Innate Immune System

Innate immunity

Innate immunity

general processes that resist offending agents

Humoral immunity acts through _______ while cellular immunity directly ___________

molecules secreted by fluids

kills pathogens by immune cells

Mechanisms of innate immune response

• recognizes pathogen

• activates cells + complement system

Main fxns of innate immunity

• slows spread

• attracts immune cells to site

• activates complement system

• breaks down immune complexes + affected cells

• activates adaptive immunity w/ antigens

biological barriers use _________ to prevent pathogen colonization

commensal bacteria

______ sense the presence of infectious agents and substances released from dead cells

receptors (of phagocytes, dendritic cells, etc)

Pathogen-associated molecular patterns (PAMPs)

Molecules associated with groups of pathogens that are recognized by cells of the innate immune system.

Damage-associated molecular patterns (DAMPs)

products of cellular damage that can be recognized by PRRs.

PRPs in plasma membrane detect ____________, endosomal ones detect _______________, cytosolic one detect _____________

extracell pathogens

ingested microbes

microbes in cytoplasm

Toll-like receptors (TLRs)

PRP that activates transcription factors that stimulate production of immune proteins

plasma membrane TLRs detect _________ and endosomal TLRs detect __________

bacterial products (LPS)

viral and bacterial RNA and DNA

NOD-like receptors (NLRs)

cytosolic receptors, plays role in inflammation (fever) and chronic disorders

Inflammasome

cytosolic multiprotein complex that is signaled by NLRs to activate caspase-1 that forms IL-1

Interleukin-1

mediator of inflammation that recruits leukocytes and induces fever

C-type lectin receptors (CLRs)

on plasma membrane of macrophages and DCs that detect fungal glycans, inflammatory rxn to fungi

G protein-coupled receptors

on leukocytes that detect short bacterial peptides w/ N-formylmethionyl, stimulates chemotaxis

Mannose receptors

detect microbial sugars and induce microbe phagocytosis

Innate immune system provides host defense by 2 rxns

• inflammation (cytokines + complement)

• anti-viral defense (type I interferons)

Steps of inflammatory rxn

• offending agent recognized

• leukocytes + plasma proteins recruited from circ to site

• leukocytes + proteins activated to destroy offending agent

____________ is a response of vascularized tissues to infections and tissue damage that brings cells and molecules of host defense from the circulation to the sites where they are needed, to eliminate the offending agents.

Inflammation

Inflammation results in exudation of fluid and plasma proteins and emigration of leukocytes, predominantly ____________

neutrophils

Inflammatory mediators are also produced from ____________ that react to the microbes or to products of necrotic cells.

plasma proteins

Inflammatory mediators do what?

• promote plasma efflux

• recruit + activate leukocytes

urate crystals in gout and cholesterol crystals in atherosclerosis can cause what

inflammation

In inflammation, as stasis develops, how does endothelium change?

leukocytes accumulate along + adhere to endothelium (migrates to interstitial tissue)

increased levels adhesion molecules

______ are rapidly recruited while ______ are slower in response to inflammation

neutrophils

macrophages

how do neutrophils phagocytose

use cytoskeletal rearrangements and enzymes assemble to create rapid responses

how do macrophages phagocytose

make slow and prolonged responses w/ growth factors

When leukocytes are strongly activated, what may occur?

collateral tissue damage that prolongs inflammation

Selectin

receptors expressed on leukocytes + endothelial cells

(mediate initial weak interactions bw them)

• bind sugars

E, P, L selectins

E - endothelial cells

P - platelets and endothelium

L - on leukocyte surface

________ are expressed at low levels or not at all on unactivated endothelium

E-selectins

Integrins

surface transmembrane glycoproteins that mediate leukocyte adhesion to endothelium (+ cells to extracell matrix)

Integrins don't adhere to a specific ligand until:

leukocytes are activated by chemokines

Chemokines

chemoattractant cytokines, secreted by cells at inflammation site

Role of chemokines

Induce leukocyte migration and accumulation in tissue sites of inflammation (endothelial surface)

cytokines TNF and IL-1

activate endothelial cells to increase ligand expression for integrins

firm integrin-mediated binding of luekocytes to endothelium (@ inflammation site) is due to what combo?

cytokine-induced expression of integrin ligands on endothelium + increased integrin affinity on leukocytes

transmigration of leukocytes occurs mainly in

postcapillary venules (maximal endothelial cell retraction)

cytokine platelet endothelial cell adhesion molecule-1 (PECAM-1)

on leukocytes + endothelial cells

mediates binding events needed for leukocyte transmigration

bacterial products, cytokines, complement components and products of AA metabolism are all examples of what?

chemoattractants of leukocytes

In acute inflammation, why do neutrophils predominate in the infiltrate first? (then replaced by macrophages)

• more of them

• respond faster to chemokines

• attach more firmly to adhesion molecules

dominant cell in chronic inflammation

macrophage

Examples of antioxidants

superoxidase dismutase, catalase, glutathione peroxidase

Oxygen-derived radicals may by released by ________ after exposure to offending agent

leukocytes

nitric oxide (NO)

soluble gas made by arginine by nitric oxide synthase (NOS) that participates in microbial killing

e(ndothelial)NOS and n(euronal)NOS

expressed at low levels, the NO made maintains vascular tone as neurotransmitter

i(nducible)NOS

expressed when macrophages activated by cytokines/microbes, induces NO production

in macrophages, NO reacts w/ superoxide to produce

peroxynitrite (free radical)

peroxynitrite (free radical)

attack lipids, proteins + nucleic acids of microbes and host cells

granule enzymes

in neutrophils and monocytes, degrade microbes and dead tissues

acid proteases

granule enzymes that degrade bacteria and debris in phagolysosomes

Neutrophil elastase

degrades virulence factors of bacteria

Neutrophil Extracellular Traps (NETs)

extracellular fibrillar networks that concentrate anti-microbial substances at infection site + prevents spread

a1-anti-trypsin is an anti-protease that inhibits

neutrophil elastase

neutrophil extracellular traps are made of

meshwork of chromatin that binds (anti-microbial) granule proteins

IL-17

induces chemokine secretion (that recruits other leukocytes)

a lack of IL-17 causes

risk of infection and cold abscesses

Classical macrophage activation - induced by

microbial products TLR-ligands and T cell-derived signals (IFN-γ)

Classical macrophage activation - actions

macrophages produce NO and ROS + lysosomal enzymes, inflammatory

Alternative macrophage activation - induced by

cytokines (IL-4+13) by T lymphocytes

Alternative macrophage activation - actions

secrete growth factors that promote tissue repair, anti-inflammatory

Cell-derived mediators of inflammation are either released from _______ or made __________ in response to stimulus

intracell granules

de novo

What types of mediators are produced in liver and are activated by proteolytic cleavages upon stimulus?

plasma-derived mediators

Vasoactive amines (histamine and serotonin)

first to be released in inflammation, stored in mast cell granules and released by degranulation

Histamine

increases vascular permeability, producing interendothelial gaps in postcapillary venules + contracts smooth muscles

Histamine is mediated by

H1 receptors

Serotonin

in platelets + neuroendocrine cells

vasoconstrictor

Arachidonic acid metabolites (prostaglandins and leukotrienes)

made by arachidonic acid in membrane phospholipids

stimulate vascular + cell rxns in acute inflammation

mediators of arachidonic acid metabolites

cyclooxygenases make prostaglandins

lipoxygenases make leukotrienes and lipoxins

Prostaglandins

generated by COX-1+2, involved in vascular + systemic rxns to inflammation

COX-1

produced in response to inflammation, homeostatic function

COX-2

induced by inflammation

low in most tissues (only makes PGs)