Ficolin

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]

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 globural 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]

References
  1. 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. doi:10.3389/fimmu.2015.00262. 262.
  2. Kilpatrick, David C.; Chalmers, James D. (2012). "Human L-Ficolin (Ficolin-2) and Its Clinical Significance". Journal of Biomedicine and Biotechnology. 2012: 1–10. doi:10.1155/2012/138797. ISSN 1110-7243.
  3. 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. 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.
  6. 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.
  7. 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.
  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.
  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.
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