Mannose-binding lectin: targeting the microbial world for complement attack and opsonophagocytosis.
Mannose-binding lectin (MBL) is an important constituent of the innate immune system. This protein binds through multiple lectin domains to the repeating sugar arrays that decorate many microbial surfaces, and is then able to activate the complement system through a specific protease called MBL-associated protease-2. We have used flow cytometry to study both the binding of MBL to microorganisms and the subsequent activation of complement. For selected Gram-negative organisms, such as Salmonella and Neisseria, we have examined the relative roles of lipopolysaccharide (LPS) structure and capsule in determining binding and conclude that the LPS is of major importance. Our results from studies with several clinically relevant organisms also show that MBL binding detected by flow cytometry leads to measurable activation of purified C4, suggesting that the bound lectin is capable of initiating opsonophagocytosis and/or bacterial lysis. There is an increasing literature suggesting that MBL deficiency, which mainly results from three relatively common single point mutations in exon 1 of the gene, predisposes both to infection by extracellular pathogens and to autoimmune disease. In addition, the protein also modulates disease severity, at least in part through a complex, dose-dependent influence on cytokine production. The mechanisms and signalling pathways involved in such processes remain to be elucidated.
Jack
D L
DL
Immunobiology Unit, Institute of Child Health, University College London, UK.
Klein
N J
NJ
Turner
M W
MW
D016667:Bacterial Capsules / Q000378:metabolism; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism; D050260:Carbohydrate Metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D037222:Collectins; D003167:Complement Activation; D003176:Complement C3 / Q000502:physiology; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D006090:Gram-Negative Bacteria / Q000378:metabolism; D016905:Gram-Negative Bacterial Infections / Q000276:immunology; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000378:metabolism; D008358:Mannose / Q000378:metabolism; D050606:Mannose-Binding Protein-Associated Serine Proteases; D009895:Opsonin Proteins / Q000276:immunology*; D010587:Phagocytosis; D017354:Point Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D012697:Serine Endopeptidases / Q000378:metabolism; D013379:Substrate Specificity
D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D037222:Collectins; D003176:Complement C3; D008070:Lipopolysaccharides; D009895:Opsonin Proteins; C105296:MASP2 protein, human; D050606:Mannose-Binding Protein-Associated Serine Proteases; D012697:Serine Endopeptidases; D008358:Mannose