October 12, 2004

IMMUNITY ADAPTIVEINNATE CELL MEDIATEDHUMORAL ANTIBODIES EFFECTOR SYSTEMS Fc Receptors Complement RECEPTORS EFFECTORS Cells Molecules ANTIGENS

First response to infection Triggered by persisting infection Protects against subsequent infection

Functions of innate immunity Initial response to infection Frequently is sufficient to eliminate the infection Effector mechanisms of innate immunity are often used to eliminate pathogens in adaptive immune response Innate immunity stimulates adaptive immune response and influences the nature of the adaptive response

Receptors recognize pathogen associated molecular patterns (PAMP) Nucleic acids unique to microbes (e.g. double stranded RNA or unmethylated CpG DNA) Features of proteins found in microbes (e.g. N-formylmethionine ) Complex lipids and carbohydrates synthesized by microbes but not mammalian cells LPS in gram-negative bacteria Teichoic acids in gram-positive bacteria Mannose-rich oligosaccharides found in microbial glycoproteins Has evolved to recognize microbial proteins often essential for their survival

Function Recognize pathogen Attract effector cells Induce effector molecules Contribute to innate immunity Influence the nature of the subsequent adaptive immune response Trigger inflammation

Overview of the events during inflammation The recruitment of leukocytes and extravasation of several plasma proteins to a site of infection with activation of the leukocytes and proteins eliminating the infectious agents

Epithelial barriers to infection Mechanical: Tight junction of epithelial cells form a physical barrier

Epithelial barriers to infection Chemical Antibacterial peptides (defensins) Enzymes (e.g. lysozyme, pepsin) Low pH

Epithelial barriers to infection Cells Mast cells Intraepithelial T lymphocyes B-1 B cells

Phagocytes Neutrophils Produced and lost in large number every day Abundant in blood Not present in healthy tissue but recruited to site of infection Short-lived (6 hours) and pus contains dead and dying neutrophils Contain granules with anti-bacterial proteins and peptides Can eliminate pathogens by phagocytosis

Phagocytes Macrophages Circulating precursors are called monocytes Longer lived than neutrophils Can divide at the site of infection

Phagocytes When pathogens cross the epithelial barrier they are recognized by phagocytes in the subepithelial connective tissues Trapping,engulfment and destruction by phagocytosis

Phagocytes When pathogens cross the epithelial barrier they are recognized by phagocytes in the subepithelial connective tissues Trapping,engulfment and destruction by phagocytosis Induction of co-stimulatory molecules Cytokine secretion by phagocyte Antigen uptake, processing and presentation

Neutrophils and monocytes are recruited from blood to sites of infection Resident tissue macrophages that recognize microbes secrete cytokines and chemokines that act on endothelial cells to produce adhesion molecules and attract circulating neutrophils and macrophages

Neutrophils and macrophages have receptors that recognize microbes and stimulate their phagocytosis and killing Receptors that directly bind microbes Mannose receptors Scavenger receptors Integrins Pathogen Associated Molecular Patterns Not clonal

Neutrophils and macrophages have receptors that recognize microbes and stimulate their phagocytosis and killing Receptors for opsonins Fc  Rs CR1, 3 and 4 (recognize cleavage products of C3) Triggering these receptors both stimulates phagocytosis and activates the phagocytes

Neutrophils and macrophages have receptors Toll-like receptors TLR-5:flagellin Activation through these receptors triggers cytokine production and expression of co-stimulatory molecules TLR-2: zymosan from yeast,bacterial lipoproteins and lipteichoic acid and peptidoglycan on Gram-positive bacteria TLR-4: LPS on Gram-negative bacteria; viral proteins TLR-9: unmethylated CpG

Neutrophils and macrophages have receptors Seven-transmembrane  -helical or G protein-coupled receptors Peptides containing N-formylmethionyl residues Activation induces migration of cells from blood through endothelium and production of microbicidal substances Receptors of this class recognize Chemokines such as IL-8 C5a

Neutrophils and macrophages have receptors for cytokines such as IFN- , the major macrophage-activating cytokine

Role of inflammation in combating infection

Combined local effects increase inflmmatory response 1. Increase in vascular diameter lead to increased local blood volume-- heat and redness from reduced velocity of blood flow 2. Decreased blood flow allows leukocytes to better interact with the vascular endothelium Extravasation: Selectins recognize certain leukocyte glycoproteins causing lymphocytes to roll. ICAM-1 on endothelium interacts with LFA-1 (a.k.a. CD11a;Cd18) and CR3 (Mac-1) so that leukocytes attach firmly to the endothelium, to cross the vascular endothelial wall and enter site of infection 3. Increase in vascular permebility leads to local accumulation of fluid- swelling and pain -- accumulation of Igs, C ’ and other blood protein in the tissue.

An increase in vascular permeability leads to local accumulation of fluid Swelling (edema) Pain Accumulation of Igs, complement and other blood proteins in tissue

Entry of fluid into blood at site of infection is prevented TNF-  Local clots in small vessels are produced. Fluid in tissue carries pathogen, either directly or within a phagocytic cell, via lymph to regional lymph nodes where an adaptive immune response is elicited

Sepsis TNF-    s released by macrophages Infection spread to the blood stream Septic shock requires signaling through TLR-4 (recognizes LPS) and mice (or humans) defective in TLR-4 do not experience septic shock Vasodilation occurs with increased vascular permeability leading to shock Mice defective in TLR-4 are highly sensitive to LPS containing pathogens.

TNF- , IL-1 and IL-6 are endogenous pyrogens which elicit acute-phase proteins

Natural Killer Cells Function against intracellular pathogens such as viruses Tumor immunity Activated by IFN- , IFN-  or IL-12 Must be able to distinguish infected from uninfected cells

Summary - Features of Innate Immunity Triggered by germline encoded receptors of limited diversity No lasting immunity or memory Elicit cytokine release by phagocytes Induced production of acute-phase proteins Elevate body temperature Induce inflammation NK cells are able to recognize infected or altered cells B-1 B cells provide pathogen specific Abs of limited diversity in the absence of T-cell help

Properties of substances that elicit an adaptive immune response

Haptens must be linked to a carrier to elicit an immune response. Abs are formed to both the hapten and carrier.

Small ligands often bind in a deep Ab pocket. There is a tight fit so Ab binding can distinguish structurally related but different haptens.

For Abs there is allelic exclusion: the products of only one allele are present within one antibody

What determines if something is effective in eliciting an immune response?

What determines if something is effective in eliciting an immune response?

What determines if something is effective in eliciting an immune response?

Granuloma: Nodule of inflammatory tissue composed of clusters of Activated macrophages and T lymphocytes often with associated Necrosis and fibrosis.