Innate Immunity - Hunter

Question 1

What is the difference between infection and colonization?

Answer 1

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

Question 2

Name some intrinsic epithelial barriers to colonization and infection.

Answer 2

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

Question 3

What is microbial pathogenesis and give an example.

Answer 3

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

Question 4

What is immunopathology and give an example.

Answer 4

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.

Question 5

Name 3 anti-microbial enzymes.

Answer 5

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).

Question 6

What is an opportunistic pathogen?

Answer 6

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

Question 7

Name the routes of infection for pathogens.

Answer 7

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

Question 8

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

Answer 8

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

Question 9

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

Answer 9

The early induced innate response kicks in.

Question 10

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

Answer 10

Inflammation.

Question 11

Name 3 classes of anti-microbial peptides.

Answer 11

Defensins (alpha and beta), Cathelicidins, Histatins.

Question 12

How are anti-microbial peptides activated?

Answer 12

By proteolysis to release amphipathic peptides.

Question 13

How do Defensins harm microbes?

Answer 13

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.

Question 14

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

Answer 14

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

Question 15

What happens when pathogens breach epithelial barriers?

Answer 15

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

Question 16

How do macrophages recognize pathogens?

Answer 16

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

Question 17

What do macrophages do when they encounter pathogens?

Answer 17

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

Question 18

What can cytokines do?

Answer 18

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.

Question 19

What can chemokines do?

Answer 19

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.

Question 20

Why does the early induced immune process take time?

Answer 20

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

Question 21

What are PAMPS and what is their significance?

Answer 21

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.

Question 22

What component of the macrophage recognizes PAMPS?

Answer 22

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

Question 23

Give examples of PRR’s on macrophages.

Answer 23

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.

Question 24

What is another term for LPS?

Answer 24

endotoxin.

Question 25

What are TLR's?

Answer 25

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

Question 26

How many human TLR genes are there?

Answer 26

10

Question 27

Where can you find TLR's?

Answer 27

On the cell surface and also intracellularly on endosomal surfaces.

Question 28

What happens upon TLR activation?

Answer 28

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.

Question 29

What are NOD-like proteins?

Answer 29

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

Question 30

What are RIG-like proteins?

Answer 30

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

Question 31

What does TLR-4 recognize?

Answer 31

LPS or endotoxin on gram-negative bacteria.

Question 32

What does TLR-5 recognize?

Answer 32

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

Question 33

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

Answer 33

The triacyl lipopeptides on microbe surfaces.

Question 34

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

Answer 34

The diacyl lipopeptides on microbe surfaces.

Question 35

What TLR's are located on endosomal surfaces?

Answer 35

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

Question 36

Name 3 inherited immunodefiencies involving defects in neutrophil function.

Answer 36

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

Question 37

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

Answer 37

Phagocytosis and intracellular killing.

Question 38

Describe the steps of phagocytosis and intracellular killing.

Answer 38

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.

Question 39

What are the 2 most important phagocytic cells?

Answer 39

Neutrophils and macrophages.

Question 40

How are the lysosomal enzymes activated?

Answer 40

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.

Question 41

Name a component of the NADPH oxidase.

Answer 41

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

Question 42

What is neutropenia?

Answer 42

Decreased absolute neutrophil count.

Question 43

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

Answer 43

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

Question 44

What is the danger of neutropenia?

Answer 44

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

Question 45

Name the two classes of neutropenia.

Answer 45

Acquired (more common) and Hereditary (rare).

Question 46

Name two types of acquired neutropenia.

Answer 46

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

Question 47

Name 3 types of hereditary neutropenia.

Answer 47

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

Question 48

What are adhesion molecules?

Answer 48

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.

Question 49

Name 4 types of adhesion molecules.

Answer 49

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.

Question 50

What is CD18?

Answer 50

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.

Question 51

What is the acute phase response?

Answer 51

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

Question 52

The acute phase response is mediated by what?

Answer 52

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

Question 53

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

Answer 53

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.

Question 54

What do virus infected cells produce?

Answer 54

alpha and beta Interferon.

Question 55

What do the Interferons do?

Answer 55

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.

Question 56

What do NK cells do?

Answer 56

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).

Question 57

How are NK cells activated?

Answer 57

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

Question 58

What is the result of NK cell deficiencies?

Answer 58

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.