Innate Immunity - Hunter Flashcards

1
Q

What is the difference between infection and colonization?

A

Microbes may reside on or in tissues (colonization) but infection can occur if they trigger a response.

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2
Q

Name some intrinsic epithelial barriers to colonization and infection.

A

Tight junctions between cells, tears, saliva, mucus, cilia, enzymes, low pH etc.

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3
Q

What is microbial pathogenesis and give an example.

A

Direct mechanisms of tissue damage by pathogens. For example endotoxin production by gram-negative bacteria.

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4
Q

What is immunopathology and give an example.

A

Indirect mechanisms of tissue damage by pathogens. For example build-up of immune complexes (antibody attached to a microbe or part of a microbe) or an over-exuberent immune response.

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5
Q

Name 3 anti-microbial enzymes.

A

Antimicrobial enzymes are part of the innate immune system. These include Lysozyme (chews up cell wall of gram-positive bacteria), secretory Phospholipase A2 (chews up lipid bilayer of microbe but not self) and, pepsin (lowers pH).

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6
Q

What is an opportunistic pathogen?

A

A pathogen that resides on or in the body but only cause disease when the host is immunosuppressed.

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7
Q

Name the routes of infection for pathogens.

A

Mucosal surfaces (GI tract, GU tract, respiratory tract) and External epithelia (thru external surface, bug bites and wounds and abrasions).

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8
Q

Name the types of barriers our body uses to resist pathogens.

A

Mechanical (cell to cell adhesions, cilia, etc), Chemical (pH, surfactant, enzymes, etc), and microbiological (normal microbiota).

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9
Q

If after initial infection the innate immune system is overwhelmed by too many pathogens or especially virulent pathogens what happens?

A

The early induced innate response kicks in.

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10
Q

What is the major feature of the early induced innate immune response?

A

Inflammation.

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11
Q

Name 3 classes of anti-microbial peptides.

A

Defensins (alpha and beta), Cathelicidins, Histatins.

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12
Q

How are anti-microbial peptides activated?

A

By proteolysis to release amphipathic peptides.

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13
Q

How do Defensins harm microbes?

A

They are amphipathic and are able to penetrate the lipid by layer. They form a pore in the membrane leading to leaking and cell death.

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14
Q

How are anti-microbial peptides different from anti-microbial enzymes?

A

Anti-microbial enzymes break down components of microbes and anti-microbial peptides form pores and lead to death of the microbe.

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15
Q

What happens when pathogens breach epithelial barriers?

A

They encounter macrophages which then trigger inflammation and they also encounter molecules of complement.

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16
Q

How do macrophages recognize pathogens?

A

Via genome encodes receptors such as TLR’s (toll-like receptors).

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17
Q

What do macrophages do when they encounter pathogens?

A

They can phagocytose and release cytokines and chemokines which then trigger inflammation and attract neutrophils.

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18
Q

What can cytokines do?

A

The cause vasodilation, increased vascular permeability, and upregulate expression of adhesion molecules on endothelium. As a result components of complement are released, and neutrophils and more macrophages can leave blood vessels. Also, components of the kinin and coagulation system are released locally leading to pain and blood clotting. TNF-alpha is an example of a cytokine.

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19
Q

What can chemokines do?

A

Chemokines attract neutrophils and monocytes. For example, the chemokine CXCL8 (also called IL-8) goes to the bone marrow and stimulates the production of new neutrophils which have short half-lives and it also attracts neutrophils to sites of inflammation.

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20
Q

Why does the early induced immune process take time?

A

Because it involves upregulating genes and the translation of new proteins.

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21
Q

What are PAMPS and what is their significance?

A

PAMPS are pathogen associated molecular patterns. Macrophages recognize these highly conserved common motifs on microbes. Examples include peptidoglycans on gram-positive bacteria and lipopolysaccharide on gram-negative bacteria.

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22
Q

What component of the macrophage recognizes PAMPS?

A

On their cell surface, macrophages have pattern recognition molecules/receptors (PRR’s). This is a form of self/nonself discrimination.

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23
Q

Give examples of PRR’s on macrophages.

A
  1. f-Met-Leu-Phe receptor for bacteria.
  2. Mannose receptor for bacteria, fungi and viruses.
  3. scavengar receptors for acetylated lipoproteins on bacteria.
  4. Dectin-1-glucan receptors for fungi
  5. LPS binding protein, TLR-4 and CD14 for gram-negative bacteria.
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24
Q

What is another term for LPS?

A

endotoxin.

25
Q

What are TLR’s?

A

They are toll-like receptors that recognize PAMPS on microbes. They are located on macrophages.

26
Q

How many human TLR genes are there?

A

10

27
Q

Where can you find TLR’s?

A

On the cell surface and also intracellularly on endosomal surfaces.

28
Q

What happens upon TLR activation?

A

The transcription factor NF-kB is activated leading to the production of inflammatory mediators. The IRAK4 protein acts a danger signal and is part of the intracellular cascade leading to NF-kB activation.

29
Q

What are NOD-like proteins?

A

These are receptors similar to TLR’s that detect cytoplasmic bacteria and lead to inflammation.

30
Q

What are RIG-like proteins?

A

These are receptors similar to TLR’s that detect viral RNA in the cytoplasm and signal inflammation.

31
Q

What does TLR-4 recognize?

A

LPS or endotoxin on gram-negative bacteria.

32
Q

What does TLR-5 recognize?

A

Flagellin protein - a component of flagella which many bacteria have.

33
Q

What does the TLR-2/TLR-1 complex recognize?

A

The triacyl lipopeptides on microbe surfaces.

34
Q

What does the TLR-2/TLR-6 complex recognize?

A

The diacyl lipopeptides on microbe surfaces.

35
Q

What TLR’s are located on endosomal surfaces?

A

TLR–3 (recognizes dsRNA), TLR-7 (recognizes ssRNA) and TLR-9 (recongizes CpGDNA).

36
Q

Name 3 inherited immunodefiencies involving defects in neutrophil function.

A

Chronic granulomatous disease, chediak-higashi syndrome and type 1 integrin deficiency.

37
Q

What is the most important means of defense against extracellular bacteria, fungi and protozoan parasites?

A

Phagocytosis and intracellular killing.

38
Q

Describe the steps of phagocytosis and intracellular killing.

A
  1. after binding to receptors, particulate microbes are endocytosed.
  2. the invagination of the cell membrane during this process creates the phagosome.
  3. lysosomes filled with antimicrobial substances fuse with phagosomes to form a phagolysosome.
  4. the lysosome is filled with chemicals that are activated and eventually lead to the killing and digesting of the microbes in the phagolysosome.
39
Q

What are the 2 most important phagocytic cells?

A

Neutrophils and macrophages.

40
Q

How are the lysosomal enzymes activated?

A

Microbe phagocytosis is coupled with G-protein receptor signaling (C5a is one molecule that causes this signaling). The signaling leads to the assembly of an NADPH oxidase in the phagolysosomal membrane. The NADPH oxidase generates ROS species such as superoxide (called respiratory burst). The ROS’s and proton pumping lower the pH inside the phagolysosome leading to the activation of acid hydrolases, enzymes and antimicrobial peptides.

41
Q

Name a component of the NADPH oxidase.

A

gp91 is a protein that is part of the NADPH oxidase. Deficiency of gp91 is an X-linked disease.

42
Q

What is neutropenia?

A

Decreased absolute neutrophil count.

43
Q

What is the lower limit for normal for absolute neutrophil count?

A

1500-2000 cells/mm3 of blood. Below 1500 is neutropenia.

44
Q

What is the danger of neutropenia?

A

Increases susceptibility to infection especially from fungi, encapsulated bacteria and gram-negative bacteria such as Staph.

45
Q

Name the two classes of neutropenia.

A

Acquired (more common) and Hereditary (rare).

46
Q

Name two types of acquired neutropenia.

A

Drug-induced - especially cytotoxic cancer drugs and autoimmune such as anti-neutrophil antibodies.

47
Q

Name 3 types of hereditary neutropenia.

A

Familial (benign), cyclic, and infantile genetic agranulocytosis (congenital).

48
Q

What are adhesion molecules?

A

Adhesion molecules are molecules on the surfaces of cells such as neutrophils, macrophages and vascular epithelial cells that bind to eachother so that these cells can cross the vasculature and go into the tissues.

49
Q

Name 4 types of adhesion molecules.

A

Vascular addressin (on neutrophil) or CD34 binds to L-selectin (on vascular epithelium), Integrin or LAF-1 (on neutrophil) binds to ICAM-1 on vascular epithelium.

50
Q

What is CD18?

A

CD-18 makes up the common beta subunits that are part of the LAF-1 family of adhesion molecules. Deficient CD18 leads to a disease called Leukocyte adhesion deficiency.

51
Q

What is the acute phase response?

A

A complex systemic early-defense system activated by trauma, infection, stress, neoplasia, and inflammation.

52
Q

The acute phase response is mediated by what?

A

Acute phase proteins. Bacteria induce macrophages to produce IL-6. IL-6 acts on hepatocytes to induce synthesis of acute phase proteins.

53
Q

What are the acute phase proteins and what is their role?

A

C-reactive protein - acts as an opsonin and is used to identify patients with active inflammatory processes.
Ferritin - binds and sequesters iron to inhibit microbial growth.
fibrinogen - a coagulation factor (the levels of fibrinogen correlate with the erythrocyte sedimentation rate which is measured as an inflammation indicator).
Albumin - production is down-regulated during acute phase response.
Mannose-binding lectin - binds to bacteria and activates complement.

54
Q

What do virus infected cells produce?

A

alpha and beta Interferon.

55
Q

What do the Interferons do?

A
  1. induce resistance to viral replication in all cells.
  2. increase expression of ligands for receptors on NK cells.
  3. activate NK cells to kill the virus-infected cell.
  4. cause viral dsRNA to activate RNAse L leading to degradation of mRNA and apoptosis.
  5. increases the expression of MHCI molecules on nucleated cells.
56
Q

What do NK cells do?

A
  1. kill virus infected cells with intracellular pathogens and tumors using cytotoxic granules with perforin and granzymes.
  2. kill infected cells and tumors that express stress molecules.
  3. bind to and kill antibody-coated pathogens - this is called antibody dependent cell-mediated cytotoxicity (ADCC).
57
Q

How are NK cells activated?

A

Virus infected cells produce Interferons (INF-a, INF-B) and cytokines (TNF-a and IL-12). These activate NK cells.

58
Q

What is the result of NK cell deficiencies?

A

The person will be susceptible to severe and/or recurrent infection with herpes viruses such as Herpes zoster, Herpes simplex, Epstein-Barr virus and Cytomegalovirus.