Complement Deficiencies

ADLI ALI*, FLORENCE BAKON**
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How Complement Fights Infections
The complement system consists of more than 30 proteins, present in blood and tissues, as well as other proteins anchored on the surfaces of cells. The primary functions of the complement system are to protect from infection, to remove particulate substances, (like damaged or dying cells, microbes or immune complexes) and to help modulate adaptive immune responses. As part of the innate immune system, complement acts immediately to start the process of removal and resolution of the problem. Complement works with the inflammatory cells of the innate immune system and those of adaptive or acquired immunity. Complement proteins in the circulation are not activated until triggered by an encounter with a bacterial cell, a virus, an immune complex, damaged tissue or other substance not usually present in the body.There are 3 major activation of complement pathways; classical (CP), alternative(AP) and leptin pathway(LP) summarized in Figure 1. The Classical Pathway (CP) is activated primarily by immunoglobulins that are bound to antigens. Aggregates of immunoglobulins such as cryoglobulins also activate the CP. Components of the CP are C1q, C1r, C1s, C2 and C4. The Lectin Pathway (LP) is initiated by of Mannose binding lectin (MBL) or one of the Ficolins to a target molecule. Both MBL and ficolins are present in complex with MBL-associated serine protease(MASP) and activates C4 and C2. The Alternative Pathway (AP) is initiated by fragments of the complement component C3. Factor B, Factor D and properdin also involved in AP. Properdin, the only positive regulator in the complement system available in AP. Properdin makes it possible for the amplification loop of the alternative pathway to set up a very efficient mechanism for putting lots of C3b onto the surface of the activating cells, protein complexes or particles in the immediate vicinity of the activation site. These 3 pathways converge at the component C3. Although each branch is triggered differently, the common goal is to deposit clusters of C3b on a target. This deposition provides for assembly of the Membrane attack complex (MAC).
The Terminal Pathway (TP) is the final set of steps in the complement activation process that forms a membrane lesion or hole (membrane attack complex or MAC) that kills susceptible bacteria or other cells that activate complement on their surfaces. The TP is dependent upon at least one of the other pathways to initiate the process that it then completes. The components of the TP are C3, C5, C6, C7, C8 and C9. Form of the MAC, called the Terminal Complement Complex (TCC) can be found in the circulation after complement activation occurs and makes a useful laboratory marker for complement activation.

Figure 1: Complement Pathways


The complement system is part of the immune system, whose major function is to protect the host from infections. In the defense both the innate and the adaptive immune systems are operative through several mechanisms. The complement system comprises an important part of the innate defense and some act bridging innate and adaptive immunity (Dunkelberger et al 2010). It promotes the inflammatory response, eliminates pathogens and enhance the immune response. Deficiencies in the complement cascade can lead to overwhelming infection and sepsis (JE Figueroa, Denssen 1991). In addition to playing important role in host defence against infection, the complement system is a mediator in both the pathogenesis and prevention of immune complex disease, such as systemic lupus erythematosus.
The importance of complement in defence against bacterial infections has become clear with some role in against fungal and parasitic infection (Hirsch RL et al 1981). The ability of Mannose binding lectin bind to HIV has been shown in in-vitro study (Saifuddin et al 2000).
Complement deficiencies are rare. However, they are poorly characterised clinically and have been difficult to detect, so there will be likely to be significantly underdiagnosed. Complement deficiencies form about 1-10% of all primary immunodeficiency disorders (Grumach et al 2014). Complement deficiencies can be inherited or acquired. The genetic deficiency of component involved classical pathway (C1q, C1r/s,C2,C4) tend to be linked with autoimmune diseases(Bryan et al 2014), whereas C5 to C9 may have enhanced susceptibility to meningococcal disease.


References
Complement Deficiencies Complement Deficiencies 02/19/2016
Complement Deficiencies and Associated Infections >>
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