Immuno 12

Question 1

The immune system is designed to respond to a wide range on antigen concentrations, but it is also designed not to respond to very low levels of antigen.

Answer 1

If the antigen burden in the host is very small, it is not indicative of an infective process that would involve replication of the pathogen. Therefore, a minimum threshold of antigen must be met before the immune system will respond.

Question 2

What happens if the necessary threshold on antigen concentration (signifying an infection) is met?

Answer 2

Once that threshold is met, the innate response initiates inflammatory responses that control pathogen replication while promoting antigen presentation to naïve T cells, and flow of antigen that can be recognized by B cells in the secondary lymphoid tissues. Once an effector T cell response is initiated, T helper cells can supply secondary activation stimuli to antigen-specific B cells. Once this adaptive immune response is formed, it can effect relatively rapid removal of the pathogen from the host’s tissues. Usually, the host is left with long lived B cell and T cell-mediated immunity to reinfection with that pathogen. This memory is in the form of clonally expanded memory B cells and T cells.

Question 3

T or F. If the innate immune response is unable to clear the infection by around day 2 of the infection, adaptive immune responses are primed and ultimately, these responses will clear the infection from the body.

Answer 3

F. Usually the innate response has around 4 days to clear the infection before the adaptive immune responses are primed and ready to go.

Question 4

What two stimuli do T cells need to be activated?

Answer 4

The first signal of activation is recognition of cognate peptide determinant (bound to MHC) via the T cell receptor. The second signal is binding of B7 (the co-stimulator molecule produced only by APCs) to CD28 on the T cell. Because B7 is only expressed when there appears to be an infection underway (determined by engagement of danger signals with pattern recognition receptors) this ensures that T cells are only activated during an infection.

The requirement for B7 co-stimulation helps to prevent activation of T cells when there is no infection…if T cells recognize their cognate determinant when there is no infection ongoing, their cognate determinant is most likely a self determinant. When they receive that 1st signal and do not receive co-stimulation, they become anergic and die (peripheral tolerance).

Question 5

What happens when T cells receive both of those stimuli?

Answer 5

When a T cell receives its two activation stimuli, it begins to produce large quantities of IL-2 (the autocrine growth factor for T cells), and it begins to proliferate and differentiate into effector cells.

Question 6

Once a T cell is activated and begins to initiate, initially most of the daughter cells are ____.

Answer 6

short-lived effector cells, while some of the daughter cells will differentiate into memory T cells.

Question 7

What are memory T cells?

Answer 7

The memory cells represent a clonally expanded population of cells that are specific for a determinant of a pathogen that will live for a very long time in the secondary lymphoid tissues.

Just know that after an immune response, memory T cells that have specificity for some determinant of the pathogen have been clonally expanded and distributed into the secondary lymphoid tissues. Because there are many more of them (10-100 fold more) than there were in the pre-infection T cell repertoire, re-exposure to that pathogen will result in much more rapid and effective T cell responses.

Question 8

What is an armed effector T cell?

Answer 8

Armed effector T cells are cells that are now programmed to perform their effector function as soon as they recognize their cognate peptide antigen bound to an MHC molecule. Effector T cells do not require costimulatory (B7) signaling.

Effector T cells also have an adhesion molecule array on their surface that allows them access to the tissue(s) in which they perform their effector function.

Question 9

How do NAIVE T cells enter 2ndary lymph tissue?

Answer 9

Their ability to express surface L-selectin makes it possible for them to enter secondary lymphoid tissues by binding to addressins (i.e. CD34/GlyCAM-1) on high epithelial venules, initiating their passage into the 2 ̊ lymphoid tissue.

Once they enter the secondary lymphoid tissues, their ability to express LFA-1 allows them to interact closely enough with APCs to sample their MHC:peptide complexes

Question 10

What surface adhesion molecules do effector T cells express?

Answer 10

Once a T cell becomes an effector cell, it expresses VLA-4 and LFA-1, making it possible for them to bind to activated vascular endothelial cells and to leave the vasculature, moving into the inflamed extravascular tissue where they can perform their effector function.

Question 11

How could IL-12 affect T cell differentiation?

Answer 11

Some viruses and bacteria induce dendritic cells to produce IL-12 which stimulates NK cells to produce IFN-y, which induced TH1 differentiation

Question 12

Is Listeria monocytogenes an intracellular or extracellular bacteria?

Answer 12

Intracellular.

NOTE: It would be handled with CTLs like viruses, not activated macrophages like other intracellular bacteria

Question 13

What are some intracellular bacteria that reside in macrophages?

Answer 13

MTB, Mycobacterium leprae, Leishmania donovani, Pneumocystis carinii

NOTE: These are killed by TH1 activation of macrophages (MTB can evade this and granulomas form)

Question 14

Most viruses are best handled via a CTL-mediated killing. What is an example and how is it handled in the body?

Answer 14

Polio virus is treated like an extracellular bacteria which causes a humoral immune response and generation of antibodies from B cells

Question 15

What is CXCL2 and what cell types make it?

Answer 15

It is aka MIP, and is made from TH1 cells as a macrophage chemotractant

Question 16

What signals do macrophages need to be activated?

Answer 16

need two signals:

1) CD40L from TH1
2) IFN-y from THI

Question 17

Full B cell activation requires two activation stimuli:

Answer 17

(1) Recognition of cognate antigen through the immunoglobulin component of the B cell receptor.
(2) T cell help that includes CD40-ligand binding to CD40 on the B cell and cytokines derived from the helper T cell.

Once these signals are received, the B cell begins to proliferate, initiates a germinal center reaction, and then daughter cells differentiate into either plasma or memory cells.

Question 18

What four things happen during a germinal center reaction?

Answer 18

(1) B cell proliferation
(2) Somatic hypermutation
(3) Affinity maturation
(4) Isotype switching

Question 19

For you to distinguish between acute phase and convalescent serum, it is important for you to understand the graph shown in the left panel. In this example, the host is being immunized and then boosted a couple of times. This could just as easily be an infection and then two re-exposures to that infection. Be aware that the Y-axis is on a log scale.
What you see here is that the initial antibody response directed against the vaccine immunogen is primarily IgM for the 1st 2-3 weeks (acute-phase serum), then IgG begins to be the predominant antibody isotype. Upon re- exposure to the vaccine immunogen, IgM levels remain level while the IgG concentration increases logarithmically. By two months, you see the pattern of a convalescent serum.

Answer 19

For you to distinguish between acute phase and convalescent serum, it is important for you to understand the graph shown in the left panel. In this example, the host is being immunized and then boosted a couple of times. This could just as easily be an infection and then two re-exposures to that infection. Be aware that the Y-axis is on a log scale.
What you see here is that the initial antibody response directed against the vaccine immunogen is primarily IgM for the 1st 2-3 weeks (acute-phase serum), then IgG begins to be the predominant antibody isotype. Upon re- exposure to the vaccine immunogen, IgM levels remain level while the IgG concentration increases logarithmically. By two months, you see the pattern of a convalescent serum.

Question 20

What antibody types are capable of neutralization?

Answer 20

IgG and IgA

Question 21

What antibody type is the best for opsonization?

Answer 21

IgG1

Question 22

What antibody is the best for activating the complement system?

Answer 22

IgM

Question 23

Different functions of dimeric IgA.

Answer 23

When IgA is underlying the epithelial lining of a mucosal surface, if it binds to a toxin in that tissue, it will essentially transport the toxin out of the tissue and into the lumen of the GALT, BALT, NALT, etc) when it is transported across the epithelium by the poly-Ig receptor.

(Next Panel): IgA can also neutralize toxins that have gained access to endosomes of the epithelial cells as it is transported by the poly-Ig receptor.

(Next Panel): This is clearly the most important function of secretory IgA.
Once IgA is transported into mucosal secretions, it binds to its cognate determinant on microbes, preventing them from binding to their cell surface receptors (neutralization). By preventing the microbe from attaching, IgA prevents infection.

(Next Panel): IgA that has bound to a pathogen can be endocytosed by M cells and taken into secondary lymphoid tissues for processing and presentation to naïve B cells.

(Right-Hand Panel): IgA in mucosal secretions can be endocytosed by M cells, and once in an M cell endosome can bind to and neutralize microbe(s) that were also endocytosed.

Question 24

Which antibody types can activate ADCC?

Answer 24

IgG1 and IgG3 via FcyRIII receptors

NK cells are the effectors of this response that kills infected host cells. (cross-linking of the FcyRIII receptors once engaged to IgG antibodies bound to a pathogen signals the NK cell to kill it)

Question 25

What is the basis of protective immunity?

Answer 25

it is immunity to re-infection by a particular pathogen via pre-formed T cell and/or B cell-mediate immune response. Immunological protection refers more to secondary exposures down the road.

Question 26

T or F. Once an immune response has been generated against a specific pathogen, reinfection with that pathogen will typically result in very rapid and highly specific immune response that should quickly mediate removal of the pathogen.

Answer 26

T.

Question 27

Acquired immune responses begin to be produced approximately ____ following initial exposure

Answer 27

one week. The T cell and B cell responses increase in intensity very rapidly once initiated. As the infection is cleared, the effector T cell response wanes pretty quickly, while the antibody response dissipates more slowly, due primarily to the long half-life of plasma cells and IgG.

What is not shown here is that the initial wave of antibodies are primarily of the IgM isotype, and then after 2-3 weeks, IgG becomes the predominant antibody isotype.

After the infection is cleared, memory B cells and T cells that have been clonally expanded now occupy the secondary lymphoid tissues all over the body, leaving the host with immunological memory to that pathogen.

Question 28

The graph shows what happens if an individual that recovered from an infection (and was left with an anamnestic or memory response) was re- exposed to that pathogen 2 years later. What you can see clearly is that the intensity of the B and T cell responses are greater than they were during the primary response. What is not shown clearly on this graph is that the secondary response is also generated much more rapidly than the primary response.
Please remember that during the primary response, activated B cells and T cells that had specificity for potentially a large number of determinants were clonally expanded as memory cells. Also, the memory B cells have already undergone affinity maturation, and they have already been class- switched to the needed isotypes of antibody. When the secondary exposure occurs, the clonally-expanded population of pathogen-specific memory CD4 T cells are much more rapidly available to supply the second signals of activation to a clonally-expanded population of pathogen-specific B cells. The process is much more efficient than it was during the primary immune response.

Answer 28

The graph shows what happens if an individual that recovered from an infection (and was left with an anamnestic or memory response) was re- exposed to that pathogen 2 years later. What you can see clearly is that the intensity of the B and T cell responses are greater than they were during the primary response. What is not shown clearly on this graph is that the secondary response is also generated much more rapidly than the primary response.
Please remember that during the primary response, activated B cells and T cells that had specificity for potentially a large number of determinants were clonally expanded as memory cells. Also, the memory B cells have already undergone affinity maturation, and they have already been class- switched to the needed isotypes of antibody. When the secondary exposure occurs, the clonally-expanded population of pathogen-specific memory CD4 T cells are much more rapidly available to supply the second signals of activation to a clonally-expanded population of pathogen-specific B cells. The process is much more efficient than it was during the primary immune response.