IBIO TF slides

Examples of intrinsic immunity

epithelial barriers, antimicrobial peptides, complement

Type of immunity: pathogen induced but not specific to a microbe.

Innate immunity

PAMPs stand for

pathogen associated molecular patterns

PRRs stand for

pattern recognition receptors

Hallmark of adaptive immunity

pathogen specific memory response

2 types of adaptive immunity

humoral immunity: antibodies 

cellular immunity: T cells kill virus infected cells

Immature dendritic cells reside in ________. Dendritic cells then migrate to __________. 

peripheral tissues; lymph nodes

What activates naive T cells?

mature DCs

_______ lineage comprises most of cells in the innate immune system?

myeloid

Examples of inflammatory inducers

bacterial lipopolysaccharides (LPS), ATP, urate crystals

Location of macrophages? What do macrophages do

Reside in tissues

Phagocytosis and activation of bactericidal mechanisms, antigen presentation, cytokine production

Have phagocytic receptors that bind to microbes

Location of neutrophils? What do they do

In circulation but go to site of infection

Phagocytosis and activation of bactericidal mechanisms

Location of eosinophils? Why do they do

GI tract

Kill antibody-coated parasites

Location of basophils? What do they do

Circulation

Promote allergic response and augment anti-parasitic immunity

Location of mast cells? What do they do

Barrier sites: skin, gut, respiratory mucosa

Release granules containing histamine and active agents

3 major  outcomes of complement? 

1. increased phagocytosis (opsonization via opsonins)

2. cell lysis (via MACs, membrane attack complex)

3. increased inflammation (via anaphylatoxin)

3 pathways of complement

classical, alternative, lectin

What steps are the same in all 3 pathways?

Only initiation is different, early/late phase are all the same

C3 convertase: cleaves C3 forming C3a (anaphylatoxin), C3b (opsonizes foreign pathogen), and C4b2a which forms complex w/ C3b to become…….

v

C5 convertase: cleaves C5 forming C5a (anaphylatoxin) and C5b (forms complex w/ C6-9 to become……

v

C5b-9: MAC (membrane attack complex)

Initiation steps of 3 pathways of complement

Lectin: mannose binding lectin (MBL) and ficolins recognize and bind carbs on pathogen surface

Classical: C1 complex (antibody mediated)

Alternative: C3 undergoes spontaneous hydrolysis to C3(H2O) to initiate

What is a PRR? What do they sense (broadly)?

pattern recognition receptor. Sense microbes

TLR4, TLR2/1+2/6, TLR5, TLR3, TLR7/8, TLR9

Target microbe, PAMP, location, transcription factors, antiviral or antibacterial response? 

What does RIG-I recognize? What TFs does it activate?

triphosphate dsRNA: 5’PPP RNA, hairpin/basepaired RNA

IRF3+NFkB

What does MDA5 recognize? What TFs does it activate?

longer dsRNA

IRF3+NFkB

What does cGAS recognize? What TFs does it activate?

dsDNA (found in viruses, bacteria, protozoa)

IRF3

Describe JAK-STAT signaling

1. Janus kinases (JAKs) bind to cytoplasmic domain of cytokine receptor

2. Cytokine receptors dimerize after being bound to cytokine, activating and phosphorylating JAKs

3. TFs (STATs) bind to receptors and get phosphorylated by JAKs

4. Phosphorylated STATs translocate to nucleus to initiate gene transcriptionS

Stages of leukocyte recruitment

1. endothelial activation (TNF)

2. blood vessel dilation slows blood flow

3. leukocytes roll on blood vessel

4. chemokines chagne integran conformation to allow for tight binding

5. metalloproteinases chew through basement membrane

6. leukocytes extravasate and follow chemokine gradients
   
   Aka rolling, tight binding, diapedesis, migration

Major functions of Type 1 IFNs

viral interference, inflammation, DC/NK activation, increases antigen presentation (by increasing MHC I expression and antigen presentation of all APCs

How do NK cells kill infected/stressed/tumor cells?

Lack of MHC I (all “self” cells have MHC I)

Presence of stress ligands detected by receptors on NK cells

Kinetics of viral response

How does Type I IFN prime the anti tumor response?

DC recruitment and activation

NK recruitment

DC cross dressing

More MHC I presentation—> MOre CD8 T cell activation—> more killing tumor cells

Activating nucleic acid sensors RIGI and cGAS

Som examples of DAMPs? PAMPs vs DAMPs

PAMPs: molecules associated/produced by pathogens. 

DAMPs: molecules produced by body’s own cells when they are stressed/damaged/dying (pyroptosis). Alert immune system to tissue damage even in absence of pathogen. Include ATP, heat shock proteins, DNA/RNA released into cytoplasm

What is pyroptosis?

inflammatory cell death (causes cells to lyse and release inflammatory molecules)

triggered by inflammasomes

Stages of inflammasome actvation

1. Priming (via TLR signalling which leads to downstream NK-kB—> NLRP3 and IL1 beta)

2. Activation (pro cytokines cleave into active cytokines, inflammasomes assemble

• Inflammasome activates caspase 1 which cleaves pro-IL1beta, pro-IL18, and gasdermin D

1. Pyropptosis (gasdermin D pore causes cell lysis and release of Il1beta and IL18)

What are caspases?

cysteine aspartic proteases. Execute events leading to inflammation/cell death

Know cyotkine receptor families

IL-1b: family, local and systemic effect (if applicable)

Family: IL-1 family; heterodimeric receptor (no common chain

Local effect: vascular endothelium, lymphocytes, increases access of effector cells

Systemic effect: fever, production of IL6

TNF alpha: family, local effect, systemic effect if applicable

Family: TNF receptor

Local effect: Activates vascular endothelium and increases vascular permeability, which leads to increased entry of IgG, complement, and cells to tissues and increase flood drainage to lymph nodes 

Systemic effect: fever, mobilization of metabolites, shock

IL6: family, local effect, systemic effect if applicable

Family: hematopoietin/heterodimers (with a common chain)

Local effect: lymphocyte activation, increased antibody production

Systemic effect: fever, induces acute phae protein production

CXCL8

Family: chemokine receptor family

Local effect: chemotactic factor recruits neutrophils, basophils, T cell to infection

No systemic effect

IL-12

Family: hematopoietin family/heterodimers with a common chain

Local effect: activates NK cells, induces differentiation of CD4 to TH1 cells. 

Systemic effect: NA

Describe DC transition from immature to mature

Immature: Increased phagocytic capacity (looking for foreign antigens), decreased MHC II expression

Things that trigger activation: cytokines, (GM-CSF, IFNgamma, IL4, PAMPs, DAMPs, pathogens)

Then migrates to lymph nodes upon activation. DC decreases expression of chmoekine receptors that keep it in tissue (Ex. CCR6, CXCR4) and increases expression of CCR7 (which guides DC to T cells)

Mature T cell: increased costimulatory molecules, MHC II expression, pro-inflammatory cytokines, CCR7, glycosis. Decreased phagocytic capacity

What things are upregulated/downregulated in immature DCs?

Increased phagocytic activity

Decreased MHC II presentation

What does CCR7 do for DCs?

Guides DCs to lymph nodes, allowing mature DCs to present antigens to T cells

What are MHC molecules for

MHC I is present on APCs/all cells, TCRs bind to antigen on MHC I, leading to T cell activation

What is MHC restriction

T cell’s TCR can only recognize an antigen when it’s bound to a specific MHC, determined by the T cell’s own MHC type

Difference btn MHC I and II

1: Present in all cells, presented to effector CD8 T cells

2: Presented on dendritic cellls, macrophages, B cells (professional APCs), presented to effector CD4 T cells.