FINAL - NEW MATERIAL

Question 1

What strategies to viruses employ to enter cells and evade the immune system?

Answer 1

Viruses typically enter a cell using a cell-surface receptor for which it has affinity. Viruses can
evade the immune system in a variety of ways, including:
a. Genomic mutation so it is harder to target
b. Develop a long latency period
c. Spread rapidly to another host
d. Facile transmission (easy and fast transmission such as through aerosols)
e. Encode proteins that interfere with innate and adaptive immune responses (such as
blocking PKR)
f. Antigen presentation inhibition (such as inhibition of TAP which blocks class I MHC
from presenting on the surface of the cell)
g. Evasion from complement (such as secretion of proteins that bind to complement)
h. Changing of surface antigens
i. Directly infecting immune cells and messing up their function/destroying them
j. Cytokine suppression (such as making a protein similar to IL-10 which inhibits cytokines
by Th1 cells)

Question 2

What is the difference between antigenic drift and antigenic shift?

Answer 2

Like the word drift implies, antigenic drift is a SLOW change over time that is caused by several point mutations to produce minor changes in the viral glycoproteins hemagglutinin (HA) and neuraminidase (NA) over time.

Antigentic shift, in contrast, in a very FAST change in HA and NA structure that is much different than what was previously seen.

Question 3

What is “original antigenic sin” and give an example of why it matters to humans?

Answer 3

The original antigenic sin involves the body’s ability to focus the immune system’s attack strategy to respond to what was seen previously in the primary response. In this way, the human body doesn’t produce a primary response when only minor changes or similar epitopes are seen. This is very useful for humans when infected with influenza virus. If the virus hasn’t drifted antigenically very much, the immune system will dispatch memory cells to fight rather than ramp up a new primary response so you don’t get sick nearly as often.

Question 4

How are extracellular and intracellular bacteria infections resolved?

Answer 4

Extracellular bacteria infections are typically resolved by antibody production, so the humoral response is the main protector against extracellular bacteria. Antibodies do this through neutralizing toxins, lysing the cells using complement, opsonization that allows for phagocytes to eat the bacteria, inducing mast-cell degranulation to allow more lymphocytes and neutrophils into the tissue, and complement-mediated chemotaxis to recruit more macrophages and neutrophils.

Intracellular bacterial infections are resolved by cell-mediated immunity, mainly by activation of NK cells, secretion of cytokines by CD4+ T cells, and activation of macrophages by IFN-γ.

Question 5

How is the parasitic worms Schistosoma mansoni able to evade the immunesystem for up to 20 years and and cause chronic disease?

Answer 5

Schistosoma mansoni is able to evade the immune system by masking its presence with the antigens of the host. They are able to decrease their own antigen expression and wrap themselves up in a glycolipid/glycoprotein coat bearing the host’s antigens, such as those of the ABO-blood group and histocompatibility antigens.

Question 6

Why are we more at risk for fungal infections after taking antibiotics and how are fungal infections normally recognized by the immune system?

Answer 6

By taking antibiotics, not only do we kill the pathogenic bacteria but also the commensal bacteria in our mucosal tissues. These bacteria help control fungal growth, so by destroying them we lose that innate defense.

Fungal infections are recognized by fungal cell wall PAMPs including β-glucans, mannans (chains of mannose), and chitin. Recognition of these cell wall PAMPs activates complement and induces phagocytosis.

Question 7

Why do infectious diseases emerge, re-emerge, or spread in our modern world?

Answer 7

One of the reasons that this happens may be overcrowding of people, particularly poorer people in large cities, so closer proximity allows for better spread or re-emergence.

Many more people travel internationally which would facilitate a larger and faster spread of virus. Contaminated food can be shipped, distributed, and imported across continents.

Overuse of antibiotics can also enhance resistance to infectious diseases, thereby increasing their chances to emerge or re-emerge.

Finally, by inhabiting land previously dominated by animals can also lead to transmission of new viruses from animals to humans.

Question 8

What conditions would warrant using passive vaccination over active vaccination?

Answer 8

Passive vaccination involves the transfer of preformed antibodies or antiserum from immune
individuals.

Conditions that warrant using passive vaccination include immune deficiencies such as B cell defects, toxin or venom exposure, or pathogen exposure that will result in death if not rapidly treated before an immune response can be mounted in the body.

Babies born with immune deficiencies, children suffering from RSV, unvaccinated people, or travelers who lack protective immunity are also passively vaccinated.

Question 9

What are the pros/cons of the attenuated vaccines?

Answer 9

Attenuated pros: strong immune response, lifelong immunity with few doses, and increased
immunogenicity.

Attenuated cons: possibility of mutating to virulent version, possible complications similar to the actual disease, and requires refrigeration so it makes it hard to transport.

Question 10

What are the pros/cons of the chemically treated vaccines?

Answer 10

Chemically treated pros: Stable, safer than live vaccines because it cannot replicate, refrigeration not required.

Chemically treated cons: requires multiple doses, less effective because it mainly produces a humoral response, some live virus may still be present.

Question 11

What are the pros/cons of the subunits vaccines?

Answer 11

Subunit pros: Adverse reactions are diminished because of specific macromolecules derived from the pathogen.

Subunit cons: cannot activate Th cells, poor affinity maturation of B cells, and little memory formation.

Question 12

What are the pros/cons of the recombinant vector vaccines?

Answer 12

Recombinant vector pros: mimics a natural infection, so a strong immune response is produced and avoiding the possibility of becoming virulent again.

Cons: unknown

Question 13

What are the pros/cons of the DNA vaccines?

Answer 13

DNA vaccines pros: strong humoral and cellular response, less expensive to produce, no
modification or denaturation necessary so antigen is exactly how it is found in the immune
system, prolonged expression improves memory, and no refrigeration.

Cons: unknown

Question 14

How do the three common adjuvants work to enhance the immune response?

Answer 14

luminum salts enhance Th2 responses by slowly releasing the antigen and it helps recruit
APCs.

MF59 is similar to aluminum salts.

AS04 contains a TLR4 agonist which helps Th1
responses.

All of these adjuvants increases the production of antibodies.

Question 15

How does malignant transformation of cells occur?

Answer 15

Malignant transformation can occur through several means, including chemical means such as formaldehyde or DDT, physical particles such as asbestos, radiation, and viruses.

These catalysts drive transformation by inducing DNA mutations.

Question 16

What are the three main types of genes associated with cancer control cell proliferation
and survival and how do they work?

Answer 16

1. Oncogenes – these genes promote cell proliferation. Typically these genes encode for growth factor, growth factor receptors, signal transducers, or transcription factors which are excessively upregulated. These genes are typically the mutated forms of proto-oncogenes which are necessary for normal growth and proliferation.
2. Tumor-suppressor genes – these genes code for proteins that negatively regulate cell proliferation by preventing the cell cycle from progressing. Mutations in these genes
   result in cancer.
3. Apoptotic genes – these genes produce proteins involved with promoting or inhibiting apoptosis. Pro-apoptotic genes prevent cells from progressing by killing them while anti-apoptotic genes allow the cell to continue proliferating. If pro-apoptotic genes don’t work or anti-apoptotic genes are enhanced, both of these will result in the development of cancer.

Question 17

How is Burkitt’s lymphoma caused?

Answer 17

Burkitt’s lymphoma is typically caused by a translocation of c-myc from chromosome 8 to
chromosome 14 or the translocation of the κ or γ light chain genes to c-myc on chromosome 8.
These translocations result in mutations in the c-myc gene which upregulates unregulated cell
growth since it is a transcription factor that is involved in cell proliferation.

Question 18

What causes Xeroderma pigmentosum and why are individuals with this sometimes called “Children of the Night”?

Answer 18

Xeroderma pigmentosum is caused by mutations that debilitates DNA repair, specifically the nucleotide excision repair pathway.

Because DNA repair cannot be completed, mutations induced by UV rays cannot be fixed in patients with Xeroderma pigmentosum, which promotes the development of unregulated proliferation and cancer in skin cells.

These individuals are sometimes called “Children of the Night” because of this UV sensitivity so they aren’t active when the sun is out to prevent UV exposure.

Question 19

What is the difference between tumor specific and tumor associated antigens?

Answer 19

Tumor specific antigens – unique proteins that develop only from mutations in cancer cells to
produce new antigens.

Tumor associated antigens – these antigens are normally found in cells only in certain
developmental stages but upregulated in cancer cells.

Question 20

What are the three “E”s of cancer immunoediting? Does the immune system protect against or promote tumor growth?

Answer 20

1. Elimination – where the immune system finds and destroys newly formed cancer cells using immunoserveillance
2. Equilibrium – where destruction and survival of cancerous cells is balanced by the immune system, so some cancer cells escape the destruction of the immune system
3. Escape – those few resistant cells that escaped begin to proliferate and allow the cancer to progress in the body.

For the most part, the immune system protects against cancer. However, the immune system can promote tumor growth, i.e. such as M2 macrophages.

Question 21

What are the main three strategies described in the book that tumor cells use to evade immune recognition and activation?

Answer 21

1. Downregulation of MHC class I proteins by mutations in genes involved in MHC
   expression, TAP or β2-microglobulin, IFNγ insensitivity and TSA secretion.
2. Mutation of apopototic genes that upregulate anti-apoptotic genes or downregulated
   pro-apoptotic genes
3. Lack of costimulatory molecules allows tumor cells to go undetected by T cells as well
   as render them anergic because of the lack of costimulatory molecules.

Question 22

What is Coley’s toxin and how does it work?

Answer 22

Coley’s toxin was used in 1891 by Dr. William B. Coley. It consisted of bacteria or bacterial proteins that were injected into tumors to produce an antitumor response by the immune system as it reacted to the bacteria.

Question 23

How can co-stimulatory signals be manipulated to improve cancer immunity?

Answer 23

By transfecting cancer cells with co-stimulatory molecules, the cancer cells now stimulate cytotoxic lymphocytes, thereby enhancing the immune response and eliminating the cancer cells.

Question 24

Why are combination cancer therapies yielding surprising results?

Answer 24

Surprisingly, some of the chemotherapeutic agents may be stimulating immune cells in the immunotherapy treatment, making the combination a much more effective option than one is by itself.

Question 25

What is a Chimeric Antigen Receptor (CAR) and how is it useful for immunotherapy?

Answer 25

A chimeric antigen receptor uses a monoclonal antibody attached to co-stimulatory domains of T cells to specifically activate T cells against certain antigens.

This is useful for immunotherapy because the specificity of the monoclonal antibody allows for specific targeting of cancerous cells.

Question 26

The structure of mucins gives mucus its characteristic protective properties, what is the
general structure and function of mucins?

Answer 26

Mucins consist of long chains of proteins with cysteine and threonine residues at the ends, which facilitate binding to other mucin proteins.

These protein superstructures are the reason that
mucus is viscous, making it difficult for pathogens and molecules to move around in it.

Question 27

How do mucins interact with secreted IgA and defensins?

Answer 27

Mucins also have a negatively charged surface provided by sialic acid and the free cysteine residues, providing the binding of positively charged molecules such as IgA and defensins.

Binding to mucins allows for IgA to trap microorganisms and defensins to kill those trapped microorganisms.

Question 28

List the five ways described in the textbook that commensal microorganisms assist the gut in
digesting food and maintaining health.

Answer 28

1. Synthesize essential metabolites: provide building blocks we cannot make ourselves
2. Break down plant fibers: provide enzymes for digestion of indigestible proteins
3. Inactivate toxic substances: render harmful substances into inert or harmless molecules that can be secreted by the body
4. Prevent pathogen entry to gut resources: deprive pathogens of resources and space due to high numbers of commensal bacteria
5. Develop healthy lymph-associated tissues: commensal bacteria necessary for normal development of tissues

Question 29

What is the difference between the strategies the systemic and mucosal immune systems use
to respond to infection?

Answer 29

Systemic:
1. Macrophages are activated by pathogen, releasing cytokines that cause inflammation

2. Adaptive immune cells are recruited to quickly squash the invasion
3. Recovery involves suppression of inflammation and immune cells and healing of
   wounded tissue
4. KEY: short, localized, intense, and reactive inflammation response to infection

Mucosal:
1. Immunity is proactive; adaptive immune response going all of the time against gut
microorganisms

2. Entrance of pathogen activates macrophages, but doesn’t inflame tissues
3. Effector T and B cells stand as sentinels to begin the battle while specific effector cells
   are recruited from the lymph node
4. Minor or no inflammation or damage
5. KEY: proactive, subdued yet efficient immune response with no damage to healthy tissues

Question 30

How do epithelial cells contribute to the defense of mucosal tissue?

Answer 30

Epithelial cells have Toll-like receptors and NOD1/2 receptors that detect bacteria that have
been able to get through the epithelium.

Recognition by these receptors induces transcription of NF-KB and building of the inflammasome. This produces antimicrobial peptides, chemokines, and cytokines, and recruits other immune cells such as neutrophils, eosinophils, monocytes, and dendritic cells that respond and quell the infection.

Question 31

How are mucosal associated macrophages different from macrophages in the systemic
immune system?

Answer 31

Mucosal associated macrophages cannot present antigen, initiate adaptive immune responses, or cause inflammation like systemic macrophages.

These mucosal associated macrophages cannot secrete inflammatory cytokines or respond to them, lack B7 costimulatory domains or cytokines for naïve T cell activation and expansion. They also lack Fc receptors for IgA and IgG, LPS receptor, complement receptors, and other adhesion molecules.

They can, however, recognize and kill pathogens like systemic macrophages.

Question 32

What is the role of paneth cells, goblet cells, and M cells in mucosal immunity?

Answer 32

These cells are found in the gut lumen.

Paneth cells secrete defensins, lysozyme, and other antimicrobial molecules that help defend the mucosal surface.

Goblet cells secrete mucus.

M cells are responsible for transporting microbes across the lumen into secondary lymphoid tissues. As pathogens bind to M cells, they are internalized and transported to the basolateral side where they encounter the intraepithelial pocket filled with dendritic cells, T cells, and B cells that respond to the pathogens.

Question 33

B cells activated in mucosal tissues give rise to plasma cells that secrete IgM and then IgA
antibodies, describe how these first and second waves of antibody production occur.

Answer 33

The first wave of antibody production involves effector B cells going to the lamina propria to produce IgM antibodies that are secreted below the epithelial layer. IgM is bound by the poly-Ig
receptor found on epithelial cells, is transported across the cell to be bound by mucus on the
other side.

The second wave of antibody production involves effector B cells that remain in the B cell area of GALT and experience enhanced (in comparison to systemic B cells) somatic
hypermutation and switch to IgA. The IgA switch is facilitated by APRIL (a proliferation-inducing ligand), BAFF (B-cell activating factor), and IL-4. IgA antibodies are carried by the poly-Ig receptor to the gut lumen.

Question 34

How do secretory IgM and IgA protect mucosal surfaces from microbial invasion?

Answer 34

These secretory antibodies do not fix complement but simply coat the pathogen to stop it from
proliferating or potentially invading the gut.

If M cells have already detected the bacteria, these
antibodies against the pathogen will bind and kill the pathogen before it can ever make it to the
epithelial surface.

IgM and IgA can also bind surface proteins of bacteria that are typically used to invade the epithelial surface, thereby preventing their invasion of the epithelium. So, in other
words, these secretory antibodies protect by binding to pathogens WITHOUT producing an inflammatory response.

Question 35

How do the IgA1 and IgA2 antibody subclasses complement one another in controlling
microbial populations?

Answer 35

Where IgA1 is deficient, IgA2 can pick up the slack.

IgA1 has a long hinge that helps it to better
bind pathogens than IgA2; however, that same hinge is susceptible to cleavage by bacteria-
specific proteases.

IgA1 Fab fragments can also allow bacteria to bind better to the mucosal surface and allow for the bacteria to penetrate. The IgA2 hinge is less susceptible to cleavage because it is protected by carbohydrates, allowing for IgA2 to pick up the slack from IgA1.