immune response that involved the B and T lymphocyte activation that leads to a pool of immunological memory with the generation of B lymphocyte clones having somatically recombined receptors.
Anaphylotoxins
Components of the complement system, like C3a and C5a, which mediate inflammatory response through cell activation to induce, for example, histamine release and chemotaxis.
Innate Immunity
An instant or immediate immune response that is mediated by recognition of pathogens via germ-line coded pattern-recognition receptors.
Opsonin
Proteins like C3b, that bind to the surface of a pathogen or a particle and enhance phagocytosis by phagocytes.
Toll-Like Receptors
A family of receptors found on cell surface or bound to cell compartments that recognize dangerous particles or pathogens by detecting a wide range of pathogen-associated molecular patterns and sometimes endogenous ligands.
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