Lectin Pathway of the complement system

The lectin pathway of the complement system is a type of cascade reaction that involves the recognition and elimination of a wide range of pathogens and apoptotic cells by the innate immune system. The lectin pathway is similar to the classical pathway in that it activates the C3 convertase and the membrane attack complex (MAC) through the cleavage of C4 and C2 by serine proteases. However, unlike the classical pathway, which is triggered by antibodies bound to antigens, the lectin pathway is initiated by carbohydrate-binding proteins called lectins that bind to specific sugars on the surface of microbes or altered self-cells.

Lectins are a group of proteins that have at least one domain that can bind to carbohydrates in a specific and reversible manner. Lectins can be classified into different families based on their structural and functional characteristics. Some of the major families of lectins involved in the lectin pathway of the complement system are:

• Mannose-binding lectin (MBL): This is a soluble protein that circulates in the blood plasma and binds to mannose, glucose, N-acetylglucosamine, and other sugars with 3- and 4-hydroxyl groups in equatorial positions on the surface of bacteria, fungi, viruses, and protozoa. MBL can also bind to apoptotic cells and necrotic cells that expose these sugars. MBL is structurally similar to C1q, the recognition molecule of the classical pathway, as it has a collagen-like region and six globular heads that can interact with multiple ligands.
• Ficolins: These are also soluble proteins that circulate in the blood plasma and bind to acetylated residues such as N-acetylglucosamine, N-acetylgalactosamine, and N-acetylneuraminic acid on the surface of bacteria, fungi, viruses, and apoptotic cells. Ficolins have a collagen-like region and a fibrinogen-like domain that forms a trimeric structure with six binding sites for ligands. There are three types of ficolins in humans: Ficolin-1 (M-ficolin), Ficolin-2 (L-ficolin), and Ficolin-3 (H-ficolin). Ficolin-1 is mainly expressed by monocytes, macrophages, and granulocytes, while Ficolin-2 and Ficolin-3 are mainly synthesized by the liver and secreted into the blood.
• Collectin 11 (CL-K1): This is another soluble protein that circulates in the blood plasma and binds to oligomannose structures on the surface of bacteria, fungi, viruses, and apoptotic cells. Collectin 11 has a collagen-like region and a C-type lectin domain that forms a hexameric structure with six binding sites for ligands. Collectin 11 is also expressed by endothelial cells, epithelial cells, and mesangial cells in various tissues.

When these lectins bind to their ligands on the surface of pathogens or altered self-cells, they activate a series of enzymatic reactions that lead to the formation of C3 convertase and MAC, which mediate various effector functions such as inflammation, opsonization, phagocytosis, and lysis of target cells. The lectins form complexes with mannose-binding lectin-associated serine proteases (MASPs), which are soluble serine proteases that cleave C4 and C2 upon activation by lectin-ligand interactions. There are four types of MASPs in humans: MASP-1, MASP-2, MASP-3, and MASP-4. MASP-1 and MASP-2 are homologous to C1r and C1s of the classical pathway, respectively, while MASP-3 and MASP-4 are unique to the lectin pathway. MASP-1 can activate MASP-2 and cleave C2, while MASP-2 can cleave both C4 and C2. MASP-3 can activate pro-factor D into factor D, which is involved in the alternative pathway of complement activation. MASP-4 can cleave prothrombin into thrombin, which is involved in blood coagulation.

The lectin pathway of complement activation is an important part of innate immunity that provides an effective defense against invading pathogens and apoptotic cells without requiring prior exposure or antibody production. The lectin pathway also interacts with other pathways of complement activation and other components of innate and adaptive immunity to modulate immune responses.

The lectin pathway is initiated by the binding of carbohydrate-binding proteins called lectins to the surface of pathogens. The most important lectin in this pathway is mannose-binding lectin (MBL), which recognizes mannose-containing sugars on bacteria, fungi, viruses and parasites. MBL is a hexameric protein with a collagen-like region and six globular heads that can bind to multiple carbohydrate targets.

When MBL binds to a pathogen surface, it forms a complex with two protease zymogens, MASP-1 and MASP-2, which are homologous to C1r and C1s in the classical pathway. MASP-1 and MASP-2 are activated by the conformational change of MBL upon binding to the pathogen. MASP-1 activates MASP-2 by cleaving its prodomain, and both MASPs can cleave C2. MASP-2 can also cleave C4.

C4 is cleaved into C4a and C4b. C4b covalently attaches to the pathogen surface or to nearby molecules. C4b then binds to C2, which is cleaved by MASP-2 into C2a and C2b. C2a remains bound to C4b, forming the C3 convertase (C4b2a) of the lectin pathway. This complex can cleave multiple C3 molecules into C3a and C3b.

C3a is released into the fluid phase and acts as an anaphylatoxin, inducing inflammation and attracting immune cells. C3b binds to the pathogen surface or to nearby molecules, enhancing opsonization and phagocytosis. Some of the C3b molecules can also bind to the C3 convertase (C4b2a), forming the C5 convertase (C4b2a3b) of the lectin pathway. This complex can cleave C5 into C5a and C5b.

C5a is another anaphylatoxin that amplifies inflammation and chemotaxis. C5b initiates the formation of the membrane attack complex (MAC), which consists of C5b, C6, C7, C8 and multiple copies of C9. The MAC inserts into the pathogen membrane, creating pores that disrupt its integrity and cause cell lysis.

The lectin pathway shares some components and steps with the classical pathway, but differs in its initiation mechanism and recognition receptors. The lectin pathway is considered part of the innate immune system, as it does not require antibodies or specific recognition of antigens. However, it can also interact with the adaptive immune system by activating complement receptors on B cells and enhancing antibody production.

The lectin pathway of the complement system can be a double-edged sword. On one hand, it helps to eliminate pathogens and apoptotic cells by activating the complement cascade. On the other hand, it can also cause tissue damage and inflammation if it is not properly regulated. Therefore, there are several inhibitors that can modulate the lectin pathway and prevent excessive or inappropriate activation.

Some of the inhibitors of the lectin pathway are:

• C1-inhibitor: This is a plasma protein that can bind to and inhibit MASP-1 and MASP-2, the serine proteases that cleave C4 and C2 in the lectin pathway . C1-inhibitor also inhibits C1r and C1s in the classical pathway, as well as factor XIIa and kallikrein in the kinin system.
• Antithrombin (AT): This is another plasma protein that can inhibit MASP-1 and MASP-2, as well as thrombin and other coagulation factors . AT can also bind to heparan sulfate on endothelial cells and enhance its inhibitory activity.
• α(2)-macroglobulin: This is a large plasma protein that can trap and inhibit MASP-1 and MASP-2, as well as other proteases such as plasmin and elastase . α(2)-macroglobulin undergoes a conformational change when it binds to a protease, exposing a receptor-binding site that allows it to be cleared by macrophages.
• Map44 (Mannose-binding lectin-associated protein of 44 Kilodalton): This is a truncated form of MASP-2 that lacks the protease domain. It can compete with MASP-2 for binding to MBL or ficolins, thus preventing the cleavage of C4 and C2 . Map44 is also known as MAp19 or sMAP.

These inhibitors help to maintain the balance between the beneficial and harmful effects of the lectin pathway. They can also be potential therapeutic targets for diseases that involve dysregulation of the lectin pathway, such as IgA vasculitis-associated nephritis, sepsis, or ischemia-reperfusion injury.

The lectin pathway is a part of the complement system, which is a defense mechanism against pathogens and apoptotic cells. It involves carbohydrate-binding proteins called lectins or collectins that bind to sugars on the surface of microbes or dying cells. The lectins activate serine proteases that trigger a cascade of reactions similar to the classical pathway, but without antibody recognition. The lectin pathway leads to various effector functions such as phagocytosis, cell lysis, inflammation, and adaptive immune response.

Some of the applications and significance of the lectin pathway are:

• This pathway effectively protects against invading pathogens and apoptotic cells by enhancing their clearance and elimination. For example, in dengue infection, this pathway has been found to prevent virus attachment to the target cells.
• This pathway induces inflammatory reactions by releasing anaphylatoxins (C5a, C4a, and C3a) that recruit and activate leukocytes, mast cells, and basophils. These cells secrete cytokines, histamine, and other mediators that increase vascular permeability and blood flow to the site of infection.
• This pathway promotes opsonization by coating the pathogens with C3b, C4b, and C1q that facilitate their recognition and ingestion by phagocytes such as macrophages and neutrophils. This also enhances antigen presentation and adaptive immune response.
• This pathway causes lysis of Gram-negative bacteria, human cells displaying foreign epitopes, and viral envelopes by forming the membrane attack complex (MAC) that inserts into the lipid bilayer and creates pores. This disrupts the membrane integrity and causes osmotic lysis or apoptosis.
• This pathway plays a role in the activation of naive B-lymphocytes during adaptive immunity by binding to C3d on their surface and providing a co-stimulatory signal that enhances antibody production.
• This pathway removes harmful immune complexes from the body by binding to C3b on their surface and facilitating their transport to the liver or spleen where they are degraded by phagocytes.

The lectin pathway is therefore an important component of the innate immune system that provides a rapid and effective response to various microbial threats and cellular debris. It also bridges the innate and adaptive immunity by modulating the antigen presentation and antibody production. However, uncontrolled activation of the lectin pathway can also lead to tissue damage and inflammatory disorders, so it is regulated by various inhibitors such as C1-inhibitor, antithrombin (AT), α(2)-macroglobulin, and Map44.

Disorders and Diseases Associated with Lectin Pathway

The lectin pathway of the complement system plays an important role in host defense against various pathogens, but it can also be involved in the pathogenesis of some autoimmune and inflammatory diseases. Some examples are:

• Rheumatic heart disease (RHD): This is a chronic condition that results from repeated episodes of acute rheumatic fever (ARF), which is caused by infection with group A streptococcus (GAS). The lectin pathway is activated by GAS antigens and contributes to the inflammation and tissue damage in the heart valves.
• Systemic lupus erythematosus (SLE): This is a systemic autoimmune disease that affects multiple organs and tissues. The lectin pathway is activated by autoantibodies and immune complexes that bind to MBL or ficolins, leading to excessive complement activation and tissue injury.
• Ischemia-reperfusion injury (IRI): This is a condition that occurs when blood flow is restored to an organ or tissue after a period of ischemia (lack of oxygen). The lectin pathway is activated by the release of damage-associated molecular patterns (DAMPs) from the ischemic tissue, causing inflammation and oxidative stress.
• Age-related macular degeneration (AMD): This is a degenerative eye disease that causes loss of central vision. The lectin pathway is activated by the accumulation of drusen, which are deposits of extracellular material under the retina. Drusen contain MBL-binding ligands and activate the lectin pathway, leading to chronic inflammation and retinal damage.

These are some of the disorders and diseases associated with the lectin pathway of the complement system. Understanding the role of this pathway in health and disease may help to develop new diagnostic and therapeutic strategies.

Challenges and Future Directions of Lectin Pathway Research

The lectin pathway of the complement system is a complex and dynamic network of interactions that involves multiple components, regulators, and effectors. Despite the advances in understanding the molecular mechanisms and biological functions of this pathway, there are still many challenges and open questions that need to be addressed by future research. Some of these are:

• The precise roles and regulation of the different lectin pathway initiators (MBL, ficolins, and CL-K1) and their associated proteases (MASPs) in various physiological and pathological conditions. For example, how do these molecules discriminate between self and non-self structures? How do they interact with each other and with other complement components? How do they modulate the inflammatory response and tissue damage?
• The genetic and environmental factors that influence the expression, activity, and polymorphism of the lectin pathway components and their impact on susceptibility, severity, and outcome of various diseases. For example, how do genetic variations in MBL, ficolins, MASPs, or their inhibitors affect the risk and progression of infections, autoimmune disorders, or cardiovascular diseases? How do environmental factors such as diet, microbiota, or stress modulate the lectin pathway function?
• The development of novel diagnostic tools, therapeutic strategies, and biomarkers based on the lectin pathway components or their modulation. For example, how can the lectin pathway be exploited for the detection, prevention, or treatment of infectious or inflammatory diseases? How can the lectin pathway be targeted to enhance or suppress immune responses in different contexts? How can the lectin pathway be used as a biomarker for disease activity, prognosis, or response to therapy?

These are some of the exciting and challenging topics that await further exploration in the field of lectin pathway research. By addressing these questions, we may gain new insights into the molecular basis and clinical implications of this important branch of the complement system.

The lectin pathway of the complement system is a vital part of the innate immune system that can recognize and eliminate various pathogens and apoptotic cells. The pathway is initiated by the binding of lectins, such as MBL and ficolins, to specific carbohydrate structures on the surface of the targets. The lectins then activate MASPs, which cleave C4 and C2 to form C3 and C5 convertases. These convertases then generate C3a, C3b, C5a, and C5b, which mediate inflammation, opsonization, phagocytosis, and lysis of the pathogens. The lectin pathway is regulated by several inhibitors, such as C1-inhibitor, MAp44, and α(2)-macroglobulin, to prevent excessive or inappropriate activation. The lectin pathway has important implications for human health and disease, as it can protect against infections, modulate adaptive immunity, and contribute to tissue injury and inflammation in some conditions.

We are Compiling this Section. Thanks for your understanding.