Module 6

Question 1

primary immune response in humans

Answer 1

describes the body’s first encounter with any given antigen
- primary immune response results in the activation and differentiation of naive B cells into antibody-secreting plasma cells
- IgM is the first antibody produced following the first antigen exposure. IgM can then undergo class switching, mostly to IgG
- as antibody concentration levels diminish to end the primary response, memory B cells that are specific to the antigen remain in circulation

Question 2

secondary immune response in humans

Answer 2

describes the response to a subsequent encounter of a specific antigen (same antigen encountered in the primary immune response)
- in this response, specific memory B cells are preferentially activated, resulting in a quick response, including a rapid shift to the production of IgG (1-3 days, compared to 4-7 days of a primary immune response)
- the higher overall antibody concentration is sustained for a longer period of time relative to the primary response, displaying a higher antibody titre

Question 3

hapten-carrier conjugates in B cell recognition

Answer 3

both the carrier and the hapten can affect the secondary immune response, through the carrier effect
- when a host has been exposed to the hapten-carrier conjugate (primed), then is re-exposed with the same carrier that was used during the priming, there is a secondary immune response to the hapten
- when the host is primed and is injected with the hapten coupled to an unrelated carrier protein, a weaker immune response occurs

Question 4

plasma cell survival niche

Answer 4

memory plasma cells that are antigen specific have been seen to survive in the bone marrow for extended periods of time, which explains why vaccines have such a long-lasting protective effect
- to achieve this longevity, the microenvironment requires maintenance by several immune factors

Question 5

plasma cell survival niche functions

Answer 5

it is thought to support the dynamic needs of the essential factors that perform maintenance, and memory plasma cells
- several cytokines have been identified as survival factors, including IL-5, IL-6, and TNF-a
- each cytokine has been shown to increase the long-term survival of plasma cells in the bone marrow niche

Question 6

plasma cell survival niche disorders

Answer 6

multiple myeloma is a cancer of the plasma cells in the bone marrow, likely associated with disregulations in the bone marrow microenvironment or the plasma survival cell niche
- unique associated morphological features include Dutcher bodies, Mott cells, and Russell bodies

Question 7

original antigen sin

Answer 7

AKA Hoksins effect
the concept of antigenic shift and drift causing major challenges for immunological memory
- memory cells specific to the original virus can inhibit activation of B cells specific to the newly altered virus, resulting in a weak immune response to the newly altered virus, which is due to the immunological memory of the original virus

Question 8

Hoskins effect steps

Answer 8

1. the immune system encounters an antigen and develops memory B cells against it
2. later, the immune system encounters the same virus that has undergone antigenic shift
3. these memory cells will differentiate into plasma cells which will make a large amount of antibodies specific to the original virus. These antibodies inhibit activation of naive B cells against the new, shifted virus. the secondary immune response is mounted, led by the memory B cells created against the original antigen virus.
4. the antibodies for the original virus cross react with the new virus, but do not display as high of an affinity as a newly developed response would have

Question 9

primary vs secondary immune response: peak antibody concentration

Answer 9

in the primary response, the amount of antibody produced is relatively low compared to that in the secondary response
- over time, antibody levels will decline to undetectable levels in the primary immune response
- alternatively, the secondary immune response will exhibit antibody levels which remain high for a longer period of time

Question 10

primary vs secondary immune response: response time

Answer 10

following the first exposure to a foreign antigen, a lag period occurs in which no antibody is produced, but activated B cells are differentiating into plasma cells. This lasts 4-7 days and the responding B cells are naive
in the secondary immune response, there is a shorter lag period due to the presence of memory B cells and their ability to quickly respond. responding B cells are memory cells

Question 11

primary vs secondary immune response: IgM:IgG

Answer 11

in the primary response, IgM is produced at nearly the same level as IgG
in the secondary immune response, IgG production is far greater than IgM production
the secondary response displays a far greater affinity for the antigen than in the primary immune response

Question 12

B cell development

Answer 12

after mature B cells exit the bone marrow, activation, proliferation, and differentiation into plasma cells occur in the periphery in response to an antigen
- most antigens are thymus dependent, meaning they require direct contact with helper T cells to activate B cells
- however, thymus independent induction can happen

Question 13

T-cell dependent B cell activation

Answer 13

when a helper T cell recognizes an antigen presented in complex with MHC Class II on a B cell, the T cell becomes activated, which in turn activates the B cell
- this part of humoral response is called T-cell dependent B cell activation

Question 14

T-cell dependent B cell activation signals

Answer 14

process consists of three signals:
1. TCR-MHC Class II complex binding
2. co-stimulatory molecule signalling
3. cytokine signalling

Question 15

T-cell dependent B cell activation signal 1, part 1

Answer 15

the first part of signal 1 requires antigen processing and presentation to T cells
- BCR (Ig) on the surface of a naive B cell binds its specific antigen (Ag), resulting in internalization of the Ig-Ag complex via endocytosis
- the antigen is then processed via the endocytic antigen processing pathway and is displayed on MHC class II molecules on the cells surface

Question 16

T-cell dependent B cell activation signal 1, part 2

Answer 16

the TCR of helper T cell recognizes the processed Ag:MHC complex presented on the B cell
- the recognition completes signal 1, which results in the activation of the helper T cell, following TCR and CD4 binding to the Ag:MHC class II complex

Question 17

T-cell dependent B cell activation signal 2, part 1

Answer 17

upon TCR recognition of the antigen (signal 1), CD40L expression is induced on the surface of the helper T cell through TCR mediated inositol lipid hydrolysis
- first step of signal 2 requires co-stimulatory molecule interaction between B and T cell
- CD40L on helper T cell interacts with constantly expressed CD40 on B cell
- CD40L - CD40 interaction activates the cytokine receptor expression on the cell surface of both B and T cell

Question 18

T-cell dependent B cell activation signal 2, part 2

Answer 18

MHC class II-mediated cAMP activation results in the increased expression of B7 on B cell surface
- B7 binds to CD28 expressed by the T cell, and provides the necessary co-stimulatory signal to activate the helper T cell

Question 19

T-cell dependent B cell activation signal 3

Answer 19

the B7-CD28 interaction induces the MAPK cascade in helper T cells, which activates c JUN and c FOS, which collectively form the AP-1 transcription factor that induces activation of the IL-2 gene
- cytokines bind to their respective receptors on B cells and T cells, initiating the proliferation and differentiation phases

Question 20

mechanism for cytokine secretion in signal 3

Answer 20

1. TCR:MHC, CD40L:CD40, and LFA-1:CAM-1 interactions between the helper T cell and B cell maintains the cell-cell contact that promotes talin mobilization towards the point of cell-cell contact. without these interactions, talin is localized
2. helper T cell reorganizes its cytoskeleton towards the B cell. MTOC, Golgi, and talin are rearranged so that cytokines can be released close to the point of contact between B and T cell
3. T cell secretes IL-4 directly towards the B cell at the point of cell-cell contact
   - IL-4 promotes B cell activation, proliferation, and differentiation

Question 21

outcome of the three signals in T-cell dependent B cell activation

Answer 21

two potential results:
proliferation or differentiation

Question 22

T-cell dependent B cell activation: proliferation

Answer 22

activated B cells can undergo proliferation by entering the G1 cell cycle. proliferation occurs following an additional IL-1 co-stimulatory signal from activated macrophages, as well as IL-2, IL-4, and IL-5 signals form helper T cells, to promote the rapid clonal expansion of B cells

Question 23

T-cell dependent B cell activation: differentiation

Answer 23

cytokines released by helper T cells differentiate B cells by inducing immunoglobulin class switching:
- IFN-y promotes switching to IgG
- IL-5 or TGF-b promotes switching to IgA
- IL-4, or IL-5, or IL-13 promotes switching to IgE
- IL-4 or IL-2, or IL-5 maintains IgM

Question 24

characteristics of CD40L

Answer 24

is inducible
induced by inositol lipid hydrolysis
interacts with CD40 which activates cytokine receptor

Question 25

defective CD40L

Answer 25

known as HIGM syndrome
occurs when there is a defect or deficiency in the CD40L on helper T cells
- HIGM is recessive X linked inherited disease
- lack of CD40L in patients results in the T cells being incapable of inducing B cell class switching from IgM to IgG, IgA, or IgE

Question 26

consequences of defective CD40L

Answer 26

lack of CD40L results in decreased levels of IgG and IgA, but abnormally high levels of IgM in circulation
- due to the various effector functions performed by these antibodies, patients have defective immunity and are susceptible to various infections
- affected individuals experience frequent infections in early infancy and may be at a greater risk for developing autoimmune disorders, neurological complications, liver disease, and GI tumours

Question 27

type 1 T-cell independent antigens

Answer 27

TI antigens activate B cells without requiring helper T cells
- majority of type 1 TI antigens are polyclonal B cell activators, meaning that binding of the antigen stimulates the proliferation of multiple clones of B cells into antibody-producing cells that are independent of the TI-1 antigenic stimuli, but specific to that B cell
- some bacterial cell wall components function as TI-1 antigens. includes lipopolysaccharide endotoxin (LPS), which can interact with TLR4 (present on all B cells), and BCR (few B cells have LPS specific BCRs)

Question 28

TI-1 binding

Answer 28

upon TI-1 binding the receptor, the PKC signalling pathway directs activation, proliferation, and differentiation of the B cell
- this part of the immune response is important in some early stages of infection by extracellular pathogens as it is rapidly activated

Question 29

Type 2 TI antigens

Answer 29

TI-2 antigens are expressed on the surface of pathogens in an organized and highly repetitive form, and can activate B cells by extensively cross linking the membrane bound Ig in a multivalent fashion
- leads to accumulation of BCR cross activation to evoke antigen-specific responses
- TI-2 antigens can include polymeric proteins or bacterial cell wall polysaccharides (ex: flagellan, dextrans)

Question 30

TI-2 and B cells

Answer 30

TI-2 antigens are not polyclonal B cell activators
although B cell response to TI-2 antigens does not require direct involvement of T-cells, cytokines derived from helper T cells are required for efficient B cell proliferation, and for class switching

Question 31

TI-2 binding

Answer 31

upon TI-2 binding, the inositol lipid hydrolysis signalling pathway directs activation, proliferation, and differentiation of the B cell