In this article, I briefly explain the diseases that happen due to complement deficiencies and strategies evolved by microbes to evade the complement attack.
The components of the complement system
The complement system consists of a set of more than fifty serum proteins that assist in both innate and adaptive immunity to eliminate harmful pathogens. The complement components can be classified mainly into seven categories:
- Initiator complement components
- Phagocytosis enhancers/ Opsonins
- Inflammatory mediators
- Enzymatic mediators
- Complement receptor proteins
- Proteins of membrane attack complex (MAC)
- Regulatory complement components
Activation pathways of the complement system
Complement components get active by three major pathways, i.e., classical pathway, lectin pathway, and alternative pathway. Though the starting event of each pathway differs, all unite in the generation of an enzyme complex that cleaves the C3 component.
The enzyme C3 convertases cleave C3 into two fragments, i.e., C3a and C3b. Both the classical and lectin pathways use the dimer C4b2a for their C3 convertase activity, whereas the dimer C3bBb is used by the alternative pathway for the same. The result of C3 convertase activities is to increase the concentration of C3b, a multifunctional protein.
Diseases related to deficiencies in complement components
There are genetic deficiencies for each of the complement components. Similar symptoms arise when there are homozygous deficiencies in any of the starting components of the classical complement pathway.
The immune-complex diseases such as glomerulonephritis, vasculitis, and SLE (systemic lupus erythematosus) have similar symptoms that arise from deficiencies of early components of the classical pathway.
The complement component C3b has a vital role in clearing immune complexes, which is marked by the effects of these deficiencies. SLE (systemic lupus erythematosus), is an autoimmune disease that arises due to the absence of binding between the complement component C1q and apoptotic cells. When apoptotic cells do not bind with C1q, they behave as auto-antigens, leading to the development of autoimmune diseases like SLE.
Early complement components, play a major role in controlling diseases and in the absence of them, individuals suffer from relapsing infections with both gram-positive and gram-negative bacteria.
The pus-forming bacteria Streptococci and Staphylococci are resistant to the MAC (membrane attack complex) induced cell lysis. However, early complement components can control the infection by inducing a localized inflammatory response and opsonization.
Mannose-binding lectin (MBL), the first component of the lectin pathway initiates complement activation and binds mannose sugar residues found on the surface of microbes. A deficiency in MBL leads to the development of severe pyrogenic infections in infants and children.
Children with a deficiency in MBL, suffer from recurrent respiratory tract infections. Infections due to bacteria Neisseria happen due to the deficiency of factor D and properdin, the initiative factors of the alternative pathway of the complement system.
Diseases related to deficiency in C3, C4 and terminal complement components
The complement component C3 plays the main role in opsonization and the formation of membrane attack complex (MAC). People with a deficiency in C3 suffer from repeated severe bacterial infections that lead to meningitis, bronchitis, and pneumonia. C3 deficiency may also lead to immune-complex diseases.
The complement factor C4 differs in individuals from two to six. The genes responsible for encoding C4 are located in the MHC (major histocompatibility complex), and low gene numbers are related to lower levels of C4 component in the plasma, which causes the development of autoimmune diseases.
A complete deficiency in the complement component C4 leads to the occurrence of frequent bacterial infections with S. pneumonia, Haemophilus influenzae, and N. meningitis.
The deficiencies of terminal complement components (C5 to C9) in individuals make them suffer from the disease meningitis by the bacterium N. meningitis. Individuals with a deficiency of terminal complement components need to vaccinate themselves against N. meningitis.
Role of complement regulatory proteins
There are complement regulatory proteins that regulate the complement components, e.g., C1INH, the C1 complement factor inhibitor prevents the hyperactivation of C2 and C4 by the complement component C1, thus regulating the activation of the classical pathway.
Apart from this, C1INH is a serine protease inhibitor, which controls two serine proteases in the blood clotting cascade. Individuals with a deficiency of C1INH suffer from a condition in which excessive production of vasoactive mediators takes place.
Vasoactive mediators control the integrity and diameter of blood vessels. The excessive production of these mediators leads to extracellular fluid accumulation and tissue swelling. The clinical condition is termed hereditary angioedema. It is tissue edema and can be subcutaneous, i.e., within the bowel causing abdominal pain, or maybe in the upper respiratory tract obstructing the airway.
How do microbes plan to evade complement attack?
Microbes carry out different evasion strategies to escape complement attacks. Different bacteria adopt different strategies to evade complement attacks. Gram-positive bacteria have thick cell walls and capsules, which aid them to brush aside the introduction of membrane attack complexes (MACs).
Some bacteria run away into intracellular vacuoles to elude immune detection. Apart from these energy-consuming strategies, many microbes apply more precise complement evasion strategies to evade annihilation.
Viruses generally hinder the classical complement pathway before its initiation. Viruses synthesize proteins and glycoproteins that precisely bind the Fc regions of antibodies, thus obstructing complement binding.
Some proteins are secreted by viruses that spur the clearance of antigen-antibody complexes from the surface of virus-infected cells. In addition, viruses secret proteins, which bring quick internalization of viral protein-antibody complexes.
The Complement cascade functions mainly based on precise protein-protein interactions between complement components. Microbes have evolved strategies that obstruct these interactions. However, not only bacteria but certain human parasites generate some molecules that inhibit the interactions between complement components.
The complement C2 receptor tri-spanning protein, generated by some species of human parasites Schistosoma and Trypanosoma, disrupts the interaction between the complement components C2a and C4b, thus preventing the production of the classical pathway C3 convertase.
Proteases produced by different types of bacteria
Bacteria mainly produce proteases that obliterate complement components. The bacterium Pseudomonas aeruginosa produces elastase and alkaline protease that degrade the complement components C1q and C3.
Streptococcal bacteria produce proteases SepA and SepB, which target the anaphylatoxin C5a. The complement regulator properdin is degraded by the streptococcal pyrogenic exotoxin, as a result of which the C3 convertase of the alternative pathway gets destabilized on the bacterial surface.
Many microbes can bind the fluid phase inhibitors of complement, C4BP, or factor H. The human pathogenic bacterium Streptococcus pyogenes synthesizes a family of proteins known as M proteins that can bind to the factor H and C4BP. As a result of the expression of these regulatory proteins on the bacterial surface, steps of complement fixation are obstructed.
Proteases produced by fungi
Among the microbes, fungi also attack complement proteins and cause damage to the immune system. The human pathogen Aspergillus fumigatus secretes Alp1, an alkaline protease that can cleave the complement components C3, C4, C5, and C1q and also the immunoglobulin IgG. This pathogen particularly targets the complement components in immunocompromised patients, thus causing more damage to the immune system.
Expression of complement inhibitory proteins by viruses
Some microbes directly get the complement proteins or mimic them to evade the complement attack. Many viruses have evolved to produce proteins that both structurally and functionally mimic the complement proteins.
The Vaccinia (cowpox) and Variola (smallpox) viruses express complement inhibitory proteins, which bind the complement factors C4b and C3b and are the cofactors for factor I, thus inhibiting complement function at the viral membrane.
Some viruses, along with the synthesis of complement regulatory proteins within the viral genome, actively persuade their synthesis within the cells of the host that anchorage the viruses. While budding from the host cells, other viruses disguise themselves by concealing within the host membrane, expressing complement components.
Some viruses imitate eukaryotic membranes by including high levels of sialic acid inside the viral membrane, easing the binding of the cofactors for factor I. Therefore, this results in obstruction of complement activation on the viral surface.
The varieties of complement evasion strategies applied by microbes emphasize the vitality of complement as a host defense mechanism.
Conclusion
The complement system consists of more than fifty serum proteins, which help innate and adaptive immunity to evade harmful pathogens. The complement system has seven components, which get activated by three major pathways, i.e., classical pathway, lectin pathway, and alternative pathway.
There are genetic deficiencies for each of the complement components. There are several diseases related to complement deficiencies. Diseases such as glomerulonephritis, vasculitis, and SLE (systemic lupus erythematosus) have similar symptoms arising from deficiencies of early components of the classical pathway.
Early complement components play a major role in controlling diseases, and in the absence of them, individuals suffer from relapsing infections with both gram-positive and gram-negative bacteria.
Different evasion strategies are carried out by microbes to escape complement attacks. Viruses synthesize proteins and glycoproteins that precisely bind the Fc regions of antibodies, thus obstructing complement binding.
Different bacteria adopt different strategies to evade complement attacks. Due to the expression of some regulatory proteins on the bacterial surface, steps of complement fixation are obstructed. Not only bacteria but certain human parasites generate some molecules that inhibit the interactions between complement components.
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I, Swagatika Sahu (author of this website), have done my master’s in Biotechnology. I have around twelve years of experience in writing and believe that writing is a great way to share knowledge. I hope the articles on the website will help users in enhancing their intellect in Biotechnology.