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.