Lectin pathway
The lectin pathway is one of the three primary activation routes of the complement system, a vital arm of the innate immune response in vertebrates that enhances pathogen clearance and modulates inflammation.[1] It is triggered when pattern recognition molecules, primarily carbohydrate-binding lectins such as mannose-binding lectin (MBL) and ficolins, bind to specific sugar motifs on pathogen surfaces or damaged host cells, distinguishing it from the antibody-dependent classical pathway and the spontaneous alternative pathway.[2] This recognition initiates a proteolytic cascade that converges with the other pathways at the formation of the C3 convertase, amplifying complement activation to promote opsonization, cell lysis, and immune cell recruitment.[1] Key components of the lectin pathway include the recognition molecules—MBL, ficolins (ficolin-1, -2, and -3), and collectins like collectin-11 (CL-11) and collectin kidney 1 (CL-K1)—which form complexes with MBL-associated serine proteases (MASPs).[1] Upon binding to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), such as microbial glycans or acetylated groups, MASP-1 undergoes autoactivation and subsequently activates MASP-2, which cleaves complement proteins C4 and C2 to generate the C4bC2b (or C4b2a) C3 convertase.[2] MASP-3 plays a supportive role, particularly in priming the alternative pathway, while regulatory MBL-associated proteins (MAps), such as MAp19 and MAp44, help fine-tune the response.[1] The pathway's activation is tightly regulated to prevent host tissue damage, primarily through inhibitors like the C1 inhibitor (C1-INH), antithrombin, and factor I, which target MASP activity and C4b degradation.[2] Dysregulation of the lectin pathway has been implicated in various diseases, including infections, autoimmune disorders like IgA nephropathy, ischemia-reperfusion injury, and rheumatic heart disease, highlighting its dual role in protection and pathology.[1] Beyond immunity, emerging evidence suggests non-canonical functions in embryonic development and tumor suppression, underscoring its broader physiological impact.[1]Overview
Introduction
The lectin pathway is a key activation route within the complement system, functioning as an innate immune mechanism that initiates complement cascade through the recognition of specific carbohydrate patterns on pathogen surfaces or damaged host cells. This pathway enables rapid host defense by binding pattern recognition molecules to microbial structures, thereby triggering proteolytic events that amplify immune responses without the need for antibodies or prior exposure to antigens.[3] The discovery of the lectin pathway occurred in the 1990s, building on earlier identification of mannose-binding protein (now termed mannose-binding lectin or MBL) in serum during the 1980s, with pivotal studies demonstrating its role in complement activation analogous to the classical pathway's C1q. Seminal research, including work by Ikeda et al. in 1987 on MBL's association with complement activity and subsequent findings by Matsushita and Fujita in 1992 on associated serine proteases, established the pathway's distinct initiation mechanism. Further confirmation in 1997 by Thiel et al. highlighted the involvement of these proteases in cleaving key complement components, solidifying the lectin pathway as a dedicated arm of innate immunity.[4][5][6] In host defense, the lectin pathway bridges the gap in innate immunity by directly sensing evolutionarily conserved microbial motifs, such as mannose residues, thereby facilitating early pathogen clearance independent of adaptive responses. This recognition-driven activation underscores its evolutionary importance in providing immediate protection against infections. The pathway culminates in the deposition of C3 fragments for opsonization, generation of anaphylatoxins like C5a to induce inflammation and immune cell recruitment, and ultimately the formation of the membrane attack complex for pathogen lysis.[3]Comparison with other pathways
The lectin pathway differs fundamentally from the other two complement activation pathways in its initiation, being antibody-independent and relying on soluble lectins such as mannose-binding lectin (MBL) or ficolins to recognize pathogen-associated molecular patterns (PAMPs) like carbohydrates on microbial surfaces.[3] In contrast, the classical pathway requires antibodies (IgG or IgM) bound to antigens, forming immune complexes that engage C1q for activation.[3] The alternative pathway initiates through spontaneous hydrolysis of C3 in plasma, leading to low-level deposition on surfaces and amplification via factor B and D, without needing prior immune recognition.[3] Despite these differences, all three pathways share downstream elements, converging at the formation of a C3 convertase that cleaves C3 into C3a and C3b, thereby initiating opsonization, anaphylatoxin release, and progression to the terminal membrane attack complex (MAC) for cell lysis.[3] The lectin and classical pathways both generate the C4b2a convertase, while the alternative uses C3bBb, but the subsequent cascade from C5 onward is identical across pathways.[3] Evolutionarily, the lectin pathway is considered an ancient innate immune mechanism, with homologs of its recognition molecules and serine proteases present in invertebrates and protochordates, predating the adaptive immunity-linked classical pathway and the more recently evolved alternative pathway in jawed vertebrates. This conservation underscores its role as a primordial defense against pathogens, maintained through vertebrates for rapid, non-specific responses.| Pathway | Initiators | Triggers | Key Regulators |
|---|---|---|---|
| Classical | C1q, C1r, C1s | Immune complexes, apoptotic cells | C1-INH, C4BP |
| Lectin | MBL, ficolins, MASPs | Carbohydrates, PAMPs on pathogens | C1-INH, MAp44/MAp19, C4BP |
| Alternative | C3, factor B, factor D | Spontaneous C3 hydrolysis, surfaces | Factor H, factor I, DAF, MCP |