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HIID > L8: Innate Immunity > Flashcards

L8: Innate Immunity Flashcards

1
Q

What is phase 1 of innate immunity?

A

Non-induced innate response (non-specific)

Includes preformed defenses such as skin barrier, mucosal barrier, pH, saliva proteases

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2
Q

What is phase 2 of innate immunity?

A

Induced innate response (broadly specific)

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3
Q

Broadly compare innate and adaptive immunity

A

Innate:
Response time of minutes/hours
Specific for molecules and molecular patterns associated w/ pathogens
Has a limited number of germ line-encoded receptors
Little to no memory responses
Self/nonself discrimination is perfect; no microbe-specific patterns in host
Soluble components of blood or tissue fluids include many antimicrobial peptides and proteins
Major cell types include phagocytes (monocytes, macrophages, neutrophils), natural killer (NK) cells, and dendritic cells

Adaptive:
Response time of days
Is highly specific
Highly diverse; large # of receptors arising from genetic recombination of receptor genes
Has persistent memory, w/ faster response of greater magnitude on subsequent infection
Self/nonself discrimination is very good; occasional failures of discrimination result in autoimmune disease
Soluble comonents of blood or tissue fluids include antibodies
Major cell types are T cell, B cells, and antigen-presenting cells

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4
Q

Where are non-induced (phase 1) responses active?

A

Sites throughout the body

Skin, epithelial lining of airway and lung, epithelial lining of alimentary canal, etc.

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5
Q

What are epithelial barriers to infection?

A

Physical barrier to infection

Killing of microbes by locally produced antibiotics

Killing of microbes and infected cells by intraepithelial lymphocytes

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6
Q

Psoriasin

A

An antimicrobial peptide in the skin that is active against E. coli

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7
Q

Once the epithelium is breached, what occurs?

A

Innate response takes over in an inflammatory response

  1. Recruitment of effector cells/mechanisms; vasodilation, permeability
  2. Blood clotting to prevent pathogen spread
  3. Tissue remodeling to repair damage
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8
Q

What does inflammation allow for?

A

Allows right cells to get to right place to interact w/ microorganism

Rather than letting toxin spread through entire body. localized blood clotting keeps it local

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9
Q

Levels of what proteins increase in serum concentrations following infection?

A

Acute phase proteins

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10
Q

Where are acute phase proteins produced? In response to what?

A

In liver in response to IL-6 (which is produced in response to microorganisms)

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11
Q

What acute phase proteins are produced in the liver?

A 
Serum amyloid protein
C-reactive protein
Fibrinogen
Mannan-binding lectin
SP-A
SP-D
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12
Q

What does C-reactive protein do?

A

Binds phosphorylcholine on bacterial surfaces, acting as an opsonin, and also activating complement

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13
Q

What does mannan-binding lectin do?

A

Binds mannose residues on bacterial surfaces, acting as an opsonin and also activating complement

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14
Q

Why is sedimentation rate altered w/ infection?

A

IL-6 regulates fibrinogen, which is an APP
Increased fibrinogen increasees erythrocyte sedimentation rate as fibrinogen binds to RBC
Used as a non-specific indicator of inflammation/bacterial infection

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15
Q

PAMPS

A

Pathogen-associated molecular patterns

Components on the pathogen that are common to different pathogens and elicit a response

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16
Q

DAMPS

A

Danger-associated molecular patterns: things that are released upon stress response

Heat shock proteins

HMGB1 - a chromatin-associated protein that is secreted in response to “danger” and can induce dendritic cell maturation, induce pro-inflammatory cytokines

Purine metabolites - ATP, adenosine, uric acid; can be released upon necrotic cell death

DNA anywhere except the nucleus and mictochondria

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17
Q

On pathogens, what is the difference b/w PAMPs and antigens?

A

Antigens are unique structures that are recognized by adaptive leukocytes

PAMPs are common structures that are recognized by innate leukocytes

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18
Q

How do innate leukocytes recognize PAMPs? What occurs after recognition?

A

They have pattern recognition receptors (PRRs)

Depending on which PRRs get triggered, can get phagocytosis, target cell lysis, or inflammation

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19
Q

What are toll-like receptors? Describe the structure.

A

An example of a PRR

Has a signaling domain called TIR domain and an extracellular domain called LRR (leucine-rich repeats)

Can occur on cell membrane or in internal component.

For those in internal compartment, the LRR is inside the compartment and the TIR is in the cytoplasm)

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20
Q

TLR4

A

Is the receptor for bacterial lipopolysaccharide (LPS) that exists on the cell surface of gram negative bacteria

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21
Q

What intracellular sensors sense cytoplasmic RNA (think RNA viruses)?

A

RIG-1

MDA5

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22
Q

What intracellular sensors sense cytoplasmic DNA (think DNA viruses)?

A

AIM
TREX
STING

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23
Q

What are the cellular components of innate immunity?

A

Neutrophils
Macrophages
Dendritic cells
Natural killer cells

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24
Q

What are the phagocytes of innate immunity?

A

Neutrophils

Macrophages

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25
Q

Are neutrophils and monocytes/macrophages long or short-lived?

A

Neutrophils: short-lived (6 hr), but life extended by infection

Macrophages: long-lived (months/years)

26
Q

Where do neutrophils and macrophages reside?

A

Neutrophils: blood

Macrophages: blood/tissues

27
Q

Do neutrophils and macrophages present antigen?

A

Neutrophils: no

Macrophages: present antigen to CD4+ T cells

28
Q

Where do neutrophils and monocytes/macrophages originate from?

A

Both have bone marrow origin

Myeloid precursor

29
Q

What is the cellular response and functional outcome of phagocytes in response to transmembrane receptors that recognize chemokines, lipid mediators, and N-formylmethionyl peptides?

A

Cellular response of increased integrin avidity; cytoskeletal changes → migration into tissues

30
Q

What is the cellular response and functional outcome of phagocytes in response to toll-like receptors (which recognize LPS)?

A

Cellular response of production of cytokines and reactive oxygen intermediates (ROIs) → killing of microbes

31
Q

What is the cellular response and functional outcome of phagocytes in response to mannose receptors?

A

Cellular response of phagocytosis of microbe into phagosome → killing of microbes

ALSO production of cytokines and reactive oxygen intermediates → killing of microbes

32
Q

Extravasation

A

Breaking open tight epithelial barriers (such as when neutrophils exit capillary and enter tissues in response to increased permeability when tissue damage causes release of vasoctive and chemotactic factors)

33
Q

Describe initiation of extravasation of neutrophils

A

Selectin on epithelial cells interacts with mucin (selectin ligand) on neutrophil surface → neutrophils rolls →chemokines/chemoattractants induce change in inegrins on neutrophils → integrins adhere firmly to the ICAMs on epithelial cell → neutrophils stop → then can pry apart endothelial cells lining blood vessels and escape into tissue

34
Q

Describe how phagocytosis occurs

A

Bacterium becomes attached to membrane evaginations called pseudopodia → bacteria is ingested, forming phagosome → phagosome fuses w/ lysosome → lysosomal enzymes digest captured material → digestion products are released from cell

35
Q

What enhances effector function of marcophages?

A

IFN-γ

36
Q

What produces IFN-γ?

A

T cells, NK cells

37
Q

What molecules are produced in activated macrophages? What effector functions do they cause in activated macrophages?

A

Phagocyte oxidase → reactive oxygen intermediates → killing of microbes

iNOS → nitric oxide → killing of microbes

Cytokines (TNF, IL-12) → inflammation, enhanced adaptive immunity

Fibroblast growth factors, angiogenic factors, metalloproteinases → tissue remodeling

Increased MHC molecules, costimulators → enhanced antigen presentation

38
Q

Oxidative burst

A

Neutrophils kill microbes by producing reactive oxygen species and therefore undergoes a metabolic burst

39
Q

What are the 2 different kinds of active species produced in activated phagocytes? How are they produced?

A

Reactive oxygen species (ROS)
Oxygen -NADP phagosome oxidase→ superoxide anion -superoxide dismutase→ hydrogen peroxide-myeloperoxidase→hypochlorite

Reactive nitrogen species (RNS)
Arginine-iNOS→nitric oxide→nitrogen dioxide

40
Q

Are natural killer cells phagocytic?

A

No

41
Q

What lineage are NK cells of?

A

Lymphoid lineage

42
Q

How do NK cells kill?

A

By release of granule contents in the area of an immunological synapse

Perforin pokes holes in the membranes and proteases digest cell

Target cell dies by apoptosis (a non-inflammatory type of cell death)

43
Q

What are NK cells activated by? What do NK cells produce in response?

A

IL-12, which is produced by macrophages

NK cells then produce IFN-γ which leads to killing of phagocytosed microbes by macrophages

44
Q

How are targets recognized by NK cells?

A

NK cells have activating receptor and inhibitory receptor

Inhibitory receptor binds self-MHC class I

Activating receptor binds antigens

45
Q

What are NK cells inhibited by?

A

Expression of MHC class I

46
Q

How do CTLs and NK cells differ?

A

CTL must see antigen with MHC class I

NK cells are inhibited by expression of MHC class I

47
Q

How is NK cell activation by cells lacking MHC class I advantageous?

A

Many viruses dowregulate Class I to escape from TCL but become sensitive to NK

48
Q

Antibody dependent cellular cytotoxicity

A

NK cells also carry out antibody dependent cellular cytotoxicity

NK cells have Fc receptors for IgG

Leads to killing of antibody-coated cell

49
Q

What do soluble mediators of innate immunity include?

A

Some antimicrobial, antiviral, and antifungal peptides

50
Q

What are effects of Type I interferons?

A

Induction of “antiviral state”

Increased expression of class I MHC molecules on infected cells → killing by CTLs

Up-regulates NK activity

Induces Th1 responses

51
Q

Where is type I interferon produced?

A

Produced by many cells in the body as well as plasmacytoid DC, the “professional” IFN producing cells

52
Q

What is the effect of IL-1β/IL-6/TNF-α on the liver?

A

Acute-phase proteins (C-reactive protein, mannose-binding lectin) → activation of complement; opsonization

53
Q

What is the effect of IL-1β/IL-6/TNF-α on the bone marrow endothelium?

A

Neutrophil mobilization → phagocytosis

54
Q

What is the effect of IL-1β/IL-6/TNF-α on the hypothalamus?

A

Increased body temperature → decreased viral and bacterial replication; increased antigen processing; increased specific immune response

55
Q

What is the effect of IL-1β/IL-6/TNF-α on fat, muscle?

A

Protein and energy mobilization to allow increased body temperature → Decreased viral and bacterial replication; increased antigen processing; increased specific immune response

56
Q

What is the effect of IL-1β/IL-6/TNF-α on dendritic cells?

A

TNF-α stimulates migration to lymph nodes and maturation → initiation of adaptive immune response

57
Q

What are the local effects of TNF-α in gram-negative bacterial infection?

A

Very good local effects

Get increased release of plasma proteins into tissue, increased phagocyte and lymphocyte migration into tissue, increased platelet adhesion to blood vessel wall → phagocytosis of bacteria; local vessel occlusion; plasma and cells drain to local lymph node → removal of infection; adaptive immunity

58
Q

What are the systemic effects of TNF-α in gram-negative bacterial infection?

A

If there is systemic infection of gram-negative bacteria (sepsis), macrophages are activated in the liver and spleen to secrete TNF into the bloodstream

This can be deadly

Systemic edema occurs → decreased blood volume, hypoproteinemia, neutropenia, followed by neutrophillia (neutrophils in tissue) → decreased blood volume causes collapse of vessels → disseminated intravascular coagulation leading to wasting and multiple organ failure → death

59
Q

IL-12

A

Produced by cells of the innate response (macrophages, DC) and activates T cells and NK cells

Stimulates IFN-γ secretion from T cells and NK cells → macrophage activation; killing of phagocytosed microbes

Causes increased cytolytic activity of NK cells and CD8+ cells → killing of infected cell

60
Q

Describe how adaptive immunity is stimulated by and interacts with innate response

A

Macrophage phagocytosis: antigen presentation, cytokine production, co-stimulation, resulting in T cell activation

ADCC: antibody plus innate effector cells

Opsonization by antibody to enhance phagocytosis

Cytokines of the innate response are essential to stimulate (and sometimes dampen) adaptive responses

HIID (27 decks)

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