The complement system is a part of the innate immunity that functions to identify foreign materials (pathogens, apoptotic cells and cellular debris), and induce immune response to eliminate these materials.

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Definition of the Complement System

It is composed of plasma and membranous proteins that complement antibody mediated immunity through activation by three pathways. They are synthesized in the liver and circulate in the blood for recognition, attachment and clearance of antigen/antibody complex.

These proteins are regulated to avoid self-harm resulting from autoimmunity against host cells. Deficiency of one of these proteins can lead to multiple disseminated infections while dysregulation can lead to autoimmune disorders.

Complement proteins C1-9 are named after C as complement and numbers as the order of activation, except that C4 is activated before C2. Complement proteins are cleaved into a smaller segment and a larger segment; e.g. C3 is cleaved into C3a and C3b.

Functions of the Complement System

C1a and C5a are potent inflammatory mediators and antimicrobial activity. They are called anaphlatoxins because of their role in vasodilation, smooth muscle contraction, increasing vascular permeability, activating mast cells, endothelial cells and macrophages. They also act as chemotactic factors to direct immune cells and hematopoietic stem cells to the site of inflammation.

Hematopoietic stem cells have a major role in regulating the inflammatory response, regeneration of tissues and limitation of fibrosis in the damaged tissue. Vascular endothelial growth factor receptor–1, interleukin-6 and TNF-alpha are all released by complement activation leading to angiogenesis with formation of new blood vessels. Age-related retinal degeneration with neovascularization is an example of complement induced angiogenesis.

Immune complexes can activate complement deposition on the antibody portion of the immune complexes leading to further activation of phagocytic and hematopoietic cells to clear the immune complexes from the circulation. Serum sickness is an example for immune complex clearance by complement proteins.

Complement Activation

The ultimate goal for complement activation is C3b deposition on the target cell membrane followed by the membrane attack complex (MAC) responsible for opsonization. This is the reason that all complement activation pathways will lead to activated C3, which is responsible for C3b attachment to target cell. Activation of C3b will lead to lysis of the bacteria by membrane attack complex MAC in addition to release of anaphylatoxins – C1a, C4a and C5a.

Classical pathway

It is mainly activated by antigen-antibody complex. C1 complex is composed of C1q, C1r and C1s subunits. The C1q subcomponent attaches to the Fc portion of IgM and IgG subclasses 1 and 3 leading to cleavage of C1r which in turn cleaves C1s. C1s is responsible for cleaving C4 and C2. IgA, IgD, IgE and IgG subclass 2 are not known to activate complement proteins. C4b and C2a form together C4b2a, which is known as the C3 convertase.

C3 is activated into C3b, which acts as an opsonin as well as C4b. Yet C3b can activate C5 to induce the lytic sequence. The complement proteins fragments mostly attach to the target with less number act to activate other proteins. Most of the C4b attach to the target cells while only few bind to C2a to form C3 convertase.

Similarly, C3a and C5a act as anaphylatoxins while most of C5b and C3b attach to target cells. Activated C3b join C4b2a to form C5 convertase which is C4b2a3b. Cleavage of C5 yields C5a which is anaphylatoxin and C5b which starts the membrane attack complex; C5b, C6, C7, C8, and C9. C7 responsible for disruption of the integrity of the membrane lipid bilayer and formation of transmembrane channels and pores which facilitate further osmotic lysis and destruction by the membrane attack complex proteins.

Lectin pathway

This is similar to the classical pathway except that the complement system is activated by lectins-sugar complex where lectins are carbohydrate-binding proteins that attach to sugar residues on the surface of pathogens. Lectins bind to mannose, fructose, glucose, N-acetylglucosamine and N-acetylmannosamine.

This binding leads to activation of MASP-1&2 with subsequent cleavage of C4 & C2 the same as classical pathway. Lectins are known for not binding to galactose and sialic acid sugars on the mammalian cell surface for recognition of self-cells.

Activation of associated proteases that cleaves C2 and C4 leading to their activation. Mannose binding lectin is an example of lectins that is associated with proteases called MASPs or mannan binding lectin associated serine proteases.

Alternative pathway

This is part of the host innate immunity, which is continuously active without binding to any antibodies or lectins. It uses auto-activated C3, which is always present in minute amounts to tick over cells and pathogens. C3 can be auto-activated in the body for screening and innate immunity, which becomes deactivated in normal environment in healthy individuals.

Activated C3 cleaves factor B into Ba and Bb, which in turn forms C3bBb, which then attaches to properdin (P) to form C3bBbP, which functions as C3 convertase to cleave more C3 into C3a and C3b. This causes amplification of activated C3 in to C3a and C3b.

Properdin is normally secreted from activated neutrophils. More C3b can bind to the C3 convertase to form C5 convertase; C3bBbC3b which in turn binds to properdin P for stabilization and forms C3bBbC3bP to follow with the MAC as in classical pathway.

Other pathways for complement activation can use Beta amyloid, C-reactive protein (CRP), Trypsin-like proteases and kallikrein in different mechanisms to lead to MAC activation and immune reaction.

Mechanism of Action of Complement Proteins

Activation and attachment of C3b to target cells will lead to opsonization, which is rapid lysis and phagocytosis of the microbial cells surrounded by a huge number of C3b. Phagocytosis is enhanced by recognition of C3b by host cell receptors on macrophages.

This process is followed by antigen presentation to B lymphocytes responsible for antibody production and humoral immune response. Sometimes, complement activation is secondary to apoptosis of self-host cells.

Complement proteins attach to surface carbohydrate of apoptotic cells leading to their phagocytosis and clearance. Interestingly, it has been proven that the complement system can also play a role intracellularly by activating C3 in the cytoplasm or recognition of the C3 coated viruses inside the cells to initiate immune response.

Regulation of the complement system

As described, complement activation can be involved in many host immune reaction that can lead to illness e.g. serum sickness and retinal neovascularization. Therefore, complement proteins must be regulated by complement control proteins. For example, C1 inhibitor which inhibits C1 activation, decay accelerating factor (DAF), which inhibits C3 convertase and CD59 or protectin, which inhibits C9 in the MAC.

Complement System Disorders

These disorders are mainly multiple recurrent infections and autoimmune diseases. Disorders related to the complement system can result from either factor deficiency or activation against self-cells.

The complement system can also be involved in many physiological aging processes that can lead to pathological impact e.g. age related macular degeneration and Alzheimer’s disease. Dysregulation or activation with autoantibodies can be involved in some pathologic conditions including systemic lupus erythematosis and paroxysmal nocturnal hemoglubinuria.

Paroxysmal nocturnal hemoglobinuria results from complement activation against blood cells due to genetic absent surface proteins related to glycosyl-phosphatidylinositol in the hematopoietic stem cells. The disease is characterized by hemolysis, thrombosis and bleeding tendency. Treatment is developed with eculizumab – a monoclonal antibody against C5 to prevent complement mediated hemolysis and bleeding.

C3 deficiency is associated with total malfunction of the complement system due to the essential rule that C3 plays in complement activation. It is transmitted as an autosomal recessive trait. Generalized infections and sepsis can occur similar to Bruton agammaglobulinemia with staphylococci, pneumococci or Hemophilus influenza. It can also be associated with diseases like SLE and glomerulonephritis.

C2 deficiency is the most common genetic complement deficiency that is autosomal recessive and leads to infection with pyogenic encapsulated bacteria – streptococcus pneumoniae, haemophilus influenza and neisseria meningitides and sometimes fatal septicemia.

C1q deficiency is commonly associated with systemic lupus erythematosis, multiple myeloma, membranoproliferative glomerulonephritis and hypogammaglobulinemia. C1q deficiency is associated with many autoantibodies including anti C1q antibodies, antinuclear antibodies and anti-dsDNA antibodies.

C4 deficiency can manifest with Henoch-Schönlein Purpura, diabetes mellitus, scleroderma, Ig A nephropathy and hepatitis.

C1 esterase inhibitor deficiency causes hereditary angioedema with attacks of nonpitting, nonpruritic, localized edema in the larynx, GI, lips and other sites with varying manifestations. It can be induced by emotional stress, trauma or exercise.

Diagnosis is suggested by a positive family history, edema with lack of accompanying pruritus or urticaria, and decreased C4 levels and C1-INH levels. Treatment options include danazol, Kallikrein inhibitor and C1 inhibitor.

Membrane attack complex deficiency is an autosomal recessive trait that leads to Neisseria meningitides meningitis and even septicemia.

Properdin deficiency is an X-linked trait with all patients are males. Death usually occurs from meningococcal meningitis.

Measurement of complement activity

Total hemolytic complement or CH50 assay is used as a screening tool for complement activity and function. The ability to lyse antibody coated sheep RBCs in a diluted serum is the main idea for complement function assessment. Intact classical pathway proteins are required for RBCs lysis in the presence of antibodies. Selective complement assays can be used next for specific factor deficiency.

Chronic Inflammation

Inflammation is the body response to injury. Injury can be physical, chemical or pathogenic. The body reacts to injurious stimuli by vasodilation to increase the blood flow to the site of inflammation, exudation of plasma by increasing capillary permeability and cellular migration derived by chemotactic factors and inflammatory mediators.

Acute inflammation is characterized by redness, hotness, swelling, pain and loss of function of the involved organ. The same vascular and cellular phases of acute inflammation are also characteristic of chronic inflammation.

Upon prolonged exposure to the offending agent, inflammatory mediators change from vasodilators and eicosanoids to interferon gamma (INF-γ) and tumor necrosis factor (TNF) and reactive oxygen species. Chronic inflammatory cells are more evident with failure of resolution of irritating factors.

Cells of immediate response – neutrophils, basophils and esinophils – are replaced by macrophages, lymphocytes, monocytes and fibroblasts. This is why chronic inflammation is characterized by more tissue destruction and more fibrosis.

Many disorders are associated with chronic inflammatory response due to persistent inflammation e.g. asthma, COPD, inflammatory bowel disease, rheumatoid arthritis, sarcoidosis and vasulitis.

Granulomatous inflammation is an example of chronic inflammation that can be caused by TB and sarcoidosis. The granuloma is composed of central necrosis, Langhans cells, epithelioid macrophages and peripheral lymphocytes.

The fate of chronic inflammation usually depends on the etiology. Resolution with permanent effects can occur when the causative factor no longer exists. Recurrent attacks are common with autoimmune disorders, persistent infection and compromised immunity.

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