Aloe Mannose Binding Lectin & the Lectin Pathway

Lectins are a family of proteins whose individual chains consist of a C-type lectin domain, attached to a collagen domain via an alpha-coiled neck region. The chains are organized into a triple collagen helix and oligomerized through N-terminally located cysteines. The lectins bind specifically to carbohydrate structures on the surface of pathogens and recruit immune cells and molecules to destroy pathogens.

The lectins include lung surfactant proteins A and D (SP-A and SP-D) found in the surfactant coating of the luminal surface of the pulmonary epithelial cells and produced by cells lining the gastrointestinal tract. Mannan binding lectin (MBL), conglutinin and collectin-43 (CL-43) are serum proteins produced by the liver. CL-43 is a new lectin identified by its calcium-dependent binding to mannan. (1)

Role of Mannose Binding Lectin

The lectins are involved in the innate first wave of immune defense. They bind to microbial surface carbohydrates, inducing aggregation, neutralizing infectivity and mediating phagocytosis through specific receptors on the phagocytes. After binding to microbial carbohydrates, MBL (also referred to as a mannan binding protein) activates the complement system through pathways which make use of two serine proteases (MASP-1 and MASP-2) to activate the complement factors C4 and C2. Low serum MBL concentrations result from mutations in the collagen region and are associated with opsonic defects.

In the course of the past 20 years, a third route of complement activation (in addition to the classical and the alternative routes) has been identified. The lectin route of mannose-binding lectin (MBL) activates complements and (from the phylogenetic and functional points of view) has the advantage of combining the classical routes (without the intervention of antibodies) with the alternative routes (high specificity). (2)

The binding of MBL to the surface of a microorganism results in the activation of two serine proteases (MASP1 and MASP2). These enzymes can activate C4 and C2 and the C3-convertase long before there are any specific antibodies. Their recruitment of classical pathway C3 convertase via the MBL pathways is critically involved in isotype switching of antibodies against antigens during immune system maturation. (2,5)

These findings imply a new role of the MBL pathway as an additional link between innate and acquired immunity. The gene for MBL is located on the long arm of chromosome 10 and consists of a promoter gene and 4 exons coding for the protein. The prevalence of mutations in the MBL gene is about 10 percent, but in Africa South of the Sahara, it is as high as 30 percent. MBL deficiency predisposes both children and adults to a wide variety of infectious diseases, chronic diarrhea, tonsillitis, otitis media, pneumonia, (meningococcal) meningitis, sepsis and osteomyelitis. (2,5)

A mannose binding protein is an oligomeric serum lectin that plays a role in innate immunity by activating the complement system. Evidence from both in-vitro and in-vivo studies trace lectins through host innate immune defenses against infectious agents. Study of lectins in specific disease settings now raises the prospects of developing further therapies exploiting the mechanisms of innate immunity. To review, Mannan-binding lectin (MBL) is a serum lectin (i.e. mosaic protein with collagenous and lectin domains) involved in the innate immune defense against various pathogens. MBL exerts its function by binding to the microbial surface through its carbohydrate recognition domains followed by direct opsonization. Complements are activated by serine proteases MASP-1 and MASP-2. In man, only one MBL form has been found while the mouse and the rat have two MBL forms in serum. (4)

Therefore, Mannan-binding lectin (MBL) plays a pivotal role in innate immunity by activating complement after binding carbohydrate moieties on pathogenic bacteria and viruses. Structural similarities are shared by MBL and Cl complexes and by the MBL- and Clq- associated serine proteases. Serine proteases, MASP-1 and MASP-2, and Cir and Cls> exhibit proteolytic activities against C3 and C4 respectively, and C2 is activated by both MASPs.8 The host defense molecules of mannan binding lectin, serum amyloid P component and the macrophage migration inhibitory factor-binding sarcolectin can be purified and labeled in the lab. (6)

The Anatomy of Lectin Structures

The human asialoglycoprotein receptor (ASGPR), also called hepatic lectin, is an integral membrane protein and is responsible for the clearance of desialylated, galactose-terminal glycoproteins from the circulation by receptor-mediated endocytosis. It can be subdivided into four functional domains: the cytosolic domain, the transmembrane domain, the stalk and the carbohydrate recognition domain (CRD). (9)

The structure provides direct confirmation for the conversion of the ligand-binding site of the mannose-binding protein to an asialoglycoprotein receptor-like specificity suggested by Drickamer and colleagues. (11)

The carbohydrate recognition domains (CRD’s) of human serum mannose-binding lectin (MBL) and pulmonary surfactant protein D (SP-D) have distinctive monosaccharide-binding properties, and their N-terminal and collagen domains have very different quaternary structures. (11) The C-type lectin domains contain 110-130 amino-acid residues arranged in a conserved sequence pattern which allows the domain to fold into a well-defined tertiary structure. The binding of these proteins can be influenced by induction with interieukin-6. Cell membrane molecules binding MBL and Cl q are not identical. Moreover, biological functions exerted by these proteins are also markedly different. (10,12)

The Signals of Mannan Recognition Response

The lipopolysaccharide structures of Salmonella enterica serovar Typhimurium and Neisseria gonorrhoeae determine the attachment of human mannose-binding lectin to intact organisms. For both organisms, the possession of the core LPS structures leads to avid binding of MBL. It is not possible to predict the magnitude of MBL binding from the identity of the LPS terminal sugar alone, indicating that the three-dimensional disposition of LPS molecules is important in determining MBL attachment. These results further support the hypothesis that LPS structure is a major determinant of MBL binding. (13)

Low concentrations of immunoglobulin G antibodies to Salmonella serogroup C in C2 deficiency suggest a mannan-binding lectin pathway-dependent mechanism. (14)

Distinctive functional properties of lectin collagenous domains and CRD’s can be exploited to generate novel human lectins with potential for therapy of influenza. (16)

Mannose-binding Lectin Deficiency

Serum mannose-binding protein (MBP) or mannose-binding lectin initiates the lectin branch of the innate immune response by binding to the surface of potentially pathogenic microorganisms and initiating complement fixation through an N-terminal collagen-like domain. Mutations in this region of human MBP are associated with immunodeficiency resulting from a reduction in the ability of the mutant MBP’s to fix complement as well as from reduced serum concentrations. Results suggest that defective secretion resulting from structural changes in the collagen-like domain is likely to be a contributory factor for MBP immunodeficiency. (17)

The codon-54 mutation and low-producing promoter polymorphisms of the MBL gene are associated with Homozygosity for MBL variant alleles, which may explain much of the increased risk of complicating infections seen in SLE patients. Additionally, it is a minor risk factor for acquiring SLE. (19) Relative deficiency of mannan-binding lectin (MBL) is associated with recurrent miscarriage. (20)

The complement system plays an important role in mediating tissue injury after oxidative stress. Consistent with our in-vitro findings, C3 and MBL immunostaining throughout the ischemic area at risk increased during rat myocardial reperfusion in-vivo. These data suggest that the LCP mediates complement activation after tissue oxidative stress inhibition of MBL may represent a novel therapeutic strategy for ischemia/reperfusion injury and other complement-mediated disease states. (21)

To review, current research examines the relationships of deficient MBL functions with such conditions as rheumatoid arthritis, lupus, oxidative ischemia, recurrent infections, kidney problems and much more. As an example of unexpected future possibilities, MApl9 plays a role in the inhibition of calcium oxalate renal stone formation. (15)