T2 innate immunity

innate immunity

physical/chemical barriers + phagocytic/NK cells activities + complement system

physical barriers

skin + mucous membranes

skin

stratum corneum → corneocytes

corneocytes - function

form tough protective layer → prevent microbes & harmful substance entering

mucous membranes

GI tract & respiratory tract

physical barriers - proteins

junctional adhesion molecules (JAMs), claudins, zonula occludins

function of physical barrier proteins

ensure cells are sealed together, prevent leakage of fluids & microbial invasion

chemical barriers

antimicrobial peptides (AMPs) + skin lipids + skin pH + microbiome

AMPs - characteristics

amphipathic

amphipathic

cationic + hydrophobic

AMPs - types

membrane active & intracellular active

membrane active AMPs

electrostatic attraction to negative charge bacterial cell wall → hydrophobic regions insert to bacterial cell membrane → pores, fluid leak, death

electrostatic attraction

negative charge on bacterial outer membrane binds to positive charge of AMP

intracellular active AMPs

penetrate into microbial cells → bind to enzymes/molecules → interfere RNA synthesis

AMPs - sources

keratinocytes/epithelial cells & skin-infiltrating leukocytes

AMPs - examples from epithelial cells

human beta defensins & cathelicidin LL-37

lipids produced by skin

sphingomyelin, glucosylceramides, phospholipids

sphingosine & dihydrosphingosine

skin lipids with direct antimicrobial activity

skin pH

acidic → inhibit growth of pathogenic microbes

microbiome - functions

prevent pathogens colonization, secrete antimicrobial substance (bacteriocins)

protective skin microbes - examples

staphylococcus epidermis & propionibacterium acnes

important PRR

toll-like receptors (TLRs)

TLRs - location

plasma membrane & endosomal membranes

plasma membrane TLRs - detect

extracellular microbes

endosomal membrane TLRs - detect

nucleic acids of microbes inside cells

plasma membrane TLRs - includes what

TLR1, TLR2, TLR4, TLR5, TLR6

endosomal membrane TLRs - includes what

TLR3, TLR7, TLR8, TLR9

TLR1: TLR2

bacterial lipopeptides

TLR2

bacterial peptidoglycan

TLR2: TLR6

bacterial lipopeptides

TLR4 (with MD2)

lipopolysaccharide from gram negative

TLR5

flagellin

TLR3

dsRNA

TLR7

ssRNA

TLR8

ssRNA

TLR9

CpG-rich DNA

phagocytic cells

neutrophils, macrophage, dendritic cells

phagocytic cells - detect microbes

PRR + PAMP

phagocytic cells - trigger what

innate immune response

innate immune response

phagocytosis, inflammation, antiviral state

phagocytosis - receptors

C-type lectin, scavenger, opsonin

phagocyte binds to…

PAMPs on microbe

phagocyte + PAMP leads to…

microbe engulfed into phagosome

after phagosome formation

fuses with lysosome → phagolysosome

phagolysosome kills microbe by…

ROS, NO, proteolytic enzymes

NETosis

NETs traps and kill microbes outside the cell

NETs

DNA mixed with antimicrobial proteins

NETs - released by

neutrophils

inflammatory response - triggered when

first line barrier broken

inflammatory response - includes what

recruitment of leukocytes

major pro-inflammatory cytokines

TNF-alpha, IL-1, IL-6

cytokines - function

recruit neutrophils, promote vascular changes, increase inflammation

vascular changes leads to…

immune cells exit blood vessels → enter tissues

membrane-associated PRR - location

surface of plasma membrane & endosomal membrane

cytosolic PRR - location

cytoplasm of host cells

inflammasome - what is it

large, multiprotein complex that forms in the cytosol of immune cells

inflammasome - form when?

NLRP subfamily of nod-like receptosr detect PAMPs or DAMPs

inflammasome - functions

activate caspase-1 → release inflammatory cytokines → trigger pyroptosis

inflammatory cytokines from caspase-1

IL-1 & IL-18

pyroptosis

programmed cell death that eliminates infected cells

leukocyte recruitment - macrophage stimulated by…

recognize PRR on microbes

leukocyte recruitment - after macrophage stimulated

release cytokines

leukocyte recruitment - cytokines released

act on endothelial cells → express selectins & chemokines

leukocyte recruitment - after selectin expression

selectin ligand + selectin → rolling of leukocyte

leukocyte recruitment - after leukocyte rolled

chemokine + chemokine receptor → activate integrins

leukocyte recruitment - integrins activated

integrin + integrin ligand → strongly attach to endothelium

leukocyte recruitment - attach to endothelium

leukocyte enters tissue → move to highest conc of chemokine → kill microbes at infection site

systemic protective effects of inflammation

inhibit microbial activity & increase activity of immune cells

systemic pathologic effects of inflammation

inhibit myocardial contraction → hypotension → septic shock

increase BV permeability → fluid leak out & thrombus

antiviral state - after viral material recognized

receptors activate IRF transcription factor → produce type I interferons

type I interferons - functions

induce antiviral state, increase ability of NK cells, activate adaptive immunity

antiviral state

resistant to viral replication

NK cells - types

CD56 bright & CD56 dim

CD56 bright NK cells

specialized for cytokine production → signal other immune cells

CD56 dim NK cells

specialized for cytotoxicity → induce apoptosis

NK cell - receptors types

activating & inhibitory

NK cells activating receptors

trigger NK cells when stress signal or antibody-coated cells are detected

NK cells inhibitory receptors

prevent NK cells from killing healthy cells

NK cells - MHC class I present

inhibitory receptors dominate

NK cells - MHC class I missing/reduced

activating receptors dominate

NK cells - functions

cytokine secretion & cytotoxicity

NK cells - cytokine secretion

IFN-gamma

IFN-gamma

activate macrophage & shape adaptive immune response

NK cells - cytotoxicity

direct cytotoxicity & antibody-dependent cellular cytotoxicity (ADCC)

NK cells - direct cytotoxicity

release perforin & granzymes

NK cells - ADCC

recognize antibody-coated pathogens via CD16

complement system

family of proteins produced by liver

complement system - pathways

classical, lectin, alternative

classical pathway - triggered by

antibodies (IgG / IgM) binds to antigens

lectin pathway - triggered by

mannose-binding lectin (MBL) binds to sugars (carbohydrates)

alternative pathway - triggered by

complement proteins binds to microbial surface

central step of complement activation

C3 convertase formation

C3 convertase

splits C3 into C3a & C3b

C3a

promote inflammation

C3b

attach to microbes (act as opsonin → easier for phagocyte to recognize and ingest) & help form C5 convertase

C5 convertase

splits C5 into C5a & C5b

C5a

promote inflammation

C5b

initiate assembly of membrane attack complex (MAC) (C5b-C9)

membrane attack complex (MAC)

form pores in microbial membranes → lysis

inflammation by C3a & C5a

increase blood vessels permeability → attract immune cells → amplifies inflammatory response