Transcript Slide 1
Innate Immunity Innate Immunity Epithelial barriers Soluble molecules Pattern-recognition receptors: TLRs, NLRs, scavenger Rs, C-type lectin Rs Macrophages Neutrophils Mannose-Binding Lectin (MBL) • Circulating in blood C-type lectin, contains multiple CRDs (carbohydrate recognition domain); • Member of collectin family of proteins, which contain both collagen-like and lectin (sugar-binding) domains. Other members of the family: surfactant proteins A and D in lung; • Binds to glycans displayed on the surfaces of microorganisms (particular orientation of certain sugar residues and their spacing are important); • Can initiate the lectin pathway of complement activation; • Once formed, the MBL-pathogen complex is bound by phagocytes; • Recognizes cryptic self-antigens, that are exposed by celldeath or reperfusion injury, or are modified by disease states. Control of MBL Production Further Reading: Teillet et al. The Journal of Immunology, 2005, 174: 2870-2877 MBL Structure and Its Selective Binding to Carbohydrates MBL Interactions with Microorganisms MBL Interactions with Altered Self • MBL binds to apoptotic and necrotic cells. • Binds to stressed or damaged cells (after ischemia reperfusion injury). • Binds to some transformed human tumor cell lines, that have abberant glycosylation patterns (colon adenocarcinoma, colorectal carcinoma). • Binds galactose isoforms on antibodies in rheumatoid joints, polymeric IgA, and certain glycoforms of IgM. MBL and Complement Activation MBL and Phagocytosis Phagocytosis without opsonization Opsonin-mediated Phagocytosis Other Receptors for Inflammatory Signaling MBL and Phagosome-dependent TLR Signaling Physiological Role of MBL • Early effect in mammals during lag period, that is required to develop an antibody response against infectious agents. • MBL alone can account for susceptibility to infection. • There’s no evolutionary advantage, nor disadvantage to different MBL alleles. • MBL can act as a disease modifier in the context of other defects in innate immunity. • Key role in containing and preventing the systemic spread of the bacterial infection. • MBL contributes to the pool of genes that together comprise to the “innate immune haplotype”, that ultimately defines the immunological fitness of the host. Summary • MBL is a pattern-recognition molecule that contains CRD for glycan interaction and is capable of activating complement via lectin pathway. • MBL is able to recognize carbohydrate structures from both infectious agents and altered self. • MBL mediates defense against microbes via phagocytosis or extracellular complement mediated effector functions. • MBL acts as a TLR2/6 co-receptor within the cell in directing intracellular signaling. • Molecules such as MBL coordinate internalization, ligand delivery and ligation of pattern recognition receptors, which ultimately define the response of the phagocytic cell to the ingested organism.