Final Concepts

Question 1

What are the three general mechanisms of action that distinguish cytokines from hormones?

Why are hormones easier to administer as drugs (versus cytokines)?

Lecture 20, Inflammation (1)

Answer 1

Pleiotropy: ability of a cytokine to act on multiple cell types w multiple mechanisms of action on each cell type; difficult to control bc usually generates unanticipated / unwanted side effects

Local Action Distance: mitigate pleiotropic effects by only acting within a certain distance (ie autocrine or paracrine, rather than endocrine); thus minimizes potential side-effects on other cells

Redundancy: takes advantage of pleiotropy in order to maintain the level of action needed by having other cytokines fill in for a missing one

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Non-redundant: hGH is the only molecule that regulates overall organismal growth

Non-pleiotropic: humans w mutations in hGH exhibit dwarfism but no other phenotype

Work systemically / as endocrine molecules (as opposed to the Local Action Distance of cytokines)

Question 2

What does the cytokine triad refer to?

• extra v intra
• STAT1 KO

Lecture 20, Inflammation (2)

Answer 2

IL-1, TNF-alpha, IL-6
Secreted by macrophages in order to initiate inflammation; activates macrophages and lymphocytes

If intracellular pathogen, then induction of Type 1 (innate) interferons (specifically, IFN-alpha and -beta) and Type 2 (adaptive) interferons (specifically, IFN-gamma)
If extracellular pathogen, then acute phase response triggered via cytokine triad

Because of the compensation that cytokines have to cover for the loss of one, it would make sense that multiple cytokines signal through common STATs
eg. STAT1 can be activated by IFN-gamma, IFN-alpha/beta, and IL-12
THUS: STAT1 KO mice are more susceptible to viral pathogens due to loss of Type 1/2 IFNs – illustrates why redundancy is important at maintaining level of action when one response is affected

Question 3

What are the two mechanisms proposed for how TNF-alpha works?

What is the relationship btwn TNF-alpha and NF-kB? How does this relate to the effectiveness of TNF-alpha blockers?

Lecture 20, Inflammation (3)

Answer 3

GAIN OF FUNCTION experiment // TRANSGENIC MOUSE MODEL: overexpression of TNF-alpha transgene driven by different immune cell promoters results in mice with constitutive inflammation

LOSS OF FUNCTION experiment // KNOCKOUT MOUSE MODEL: targeted deletion of TNF-R1 gene creates TNF-alpha KO mouse that is resistant to LPS / endotoxin

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TNF-alpha activates feed forward loop by NF-kB transcription factors. NF-kB activates inflammatory response mostly through TNF-R1 (not R2)
THUS, limiting this loop will limit the TNF-alpha response → TNF-alpha blockers are important drugs in treatment of chronic inflammation

Success of TNF-alpha blockers depends on several factors:

• Critical non-redundant apex position in inflammatory response
• Feed forward loop that heightens sensitivity to levels of TNF-alpha in regulating inflammatory responses
• More modest side effects (compared to interferons)

Question 4

What is sepsis?

What is Centoxin and why did it fail?

Lecture 20, Inflammation (4)

Answer 4

Situation where TNF-alpha acts as an endocrine model, thus creating a systemic inflammatory response
eg. LPS is usually antigen bc it can bind to TLR4 of macrophages, which begin secretion of the cytokine triad

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Centoxin = early form of immunotherapy against sepsis that focused on production of anti-LPS antibodies; found to be effective only in early stages of sepsis when TNF-alpha was still present (but this usually wasn’t the case bc TNF-alpha has a short life span)

Question 5

Why are platelets so important?

Lecture 20, Inflammation (5)

Answer 5

Immune complexes can cause platelets to upregulate expression of Fc-gamma-RIIA, which can bind to IgG, which causes degranulation of serotonin from platelets into the bloodstream

Serotonin will cause vasodilation in the body, thus increasing the rate of progression of sepsis

Question 6

What is the Ouchterlony test?

Lecture 21, Response to Infection (1)

Answer 6

allowed for visualization of formation of immune complexes by allowing diffusion of Ag and Ab on an agar matrix – IC formed in equivalence zone

Early = antigen excess zone = not enough removal ; Ab still being formed due to maximal B cell activation
Middle = 1:1 ratio is the best ratio, allowing for extensive complex formation and pathogen clearance
Late = if successful at clearing, then it will be an antibody-excess zone ; requires active / passive mechs to shut down the response
- Passive = less antigen means less triggers for Ab, thus reduces population
- Active = literally seeking out Ab for removal via Fc-gamma-IIb on B cells

Question 7

Describe the Network Hypothesis vs the Strong Form Hypothesis

Lecture 21, Response to Infection (2)

Answer 7

Idiotype = antigenic target on the first Ab
Anti-idiotype = binding surface of second Ab

Network hypothesis: strong Ab responses often elicited a second wave of Ab that were made against the first Ab as these were seen as “new” antigens by the immune system → could also elicit a third wave and so on
- has been largely discredited in favor of the strong form hypothesis

Strong form hypothesis: Ab will form a network of binding interactions where sophisticated regulation of Ab responses are maintained at the protein level → DIRECT CONTROL of the ability to bind to Ag

Question 8

What is the relationship btwn B-1 B cells and antibodies?

Innate cellular and adaptive effector responses
Lecture 21, Response to Infection (3)

Answer 8

protect against extracellular bacteria

B-1 B cells can spontaneously secrete “natural” antibodies in the form of IgM – T cell independent

Antibodies will work in coordination w innate serum complement proteins to facilitate phagocytosis via opsonization or killing via pore formation
- classical pathway!

Question 9

What is the relationship btwn FcR and antibodies vs pathogens?

Innate cellular and adaptive effector responses
Lecture 21, Response to Infection (4)

Answer 9

FcR found on innate cells – specifically CTLs / gamma-delta cells / NK(T) cells

If binds an Ab, innate cells obtain antigen specificity via up/down-regulation of certain receptor functions

If binds pathogen, can lead to ADCC (antigen-dependent cellular cytotoxicity)

Question 10

What circumstances trigger the two different CTL effector functions?

Innate cellular and adaptive effector responses
Lecture 21, Response to Infection (5)

Answer 10

CTLs can secrete IFN-gamma and express NKG2D receptors → pathway depends on type of pathogen, site, and conditions involved

Cytopathic viruses replicate and kill a host cell very quickly, thus cytotoxicity is ineffective → can be prevented by secretion of IFN-gamma, which prevents the initial infection of cells

Noncytopathic viruses spend a lot of time in a host cell in order to replicate, thus lysis of the host cell is an effective way of limiting viral production (thus, cytotoxicity)

Question 11

What is the relationship btwn complements and antibodies? What are the downstream effects?

Innate cellular and adaptive effector responses
Lecture 21, Response to Infection (6)

Answer 11

Classical pathway!

utilizes antibodies that have bound to the surface of the pathogen ;; REMEMBER C1qrs + C3ab timeline → Binding of C1q to Ig activates C1r, which cleaves and activates the serine protease C1s → triggers cleavage of C3 molecule, C3b remains on surface of pathogen and the soluble C3a is released

DOWNSTREAM EVENTS:

• C3a recruit phagocytic cells to the site of infection and promote inflammation
• Phagocytes with receptors for C3b engulf and destroy the pathogen
• Completion of the complement cascade leads to formation of a membrane-attack complex (MAC), which disrupts cell membrane and causes cell lysis
• Co engagement of the BCR by the antigen, and the Cr2 by C3 product leads to a strong signal and enhanced B cell activation to its surface

Question 12

Describe the four strategies of evasion / subversion used by pathogens. Provide a brief example for each.

Lecture 22, Immune Evasion (1)

Answer 12

(1) Antigenic variation: alteration of surface pathogens to “disguise” themselves
- Trypanosomes have variable surface glycoproteins (VSGs) that coat the parasite and allow escape from antibodies

(2) Latency: “lay low” strategy where proliferation of pathogen occurs after initial immune response dies down
- Herpes simplex virus (HSV) have low levels of MHC expression and persist in areas occupied by sensory neurons, thus not ever fully eradicated

(3) Hide from killing: passive or active action taken to “avoid the line of fire” that is the immune system
- Listeria monocytogenes use “jets” to escape into cell cytoplasm

(4) Immunosuppression: inhibition of host mechanisms that would normally be able to clear the target pathogen
- KSHV-FLIP inhibits Caspase-8 activation, thus preventing apoptosis of infected cells

Question 13

What is the influenza virus?

Lecture 22, Immune Evasion (2)

Answer 13

Example of antigenic drift (point mutations) and antigenic variation (new subtype creation)
- Segmented RNA virus

Point mutations in surface hemagglutinin (H) and neuraminidase (N) occur at an increased rate due to genetic reassortment, which arise when 2 viruses infect the same cell and allow new viral combination to be made (new subtype!)

Mutations decrease likelihood of antibodies binding to the specificity of the antigen epitopes, thus allowing for escape from neutralizing antibodies

Question 14

What is toxoplasma gondii?

Lecture 22, Immune Evasion (3)

Answer 14

Example of latency (two states of being) and hiding from killing (can create its own vacuole)
- parasite spread by consumption of infected animals

TIMELINE:

(1) In acute infection, T. gondii exists in a rapidly replicating form that spreads quickly to infect neighboring cells → Tachyzoite, fast-replicating form
(2) Conversion to formant bradyzoite form occurs when parasite senses stress (eg immune response) → Bradyzoite, dormant form
- Bradyzoites form LONG LIVED TISSUE CYSTS in brain, muscle, and retina that are no longer immune targets
(3) Immunosuppression or eating encysted meat reactivates bradyzoites to tachyzoite form, thus back to being activated / rapid replication
- Toxoplasmosis causing dementia following reactivation of dormant cysts in immunosuppressed AIDS patient

Question 15

What are viral strategies to subvert the immune response? (4)

Immunosuppression, expanded
Lecture 22, Immune Evasion (4)

Answer 15

(1) Inhibition of humoral immunity / antibodies → blockage of complement dependent pathways or effector functions of antibodies bound to infected cells, thus affecting junction btwn innate and adaptive response
(2) Inhibition of inflammatory response → sensitization to or blockage of cytokines, thus blocking secreted messages needed for communication and progress to downstream effects

(3) Blocking of antigen processing / MHC-1 specifically: interference with beta-2-microglobulin (thus remains unstable) or TAP transporter (thus no antigen brought into loading zone)
- Why MHC-1 and not MHC-2? → Viruses are intracellular, thus only want to prevent damage to their own cell and the MHC-1 pathway presents cytoplasmic / intracellular peptides (whereas MHC-2 presents exogenous / extracellular ones) – thus, MHC-1 poses a greater risk to the virus than MHC-2

(4) Immunosuppression of host
- Resistance: KSHV-FLIP example
- Counterattack: HIV nef protein induces FasL expression on infected cells; infected CD4 T cell can now kill Fas expressing anti-HIV-specific CD8 T cells → results in mutual killing (“you’re going down with me!”)

Question 16

What are exotoxins?

Lecture 22, Immune Evasion (5)

Answer 16

Produced and secreted by extracellular bacteria as a means of immunosuppression
eg. Staphylococcus and Streptococcus

Can be considered SUPERANTIGENS: proteins that bind Ag receptors of large numbers of T cells → inducing too strong of a response can lead to an inhibitory response of the immune system

Leads to the following response

• Cytokine dysregulation
• T cell proliferation
• Depletion of T cells (ie apoptosis of T cells)

Question 17

How does HIV manage to subvert the immune system?

Lecture 23, HIV and Vaccine Strategies (1)

Answer 17

Antigenic variation via mutation: overwhelm the host with epitopes that are constantly mutating such that no antibody can bind enough to begin eradication

Antigenic silence via latency: reverse transcriptase (RT) can integrate itself into the host genome (of infected host cells) and shut down gene expression to not present antigens

Question 18

How does HIV enter a cell?

Lecture 23, HIV and Vaccine Strategies (2)

Answer 18

BREAKDOWN: Virus binds to receptors on cell surface, triggering receptor-mediated endocytosis BUT the acidification of endosomes that would normally break down the pathogen for presentation instead triggers fusion of virus with cell, thus introducing viral DNA into the host genome

CD4 binding pathway:

(1) CD4 binds to exposed V3 loop of GP120 from HIV virus → conformational change in gp120 subunit releases coreceptor binding site, to which the T cell also binds to
(2) Binding of glycoprotein (T cell) with chemokine/coreceptor causes gp41 of HIV virus to “unfold” via hinge mechanism → allows for insertion of fusion peptide into cell membrane, thus anchoring virus to T cell membrane
(3) Gp41 then folds itself into a “hairpin” structure, bringing cell membrane and virus membrane into close proximity for fusion to take place → after membrane fusion, viral contents are expelled into the cell

Question 19

How does the tropism of HIV contribute to the collapse of the CD4 compartment?

Lecture 23, HIV and Vaccine Strategies (3)

Answer 19

Tropism: cells and tissues of a host that support growth of a particular virus

Early after infection, HIV infects mature T cells and macrophages by using CCR5 → thus no memory remains in order to help body better respond to HIV
- Immune system will send neutralizing Ab that will focus on targeting the V3 loop / gp120 / gp41 of the HIV virus

Later in infection, HIV changes its preferred cell type from mature to naive T cells that express CXCR4 → with no memory T cells, naive T cells are unable to arm themselves effectively against HIV
- Neutralizing Ab less effective as more mutations take place

THUS, changing tropism correlates with collapse of CD4+ compartment and a decreased ability to control infection, which results in rapid disease progression

Question 20

What do individual MHC alleles, specifically HLA-B27 and HLA-B*35, recognize from the HIV genome and how does this relate to the speed of the virus’ progress?

Lecture 23, HIV and Vaccine Strategies (4)

Answer 20

HLA-B27 recognizes and present [KRYL] peptides = slow progression
- [KRYL] peptides are critical parts of HIV genome where mutations are not permitted in MHC anchors or TCR recognition residues, thus viral replication / evolution is greatly slowed

HLA-B35 recognizes and present Y peptides = rapid progression
- Not many BUT if present, will be found in non critical parts of HIV genome, thus permitting mutations in only the MHC anchor residues → act as a weak stimulator to the immune system, so allows for rapid replication / evolution of virus if not restrained

Note: high HLA-A expression or heterozygosity of MHC allele is bad for HIV bc it provides the immune system more opportunities to identify it

Question 21

What are bNABs (broadly neutralizing antibodies)?

Lecture 23, HIV and Vaccine Strategies (5)

Answer 21

TWO KEY PROPERTIES

• Effective in blocking infection by many HIV strains
• Neutralizing at very low titers of antibody, suggesting efficacy in vivo

ARMS RACE: Ab will mutate to match rate of viral mutation in order to continue binding / neutralizing

While all antibodies can mutate, normal antibodies will mutate, eventually obscuring their binding site with their light chain with more and more mutations → on the other hand, bNAbs have the flexibility to move their light chain and thus continue to both bind and mutate to keep up with the mutations of the virus

Question 22

What are the three layers in triggering autoimmunity?

What is the key immune cell that drives most autoimmune diseases?

Lecture 24, Autoimmunity (1)

Answer 22

(1) Immune response to self-antigen
(2) Tolerance threshold that is broken that leads to response to self-antigen
(3) Environmental trigger that leads to break in the tolerance threshold

CD4 T CELLS
T cells with TCRs that recognize self-antigens are rarely seen in healthy individuals as a result of the combined effectiveness in central and peripheral tolerance mechanisms.
- Vs. B cells having a 20% self-recognition rate that have some capacity to initiate autoimmunity, but are still reliant on signal from T cells to initiate an immune response
- in absence of T cell help, autoreactive B cells do not cause disease

THUS, autoreactive CD4 T cells are the key cellular trigger for autoimmunity involving B cells

Question 23

What are the three animal studies used to study autoimmunity? Provide brief examples.

Lecture 24, Autoimmunity (2)

Answer 23

Spontaneous: genetic triggers
- NOD, KBxN

Induced: antigen dependent
- Collagen induced arthritis, EAE

Transfer: roles of Tregs and gut flora
- Autoimmune hemolytic anemia

Question 24

What was the takeaway of the Matsumoto paper?

How does this understanding of the Matsumoto paper relate to the KBxN model?

Lecture 24, Autoimmunity (3)

Answer 24

GPI antigen = ubiquitous glycolytic enzyme made by all cells; primarily cytoplasmic with very small extracellular amounts released with cells
- Found that anti-GPA antibodies lead to autoimmunity

Showed how a non-tissue specific antigen can cause tissue-specific disease- incredibly essential in our understanding of autoimmunity.

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Big breakthrough in Matsumoto paper was that anti-GPI Antibodies were produced in K/BxN mice after only several weeks of life → Anti-GPI antibodies in serum are sufficient to transfer disease not just to NOD (non-obese diabetic strain) mice, but most mouse strains.

KBxN model requires KRN TCR cross to NOD mice to cause arthritis

• NOD mice alone spontaneously develop insulitis and “diabetes-like” disease; the latter requires NOD MHC-2 allele
• When crossed w KRN TCR, mice will spontaneously develop a disease that phenocopied rheumatoid arthritis in humans

Question 25

Describe the collagen-induced model of arthritis

How does this relate to the experimental autoimmune encephalomyelitis (EAE) mouse model?

Lecture 24, Autoimmunity (4)

Answer 25

immunization with collagen and a strong adjuvant to invoke an autoimmune response that partially resembles what is seen in human arthritis

Presence of strong adjuvant is required for triggering the autoreactive CD4 T cells.
- Give rise to cytokines, cause direct damage, induce macrophages to attack the myelin sheath or activate the CD8+ T cells for CTL response.

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Animal model of brain inflammation, resulting in demyelination of the central nervous system

Start with autoreactive cell being triggered by APC presenting the self peptide myelin on its surface → Autoreactive CD4 T cells can activate both CTL and Ab against myelin-coated axons of neurons → Because myelin is the wrapping around axons that allows signaling, damaging it will cause paralysis.

Question 26

How does autoimmune hemolytic anemia arise?

Lecture 24, Autoimmunity (5)

Answer 26

IgM / IgG antibodies against red blood cells lead to lysis in two ways

• FcR+ cells in fixed mononuclear phagocytic system
• Complement activation and intravascular hemolysis

Mouse model of this disease helped identify regulatory T cells function (or lack of function as immune cells were actively targeting host cells and Tregs were not regulating them)

Question 27

What are the different scenarios in which a breakdown of tolerance is observed? (5)

Second layer, expanded
Lecture 24, Autoimmunity (6)

Answer 27

Scenario 1: Infection breaks immunological ignorance of immunoprivileged sites at tissue level (e.g. brain, eye, testes) or inaccessible antigens (e.g. nuclear) exposed by tissue or cellular damage.

Scenario 2: Infection induces high level expression of B7s and MHC on APCs resulting in the inappropriate activation of rare CD4 (or CD8) T cells capable of binding to self-peptide-MHC complexes.

Scenario 3: Recall the ability of treponemes and schistosomes to coat themselves with host proteins

Scenario 4: The TCRs or BCRs on lymphocytes that are activated in response to pathogen infection inadvertently cross-react to self-antigens and initiate tissue damage.

Scenario 5: Superantigens polyclonally activate T cells independent of their antigen specificity.

Question 28

What is the heart example from class?

Lecture 24, Autoimmunity (7)

Answer 28

A distinct heart-specific set point in immune responsiveness as the cause of dilated cardiomyopathy

PD-1 is an inhibitory receptor that opposes activation of lymphocytes
- Heart-specific expression of PD-1 ligands sets a higher threshold for lymphocyte reactivity in heart.

Why might this be?
People work out- Immune consequence of working out = inflammation. The heart is the only muscle that has to keep moving all the time. So the muscle has evolved to have higher capacity to have low-level inflammation.

Removal of this normal higher threshold for responses in heart causes spontaneous autoimmunity in PD1 KO mice.

Question 29

What are the one example in which environmental triggers breakdown tolerance? Covered in review lecture.

Lecture 24, Autoimmunity (8)

Answer 29

Segmented filamentous bacteria (SFB) in gut as a driver of autoimmunity in KBxN model.

In commensal bacteria in the gut, the presence of segmented filamentous bacteria (SFB) can markedly increase the development of proinflammatory Th17 cells, especially in KBxN mice → dramatic shift to Th17 instead of Tregs is a deadly duo

• Increased levels of Th17 cells in the gut is sufficient to initiate arthritis due to its proinflammatory downstream effects
• Decreased level of Tregs allow self-reactive immune cells to run rampant

Thus, SFB in the gut is sufficient to drive autoimmunity in a body tissue site.

Question 30

What are the two patterns of clinical rejection associated with solid organ transplantation?

Lecture 25, Transplantation (1)

Answer 30

Acute rejection: leads death of graft in first few weeks after transplant via Ab and CD4 T-cell mediated inflammation
- reliance on MHC locus rejection

Chronic rejection: rejection usually occurs 6 months or even years after transplant via CD4 and CD8 T-cell-mediated alloreactive response

Question 31

Describe how immunosuppressive drugs work?

What are the downsides?

Lecture 25, Transplantation (2)

Answer 31

Target both initial activation of T cells and their subsequent proliferation

THREE LEVELS:

• Surface blockage of Signal 1 (TCR) and Signal 2 (CD28) and CD40 → primary focus on CD4 cells
• Blockage of NFAT transcription factor required by T-cell Activation
• Cancer drugs to target proliferating cells

DOWNSIDES:

• Increased susceptibility to infections
• Increased risk for virus-associated cancers
• Increased for post-transplant diabetes

Question 32

Describe how bone marrow transplantation (BMT) works?

What are the two types of HSCs? What are the pros and cons of both?

Lecture 25, Transplantation (3)

Answer 32

Reconstitutes diseased hematopoietic system w hematopoietic stem cells (HSCs)

Patient is treated w high dose radiation and/or chemotherapy to remove cancerous cells leading to ablation of entire hematopoietic system → patient is then reconstituted with HSCs → If successful, after several weeks, patient’s hematopoietic system is health and regenerated w donor HSCs

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Allogeneic HSCs: derived from donors usually by bone marrow harvest

• Pros: already purified; stronger response against cancer
• Cons: search for donor can take a long time

Autologous HSCs: derived from patient before irradiation / chemotherapy

• Pros: no need to wait for donor
• Cons: more expensive; purification required in order to remove any cancerous cells that remain

Question 33

What are anti-HLA antibodies?

What is the process of desensitization?

Lecture 25, Transplantation (4)

Answer 33

Antibodies armed against donor cells; lead to varied rates of rejection during transplantation → the biggest reason behind why finding a match is so difficult

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Involves first filtering the antibodies out of all of the patient’s blood then injecting the patient with an infusion of other antibodies to provide some protection while the immune system regenerates its own antibodies

Regenerated antibodies are less likely to attack the new organ, despite presence of B cells that produce the original anti-HLA antibodies were not removed in the initial purge

Question 34

What is the pathway of tumor development?

Lecture 26, Tumor Immunology (1)

Answer 34

(1) EARLY TRANSFORMATION OF NORMAL CELLS induces:
- Expression of stress ligands recognized by innate cells
- Expression of tumor antigenic-MHC complexes recognized by adaptive cells

(2) IMMUNOEDITING / ELIMINATION
Many nascent tumors are eliminated by inn and adaptive immunity, THUS are never seen bc never given the chance to fully develop
- Cells involved: CD8 T cells + CD4 T cells + NK (T) Cells + macrophages + gamma / delta cells

(3) EQUILIBRIUM
During this phase, imm sys keeps nascent tumor in check with a back and forth battle as cells continue to mutate in response to immunoediting
- Elimination of nascent cells continue as those kinds of cells emerge out of the mutation
- Cells involved: CD8 T cells + NK (T) Cells + gamma / delta cells

(4) ESCAPE
Some tumor cells will evade the ability of the immune system to check its growth, thus going into the body and fully develop into its cancerous growth
- Cells involved: CD8 T cells + NK (T) Cells + Tregs

Question 35

How are “real” cancer antigens in humans identified by the human body?

Lecture 26, Tumor Immunology (2)

Answer 35

Expression of germline antigens: tumor cells may reactivate certain germline / embryonic genes that are not normally expressed by a differentiated cell, thus resulting in the expression of antigens novel to the adult immune system

Overexpression of melanocyte proteins: tumors may overexpress the normal self protein, thus changing the density of peptide presentation, which can alert T cells that something is wrong

Question 36

What are the three “classic” types of cancer therapies?

Lecture 25, Tumor Immunology (3)

Answer 36

Surgery = slash; extracation of tumor

Radiation = burn

Chemotherapy = poison by generally targeting a SINGLE MOLECULAR mechanism that cancer cells use for survival

Question 37

What is checkpoint therapy?

• anti PD1
• anti CTLA4

Lecture 26, Tumor Immunology (4)

Answer 37

CHECKPOINT : Harnesses natural ability of immune system to find and target cancer mutations → treats the immune system (not the cancer) by targeting inhibitory pathways on T cells to unleash multiple responses against tumors

Binding of CTLA4 or PD1 (on T cells) to ligands on tumor cells inhibits anti-tumor immune responses → THUS, blocking this inhibition with CTLA4 or PD-1 antibodies that would compete with binding will amplify the T cell response, resulting in immunotherapeutic effects ⇒ two negatives make a positive!

Question 38

PD-1 antibody therapy is better than CTLA4 blockade BUT combined, the two are even better!

Why?

Lecture 26, Tumor Immunology (5)

Answer 38

CTLA4 blockade improves initiation of T cell response (specifically CD4) and expands clonal diversity

PD-1 blockade removes block on effector / memory cells (ie re energizes exhausted CD8 cells), thus can continue to fight and eventually overwhelm cancer cells

Note: CTLA-4 engagement on T cells isn’t equal to all → higher affinity T cells will be more inhibited than low affinity ones, THUS preventing the dominance of T cell response by highest affinity clones

• This strategy of constraining the “best fit” T cells is opposite to what is found in B cell response → why?
• T cells provide B cells with Signal 2 → sucky T cell + great B cell = not a notable level of response

Question 39

Memorize the chart.

• Types of hypersensitivity
• Their mediators
• C3 deficient
• IL-4R deficient

Lecture 27, Allergy and Hypersensitivity (1)

Answer 39

See study guide.

Question 40

Specifically for Type 4, what are the downstream effects of the cytokines involved?

Lecture 27, Allergy and Hypersensitivity (2)

Answer 40

IFN-gamma, TNF-alpha / beta cause tissue destruction and inflammation

IL-2 that activates T cells and CTLs

Chemokines for macrophage recruitment

IL-3 and Gm-CSF for increased macrophage activation

Question 41

Specifically for Type 3, how are immune complexes usually removed from the bloodstream?

Lecture 27, Allergy and Hypersensitivity (3)

Answer 41

• Phagocytosis by macrophages and neutrophils
• Trapping in lymph nodes and kidney
• Piggybacking onto pathway to remove old RBCs that upregulate CR1 in liver

High levels of IC formation that are not removed quickly enough can trigger Type 3 Hypersensitivity → Inflammation arises out of C3a, C4a, C5a, and “frustrated” phagocytes

Puzzling paradox where too little and too many IC causes autoimmunity

Question 42

Specifically for Type 2, explain the hemolytic disease of newborns.

Lecture 27, Allergy and Hypersensitivity (4)

Answer 42

Caused by Rh factor incompatibility

IgG Abs against Rh, which is an innocuous RBC antigen

Rh+ baby born to Rh- mother → first time fine, but second time can have Abs to Rh from the first pregnancy
- CONSEQUENCE: Ab crosses placenta and baby kills its own RBCs

TREATMENT: treat mother with Ab to Rh Ag (aka Rhogam) right AFTER first birth, so that the mother never makes the anti-Rh Ab (remove the immune response for the second pregnancy)
- Rhogam treatment binds to and shields Rh antigen from the mother’s imm sys

Question 43

What is peptide immunotherapy (PIT)?

Lecture 27, Allergy and Hypersensitivity (5)

Answer 43

first mechanism-based approach in treating allergies

High dose of peptide = peptide generating strong but transient TCR signal → leads to deletion of peptide reactive T cell

• Pros: permanent removal of pathogenic T cells
• Cons: lack of ongoing regulatory effects to further control other potentially pathogenic T cells

Persistence of peptide with no strong reaction = adaptive tolerance

• Pros: loss of effector T cell proliferation and cytokine production
• Cons: Tolerant T cells may revert to pathogenicity

Multiple doses but low amount of peptide = regulation
- Pros: potential for regulation of allergic responses to additional allergens (aka bystander suppression)