innate immunity
DESCRIPTION
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). - PowerPoint PPT PresentationTRANSCRIPT
Innate Immunity
Innate Immunity
Epithelial barriers Soluble molecules
Macrophages
Neutrophils
Pattern-recognition receptors:TLRs, NLRs, scavenger Rs, C-type lectin Rs
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 cell-
death or reperfusion injury, or are modified by disease states.
Control of MBL ProductionFurther 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.