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The Lectin Pathway of the Complement System-Activation, Regulation, Disease Connections and Interplay with Other
József Dobó1, Andrea Kocsis1, Bence Farkas1
1Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Hungarian Research Network, 1117 Budapest, Hungary.
Insights
The lectin pathway (LP) is a key part of the complement system, involved in immunity and disease. This review covers its components, activation, regulation, and diverse roles beyond complement, including in development and coagulation.
Area of Science:
- Immunology
- Biochemistry
- Molecular Biology
Background:
- The complement system is a critical proteolytic cascade in vertebrate blood, alongside coagulation-fibrinolysis.
- The lectin pathway (LP), a recently discovered complement activation route, is crucial for innate immunity.
- Pattern recognition molecules (PRMs) like MBL initiate LP activation by binding to microbial patterns.
Purpose of the Study:
- To provide a comprehensive review of the lectin pathway (LP) of complement.
- To detail the history, components, activation, and regulation of the LP.
- To explore the non-canonical functions and disease associations of LP components.
Main Methods:
- Literature review and synthesis of existing research on the complement system and LP.
- Analysis of the roles of Mannose-Binding Lectin (MBL)-associated serine proteases (MASPs) and other LP components.
- Examination of the connections between LP function, blood coagulation, and cellular effects.
Main Results:
- The LP involves PRMs (MBL, collectins, ficolins) and effector proteases (MASPs).
- MASP-1 and MASP-2 activate the LP, while MASP-3 influences the alternative pathway.
- LP components exhibit "moonlighting" functions in development, coagulation, and potentially tumor suppression.
Conclusions:
- The lectin pathway plays a significant role in innate immunity and disease pathogenesis, including stroke, kidney diseases, and COVID-19.
- Understanding LP's diverse functions, including its links to coagulation and cellular effects, is crucial for therapeutic development.
- Further research into LP's non-canonical roles offers potential for novel treatment strategies.
Abstract:
The complement system is the other major proteolytic cascade in the blood of vertebrates besides the coagulation-fibrinolytic system. Among the three main activation routes of complement, the lectin pathway (LP) has been discovered the latest, and it is still the subject of intense research. Mannose-binding lectin (MBL), other collectins, and ficolins are collectively termed as the pattern recognition molecules (PRMs) of the LP, and they are responsible for targeting LP activation to molecular patterns, e.g., on bacteria. MBL-associated serine proteases (MASPs) are the effectors, while MBL-associated proteins (MAps) have regulatory functions. Two serine protease components, MASP-1 and MASP-2, trigger the LP activation, while the third component, MASP-3, is involved in the function of the alternative pathway (AP) of complement. Besides their functions within the complement system, certain LP components have secondary ("moonlighting") functions, e.g., in embryonic development. They also contribute to blood coagulation, and some might have tumor suppressing roles. Uncontrolled complement activation can contribute to the progression of many diseases (e.g., stroke, kidney diseases, thrombotic complications, and COVID-19). In most cases, the lectin pathway has also been implicated. In this review, we summarize the history of the lectin pathway, introduce their components, describe its activation and regulation, its roles within the complement cascade, its connections to blood coagulation, and its direct cellular effects. Special emphasis is placed on disease connections and the non-canonical functions of LP components.
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