Complement 3 deficiency

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Complement 3 deficiency
Specialty Immunology

Complement 3 deficiency is a genetic condition affecting complement component 3 (C3). People can suffer from either primary or secondary C3 deficiency. Primary C3 deficiency refers to an inherited autosomal-recessive disorder that involves mutations in the gene for C3. [1] Secondary C3 deficiency results from a lack of factor I or factor H, two proteins that are key for the regulation of C3. [2] Both primary and secondary C3 deficiency are characterized by low levels or absence of C3. [3]

Contents

C3 function

Complement component 3 (C3) is a protein involved in both the innate and adaptive immune response. C3 is one of over 30 complement proteins circulating in the blood. [3] C3 circulates in an inactive form but can be activated in order to aid the immune system's response to a foreign invader. [4] C3 is the most abundant complement component and is a particularly important complement component because there are three ways to activate the complement system, but C3 plays a central role in all three of these pathways [1] (see the pages for the classical pathway, alternative pathway, and the lectin pathway). Each of these pathways involves the formation of a C3-convertase, which will cleave C3 molecules into C3a and C3b fragments. [4] This is important because an unregulated C3-convertase will cause a deficiency of intact C3 molecules by generating these fragments. [2]

The human gene for C3 is located on chromosome 19. [4] In a healthy individual, C3 is secreted by hepatocytes (liver cells) as well as monocytes and macrophages, dendritic cells, polymorphonuclear leukocytes, fibroblasts, and endothelial cells. These cells will increase production of C3 in response to cytokine signaling (from IL-1, IL-6, TNF-alpha, or interferon gamma) or in response to the presence of lipopolysaccharide, which is expressed in the outer membrane of gram-negative bacteria. [4]

Cases of complement 3 deficiency

As of 2016, primary C3 deficiency had been reported in 37 individuals (from 29 families) around the world. [1] Patients with primary or secondary C3 deficiency generally displayed symptoms (i.e. suffered from infection) within the first 2 years of life. [1] [4]

In addition to studying C3 deficiency in diagnosed human patients, researchers have studied C3 deficiency in animals. C3 deficiency can be induced by injecting animals with cobra venom factor, which functions like an unregulated C3-convertase because factor I and factor H do not regulate it, cleaving most C3 molecules in the serum into C3a and C3b fragments, which depletes the amount of intact C3. [4]

Clinical implications

C3 deficiency makes an individual susceptible to severe, recurrent infections from encapsulated bacteria. [4] [5] [6] These infections are more often caused by gram-negative bacteria (such as Neisseria meningitidis, Haemophilus influenzae, Klebsiella aerogenes, and Escherichia coli), but can also be caused by gram-positive bacteria (such as Streptococcus pneumoniae, Streptoccocus pyogenes, Staphylococcus aureus, and Streptococcus milleri). [4] [1] Infections of the respiratory tract, such as pneumonia, have commonly been observed in C3 deficient patients. [4]

In some cases, primary and secondary C3 deficiency have been associated with the onset of rheumatic or renal (kidney) diseases, such as systemic lupus erythematosus [7] and membranoproliferative glomerulonephritis. [3] (Note that some studies have grouped rheumatic and renal diseases under the broader category of immune complex-mediated diseases.) There have been recorded cases of C3 deficient patients that suffer only from immune complex-mediated diseases and not severe, recurrent infections. [1]

Treatment for C3 deficiency has generally involved the prescription of regular antibiotics intended to prevent infection. [4]


Related Research Articles

<i>Streptococcus pyogenes</i> Species of bacterium

Streptococcus pyogenes is a species of Gram-positive, aerotolerant bacterium in the genus Streptococcus. These bacteria are extracellular, and made up of non-motile and non-sporing cocci. It is clinically important for humans. It is an infrequent, but usually pathogenic, part of the skin microbiota. It is the predominant species harboring the Lancefield group A antigen, and is often called group A Streptococcus (GAS). However, both Streptococcus dysgalactiae and the Streptococcus anginosus group can possess group A antigen. Group A streptococci when grown on blood agar typically produces small zones of beta-hemolysis, a complete destruction of red blood cells. It is thus also called group A (beta-hemolytic) Streptococcus (GABHS), and it can make colonies greater than 5 mm in size.

Rheumatic fever Post-streptococcal inflammatory disease

Rheumatic fever (RF) is an inflammatory disease that can involve the heart, joints, skin, and brain. The disease typically develops two to four weeks after a streptococcal throat infection. Signs and symptoms include fever, multiple painful joints, involuntary muscle movements, and occasionally a characteristic non-itchy rash known as erythema marginatum. The heart is involved in about half of the cases. Damage to the heart valves, known as rheumatic heart disease (RHD), usually occurs after repeated attacks but can sometimes occur after one. The damaged valves may result in heart failure, atrial fibrillation and infection of the valves.

Complement system Part of the immune system that enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells

The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and attack the pathogen's cell membrane. It is part of the innate immune system, which is not adaptable and does not change during an individual's lifetime. The complement system can, however, be recruited and brought into action by antibodies generated by the adaptive immune system.

Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that affect the patient's immune system. Examples of these extrinsic factors include HIV infection and environmental factors, such as nutrition. Immunocompromisation may also be due to genetic diseases/flaws. An example here is SCID.

Classical complement pathway

The classical complement pathway is one of three pathways which activate the complement system, which is part of the immune system. The classical complement pathway is initiated by antigen-antibody complexes with the antibody isotypes IgG and IgM.

Alternative complement pathway

The alternative pathway of the complement system is an innate component of the immune system's natural defense against infections.

C3-convertase

C3 convertase belongs to family of serine proteases and is necessary in innate immunity as a part of the complement system which eventuate in opsonisation of particles, release of inflammatory peptides, C5 convertase formation and cell lysis.

Complement membrane attack complex

The membrane attack complex (MAC) or terminal complement complex (TCC) is a complex of proteins typically formed on the surface of pathogen cell membranes as a result of the activation of the host's complement system, and as such is an effector of the immune system. Assembly of the MAC leads to pores that disrupt the cell membrane of target cells, leading to cell lysis and death.

Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils and epithelial cells, to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or death. They are also called primitive pattern recognition receptors because they evolved before other parts of the immune system, particularly before adaptive immunity. PRRs also mediate the initiation of antigen-specific adaptive immune response and release of inflammatory cytokines.

Complement component 3

Complement component 3, often simply called C3, is a protein of the immune system. It plays a central role in the complement system and contributes to innate immunity. In humans it is encoded on chromosome 19 by a gene called C3.

C5-convertase Serine protease that plays key role in the innate immunity. It participates in the complement system ending with cell death.

C5 convertase is an enzyme belonging to a family of serine proteases that play key role in the innate immunity. It participates in the complement system ending with cell death.

Innate immune system

The innate immune system is one of the two main immunity strategies found in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the dominant immune system response found in plants, fungi, insects, and primitive multicellular organisms.

Complement component 5a Protein fragment

C5a is a protein fragment released from cleavage of complement component C5 by protease C5-convertase into C5a and C5b fragments. C5b is important in late events of the complement cascade, an orderly series of reactions which coordinates several basic defense mechanisms, including formation of the Membrane Attack Complex (MAC), one of the most basic weapons of the innate immune system, formed as an automatic response to intrusions from foreign particles and microbial invaders. It essentially pokes microscopic pinholes in these foreign objects, causing loss of water and sometimes death. C5a, the other cleavage product of C5, acts as a highly inflammatory peptide, encouraging complement activation, formation of the MAC, attraction of innate immune cells, and histamine release involved in allergic responses. The origin of C5 is in the hepatocyte, but its synthesis can also be found in macrophages, where it may cause local increase of C5a. C5a is a chemotactic agent and an anaphylatoxin; it is essential in the innate immunity but it is also linked with the adaptive immunity. The increased production of C5a is connected with a number of inflammatory diseases.

Lectin pathway

The lectin pathway is a type of cascade reaction in the complement system, similar in structure to the classical complement pathway, in that, after activation, it proceeds through the action of C4 and C2 to produce activated complement proteins further down the cascade. In contrast to the classical complement pathway, the lectin pathway does not recognize an antibody bound to its target. The lectin pathway starts with mannose-binding lectin (MBL) or ficolin binding to certain sugars.

Factor D

Factor D a protein which in humans is encoded by the CFD gene. Factor D is involved in the alternative complement pathway of the complement system where it cleaves factor B.

C3b

C3b is the larger of two elements formed by the cleavage of complement component 3, and is considered an important part of the innate immune system. C3b is potent in opsonization: tagging pathogens, immune complexes (antigen-antibody), and apoptotic cells for phagocytosis. Additionally, C3b plays a role in forming a C3 convertase when bound to Factor B, or a C5 convertase when bound to C4b and C2b or when an additional C3b molecule binds to the C3bBb complex.

Porphyromonas gingivalis belongs to the phylum Bacteroidetes and is a nonmotile, Gram-negative, rod-shaped, anaerobic, pathogenic bacterium. It forms black colonies on blood agar.

Complement deficiency

Complement deficiency is an immunodeficiency of absent or suboptimal functioning of one of the complement system proteins. Because of redundancies in the immune system, many complement disorders are never diagnosed. Some studies estimate that less than 10% are identified. Hypocomplementemia may be used more generally to refer to decreased complement levels, while secondary complement disorder means decreased complement levels that are not directly due to a genetic cause but secondary to another medical condition.

C3a (complement)

C3a is one of the proteins formed by the cleavage of complement component 3; the other is C3b. C3a is a 77 residue anaphylatoxin that binds to the C3a receptor (C3aR), a class A G protein-coupled receptor. It plays a large role in the immune response.

An innate immune defect is a defect in the innate immune response that blunts the response to infection. These defects may occur in monocytes, neutrophils, natural killer cells, basophils, mast cells or complement proteins.

References

  1. 1 2 3 4 5 6 Okura, Yuka; Kobayashi, Ichiro; Yamada, Masafumi; Sasaki, Satoshi; Yamada, Yutaka; Kamioka, Ichiro; Kanai, Rie; Takahashi, Yutaka; Ariga, Tadashi (2016). "Clinical characteristics and genotype-phenotype correlations in C3 deficiency". Journal of Allergy and Clinical Immunology. 137 (2): 640–644.e1. doi: 10.1016/j.jaci.2015.08.017 . ISSN   0091-6749. PMID   26435005.
  2. 1 2 Degn, Søren E.; Jensenius, Jens C.; Thiel, Steffen (2011). "Disease-Causing Mutations in Genes of the Complement System". The American Journal of Human Genetics. 88 (6): 689–705. doi:10.1016/j.ajhg.2011.05.011. ISSN   0002-9297. PMC   3113252 . PMID   21664996.
  3. 1 2 3 Skattum, Lillemor; van Deuren, Marcel; van der Poll, Tom; Truedsson, Lennart (2011). "Complement deficiency states and associated infections". Molecular Immunology. 48 (14): 1643–1655. doi:10.1016/j.molimm.2011.05.001. ISSN   0161-5890. PMID   21624663.
  4. 1 2 3 4 5 6 7 8 9 10 S. Reis, E.; Falcao, D. A.; Isaac, L. (2006). "Clinical Aspects and Molecular Basis of Primary Deficiencies of Complement Component C3 and its Regulatory Proteins Factor I and Factor H". Scandinavian Journal of Immunology. 63 (3): 155–168. doi: 10.1111/j.1365-3083.2006.01729.x . ISSN   0300-9475. PMID   16499568.
  5. ↑ Parija (2009-01-01). Textbook of Microbiology & Immunology. Elsevier India. pp. 125–. ISBN   978-81-312-2163-1 . Retrieved 13 November 2010.
  6. ↑ Gorbach, Sherwood L. (2003). Infectious Diseases. Bartlett, John G., Blacklow, Neil R. (3rd ed.). Philadelphia: LWW (PE). ISBN   978-1-4698-7418-0. OCLC   923530065.
  7. ↑ Matsuyama W, Nakagawa M, Takashima H, Muranaga F, Sano Y, Osame M (December 2001). "Molecular analysis of hereditary deficiency of the third component of complement (C3) in two sisters". Intern. Med. 40 (12): 1254–8. doi: 10.2169/internalmedicine.40.1254 . PMID   11813855.
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