Alternative Pathway of Complement System

Alternative Pathway of Complement Activation

• Pillemer described the alternate method for the first time in 1954. It differs from the traditional pathway in (a) the activating chemicals and (b) the order of events.
• The alternative pathway is unique in that complement activation does not require antigen–antibody complexes.
• This mechanism does not require antibodies and does not include the early complement components (C1, C2, and C4) in complement activation.
• Therefore, it can be activated before an immune response to an invading pathogen has developed.

Activators of the alternative pathway

Activators of the alternative pathway of complement activation include 

• IgA,
• IgD,
• bacterial endotoxin, 
• cobra venom factor, 
• nephritic factor.

Steps of activation of alternative pathway

Four serum proteins comprise the initial component of the alternative pathway: C3b, factor B, factor D, and properdin.

1. C3bB complex Formation

• C3b and factor B combine to generate the C3bB complex. Mg2 stabilises the connection between C3b and factor B and is the only ion necessary for functional activation of the alternative pathway.
• In order to distinguish between the two complement activation routes, tests are frequently predicated on the selective chelation of Ca2 (to disrupt C1q, C1r, and C1s2) and the addition of sufficient Mg2 to allow activation of the alternate pathway.

2. C3bB Cleavage

• By another serum protein called factor D or C3 proactive convertase, the C3bB is divided into two fragments, Ba and Bb.
• Since factor D has never been isolated in its proenzyme form, it is often thought that it is activated as soon as it leaves the hepatocyte where it is generated.
• Ba is released into the medium, while Bb binds to C3b to create the C3bBb complex, which has C3 convertase activity.

3. Formation of C3bBb

• The C3bBb complex activates additional C3, which results in the creation of additional C3bBb, which is capable of activating C5 and the MAC.
• The C3bBb complex has a half-life of only 5 minutes, but upon binding with properdin, it produces the relatively heat-stable PC3bBb complex.

4. Formation of MAC

• Similarly to the traditional method, the alternative pathway continues from C3 to yield MAC as an end product.

Regulation

Since C3b is plentiful and abundant in plasma, it can bind to either the surface of a host cell or a pathogen. There are numerous types of regulatory proteins that disrupt the complement activation pathway in order to prevent complement activation from occurring on the host cell.

• Complement Receptor 1 (CR1 or CD35) and DAF (decay accelerating factor or CD55) compete with Factor B in binding with C3b on the cell surface and can even remove Bb from a previously formed C3bBb complex.
• A plasma protease called complement factor I can also block the synthesis of C3 convertase by cleaving C3b into its inactive form, iC3b. Factor I needs a C3b-binding protein cofactor like complement factor H, CR1, or Membrane Cofactor of Proteolysis (MCP or CD46)
• Complement Factor H can suppress the production of C3 convertase by competing with factor B for binding to C3b, accelerate the decay of C3 convertase, and function as a cofactor for Factor I-mediated cleavage of C3b.
• Due to its affinity for sialic acid residues, complement factor H preferentially attaches to vertebrate cells, thereby protecting host cells (as opposed to bacterial cells) from complement-mediated harm.
• CFHR5 (Complement Factor H-Related protein 5) can bind to function as a cofactor for factor I, possesses decay-accelerating activity, and can bind preferentially to C3b at host surfaces.

Alternative pathways to initiate alternative pathway

Three unique alternative route initiation pathways have been identified:

1. The alternative tickover pathway

• The mechanism that results in the spontaneous hydrolysis of C3 to C3(H2O) is known as the tickover pathway.

2. The alternative properdin-activated pathway

• Properdin, a serum protein, stimulates the creation of AP convertases. Monocytes, granulocytic cells, and T lymphocytes produce it.
• Under physiological settings, the C3Bb complex has a half-life of only 90 seconds, however properdin’s association with this complex makes it more stable.
• Properdin, in addition to preserving the stability of convertases, may potentially launch an alternate pathway.
• Properdin may now bind C3b and factor B when attached to components of microbial membranes in the presence of Mg2+.

3. The alternative protease-activated pathway

• C3 and C5 could be cleaved by blood coagulation pathway proteases such as thrombin and plasmin, releasing C3a and C5a, respectively.
• This method can boost complement cascade activation.

Deficiencies of the Alternative Pathway

Factors D, B and Properdin

• Factor D insufficiency is extremely uncommon and has only been documented in two families. Multiple members of both of these families have a history of severe infections. Factor B is a protein of the acute phase that increases during inflammation.
• One unverified report of this defect in humans exists. Properdin is the sole X-linked complement protein.
• Protein synthesis is performed by monocytes, granulocytic cells, and T-cells. Several mutant versions of the protein that diminish AP function have been found.
• A lack of properdin increases vulnerability to bacterial infections caused by the Neisseria genus.
• The most notable member of the group is N. Meningitis, the causative agent of a severe form of meningitis. Typical family histories include male ancestors who have experienced Neisseria illnesses or died from them.

Alternative Pathway Control Proteins

• Factor H deficiency is associated with a wide range of symptoms. Complete H deficit results in uncontrolled activation of the AP and C3 depletion.
• Due to low or missing amounts of C3, this form of factor H deficit manifests similarly to late-onset component deficiencies.
• Recent research has demonstrated the importance of this complement regulatory protein in regulating the health of a variety of tissues.
• In addition to bacterial infections, factor H loss or dysfunction and the subsequent dysregulation of the AP are associated with many kinds of kidney disease, including atypical Hemolytic Uremic Syndrome (aHUS), as well as age-related macular degeneration (AMD).
• These disorders are examples of malfunctioning control processes on the affected organs’ surfaces.

Applications of Alternative pathway

• This pathway monitors the entry of pathogens under normal physiological settings.
• C5a and C3a are essential inflammatory mediators.
• MAC induces both cell death and inflammation.
• Neutrophils and other infiltrating cells deliver C3 and properdin, which can begin alternate pathways.
• Factor B is a protein of the acute phase that increases during inflammation.

References

• The alternative complement pathway revisited – PubMed (nih.gov)
• Owen JA et al (2013). Kuby Immunology. 7th edition. W.H. Freeman Company. New York
• https://www.sinobiological.com/research/complement-system/complement-activation-alternative-pathway
• https://www.creative-biolabs.com/complement-therapeutics/alternative-pathway.htm
• https://primaryimmune.org/about-primary-immunodeficiencies/specific-disease-types/complement-deficiencies
• https://microbenotes.com/alternative-pathway-of-the-complement-system/
• https://en.wikipedia.org/wiki/Alternative_complement_pathway