ch. 2 - innate immunity

barrier tissues

keeps the outside OUT

epithelia = outside

endothelia = inside

mucosa

antimicrobial proteins

defensins

lysozyme

complement

mucosal barriers ______ microbial colonization of host tissues

prevent

mucosal barriers layer order

1. lumen

2. outer mucus layer

3. inner mucus layer

4. epithelial cells

outer mucus layer contents

healthy bacteria prevent colonization from foreign bacteria

inner mucus layer contents

antimicrobial proteins

IgA antibodies

mechanical bariers to infection

• flow of air/ fluid

• containment/expulsion in mucus

• tight junctions btw epithelia/ endothelia

tight junctions prevent _________ __________ of pathogens across barrier tissues

paracellular diffusion

occlusin

stops pathogens from entering brain parenchyma

chemical barriers to infection

• low (acidic) pH

• enzymes in tears/ saliva (lysozyme)

• antimicrobial peptides (defensins)

lysozyme

degrades bacterial peptidoglycans

peptidoglycans

lie on top of the bacterial cell membrane

• when broken, leaves membrane exposed

defensins

disturb microbial plasma membrane integrity

• charged

how do defensins work

their own charges repel eachother

• causes membrane to separate + creates a pore

commensal microbiome

microbiological barrier to infection

• good bacterias

symbiotic bacteria

good bacteria

• MUST STAY WHERE THEY ARE

• can be pathogenic if they move around

commensal gut bacteria

provide colonization resistance to invading bacteria

• K. mich → E. coli

• K. oxy → salmonella

K. mich

hogs all nutrients from E. coli

K. oxy

produces toxins that suppress salmonella

complement system

system of inante antimicrobial proteins

complement system steps

1. synthesized in liver

2. secreted into blood INACTIVE

3. attaches to pathogens + ACTIVATES

3 stages of complement activation

1. pattern recognition

2. enzymatic cascade

3. effector responses

3 pathways of complement initiation

• classical pathway

• lectin pathway

• alternative pathway

classical pathway

attaches to pathogen via interaction w/ antibody

lectin pathway

attaches to pathogen via interaction w/ microbial sugars

alternative pathway

attaches to pathogen surface directly w/ enzymatic products

_____ binding to antibody initiates classical complement pathway

C1

C1 complex

C1q = binds to antibody

C1r/ C1s = proteolytic domains

C2 and C4 cleaved into 2 pieces each

lectin pathway initiation

bind to carbohydrate PAMPs

• MBL + ficolin

• also cleave C4 and C2 into 2 pieces each

C3 convertase for the classical and lectin pathways

C4bC2a

• C3b is KEPT

which parts of C2 and C4 are kept?

C4b and C2a

alternative pathway using existing C3b

1. C3b attaches to microbe + factor B

2. factor Bb binds to C3bB

3. Ba is lost

4. C3bBb (C3 convertase is formed)

5. C3 binds to this new C3 convertase + makes new copies of C3b and C3a

alternative pathway using hydrolysis of C3

1. H2O binds to C3 → C3H2O

2. C3H2O binds to factor D

3. factor D binds to C3H2OB

4. Ba is lost

5. C3H2OBb (C3 convertase is formed)

6. C3 binds to this new C3 convertase + makes new copies of C3b and C3a

all complement pathways can form a _______

C5 convertase!

classical/ lectin C5 convertase

C4b2a3b

alternative C5 convertase

C3b₂Bb

3 effector outcomes of complement reactions

1. MAC

2. opsonization for phagocytosis

3. anaphylatoxin-induced inflammation

membrane attack complex steps

1. C5b, C6 and C7 → C5b-7

2. C8 → C5b-8

3. C9 → MAC

membrane attack complex mechanism

causes fluid to rush into the cell, causing the cell to pop

anaphylatoxin-induced inflammation

• USE GCPRs

C3a, C4a and C5a bind to their receptors: C3aR, C4aR and C5aR

immune effector functions stimulated from anaphylatoxins

• degranulation

• phagocytosis

• cytokine production

• chemotaxis

degranulation

releases contents of granules (antimicrobial/ inflammatory molecules)

cytokines

signal molecules

chemotaxis

direct movement of immune cells

properties of an inflammed capillary

• extravasation of Ab + complement (LEAK)

• leukocyte diapesis (WBCs LEAVE)

• activated endothelium

• vasodilation

opsonization for phagocytosis

1. extra C3b coats pathogen

2. coincidence detection

3. phagocytosis

coincidence detection

C5a → C5aR

C3b → CR1

C3b clearance of immune complexes

1. immune complex forms

2. opsonization

3. capture by erythrocyte

4. delivery to macrophages in liver + spleen

surface receptors of innate phagocytes

• Fc receptors (FcRs)

• C-type lectin receptors (CLRs)

• complement receptors

• scavenger receptors

Fc receptors (FcRs)

recognize pathogens bound to antibody

C-type lectin receptors (CLRs)

recognize microbial sugars

complement receptors

recognize phagocytosis-inducing proteins of the complement system

scavenger receptors

recognize wide array of surafce signals associated w/ pathogens + dead host cells

phagolysosome definition

produced by phagocytosis

• phagosome + lysosome

phagolysosome mechanisms

• acidic pH: 3.5-4

• reactive oxygen + nitrogen species (RONS)

• antimicrobial peptides

• degradative enzymes

_______ enhance phagolysosome functions by using antimicrobial granules

neutrophils

phagocytosis antigen presentation via MHC-2

1. phagolysosome forms

2. MHC-2 fuses with phagolysosome

3. MHC-2 picks up antigen from phagolysosome

4. antigen is presented to CD4 T cell

efferocytosis

how phagocytic macrophages clear dead cells

find me signals

• released by apoptotic cells

  • nucleotides (ATP, UTP)

  • phosphokipids (S1P, LPC)

  • chemokines (CX₃CL1)

eat me signal

phosphatidylserine (PtdSer)

• released by apoptotic cells

apoptosis

formation of blebs/apoptotic bodies

• maintenance of membrane integrity

• sequestration of DAMPs

necrosis

result of physical/chemical injurt

• loss of membrane integrity

• release of DAMPs = INFLAMMATORY

lytic cell death

result in release of DAMPs + highly inflammatory

necroptosis

MLKL -RIPK3→ MLKL phosphorylation

• result: pore

pyroptosis

gasdermin-D -caspase 1→ subunit cleaved

• result: HUGE pore

DAMPs

danger signals to other cells

• nucleic acids (mtDNA)

• metabolites (ATP, uric acid)

• alarmins (HMGB1, IL-33)