Innate Immune Response 8/20

immunity

resistance to disease; prevent or eradicate infections and other diseases

types of immunity

innate and adaptive

features of innate immunity

rapid, limited, non-specific, do not have memory

cells of the innate immune system

epithelial, phagocytes, innate lymphoid cells, and natural killer cells

cellular receptors for innate immune response

TLRs, NLRs, CLRs, RLRs, CDSs

innate immune reaction/response

inflammation and antiviral defense

molecules of the innate immune response

complements and cytokines

features of the innate immunity - rapid

first line of defense against infection

features of the innate immunity - limited

receptors are encoded by inherited genes that are identical in all cells

features of the innate immunity - nonspecific

recognizes structures that are shared by various classes of microbes and are not present on normal host cells

key features of the innate immunity

does NOT react against the normal host and recognizes molecules that are released from damaged or necrotic host cells

features of the innate immunity - no memory

responds in essentially the same way to repeat encounters with a microbe

5 types of phagocytes

neutrophils (circulating), monocytes (circulating), macrophages, dendritic cells, and mast cells

epithelial barriers key roles

physical barrier to infection, killing of microbes by locally produced antibiotics, and killing of microbes and infected cells by intraepithelial lymphocytes

phagocytes

cells that protect the body by ingesting harmful foreign particles (such as bacteria) and dead/dying cells

neutrophils

phagocytes that circulate in blood/migrate to site of infection, are abundant, ingest/engulf/destroy microbes, and clear cell debris

monocytes

phagocytes that circulate in blood/migrate to site of infection

are less abundant

ingest/engulf/destroy microbe

differentiate into macrophages and dendritic cells

macrophages

phagocytes that are present in tissues, rich in lysosomes, ingest/enguld/destroy microbes, clear death tissues, produce cytokines (secrete TNF and IL-1 chemokines to recruit phagocytes and secrete IL-12 to activate NK cells), and have adaptive immunity (bridge innate and adaptive as antigen-presenting cells)

dendritic cells

phagocytes that reside in tissues, have cytoplasmic projections, ingest/engulf/destroy microbes, produce cytokines (secrete TNF and IL-1 chemokines to recruit phagocytes), and have adaptive immunity (bridge innate and adaptive as antigen-presenting cells)

mast cells

phagocytes that are present in skins, have abundant cytoplasmic granules that are released during inflammation (ex. histamine), ingest/engulf/destroy microbes, cause vasodilation, recognize helminths (parasites), and are involved in allergies/allergic response

lymphocytes/innate lymphoid cells (ILC)

innate immune cells that have no antigen receptors and function to produce cytokines

natural killer (NK) cells

innate immune cells that make up 10% of lymphocytes in blood, have no antigen receptors, have abundant cytoplasmic granules, have antiviral defense, and secrete IFN-y

natural killer (NK) cells functions

recognize and kill infected cells (antiviral defense) and secrete cytokines (IFNy) to activate macrophages

general features of innate immune receptors

• expressed on/in the immune cells (innate and adaptive)

• expressed in different cellular compartments (cell surface, endosomes, cytosol)

• have nonspecificity,

• recognize PAMPs and DAMPs

5 receptors for PAMPs (pathogen-associated molecular patterns)

1. bacterial endotoxin (lipopolysaccharide/LPS)

2. peptidoglycans

3. terminal mannose residues of glycoprotein

4. dsRN

5. unmethylated CG-rich (CpG) oligonucleotides

receptors for DAMPs (damage-associated molecular patterns)

molecules that are released from damaged or necrotic host cells

toll-like receptors (TLRs)

receptors that are either expressed on plasma membrane (microbial proteins, lipids, polysaccharides) or in endosome (microbial nucleic acid), undergo localization and specification, and activate NF-KB and IRFs to stimulate inflammation and antiviral defense

TLR-1/TLR-2/TLR-6

expressed on plasma membrane; recognize lipopeptides and peptidoglycans on gram-positive bacteria

TLR-4

expressed on plasma membrane; recognize lipopolysaccharide (LPS) on gram-negative bacteria

TLR-5

expressed on plasma membrane; recognizes flagellin on all flagellated bacteria

TLR-3

expressed in endosome; recognizes double-stranded RNA (dsRNA)

TLR-7/TLR-8

expressed in endosome; recognize single-stranded RNA (ssRNA)

TLR-9

expressed in endosome; recognizes unmethylated CpG DNA

TLR-mediated signals

responsible for the activation of the transcription factors nuclear factor KB (NF-KB) and interferon regulatory factors (IRFs)

NF-KB

TLR-mediated signal that promotes expression of cytokines and endothelial adhesion molecules and play important roles in inflammation (acute inflammation and stimulation of adaptive immunity)

IRFs

TLR-mediated signal that stimulates production of the antiviral cytokines type I IFNs and play important roles in antiviral defense

NOD-1/NOD-2

NOD-like receptors that are cytosolic, recognize bacterial peptidoglycans (common components of bacterial cell walls), activate NF-KB and promote expression of inflammatory cytokines, and play important roles in inflammation

NOD-3

NOD-like receptors that are cytosolic, recognize many unrelated PAMPs and DAMPs, form NLRP-3 inflammasome, and activate caspase 1 to produce biologically active interleukin IB (IL-IB) and promote inflammation

lectin receptors (CLRs)

extracellular receptors that recognize fungal glycans and induce phagocytosis of fungi

mannose receptors

extracellular receptors that recognize bacterial products and induce phagocytosis of bacteria

RIG-like receptors (RLRs)

cytosolic receptors that recognize viral RNA and produce type I interferon

cytosolic DNA sensors (CDSs)

cytosolic receptors that recognize microbial DNA and produce type I interferon

two major types of innate immunte reactions

inflammation (extracellular microbes and damaged tissues) and antiviral defense (viruses and intracellular)

inflammation

a tissue reaction that delivers mediators of host defense to the sites of infection and tissue damage (via blood)

process of inflammation

1. release of proinflammatory mediators (site of infection/tissue damage)

2. leakage of plasma proteins (complement proteins, antibodies)

3. recruitment of cells (neutrophils, monocytes, lymphocytes)

4. activation of cells and proteins in extravascular tissues (mast cells, dendritic cells, macrophage)

5. phagocytes engulf and destroy microbes and dead materials

inflammation process when proinflammatory mediators are released in tissue

1. increase in local blood flow (redness and heat)

2. exudation of plasma proteins (swelling)

3. triggering of nerve endings (pain)

migration of phagocytes

rolling (selectin), stable adhesion (integrin/chemokines), migration

phagocytosis

killing of microbes by ROS, NO, and lysosomal enzymes in phagolysosomes

phagocytosis and destruction of microbes

phagosomes fuse with lysosomes to form phagolysosomes that contain ROS, NO, and enzymes

opsonization

to enhance phagocytosis by "tagging" the microbe for destruction so that is more easily identified by the immune system

antiviral defense

defense against viruses is a special type of host response that involves interferons, NK cells, and other mechanisms

mechanism of antiviral defense

NK cells kill infected cells through emptying the contents of the cytoplasmic granules (apoptosis) and type I interferons (IFN-a and IFN-B) are secreted by infected cells/DC and inhibit viral replication and destroy viral genomes

antiviral defense - NK cells

when the inhibitory receptor is engaged on a normal cell by binding to self class I MHC - self peptide complex the NK cell is not activated so no cell killing occurs; when the inhibitory receptor is not engaged on a virus-infected cell that inhibits the class I MHC expressing then the NK cell is activated so killing of the infected cell occurs

perforin

protein made by NK cells that facilitates entry of granzymes into the cytosol which then activate apoptosis

antiviral defense - type I interferons

virus-infected cells and dendritic cells express type I IFN that is recognized by IFN receptors and downstream pathways occur that result in inhibition of viral replication

complement system

a collection of circulating and membrane-associated proteins that are important in defense against microbes; many complement proteins are proteolytic enzymes and complement activation involves the sequential activation of these enzymes

3 complement system pathways

1. classical pathway (adaptive) - antibody-antigen (microbe) complex activate

2. alternative pathway (innate) - microbes directly activate

3. lectin pathway (innate) - mannose binding lectin binding to microbe activates

complement system - early steps

C3 cleaved into C3a and C3b by any of the three pathways; C3a involved in inflammation and C3b involved in opsonization/phagocytosis and is deposited on a microbe (attaches)

complement system - late steps

C5 cleaved in C5a and C5b by C3b on microbe; C5a involved in inflammation and C6-C9 involved in lysis of microbe; complement proteins form membrane attack complex (MAC)

function of complement system - opsonization and phagocytosis

covalent binding of C3b to microbe (opsonization) causes recognition of bound C3b by phagocyte C3b receptors (ex. complement receptor 1/CR1) and results in phagocytosis and killing of the microbe

function of complement system - complement-mediated cytolysis

binding of C3b to microbe causes activation of late components of complement and the formation of the membrane attack complex (MAC) which results in osmotic lysis of the microbe; polymeric protein complex inserts into microbial cell membrane which disturbs permeability barrier and causes either osmotic lysis or apoptosis

function of complement system - stimulation of inflammatory reactions

proteolysis of C3 and C5 to release C3a and C5a (proteolytic fragments of complement proteins) are chemoattractants for leukocytes which leads to recruitment and activation of leukocytes (neutrophils and monocytes) by C5a and C3a which results in inflammation at the sight of complement activation and the destruction of microbes by leukocytes

cytokines

any substances that are secreted by immune cells and have effects of the same cells or other cells

cells that produce cytokines

macrophages, DC, mast cells, NK cells, lymphoid cells, virus-infected host cells

factors that regulate the production of cytokines

bacterial components (lipopolysaccharide/LPS) and viral molecules (dsRNA)

cytokines produced during innate immune response

interleukins (ILs), tumor necrosis factor (TNF), interferons (IFN), chemokines

production of cytokines

activation of dendritic cells, macrophages, and NK cells in the tissue by microbes causes the release of pro-inflammatory cytokines such as TNF, IL-1, and chemokines so that neutrophils in the bloodstream are able to migrate out to the extracellular tissue and induce inflammation

natural killer cell activation/secretion

NK cells activated by IL-12 secreted by dendritic cells and macrophages and then release IFN-y that in turn activates and strengthens the immune response of the dendritic cells and macrophages (cytokines regulate immune response)

how cytokines work

secreted in small amounts in response to an external stimulus and bind to high-affinity receptors on target cells

3 cytokine actions

autocrine, paracrine, and endocrine

autocrine actions of cytokines

act on the cells that produce them; virus-infected cells secrete IFN-a/B which is recognized by IFN receptor expressed in virus infected cells or T cells secrete interleukin-2 (IL-2) which is recognized by IL-2 receptor expressed on T cells

paracrine actions of cytokines

act on the adjacent cells; macrophages and dendritic cells secrete TNF and IL-1 which are recognized by TNF and IL-1 receptors expressed on endothelial cells, secrete IL-12 which is recognized by IL-12 receptors expressed on NK cells, and NK cells secrete IFN-y which is recognized by IFN receptors expressed on macrophages

endocrine actions of cytokines

active distant from the site of excretion; kidneys secrete erythropoietin (EPO) which is recognized by immature erythroid cells in bone marrow

functions of cytokines

• recruitment of phagocytes (TNF, IL-1, chemokines),

• activation of innate immune cells (IL-12, IFNy),

• microbial killing,

• septic shock

cytokines in recruitment of phagocytes

tumor necrosis factor (TNF), interleukin-1 (IL-1), chemokine (chemoattractant cytokines) recruit neutrophils and monocytes from blood to extravascular tissues

cytokines in activation of innate immune cells

interleukin-12 (IL-12) activates NK cells and IFNy activates macrophages

cytokines in microbial killing

interleukin-26 (IL-26)

cytokines in septic shock

organ damage in response to infection as a result of a cytokine storm and characterized by low blood pressure, disseminated intravascular coagulation, and metabolic disturbances

cells of innate immunity

epithelial barriers, phagocytes, and other cells including natural killer (NK) cells

types of epithelial barriers

physical barriers, chemical barriers, and intraepithelial lymphocytes

5 classifications of phagocytes

neutrophils, monocytes, macrophages, dendritic cells (DC), and mast cells

neutrophil key roles

phagocytes that migrate to site of infection and engulf/destroy microbes

monocyte key roles

phagocytes that migrate to site of infection, engulf/destroy microbes, and differentiate into macrophages and DCs

macrophage key roles

phagocytes that engulf/destroy microbes, secrete TNF, IL-1, chemokines to recruit phagocytes, and IL-12 to activate NK cells

dendritic cell key roles

phagocytes that engulf/destroy microbes and secrete TNF, IL-1 and chemokines to recruit phagocytes

mast cell key roles

phagocytes that engulf/destroy microbes and have abundant cytoplasmic granules that are released during inflammation such as histamine

natural killer (NK) cell key roles

antiviral defense and secrete IFNy

key cellular receptors for innate immune response

TLRs, NLRs, lectin receptors, mannose receptors, RIG-like receptors, and cytosolic DNA sensors

general features of cellular receptors for innate immune response

express on innate immune cells in different cellular compartments, have nonspecificity, and recognize PAMPs and DAMPs

toll-like receptor (TLR) key roles

express on cell surface (microbial proteins, lipids, polysaccharide), express in endosomes (microbial nucleic acid), activate NK-KB and IRFs to stimulate inflammation and antiviral defense

NOD-1/NOD-2 key roles

cytosolic, bacterial peptidoglycan, and activate NF-KB

NLRP-3 key roles

cytosolic

PAMPs and DAMPs

NLRP-3 inflammasome

generating biologically active IL-1B

key innate immune reactions

inflammation (deliver mediators of host defense) and antiviral defense

key inflammation process

release of mediators, leakage of plasma proteins, recruitment of cells, activation of cells and proteins, engulf and destroy microbes

migration of phagocytes in inflammation

rolling (selectin), stable adhesion (integrin/chemokines), migration

phagocytosis and destruction of microbes in inflammation

phagosomes fuse with lysosomes to form phagolysosomes that contain ROS, NO, and enzymes

key players in antiviral defense

NK cells and type I interferons

NK cells in antiviral defense

recognize viral infected cells and release proteins that mediate apoptosis

type I interferons in antiviral defense

viral infected cells and DC secrete IFNa/B, activate IFN receptor, and inhibit viral replication

key molecules of innate immunity

complement system and cytokines