Lectin pathway

From Wikipedia, the free encyclopedia
Jump to navigation Jump to search
Structure of mannose in its α-D mannopyranose form. Mannan is a polymer of mannose.

The lectin pathway or lectin complement pathway is a type of cascade reaction in the complement system, similar in structure to the classical complement pathway,[1] 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.

In this pathway, mannose-binding lectin binds to mannose, glucose, or other sugars with 3- and 4-OH groups placed in the equatorial plane, in terminal positions on carbohydrate or glycoprotein components of microorganisms including bacteria such as Salmonella, Listeria, and Neisseria strains. Fungal pathogens such as Candida albicans and Cryptococcus neoformans as well as some viruses such as HIV-1 and Respiratory syncytial virus (RSV) are bound by MBL.

Mannan-binding lectin, also called mannose-binding protein, is a protein belonging to the collectin family that is produced by the liver and can initiate the complement cascade by binding to pathogen surfaces.

Lectin Pathway has been associated with acute respiratory distress syndrome caused by Covid-19 as well as the Sequelae or “Long Covid” symptoms as one study claims.[2] It's known that the Covid-19 virus causes a systemic disease, rather than a localized lung infection. The disease is transmitted throughout a patient’s body by the circulatory system. Along the way, the virus invades and injures the endothelial cells, which line all our blood vessels. Endothelial cell injury results in inflammation and leads to the generation of minute blood clots or thrombi (hyper-coagulation) that travel throughout the blood stream until they lodge in the smallest blood vessels (capillaries) where they restrict blood flow to virtually every organ system. This condition is known as thrombotic microangiopathy. A primary driver of the inflammatory response to endothelial cell injury is the lectin pathway of complement, part of the body’s immune system. Activation of the lectin pathway in Covid-19 has been shown to cause an inflammatory cascade, including the “cytokine storm.” The consequence of lectin pathway activation and thrombotic microangiopathy in Covid-19 can be irreparable damage to the lungs, heart, kidney, liver, brain and other vital organs.

Clinical and nonclinical data now show that lectin pathway inhibition by a therapeutic (Narsoplimab) targeting the key enzyme in the lectin pathway, MASP-2, mitigates the Covid-19 related inflammatory response and improves outcomes in critically ill Covid-19 patients.


MBL forms oligomers of subunits, which are trimers (6- to 18-heades correspond to a dimer and a hexamer, respectively). Multimers of MBL form a complex with MASP1 (Mannose-binding lectin-Associated Serine Protease), MASP2 and MASP3, that are protease zymogens. The MASPs are very similar to C1r and C1s molecules of the classical complement pathway, respectively. When the carbohydrate-recognising heads of MBL bind to specifically arranged mannose residues on the surface of a pathogen, MASP-1 and MASP-2 are activated to cleave complement components C4 and C2 into C4a, C4b, C2a, and C2b. In f, two smaller MBL-associated proteins (MAps) are found in complex with MBL. MBL-associated protein of 19 kDa (MAp19) and MBL-associated protein of 44 kDa (Map44). MASP-1, MASP-3 and MAp44 are alternative splice products of the MASP1 gene, while MASP-2 and MAp19 are alternative splice products of the MASP-2 gene. MAp44 has been suggested to act as a competitive inhibitor of lectin pathway activation, by displacing MASP-2 from MBL, hence preventing cleavage of C4 and C2 [3]

C3 convertase[edit]

C4b tends to bind to bacterial cell membranes. If it is not then inactivated, it will combine with C2b to form the classical C3 convertase (C4bC2b) on the surface of the pathogen, as opposed to the alternative C3 convertase (C3bBb) involved in the alternative pathway. C4a and C2b act as potent cytokines, with C4a causing degranulation of mast cells and basophils and C2b acting to increase vascular permeability.[4] Historically, the larger fragment of C2 was called C2a but some publications now refer to it as C2b in keeping with the convention of assigning 'b' to the larger fragment.[5]

Clinical significance[edit]

Mannose-binding Lectin deficiency - These individuals are prone to recurrent infections, including infections of the upper respiratory tract and other body systems. People with this condition may also contract more serious infections such as pneumonia and meningitis. Depending on the type of infection, the symptoms caused by the infections vary in frequency and severity.[6] Although the clinical significance of MBL-Deficiency is debated.[7]

Infants and young children with mannose-binding lectin deficiency seem to be more susceptible to infections, but adults can also develop recurrent infections. In addition, affected individuals undergoing chemotherapy or taking drugs that suppress the immune system are especially prone to infections.[6]

Endothelial Injury Syndromes (EIS) - any disorder which causes damage to the endothelium puts patients at risk of thrombotic microangiopathy or TMA. endothelial damage triggers the lectin pathway of the Complement System. This initiation leads to coagulation and activation of the classical pathway of complement. EIS examples: atypical hemolytic uremic syndrome (aHUS), Hematopoietic stem cell transplantation (HSCT), Corona Virus Disease 2019 (COVID-19), Graft vs. Host Disease (GVHD) and many others. Additional resources on Endothelial Injury Syndrome

See also[edit]


  1. ^ Wallis R, Mitchell DA, Schmid R, Schwaeble WJ, Keeble AH (2010). "Paths reunited: Initiation of the classical and lectin pathways of complement activation". Immunobiology. 215 (1): 1–11. doi:10.1016/j.imbio.2009.08.006. PMC 2824237. PMID 19783065.
  2. ^ Rambaldi, Alessandro; Gritti, Giuseppe; Micò, Maria Caterina; Frigeni, Marco; Borleri, Gianmaria; Salvi, Anna; Landi, Francesco; Pavoni, Chiara; Sonzogni, Aurelio; Gianatti, Andrea; Binda, Francesca (1 November 2020). "Endothelial injury and thrombotic microangiopathy in COVID-19: Treatment with the lectin-pathway inhibitor narsoplimab". Immunobiology. 225 (6): 152001. doi:10.1016/j.imbio.2020.152001. ISSN 0171-2985. PMC 7415163. PMID 32943233.
  3. ^ Degn, Søren; Annette G. Hansen; Rudi Steffensen; Christian Jacobsen; Jens C. Jensenius; Steffen Thiel (November 2009). "MAp44, a Human Protein Associated with Pattern Recognition Molecules of the Complement System and Regulating the Lectin Pathway of Complement Activation". Journal of Immunology. 183 (11): 7371–7378. doi:10.4049/jimmunol.0902388. PMID 19917686.
  4. ^ Stanley, Jacqueline (1 January 2002). Essentials of Immunology & Serology. Cengage Learning. p. 103. ISBN 978-0766810648.
  5. ^ First Aid for the USMLE Step 1 2015
  6. ^ a b "Mannose-binding lectin deficiency". Genetics Home Reference. US National Library of Medicine. Retrieved 23 October 2016. This article incorporates text from this source, which is in the public domain.
  7. ^ Bradley, D. T.; Bourke, T. W.; Fairley, D. J.; Borrow, R.; Shields, M. D.; Young, I. S.; Zipfel, P. F.; Hughes, A. E. (August 2012). "Genetic susceptibility to invasive meningococcal disease: MBL2 structural polymorphisms revisited in a large case-control study and a systematic review". International Journal of Immunogenetics. 39 (4): 328–337. doi:10.1111/j.1744-313X.2012.01095.x. PMID 22296677. S2CID 205900750.

External links[edit]