Ficolin

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Ficolins are pattern recognition receptors that bind to acetyl groups present in the carbohydrates of bacterial surfaces and mediate activation of the lectin pathway of the complement cascade. [1]

Contents

Structure

Ficolins (Fi+Col+Lin) are a group of oligomeric lectins with N-terminal collagen-like domain and a C-terminal fibrinogen-like domain. The primary ficolin structure contains 288 amino acids. The combination of collagen-like and fibrinogen-like domain allows the protein to form a basic subunit containing a triple helical tail and a trio of globular heads. [2]

Ficolins are produced in the liver by hepatocytes and in the lung by alveolar cells type II, neutrophils and monocytes. [3]

Role in innate immunity

We now know that innate immune recognition mechanisms are sophisticated. Exocrine secretions provide a variety of soluble factors that are able to protect the body from potential pathogens. [4]

Together with pentraxins, collectins and C1q molecules, ficolins constitute the soluble pattern-recognition molecules (PRMs) which play an important role in humoral innate immunity. [4] Ficolins recognise carbohydrate structures on pathogens' surfaces as their pathogen-associated molecular pattern (PAMP) and activate the lectin pathway of the complement cascade. [3] [5] Specifically, ficolins bind to acetyl groups present in certain bacterial molecules, such as N-acetylglucosamine, a component of peptidoglycan in the bacterial cell wall. [1] [6] When ficolins bind to their PAMP ligands by their C-terminal fibrinogen-like domain, [1] they initiate the proteolytic complement cascade, facilitated by the mannose-binding protein-associated serine proteases (MASPs) that ficolins are associated to and co-circulate with. [1] [6] Serine proteases then cleave a number of soluble complement proteins leading to complement activation, opsonisation, generation of proinflammatory mediators, and cell lysis. [7]

Collectins and ficolins are also called collagenous lectins. The collectin family constitutes calcium-dependent proteins. In contrast, the ficolin family does not bind to PAMPs in a calcium-dependent way. [3]

Types of ficolin

Three ficolins have been identified in humans:

  1. M-ficolin (FCN1), monocyte ficolin
  2. L-ficolin (FCN2), liver ficolin
  3. H-ficolin (FCN3), hakata antigen. [2] [3]

Ficolin-1 and ficolin-2 are encoded be a gene localised on chromosome 9 (9q34) and they share approximately 80% identity in amino sequence. Whereas, ficolin-3 is encoded by chromosome 1 and therefore it has only about 50% identity with the other two ficolins. [2] A cross-reactivity of the ficolins in human serum has been observed. [7]

Clinical references

The concentration of ficolins in healthy serum is between 3 and 5 μg/mL. [2]

As Ficolin-2 and 3 are expressed by hepatocytes, their levels decrease in advanced liver diseases like cirrhosis. Low ficolin levels contribute to cirrhosis-associated immune dysfunction. [8]

Immunologist Jeak L. Ding and her team found that natural IgG (nIgG; a non-specific immunoglobulin of adaptive immunity) is not quiescent, but plays a crucial role in immediate immune defense by collaborating with ficolin (an innate immune protein). [9]

Related Research Articles

Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like peptidoglycan layer (sacculus) that surrounds the bacterial cytoplasmic membrane. The sugar component consists of alternating residues of β-(1,4) linked N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM). Attached to the N-acetylmuramic acid is an oligopeptide chain made of three to five amino acids. The peptide chain can be cross-linked to the peptide chain of another strand forming the 3D mesh-like layer. Peptidoglycan serves a structural role in the bacterial cell wall, giving structural strength, as well as counteracting the osmotic pressure of the cytoplasm. This repetitive linking results in a dense peptidoglycan layer which is critical for maintaining cell form and withstanding high osmotic pressures, and it is regularly replaced by peptidoglycan production. Peptidoglycan hydrolysis and synthesis are two processes that must occur in order for cells to grow and multiply, a technique carried out in three stages: clipping of current material, insertion of new material, and re-crosslinking of existing material to new material.

An immune response is a physiological reaction which occurs within an organism in the context of inflammation for the purpose of defending against exogenous factors. These include a wide variety of different toxins, viruses, intra- and extracellular bacteria, protozoa, helminths, and fungi which could cause serious problems to the health of the host organism if not cleared from the body.

Humoral immunity is the aspect of immunity that is mediated by macromolecules – including secreted antibodies, complement proteins, and certain antimicrobial peptides – located in extracellular fluids. Humoral immunity is named so because it involves substances found in the humors, or body fluids. It contrasts with cell-mediated immunity. Humoral immunity is also referred to as antibody-mediated immunity.

<span class="mw-page-title-main">Complement system</span> Part of the immune system that enhances the ability of antibodies and phagocytic 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.

<span class="mw-page-title-main">Classical complement pathway</span> Aspect of the immune system

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.

<span class="mw-page-title-main">Alternative complement pathway</span> Type of cascade reaction of the complement system

The alternative pathway is a type of cascade reaction of the complement system and is a component of the innate immune system, a natural defense against infections.

Opsonins are extracellular proteins that, when bound to substances or cells, induce phagocytes to phagocytose the substances or cells with the opsonins bound. Thus, opsonins act as tags to label things in the body that should be phagocytosed by phagocytes. Different types of things ("targets") can be tagged by opsonins for phagocytosis, including: pathogens, cancer cells, aged cells, dead or dying cells, excess synapses, or protein aggregates. Opsonins help clear pathogens, as well as dead, dying and diseased cells.

Pathogen-associated molecular patterns (PAMPs) are small molecular motifs conserved within a class of microbes, but not present in the host. They are recognized by toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) in both plants and animals. This allows the innate immune system to recognize pathogens and thus, protect the host from infection.

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, as well as by 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.

<span class="mw-page-title-main">DC-SIGN</span> Protein-coding gene in the species Homo sapiens

DC-SIGN also known as CD209 is a protein which in humans is encoded by the CD209 gene.

<span class="mw-page-title-main">Innate immune system</span> Immunity strategy in living beings

The innate immune system or nonspecific immune system is one of the two main immunity strategies in vertebrates. The innate immune system is an alternate defense strategy and is the dominant immune system response found in plants, fungi, prokaryotes, and invertebrates.

<span class="mw-page-title-main">Lectin pathway</span>

The lectin pathway or MBL 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.

<span class="mw-page-title-main">MASP1 (protein)</span> Protein-coding gene in the species Homo sapiens

Mannan-binding lectin serine protease 1 also known as mannose-associated serine protease 1 (MASP-1) is an enzyme that in humans is encoded by the MASP1 gene.

Collectins (collagen-containing C-type lectins) are a part of the innate immune system. They form a family of collagenous Ca2+-dependent defense lectins, which are found in animals. Collectins are soluble pattern recognition receptors (PRRs). Their function is to bind to oligosaccharide structure or lipids that are on the surface of microorganisms. Like other PRRs they bind pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) of oligosaccharide origin. Binding of collectins to microorganisms may trigger elimination of microorganisms by aggregation, complement activation, opsonization, activation of phagocytosis, or inhibition of microbial growth. Other functions of collectins are modulation of inflammatory, allergic responses, adaptive immune system and clearance of apoptotic cells.

<span class="mw-page-title-main">Mannan-binding lectin</span> Mammalian protein found in Homo sapiens

Mannose-binding lectin (MBL), also called mannan-binding lectin or mannan-binding protein (MBP), is a lectin that is instrumental in innate immunity as an opsonin and via the lectin pathway.

<span class="mw-page-title-main">FCN2</span> Protein-coding gene in the species Homo sapiens

Ficolin-2, which was initially identified as L-ficolin, is a protein that in humans is encoded by the FCN2 gene.

<span class="mw-page-title-main">FCN1</span> Protein-coding gene in the species Homo sapiens

Ficolin-1, and also commonly termed M-ficolin is a protein that in humans is encoded by the FCN1 gene.

<span class="mw-page-title-main">C3a (complement)</span>

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.

<span class="mw-page-title-main">Cell–cell recognition</span>

Cell–cell recognition is a cell's ability to distinguish one type of neighboring cell from another. This phenomenon occurs when complementary molecules on opposing cell surfaces meet. A receptor on one cell surface binds to its specific ligand on a nearby cell, initiating a cascade of events which regulate cell behaviors ranging from simple adhesion to complex cellular differentiation. Like other cellular functions, cell-cell recognition is impacted by detrimental mutations in the genes and proteins involved and is subject to error. The biological events that unfold due to cell-cell recognition are important for animal development, microbiomes, and human medicine.

Apoptotic-cell associated molecular patterns (ACAMPs) are molecular markers present on cells which are going through apoptosis, i.e. programmed cell death. The term was used for the first time by C. D. Gregory in 2000. Recognition of these patterns by the pattern recognition receptors (PRRs) of phagocytes then leads to phagocytosis of the apoptotic cell. These patterns include eat-me signals on the apoptotic cells, loss of don’t-eat-me signals on viable cells and come-get-me signals ) secreted by the apoptotic cells in order to attract phagocytes. Thanks to these markers, apoptotic cells, unlike necrotic cells, do not trigger the unwanted immune response.

References

  1. 1 2 3 4 Merle, Nicolas S.; Church, Sarah Elizabeth; Fremeaux-Bacchi, Veronique; Roumenina, Lubka T. (2015). "Complement System Part I - Molecular Mechanisms of Activation and Regulation". Frontiers in Immunology. 6: 262. doi: 10.3389/fimmu.2015.00262 . PMC   4451739 . PMID   26082779. 262.
  2. 1 2 3 4 Kilpatrick, David C.; Chalmers, James D. (2012). "Human L-Ficolin (Ficolin-2) and Its Clinical Significance". Journal of Biomedicine and Biotechnology. 2012: 138797. doi: 10.1155/2012/138797 . ISSN   1110-7243. PMC   3303570 . PMID   22500076.
  3. 1 2 3 4 Matsushita, Misao (2018). "Chapter 5 - Ficolins". In Barnum, Scott R.; Schein, Theresa N. (eds.). The Complement FactsBook (Second ed.). Elsevier. pp. 45–56. doi:10.1016/B978-0-12-810420-0.00005-5. ISBN   978-0-12-810420-0.
  4. 1 2 Hajishengallis, George; Russell, Michael W. (2015). "Chapter 15 - Innate Humoral Defense Factors". In Mestecky, Jiri; Strober, Warren; Russell, Michael W.; Kelsall, Brian L.; Cheroutre, Hilde; Lambrecht, Bart N. (eds.). Mucosal Immunology (Fourth ed.). Elsevier. pp. 251–270. doi: 10.1016/b978-0-12-415847-4.00015-x . ISBN   978-0-12-415847-4.
  5. ↑ Endo, Yuichi; Matsushita, Misao; Fujita, Teizo (June 2007). "Role of ficolin in innate immunity and its molecular basis". Immunobiology. 212 (4–5): 371–379. doi:10.1016/j.imbio.2006.11.014. ISSN   0171-2985. PMID   17544822.
  6. 1 2 Krarup, Anders; Thiel, Steffen; Hansen, Annette; Fujita, Teizo; Jensenius, Jens C. (2004). "L-ficolin Is a Pattern Recognition Molecule Specific for Acetyl Groups". Journal of Biological Chemistry. 279 (46): 47513–47519. doi: 10.1074/jbc.M407161200 . PMID   15331601.
  7. 1 2 Jarlhelt, Ida; Pilely, Katrine; Clausen, Jytte Bryde; Skjoedt, Mikkel-Ole; Bayarri-Olmos, Rafael; Garred, Peter (2020-02-24). "Circulating Ficolin-2 and Ficolin-3 Form Heterocomplexes". The Journal of Immunology. 204 (7): 1919–1928. doi: 10.4049/jimmunol.1900694 . ISSN   0022-1767. PMID   32094208. S2CID   211477247.
  8. ↑ Foldi, Ildiko; Tornai, Tamas; Tornai, David; Sipeki, Nora; Vitalis, Zsuzsanna; Tornai, Istvan; Dinya, Tamas; Antal-Szalmas, Peter; Papp, Maria (2017). "Lectin-complement pathway molecules are decreased in patients with cirrhosis and constitute the risk of bacterial infections". Liver International. 37 (7): 1023–1031. doi:10.1111/liv.13368. hdl: 2437/234045 . ISSN   1478-3231. PMID   28109038. S2CID   4724419.
  9. ↑ Panda, Saswati; Ding, Jeak L. (2015). "Natural Antibodies Bridge Innate and Adaptive Immunity". The Journal of Immunology. 194 (1): 13–20. doi: 10.4049/jimmunol.1400844 . PMID   25527792.
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