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Immunology > Lecture 2 - Innate Immunity > Flashcards

Lecture 2 - Innate Immunity Flashcards

1
Q

Anatomical Barriers

A
  • Skin (epidermis, dermis)
  • Mucous membranes (cilia)
  • Sebum (oil)
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2
Q

Sebum

A
  • lactic and fatty acids

- lowers skin pH to 3-5

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3
Q

Innate organ protection

A

1) Urinary tract - acidic pH, long urethra, IgA
2) Vagina - acidic pH, IgA
3) Milk - enzymes
4) Mucous mem, tears, saliva

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4
Q

IgA

A

Immunoglobulin A

Opsonizes organisms

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5
Q

Defense barriers

A

1) Anatomical
2) Physiologic
3) Inflammatory
4) Phagocytic

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6
Q

Inflammation

A
  • results from injury
  • protective function, but can cause damage
  • Can be chronic if infection remains
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7
Q

Signs of Acute Inflammation

A

1) Tumor - swelling
2) Rubor - redness
3) Calor - heat
4) Dolor - pain

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8
Q

Inflammatory Vasoactive Mediators & Function

A
  • Signal inflammation
  • Pain, vasodilation
  • prostaglandins (Mast cell)
  • histamine (Mast cell)
  • bradykinin
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9
Q

Steps of Acute Inflammation

A

1) Injury, microbe entry
2) Sentinel cells activated
3) Sentinel cells secrete inflammatory mediators
4) Infection red and warm
5) Vasodilation, vessel become permeable to cells, which kill microbes at infected site

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10
Q

Fever

A
  • Cause of strong inflammatory response lead by cytokines TNF, IL-1, IL-6 in macrophages
  • Elevated temperature bad for pathogens
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11
Q

PAMPs (and examples)

A
  • Pathogen Associated Molecular Patterns
  • Allows discrimination of self and non-self

-Porins, lipoproteins, etc.

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12
Q

PAMP properties

A

1) Unique to each pathogen class
2) Cannot be concealed since they are necessary for pathogen survival
3) No similarity to host Ags

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13
Q

PRR

A
  • Pattern Recognition Receptor
  • How host cells detect pathogens (ex. Mannose Receptor can identify glycan, which is not present on terminal mannose in humans)
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14
Q

Nonclonal Distribution

A

Receptors (PRR) are identical on every cell — not unique specificity from host cell to cell in innate immunity

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15
Q

TLRs

A
  • Toll-Like Receptor
  • Recognize PAMPs by forming pairs with each other, activate inflammation, adaptive response, tissue injury response
  • Endosomal (nucleic acids), epidermal (extracellular microbes),
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16
Q

TLR Pairings, Ligands, microorganisms recognized, receptor location

A

1) TLR1/2 & TLR2/6 – lipopeptides/GPI; bacteria/parasites/fungi; membrane
2) TLR3 – Double-strand viral RNA; Viruses; Endosome
3) TLR4 – Lipopolysaccharide, gram-negative bacteria; membrane
4) TLR5 – flagellin; flagella-bacteria; membrane
5) TLR7, 8 — SingleStrand viral RNA; viruses; endoscopes
6) TLR9; CpG-rich DNA; bacterial virus; endosome
6) TLR10 – unknown

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17
Q

Transcription Factors

A
  • Activated by TLR signals
  • Stimulate inflammatory mediator release
  • Nuclear Factor-kB
  • Interferon Regulator Factor
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18
Q

NF-kB

A

Nuclear Factor-kB

Promotes cytokine release and adhesion molecule for inflammation response

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19
Q

IRF

A

Interferon Regulatory Factors

Activate production of antiviral cytokines (IFN-a/b), called Type I Interferons

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20
Q

Signalling Pathways of TLRs

A

1) TLR1,2,5,6,7,8,9 – activated by respective pathogen, signal MyD88, which produces NFkB or IRF
2) TLR3 — activated by pathogen, signal MyD88, which produces NFkB or IFF
3) TLR 4 – activated by pathogen, signal MyD88 or TRIF, which produces NFkB or IRF

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21
Q

MyD88

A
  • TLR signalling

- an adaptor protein that signals cell to get shit done and make proteins for immune response

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22
Q

TRIF

A
  • TLR signalling

- Adaptor protein that signals cell to get shit done and make proteins for immune response

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23
Q

IRF

A
  • TLR signalling

- Transcription factor

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24
Q

NF-kB

A
  • Transcription factor for protein

- MOST IMPORTANT FOR INFLAMMATION

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25
Q

Extracellular TLR Signaling for NFkB

A

MyD88 —> IRAK enzymes –> TRAF adaptor protein —> NFkB translocation —> gene activation in the nucleus

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26
Q

TLR4-Dependent Cell Activation

A

1) TLR4 Complex assembled at macrophage surface
2) MYD88 binds to TLR4, activating IRAK and Phosphorylating TRAF.
3) IKK activated, which inactivates IKB and release of NFkB
4) NFkB activates gene transcription of cytokines

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27
Q

TLR Deficiencies (and two types)

A
  • Results in immune cell not able to kill microbe — recurrent infections in patients and infection susceptibility
    1) MyD88 deficiency
    2) IRAK-4 deficiency
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28
Q

NLRs

A
  • NOD-Like Receptors (NLRP3 most important)
  • Present in inflammasomes, activated by PAMPs
  • Scaffolding Proteins that aid activation of NFkB and MAPK pathways
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29
Q

Inflammasome

A
  • Protein complex triggered by PAMPs
  • Activate Protease caspase-1, which processes active IL-1B and IL-18 that comes from the nucleus of the immune cell, which drives inflammation
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30
Q

IL-1B & IL-18

A

Important interleukins that are activated by caspase-1 and are very potent cytokines that drive inflammation

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31
Q

NLRP3 Inflammasome & Gout

A
  • IL-1B is key Gout cytokine that promotes acute inflammatory response in the gout joint and accumulation of monosodium urate
  • Anti-IL-1 therapy is good treatment
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32
Q

DAMPs

A
  • Damage-Associated Molecular Patterns
  • Released from damaged/dying cells (i.e. NECROSIS) —> NOT APOPTOSIS
  • Induce non-infection inflammatory response via NF-kB
  • Activated by PRR interaction and Macrophage signaling for inflammation response
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33
Q

DAMP examples (relevant TLR and NLR)

A

1) HMGB1 - necrotic cells (TLR2/TLR3)
2) Uric Acid (NLRP3)
3) Heat Shock Proteins - cytoplasmic proteins (TLR2/TLR4)

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34
Q

DAMPs In Autoimmune Diseases

A
  • Impact/promote adaptive immunity which can backfire:

- multiple sclerosis, Type 1 Diabetes, lupus, Rheumatoid Arthritis

35
Q

Neutrophils vs Macrophages (origin, lifespan, cytokine production)

A

Neutrophils
-Marrow, 1-2 days, low
Macrophages
-Marrows, days (inflammatory) to years (tissue), very high

36
Q

PRR-Triggered Responses in Phagocytes (explain migration)

A

1) Killing Microbes

2) Migration

37
Q

Macrophage Functions

A

1) Respond to Danger Signals (PAMP & DAMP)
2) Regulate Extravasation of blood into tissues
3) Phagocytosis
4) Tissue Repair
5) Inflammatory
6) Antigen Presentation

38
Q

Inflammatory Mediators examples

A

1) Cytokines
2) Reactive oxygen intermediates
3) Nitric oxide
4) Prostaglandins
5) Defensins

39
Q

Mast Cells

A
  • Important for allergic rxns
  • Has PAMP/DAMP receptors
  • Live for long time
  • Secrete inflammatory, anti-inflammatory, immunosuppressive products
40
Q

Strategic location off Mast Cells

A
  • Near skin and exposed sites cause sentinel cells
  • Near blood vessels to regulate vascular permeability
  • Modulate local cell responses through chemical mediators
41
Q

Mast Cell Activators

A 
Chemical
     -PAMPs
     -IgE (Abs)
     -Ags
     -Cytokines
     -Chemokines 
Physical
     -Temperature
     -Pressure
42
Q

Mast Cell Effector Molecules (release time)

A 
Seconds
    -Histamine, Proteases, TNF
Minutes (De novo mediator production)
    -Prostaglandins, Leukotrienes
Hours (De novo mediator production)
    -TNF, IL-4

Granules replenished after days

43
Q

Cytokines

A
  • Peptides secreted to mediate:
    • Inflammation, Immunity, hematopoiesis
  • Pro-inflammatory and anti-inflammatory
  • Endocrine (long distance), paracrine or autocrine
  • Function dependent on cell it binds to
44
Q

Chemokines

A

Chemoattractants that help move immune cells

45
Q

IL-10

A
  • Anti-inflammatory cytokine
  • Macrophages principle source
  • Inhibition of cytokines and chemokines, target dendritic cels and macrophages
46
Q

TGF-B

A
  • Anti-inflammatory cytokine
  • Macrophages principle source
  • Target T-cell, stop inflammation
47
Q

IL-1B (Local & Systemic)

A

Local
-Activates: lymphocytes, vascular endothelium permeability

Systemic
-Fever, IL-6 production

48
Q

TNF-a

A

Local
-Increase vascular permeability to let IgA into tissues

Systemic
-Fever, shock, metabolite mobilization

49
Q

IL-6

A

Local
-Lymphocyte activation, antibodies

Systemic
-Fever, acute phase protein production

50
Q

IL-8

A

Local Only

-Recruits neutrophils, basophils, Tcells to infection

51
Q

IL-12

A

Local Only

-Activates NK cells, induces transition of CD4 TCells into THelper cells

52
Q

Sickness Behavior Syndrome

A
  • From systemic release of TNF-a, IL-1, IL-6

- Lethargy, depression, anorexia, fever, cognitive impairment

53
Q

Complement System

A
  • Activation results in the production of polypeptide fragments that are essential for inflammation and immunity — enhances ability of body to kill microbes
  • 30 proteins make it up
  • All make C3b fragment
  • Forms MACs
54
Q

MACs

A
  • Membrane attack complex
  • Create holes in membranes and kills pathogens via osmotic shock
  • C5b triggers self-assembly of MAC
55
Q

IL-6, IL-1 and TNF-a

A

Act on hepatocytes for increase in APR proteins — major signalers for Acute Phase Protein Response

56
Q

Acute Phase Protein (APP) (Types and Roles)

A

1) C-reactive —- opsonizes, fixes complement system
2) Mannose binding —- opsonizes, fixes complement system
3) Acid glycoprotein - transporter
4) Serum Amyloid — Amyloid component precursor

57
Q

APP serum concentrations

A
  • Low concentration levels in healthy people
  • After inflammation, APP levels high, peaking 24-48 hours after onset
  • ALLOWS FOR DETECTION OF INFLAMMATION!!!
58
Q

Innate immune cell movement to tissues

A
  • Neutrophils and monocytes enter through:
    1) Post-capillary venules - all
    2) Capillaries - liver, lungs, kidney
59
Q

Chemotaxis

A

-Substance released by bacteria or damaged cell that stimulates the movement of neutrophils to that area

60
Q

What is hemodynamic shear?

A

Friction force acting on the blood vessel as a result of blood flow
(Venules have low hemodynamic shear, which is why they are good for migration)

61
Q

What are the steps for neutrophil/monocyte migration?

A

1) Endothelial activation – TNF & IL-1 activate endothelial cells, which express P-, E-selectin
2) Tethering – Neutrophils bind to selectin with their carbs (PSGL-1; ESL-1)
3) Rolling – Blood flow disrupts carb-selectin bond, which reattaches downstream (this causes rolling)
4) Binding – Integrin affinity on leukocytes increased by endothelial cytokines binding to leukocyte chemokine receptor, arresting the cell
5) Tissue Entry – leukocyte moves through the cell wall and into the tissues
6) Migration/Chemotaxis — IL-8 directs neutrophils to inflammation site

62
Q

What are LFA-1, VLA-4?

A
  • Late Function Antigen 1 & Very Late Antigen 4
  • Neutrophil integrin proteins
  • Bind to ICAM-1 and VCAM-1 on endothelial cells, stopping neutrophil roll
  • Chemokine receptor increases intern affinity for ligands (Extended conformation)
63
Q

What are ICAM-1, VCAM-1 and PSGL-1?

A
  • Intercellular Adhesion Molecule 1 & Vascular Cell Adhesion Molecule 1
  • Ligands that LFA-1 and VLA-4 bind to
  • Present on endothelium cells

PSGL-1 is the main endothelial adhesion molecule for MONOCYTE migration for P-Selectin

64
Q

What are the chemokines used in neutrophil and monocyte migration?

A
  • IL-8, which lines endothelium and attaches to IL-8 receptor on neutrophil
  • MCP-1 — for monocytes
65
Q

Neutrophil rolling is……

A

….selectin dependent

66
Q

What is MCP-1?

A
  • Monocyte chemoattractant protein 1
  • Helps arrest MONOCYTES to endothelium during migration
  • MOST IMPORTANT FOR MONOCYTES
67
Q

How are monocyte activated to become macrophages by the Classical Pathway?

A
  • Activated by
    1) microbial ligand binding to TLR
    2) IFN-gamma (cytokines)
68
Q

What is the function of Classically Activated Macrophages?

A

1) Microbe kiling

2) Inflammation activation

69
Q

How are monocyte activated to become macrophages by the Alternative Pathway?

A

Activated by:

1) IL-13 and IL-4

70
Q

What us the function of Alternatively Activated Macrophages?

A
  • Anti-inflammatory
  • Tissues repair
  • Fibrosis
71
Q

Immunomodulation

A

Process that modulates the immune response to a desired level (pro-inflammatory and anti-inflammatory)

72
Q

What is the Role of PRR in Phagocytosis?

A

-They bind to the microbes, triggering a signal to the cell to ingest the microbe

73
Q

What ROSs kill microbes and how are they created?

A
  • Radical Oxidative Speciaes
  • OH (Hydroxyl radical); OCl (hypochlorite); H2O2 (peroxide)

1) Respiratory Burst

74
Q

What are the steps of the Respiratory Burst?

A

1) O2 -> O2- (superoxide) via NADPH oxidase
2) O2- —> H2O2 (peroxide) (via Superoxide dismutase)
3) H2O2 —-> OCl (hypochlorite m– MOST ANTIMOCRIBIAL) + OH+ (hydroxyl radical) via myeloperoxidase

75
Q

What mediates Innate Immune Response against viruses and what do they do?

A

1) Type I Interferons (alpha/beta) – block viral replication
2) Natural Killer (NK) Cells – kill infected cells

76
Q

Why are Type I Interferons important and how do they achieve their function?

A

Regulators of the killing of virally-infected cells

  • Released by dendritic cells -> bind to infected cell receptor -> signal transduction to:
    1) Inhibit protein syntheis
    2) Degrade RNA
    3) Inhibit gene expression
77
Q

What are the (basic) steps of killing for NK cells?

A

1) Recognize ligand on infected/stressed cells
2) Kill infected cells or stressed host cells
3) Eliminate infection reservoirs (kill host cells and release pathogens for host phagocytosis)

78
Q

How do NK cells stimulate macrophages?

A

-By secreting IFN-gamma (Type II Interferon), which is the most powerful macrophage activator to kill microbes

79
Q

What is the activation mechanism in NK cells?

A
  • Killer cell immunoglobulin (Ig)-like receptors (KIRs)

- Stress molecules on cell recognized -> KIRs activate protein tyrosine kinases (PTKs)

80
Q

What is the inhibitory mechanism in NK cells?

A

-KIR receptors recognize MHC-I and activate “protein tyrosine phosphotases” (PTP) that inhibit signal.

Key: Insufficient binding of MHC-I by KIRs will not override kill signal

81
Q

How do NK cells kill infected cells?

A

1) PERFORINS are released by NKs, make hole in infected cell (think “perforate”)
2) Granzymes enter infected host, initiate apoptosis
3) Infected cell dies
4) Macrophage eats dying cell and detritus

82
Q

Explain some mechanisms for bacterial escape from innate immune system defense

A

1) Polysaccharide inhibits phagocytosis
2) Breakdown of ROS in phagolysosomes
3) Inhibition of C3 and C5 convertase

83
Q

How does the innate immune system link to the adaptive immune system and what does it lead to?

A
  • Two signal activation:
    1) Signal 1 – microbe binds./recognized by lymphocyte
    2) Signal 2 – Molecules from APCs (costimulatory molecules)

Leads to…..Lymphocyte proliferation!!!

INNATE indirectly controls Ab-mediated response of adaptive immunity

84
Q

Steps for Innate-Adaptive linkage

A

1) PRR recognizes pathogen
2) PRR activates and APC, allowing it to mature
3) APC presents antigen to you T Cell
4) Cytokines secreted, assist in T cell development

Immunology (20 decks)

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