Chapter 3: innate imunity the induced reponse to infection

most microbial ligands are

carbohydrates and lipids

recognition

macrophage receptors recognize the distinctive cell-surface carbohydrates of bacterial cells and some NK cell receptors recognize changes to surface proteins of human cells caused by viral infection

Toll-like receptors

PRR that don’t phagocytosis

TLRs are always located

on the plasma membrane

TLR steps on a macrophage

1. LPS binds to TLR4

2. signal transduction

3. activation of NFkB (transcription factor)

4. gene expression of inflammatory cytokines

LBP

LPS binding protein

what is a cytokine

proteins secreted by cells of innate/adaptive immunity that mediate any functions of these cells

what are cytokines made by

leukocytes, sometimes they’re called interleukins

what do chemoattractants do

attract cells to the source

purpose of cytokines

induce/regulate the immune response

4 characteristics of cytokine secretion

1. synthesis is initiated by new gene transcription (highly regulated)

2. mRNAs unstable

3. also regulated post-transcriptionally

4. very fast and very brief

Pleiotropism

one single cytokine can have multiple functions

redundancy

multiple cytokines can do the same function

synergy

2 cytokines have the same response but amplify each other

antagonism

2 cytokines block each other functions

Where cytokines can act

locally or systemically

how do cytokines function

by binding to specific membrane receptors on target cells

cytokines have a high affinity=

very potent

what contributes to cytokine specificity

receptor expression is regulated

cytokines function by

changing gene expression in their target cells

cellular responses to cytokines are tightly regulated

feedback inhibition (inhibits own production) and inhibition of signaling (something external inhibiting the pathway)

PRR+ PAMP =

NFkB activation and cytokine production

5 types of cytokines

TNF-a, IL-6, CXCL8, CCL2, IL-12

TNF-a functions

increases vascular permeability and turns on the expression of adhesion proteins. responsible for swelling

IL-6 functions

binds to fat and muscle cells to metabolize them which generates heat and raises the temperature in the infected tissue

CXCL8 functions

recruits neutrophils from the blood and directs them to the infected tissue

CCL2 function

recruits monocytes from the blood and directs them to the infected tissue

IL-12 function

recruits and activates natural killer cells to secrete cytokines (IFN gamma) that strengthen macrophages response to infection

TNF-alpha is produced by

macrophages as a result of TLR stimulation

TNF-alpha is the primary cause of

septic shock

sepsis

presence of bacteria in the blood stream

septic shock process

systemic edema causes decreased blood volume and the blood vessels collapse. Clots get through all over the place and it leads to wasting and multiple organ failure

two main phagocytes of the immune system

macrophages and neutrophils

macrophages come from

monocytes

macrophage characteristics

long lived, reside in tissues, raise the alarm by producing inflammatory cytokines, help clean up and repair tissues

neutrophil characteristics

short lived, circulate in blood, only function is to phagocytose, most abundant white blood cell (50 billion)

selectin-mediated adhesion

allows neutrophils to roll along the endothelium

Extravasation purpose

to get the neutrophil out of the blood stream into the tissue

extravasation steps

1. rolling adhesion

2. tight binding

3. diapedesis

4. migration

rolling adhesion

neutrophil: s-lex

vasc. endo cells: selectins

what happens in tight binding

CXCL8 acts on neutrophil to trigger a conformational change in LFA-1 that pushes the snapped pieces together

ICAM-1 adhesion molecule is turned on by TNF-alpha

LFA-1 and ICAM-1 are latched together

diapedesis

neutrophil turns into a pancake and squeezes into the tissue

neutrophil: cytoskeleton proteases

vasc. endo cells: increased vascular permeability (TNF-alpha)

migration

neutrophil has to find the SOI. follows the trail of CXCL8

bacteria binding to neutrophil receptors induce phagocytosis and killing

the neutrophils are completely covered with PRRs and complement receptors to grab and engulf the pathogen

neutrophils injest bacteria and the bacteria becomes a

phagolysosome

IL-6 affect on the liver

binds to liver cells and turns on production of acute phase proteins

IL-6 and TNFa affect on bone marrow endothelium

neutrophil mobilization which leads to phagocytosis

IL-6 and TNFa affect on hypothalamus

increased body temperature which leads to decreased viral and bacterial replication

IL-6 and TNFa affect on fat and muscle

protein and energy mobilization to generate increased body temp which leads to decreased viral and bacterial replication

acute-phase proteins

C-reactive protein, mannose-binding lectin

job of C-reactive protein and mannose-binding lectin

pathogen recognition

acute phase functions

opsonize and activate complement

Lectin pathway of complement is initiated by

mannose binding lectin

CRP triggers ______ pathway of complement activation

classical

all infected cells can induce the

interferon response

vius infected cell process

internal recepors tell the cell to produce cytokines IFNa and IFNb (type 1) which set off the interferon reponse

interferon response function

1. inhibit viral replication: leads to cell death

2. warn neighboring cells

3. recruit/activate NK cells

plasmacytoid dendritic cells (pDCs)

make lots of type 1 interferons, circulate in the blood. reason that you always have a systemic reaction with viruses

NKs activated by type I interferons

1. virus infection of cells triggers the interferon response

2. type 1 interferon drives the proliferation of NK cells

3. differentation of NK cells into cytotoxic effector cells

4. inducing apoptosis on virus infected cells

virus infected cells express

MIC ligands