Innate Immunity

Azad K. Kaushik, BVSc (Honors), MVSc, DSc (Paris)University of Guelph

Azad Kaushik (Illustrations from Kuby Immunology, 7th Edition)

Anatomical barriers to infection

n Several barriers, both physical and chemical, exist to prevent pathogens from gaining access to tissues Should those barriers be breached, innate immune

system receptors recognize the threatn Conserved pathogen-associated molecular patterns

(PAMPs) found on microbes Aging, dead, or damaged self structures can also be

recognizedn Damage-associated molecular patterns (DAMPs)

Pattern recognition receptors (PRRs) recognize these structures and target them for clearance

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Anatomical barriers to infection

Anatomical barriers to infectionn Barriers are just one difference between innate and

adaptive immune responses

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Anatomical barriers to infectionn Epithelial barriers prevent pathogen entry into the

bodys interior Skin Mucosal membranes

Anatomical barriers to infectionn Epithelial layers produce protective substances

Acidic pH Enzymes and binding proteins Antimicrobial peptides

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Phagocytosis

n Defined as engulfment and internalization of materials such as microbes for their clearance

Phagocytosis: accessory cells (Macrophage, Neutrophils etc.) a. chemotaxisb. adherence to cell wallc. formaJon of phago-lysosomed. proteolyJc digesJon; and e. eliminaJon by exocytosis.

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Phagocytosis

n Microbes are recognized by receptors on phagocytes May recognize PAMPs

directly May recognize soluble

opsonin protein bound to microbes

Phagocytosis

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Phagocytosisn Opsonins

Mannose-binding lectin (Collectin) H-ficolin C1 bound to Antibody or LPS

Phagocytosisn Ingested materials are taken into phagosomes

Phagosomes are fused with lysosomes or granulesn Destruction occurs through enzyme degradation,

antimicrobial proteins, and toxic effects of reactive oxygen and reactive nitrogen species (ROS and RNS)

Induced cellular innate responsesn Families of PRRs recognize a variety of PAMP ligands

TLRs CLRs RLRs NLRs

n Signaling pathways are activated, contributing to innate/inflammatory responses

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Induced cellular innate responsesn Toll-like receptors (TLRs) recognize many types of

pathogen molecules Homologous to fruit fly Toll receptor Dimers with extracellular leucine-rich (LRR)

domains that bind PAMPs and DAMPs

Induced cellular innate responsesn TLRs recognize many types of pathogen molecules

Of 13 TLRs in mice and humans, some are in lysosomes and some are surface bound

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Induced cellular innate responses Location helps determine what each binds

n TLR binding of PAMPs activates signaling pathways

Induced cellular innate responses

n C-type lectin receptors (CLRs) Heterogeneous population of surface PRRs

expressed on Macrophages, dendritic cells, PMNs, B and T cells

Recognize cell wall componentsn Sugars/polysaccharides of bacteria/fungi

Trigger a variety of pathwaysn Some similar to those activated by TLRs

n RIG-I-like receptors (RLRs; Retinoic Acid inducible gene) RNA helicases Function as cytosolic PRRs Recognize viral double-stranded RNAs Trigger signaling pathways

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Induced cellular innate responses

n NOD-like receptors (NLRs) Large family of cytosolic PRRs Activated by intracellular PAMPs Can also sense changes in intracellular environment

n Activates caspase-1 proteasen Caspase-1 cleaves IL-1/IL-18 into active forms for release

n PRR signaling pathways activate expression of various genes Antimicrobial peptides Type I interferons (potent antiviral activity) Cytokines (inflammatory IL-1, TNF-, and IL-6) Chemokines Enzymes: iNOS and COX2

Induced cellular innate responses

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Induced cellular innate responses

Induced cellular innate responses

n PRR signaling pathways activate expression of a variety of genes Type I interferons (potent antiviral effects)

Inflammatory responses

n Proinflammatory cytokines and chemokines triggered by innate responses to infection, damage, or harmful substances

n Early components of inflammation include: Increased vascular permeability Recruitment of neutrophils and other leukocytes

from the blood to the site of damage/infection

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Inflammatory responses

Inflammatory responses

n Later stages of inflammation are the acute phase responses (APRs) Induced by proinflammatory cytokines (IL-1, TNF-

, and IL-6) APR involves:

n Increased synthesis/secretion of antimicrobial proteins from the liver MBL CRP Complement components

n Liver acute phase proteins activate other processes that help eliminate pathogens

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Natural killer (NK) cells

n NK cells are lymphocytes with innate immune functions Express a set of receptors for self proteins

induced by:n Infectionsn Malignant transformationsn Other stresses

Activated NK cells perform one of two functions:n Kill the altered self celln Produce cytokines that induce adaptive responses

against the altered self cell

Interactions between the innate and adaptive immune systems

n A constant interplay between the two systems exists Several innate systems have been co-opted by

adaptive immunity to contribute to antibody-mediated pathogen eliminationn Opsonizationn Complement activation

Some lymphocytes express TLRs, but use them as co-stimulatory receptors

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Interactions between the innate and adaptive immune systems

n A constant interplay between the two systems exists Dendritic cells are a key bridge

n They bring antigens from the site of infection and present them to T cells in lymph nodes

n This activates the T cells, allowing them to differentiate into particular pathogen-specific subsets for the best antigen clearance TH cell subsets TC cells

Ubiquity of innate immunityn Innate immunity is evolutionarily older

TLRs are unique to animals, BUT PRRs with leucine-rich repeats (LRRs) are found in

virtually all plants and animals

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iClick Questions

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Indicate whether each of the following statements is true (A) or false (B):

i. Low pH in stomach is not a host defense mechanism

ii. Destruction occurs through enzyme degradation only in the phagosome

iii. Mannose-binding lectin acts as opsonin

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