Lectins are a diverse group of proteins which bind carbohydrates and other ligands such as proteins, lipid, and nucleic acids.  Many function in the immune system in recognizing pathogens and the prevention of autoimmune reactions (Kilpatrick, 2002). Some lectins (such as tachylectin homologs in cnidarians) can be structurally similar to those used in immunity in other organisms but function in processes unrelated to immunity ( Mali, 2006). Plants have adapted lectins for a variety of functions such as the use in mistletoe as a component of its semi-parastitic lifestyle (Meyer, 2007).

The term lectin was originally used to describe proteins other than immunoglobulins which could distinguish between blood group glycoproteins on red blood cells.  Mollusks and arthropods possess a number of lectins which can bind to human blood groups (Kilpatrick, 2002). Sponges utilize a lectin molecule in anti-bacterial immune defenses (Schroder, 2003).  Differences in the carbohydrate-binding domains are the basis for the classification of animal lectins as C-type, galectin, I-type, heparin binding proteins, and pentraxin groups (Suzuki, 2003a).  C. elegans possesses 135 proteins with the C lectin domain compared to the 35 known in Drosophila (Nicholas, 2004).

     Collectins form a subgroup of C-type lectins with collagen-like domains.  Five collectins are known in mammals: Mannose binding lectins (MBL), lung surfactant proteins sp-A and sp-D, conglutinins, and serum collectin-43 (Lundqvist, 1999).  Collectin molecules often form homotrimers in which their collagen-like domains interact. (Lundqvist, 1999).  C-type lectins which block coagulation and formation of platelet pugs are among the harmful substances in the venom of some poisonous snakes (such as vipers) (Harrison, 2003) .

     C-lectins bind carbohydrates in a calcium dependent fashion.  They share a conserved region within the 130 amino acid carbohydrate recognition domain (CRD).   Some possess fibronectin domains.  Most C-lectins cause the endocytosis of glycoproteins (Weng, 2002).  Lectins recognize differences between the carbohydrates of self and nonself because of differences between the carbohydrates expressed on the surfaces of vertebrate and microbial cell membranes.   Vertebrate oligosaccharides rarely end with a fucose, mannose, or GlcNAc residues as do those of many microbes (Botos, 2004).  Sialic acids are often located at the distal end of the membrane oligosaccharides of microbes and thus represent good recognition targets (Angata, 2002).  Collectins recognize a diversity of carbohydrates (Lu, 2002).  Ficolins recognize carbohydrate patterns specific to microbes (an abundance of N-acetyl-D-glucosamine, for example) (Lu, 2002).

     MBL is produced by liver hepatocytes (pictured below)and functions in the blood . 


MBL can bind Staphylococcus aureus, many Streptococcus, E. coli, Klebsiella, Haemophilus influenzae type b, yeast, other fungi, and viruses such as  HIV, IAV, and RSV.  Although these monosaccharides do exist in higher animals, they do not occur in the repetitive manner in which they are found in many microbes.  Cancer cells and virally infected cells change sugar patterns and MBL can inhibit tumor growth.  Deficiency of MBL in humans lessens complement binding to microbes (Lu, 2002; Gadieva, 2001).   Children without MBL suffer recurrent infections (Kilpatrick, 2002).  MBL can bind to the multiple mannose and N-acetyl glucosamine sugars on the surface of yeast, Salmonella, and gonorrhea and can bind gp120 on HIV-1 (Botos, 2004).  

     Galectins (S-type lectins) mediate the interaction between macrophages and complement proteins and the interaction between macrophages and lymphocytes.  Galectins bind β-galactosides.  Galectins are known in sponges, nematodes, and fungi but not in protozoa or plants (Muller, 2001; Vasta, 1999).  Galectin-10 composes more than 7% of the protein in eosinophils (Kilpatrick, 2002). 


The myxomycete Plasmodium polycephalum uses lectins called tectonins during the phagocytosis of bacteria (Huh, 1998). Lectins on the surface of the trypanosome (pictured in the infected human blood below) which causes Chaga’s disease can be used as the basis for tests for diagnosing infection (Marcipar, 2003). 


Legume lectins can join to form dimers and tetramers (Srinivas, 2001).  A number of lectins are known in plants (Knozy, 2003)  and lectins are known in sponges, the most primitive animals (Schacke, 1994a).  Tunicates produce multiple kinds of lectins in response to infection (Green, 2006).A number of lectins are known in the skin mucus of fish, where they bind microbes (Suzuki, 2003a).

     The blood of some invertebrates can clot in response to injury, but not through the action of the clotting cascade found in vertebrates.  The invertebrate clotting protein coagulogen is not related to fibrinogen (coagulogen is instead similar to nerve growth factor).   However, there are fibrinogen-like molecules, in both vertebrates and invertebrates, including a group of lectins.  (Xu and Doolittle, 1990).  One of the first described lectins was the limulin protein from horseshoe crabs which agglutinates the haemolymph (Kilpatrick, 2002). 

     Invertebrate lectins are homologs of lectins which vertebrates use in immune reactions and to the vertebrate clotting factor fibrinogen. In horseshoe crabs, the tachylectin 5A produced in the hemolymph (rather than being expressed on the cells of the hemolymph as are other tachylectins) and causes the agglutination of bacteria (Adema, 1997; Gokudan, 1999; Kairies, 2001).  Its amino acid sequence, 3-dimensional shape, and calcium binding site are homologous to those of fibrinogen.  The differences in binding (tachylectin 5A binds carbohydrates while fibrinogen binds the protein of other fibrinogen monomers) is due to 2 loops in fibrinogen (P3 and P1) which are 7 and 14 amino acids shorter than the corresponding loops in tachylectin.  Vertebrates, including humans, have homologues of fibrinogen which function in innate immunity called ficolins which recognize carbohydrate groups on bacteria.  Human ficolins bind the same molecules as tachylectin 5A and are more closely related to tachylectins than to fibrinogen (Kairies, 2001).Fly genomes include about 30 genes for lectins which include several which function in immune responses (Ao, 2007).

     Many lectins function outside the immune system performing tasks such as transporting lysosomal enzymes and chaperoning in the ER.  In invertebrates, lectins can function in way similar to antibodies in opsonization and promoting phagocytosis.   In humans, collectins, ficolins, and the membrane-bound mannose receptor bind antigens and help to eliminate them (Kilpatrick, 2002).  Lectins and other molecules can bind to the glycoproteins of the HIV envelope and thus block the virus’ lytic cycle (Botos, 2004). Dendritic cells express lectin receptors to recognize microbes ( Kanazawa, 2007).

     Human lungs depend on surfactant proteins to decrease water tension in air sacs.  The epithelia of an air sac is pictured below.

These surfactant proteins are actually lectins which evolved prior to the evolution of lungs and vertebrate life on land.  The swim bladder of primitive bony fish (pictured below) is homologous to lungs and expresses surfactant proteins.

More than 95% of infections begin at the mucosa of the digestive, respiratory, urinary, or reproductive tracts.  Surfactants not only occur in the lung, but also along the mucosa of the esophagus, stomach, intestine, and pharyngotympanic tube.  The complement system functions in body fluids and therefore offers virtually no protection on mucosal surfaces (Haagsman, 2001).  Surfactants not only reduce surface tension in the lungs, they can bind microbes in the lungs (and perhaps also in the gastrointestinal tract) in innate immune responses.  SP-A and SP-D are collectins (Haagsman, 2001).  SP-C is the only surfactant protein which is solely expressed in the lungs and the function of SP-C is not clear since mutations in mice have not been shown to negatively affect lung function.  These lung surfactant proteins bind both microbes and allergens (Haagsman, 2001).  Sp-B is a member of the saposin family and may have antibacterial activity (Haagsman, 2001).

    SP-A is expressed in the lung and intestinal mucosa, in addition to other tissues.  It can bind Staphylococcus aureus, many Streptococcus, Haemophilus influenzae, E. coli,  Klebsiella, Mycoplasma, some fungi, and viruses such as  HIV, IAV, and RSV.  It also bind a number of allergenic substances such as the pollen of grass and ragweed and inhibits allergic reactions to them (Lu, 2002).
SP-D lung and epithelium of stomach and intestine, others.  It can bind Mycobaterium tuberculosis, E. coli,  Klebsiella, Pseudomonasa aeruginosa, yeast and other fungi, rotavirus, IAV, and RSV.  It can also bind dust mite extract and other allergens inhibiting inflammatory reactions to them (Lu, 2002).  The surfactant SP-A and similar proteins are expressed in areas other than the lung such as the intestinal mucosa, sinuses, synovial membranes, and the prostate (Lu, 2002). 

Surfactant protein D is part of the innate immune system that recognizes microbial carbohydrates and binds them in aggregates in both the lung and intestine . It also enhances the acquired immune system by binding most types of antibodies which in turn promotes phagocytosis by macrophages (Nadesalingam, 2005; Hogenkamp, 2007).

The intestinal mucosa is pictured below.


     A number of lectin molecules can be autoantigens involved in autoimmune diseases such as calreticulin (in Sjogren’s syndrome an celiac disease), cerebellar lectins (in multiple sclerosis), galectins (in Crohn’s disease, Hodgkin’s disease), Hakata antigen (lupus), hepatic asialoglycoprotein receptor (in autoimmune hepatitis) and myelin-associated glycoprotein (in disorders involving demyleination) (Kilpatrick, 2002).


The pentraxin family possess a fold which forms a “jelly roll”.  There are three human pentraxins (CRP, serum amyloid P component, and PTX3).  Pentraxins are known in arthropods, tunicates, and a number of vertebrates (Kilpatrick, 2002).  .  Shark pentraxins are known and possible pentraxins exist in mollusks and arthropods (Magor, 2001).


CRP binds galactans and galactose phosphates and activates complement.


PTX3 is expressed in blood cells.


Two molecules similar to collectin have been isolated from the liver and A lectin isolated from the placenta performs opsonization of bacteria and yeast there (Kilpatrick, 2002).  .


L-selectin, E-selectin, and P-selectin are lectins which serve as adhesion molecules.


Interleukin 1-8, interleukin 12, and TNF α have lectin activity in that they can bind carbohydrates in addition to their well known interactions with protein (Kilpatrick, 2002).  .


Kupferr cell receptor


Chondrolectin is expressed in a number of tissues such as the testis, prostate, heart, and spleen (Weng, 2002).  Cells of the spleen are depicted below.


Sialoadhesion family

    The sialoadhesion family of immunoglobulin-like lectins are primarily expressed in hematopoeitic cells, the immune system, and the nervous system.  The proteins are involved with protein-carbohydrate interactions (such as the sialic acid of glycoproteins and glycolipids).  There are no known members of this family in Drosophila or C. elegans.  The genes of this family are named SIGLEC1 through 10 (plus SIGLECL1).  One group of siglecs are related to CD33 and are known in primates and mice.  It seems that siglec proteins are evolved in the deuterosotomes.  Siglec-4 is expressed in oligodendocytes and Schwann cells.  Sixteen siglec pseudogenes are known in the human genome (Crocker, 2002; OMIM)  Chromosome 19 possesses a number of receptors involved in the immune system including KIRs, CD33-like siglecs, and the carcinoembryonic antigen family (CEA) (Crocker, 2002). Among the Siglec lectins (which contain immunoglobulin domains), CD33-related siglecs function in innate immunity and are expressed on the surfaces of the diverse cell types which function in innate immunity (Crocker, 2005).


Siglec-1 is found on macrophages.


Siglec-2 is expressed on B cells.


Siglec-3 is expressed on monocytes (such as that pictured below).

Siglec 4 is expressed on oligodendrocytes and Schwann cells (Schwann cells are depicted in the following image).

Siglec-5 is expressed on monocytes and neutrophils


Siglec-6 is expressed on B cells and in the placenta.


Siglec-7 is expressed in NK cells and monocytes.


Siglec-8 is expressed in eosinophils and mast cells.


Siglec-9 is expressed in monocytes, neutrophils, and NK cells.


Siglec-10 is expressed on B cells, eosinophils, and monocytes.




KLRNK2a binds to MHC proteins and inhibits the activity of cytotoxic cells.


 KLRF1 is also expressed in monocytes.


I-type lectins are members of the immunoglobulin superfamily which can bind a number of sugars and glycosaminoglycans. (The “I” refers to immunoglobulin) (Angata, 2002).  I-type lectins include siglec 1-11, CD83, NCAM, Po, ICAM-1, CD2, and hemolin (known in insects) (Angata, 2002)


The lectin DC-SIGN binds ICAM-2 and ICAM-3 and helps to induce immune responses (Caminschi, 2001).


CIRE is a lectin expressed on dendritic cells of the spleen which binds ICAM3 and can also bind HIV virus, promoting further infection of T cells (Caminschi, 2001).


Conglutinin is a serum lectin produced by the liver. It can bind some fungi and viruses. A liver lobule is depicted below.


CL-43 is a serum lectin produced by the liver.  It can bind some fungi and viruses.

CL-L1 is expressed in a number of tissues

CL-P1 is expressed in blood vessels and the placenta.  It can bind Staphylococcus aureus and E. coli (Lu, 2002).



Ficolins are lectins with a collagen-like structure (like MBL) (Gadieva, 2001).


H-Ficolin is produced in the liver and lung


L-ficolin is produced in the liver.  It can bind Salmonella.


M-ficolin is expressed in monocytes and the uterus (Lu, 2002).


P-type lectins, such as mannose-6-phosphate receptor (CD-MPR) and insulin-like growth factor II/mannose 6-phosphate receptor (IGF-II/MPR) can recognize mannose sugars which have bound a phosphate, unlike other lectins.  Phosphorylated mannose sugars are attached to lysosomal enzymes as they are processed in the ER-Golgi route as a localization signal that then bind P-type lectins (Dahms, 2002).


The group of enzymes known as GalNAc-transferases which transfer GalNAc from nucleotide-sugar groups to amino acids in proteins possess three tandem lectin domains (Tenno, 2002).




Lectins are the primary opsonins in tunicates.  Lectins also perform opsonization in mollusks and arthropods (Pearce, 2001).  In addition to attracting white blood cells through opsonization, lectin-bound microbes attract other factors in the innate immune system, the complement proteins.  Collectins and ficolins perform also these functions--they bind microbe carbohydrates, serving as opsonins, and activate the complement cascade (Lu, 2002).



     All gnathostomes possess adaptive immunity while jawless fish lack it.  Although the complement system is an important component of adaptive immunity, it also functions in innate immunity.  Jawless fish possess complement proteins which function in the lectin pathway.  Cartilaginous fish were the first vertebrates to develop a classical pathway of complement proteins and this pathway had developed components similar to the mammalian pathway by the evolution of bony fish.

     Complement pathways involve enzymes called proteases which cleave inactive proteins to produce their active forms.  Hemolymph coagulation is part of innate immunity in many invertebrates.  Horeshoe crab proteases involved in the coagulation cascade possess homologous sequences to those found in complement cascades.  Some ectotherms have duplications of complement genes and a more elaborate innate set of immune mechanisms while mammals have elaborated their adaptive immune mechanisms (Zarkadis, 2001).

     The complement system is thought to have evolved from a simple mechanism similar to that found in lectin and alternative pathways. 


Three proteins might have functioned in this system: a C3-like protein (magenta, in the above drawing), a serine protease similar to factor B (green), and a complement receptor on immune cells (red).  Complement proteins (factor B and C3) are known in echinoderms and complement-like proteins are known in more primitive invertebrates.  The complement system seems to have evolved from a simple pathway involved in opsonization (Zarkadis, 2001).  C3 is the main component in all 3 complement pathways.  In all three pathways, it is cleaved (by C3bBb in the alternative pathway and C4bC2a in the classical and lectin pathways) into two fragments, and exposes its thioester region which binds the target molecule (Nakao, 2003; Gal, 2007).  The thioester bond of C3 can bind to microbes serving in opsonization and as the site for the late complement proteins (C5 through C9 to generate a membrane pore) (Fujita, 2004).  In the response of the complement system to a microbe, active proteins of C3a and C5a function as anaphylatoxins which initiate the inflammatory response. These activated complements then bind to GPCR receptors (C3a and C5a receptors) (Sunyer, 2005). The protein C3, which is an essential element of immune cascades in vertebrates, has been identified in arthropods and even in cnidarians, along with several proteins which may represent a simple, prototypical cascade. (Otherwise, C3 might merely function in opsonization rather than in a cascade.) (Hemmrich, 2007).

     From this simple opsonization pathway, three additional pathways developed which involve additional complement proteins which form a permanent membrane hole on the microbe, causing its lysis.  The most complex and most well-known of the three is the Classical Pathway, a part of the adaptive immune response which involves antibodies.  However, most of the same components in the complement cascade of adaptive immunity are also functional in the Lectin and Alternate Pathways, which function in innate immunity.  The classical pathway originated in cartilaginous fish and the lectin pathway in urochordates (Matsushita, 2004)

    Although primitive invertebrates possess the domains used by the complement system, a complement system did not evolve until the deuterostomes.  Primitive deuterostomes evolved the components of the complement cascade and the genome duplications early in the history of the vertebrates allowed the integration of several related pathways (Fujita, 2004).

The complement pathway can also be activated by the serum mannose binding lectin (MBL, a C-type lectin) to the carbohydrates of microbes.  The serine protease MASP (MBL-associated serine protease) activates complement C3 which can either result in opsonization or the assembly of the complement factors which put a hole in the microbial membrane (Vasta, 1999).

     Sponge molecules possess the SCR/CCP domains which are found in complement proteins (Zarkadis, 2001).  Homologs of C3 and C4 are known in coral (Dodds, 2007). In primitive deuterostomes, it is not obvious that the lectin and alternative pathways have different functions (Zarkadis, 2001).  Elements of the lectin pathway, MBL and MASP, are known since protochordates.  Elements of the alternative pathway, C3 and factor B, are known in echinoderms and factor D in bony fish. (Zarkadis, 2001; Lundqvist, 1999;Pearce, 2001). The sea urchin protein SpBf is a complement protein which possesses SCR domains, a von Willebrand factor domain, and a serine protease domain.  Sea urchins possess complement C3 proteins which seem to function in opsonization and whose levels increase in response to infection.  Sea urchin proteins possess a thioester region, which in vertebrate complement proteins C3, C4, and C5, is the region which are exposed and bind target molecules in complement activation.  Some insect proteins have molecules similar to complements with thioester regions (Smith, 2002). 

     Urochordates possess proteins in both the alternative pathway (C3, Bf) and lectin pathway (MBL, MASP).  Although tunicates lack acquired immunity, they do possess complement genes, lectins, and 2 interleukin receptor genes which probably function in innate immunity (Dehal, 2002).  Tunicates seem to have homologs of complement receptors and complement proteins are known to mediate phagocytosis in bony fish (Zarkadis, 2001).

       The lectin-based opsonization pathway seems to be the original pathway.  Tunicates seem to have a minimal complement system involving a lectin which binds to serine proteases (forming GBL-MASP complex), C3, and a C3 receptor on blood cells (Fujita, 2004).

α2M/C3/C4/C5 form a gene family.  Tunicates have 2 molecules similar to α2M and two which are similar to C3.  They also possess 3 linked Bf genes, nine ficolin-like molecules, and 2 C1q like molecules (Fujita, 2004).

     Hagfish possess a protein CLP (complement-like protein) which functions in immune defenses is structurally similar to a mammalian complement protein (Hanley, 1992).  Lampreys possess homologs of C3, MASP, factor B (which has 3 SCR domains like those of gnathostomes and unlike sea urchins which have 5), and probably possess complement receptors.  Both hagfish and lamprey C3 function in opsonization (Zarkadis, 2001; Dodds, 2007). In the classical pathway, antibodies are bound by C1q which activates serine proteases (C1r and C1s) which activate C3 which is both an opsonin and part of the membrane pore which can kill a microbe.  Lampreys lack antibodies, but they possess C1q, serine proteases of the C1s/C1r/MASP family, and C3.  It seems that C1q originally functioned as a lectin before it was modified to bind antibodies.  (In mammals, C1q can bind to substances other than antibodies to initiate the complement cascade (Matsushita, 2004).  Classical and lytic pathways not known in lampreys (Fujita, 2004).

     Sharks possess homologs of C3, C4, and MASP, (Zarkadis, 2001).  Of the classical pathway which involves C1, C2, and C4, C4 is known in sharks and bony fish.  Of the terminal lytic proteins C5-C9, C5 and C8 are known in sharks (Zarkadis, 2001). Factors C6, C7, C8, and C9 form a gene family (Fujita, 2004).  Complement factors C1r and C1s bind to form a heterotetramers with two subnits of each enzyme (Presanis, 2003).

     In teleosts, many of the complement proteins genes are duplicated resulting in a greater functional diversity than possessed in mammals (Nakao, 2003; Zarkadis, 2001). In teleost fish, the complement cascade can be activated through the classical pathway, lectin pathway, and alternate pathway. The complement components of fish can function at lower temperatures than those found in mammals and are present in the plasma at much higher concentrations than their mammalian homologs (Boshra, 2006).

     Most of the components of the classical complement pathway have paralogs which function in the lectin or alternate complement pathways, suggesting that large-scale duplications led to three pathways derived from a single ancestral pathway (Fujita, 2004).

The gnathostome complement pathways were established before the branching of cartilaginous fish from the other lineages.  The C1q which binds antibodies in the classical pathway is a lectin homolgous to those which activate the lectin pathway (Fujita, 2004).

     More than 41 variants of C4 complement genes are known.  Most haploid genomes possess 2 tandem C4 genes (C4A and C4B) but duplications and deletions are known.  Often these genes are deleted/duplicated along with three nearby genes (serine/threonine nuclear protein kinase RP, steroid 21-hydroxylase CYP21, and tenascin TNX) and the entire region is referred to as the RCCX module.  Partial deletions and point mutations are fairly common in Caucasians and may have a role in autoimmune diseases and other disorders (Blanchong, 2000).

C1q not only binds antibodies IgG and IgM to initiate the classical pathway, it can also interact with a variety of microbial and self molecules. In addition, it mediates several immune responses outside the complement cascade such as virus neutralization, phagocytosis, removal of apoptotic cells, and maturation of immune cells (Ghai, 2007). The C1q domain is a component of 32 genes in the human genome, including the collagens, elastin, and adiponectin (Ghai, 2007).