10. Generation of Immune Responses

Question 1

the primary B cell response is mostly what isotype Ab? Secondary response?

Answer 1

IgM; IgG

Question 2

mature B cells express chemokine receptor _____, which responds to chemokines (______) produced where?

Answer 2

CxCR5; cxcl13, produced in follicles in secdonary lymphoid tissues (lymph nodes, spleen, peyer’s patches, etc)

Question 3

the formation of immature B cells, occurs in the bone marrow, depends upon V(D)J recombination, and is antigen-________.

Answer 3

independent (RAG)

Question 4

the differentiation of mature B cells occurs in the lymph nodes/spleen, depends upon somatic hypermutation and class switch recombination, and is antigen-_______.,

Answer 4

dependent (AID)

Question 5

T cell chemokine receptor is what?

Answer 5

CCR7 - chemotaxis to T cell zones

Question 6

B cell chemokine receptor is what?

Answer 6

CXCR5 (chemotaxis to follicles)

Question 7

DC in the T cell zones are derived from _____ and FDC are derived _____.

Answer 7

hematopoietic precursors, in situ

Question 8

when are highest affinity responses (B cells) made?

Answer 8

when low amount of antigen is provided after antibody titers to the first immunization have dropped

Question 9

Tcell Bcell interactions in the lymph node lead to what 3 general things?

Answer 9

1. early antibodies (stimulation of B cells yb antigen and antigen-specific T cells) in the primary response
2. immunoglobulin isotype (class) switch
3. affinity maturation of the response (mutation and selection)

Question 10

coreceptor for B cells?

Answer 10

CD19, CR2

Question 11

activation requirements for B cells?

Answer 11

antigen + T cell help or antigen + other factors

CD40-CD40L

Question 12

effector cells for B cells?

Answer 12

plasma cells

Question 13

when innate talks to adaptive, covalently bound ____ interacts with the B cell coreceptor to lower threshold for activation

Answer 13

C3d (binds to CR2 on B cell)

Question 14

antigen specific IgG antibodies of high affinity are the end result of B cell clona selection and requires what?

Answer 14

help from T cells

Question 15

T-independent responses of B cells result in antibodies of both IgM and IgG type (mostly IgM) but they are generally what?

Answer 15

low affinity and have evolved to recognize conserved epitopes on the surface of pathogens (like LPS)

Question 16

stimulation of a B cell clone with antigen has what 2 primary consequences?

Answer 16

1) a signal is induced via molecules 
associated with the IgM molecule (Igα and Igβ) resulting in entry into cell cycle and increased expression of cytokine receptors (Fig 7-4), and 2) antigen bound by the surface IgM is internalized, degraded into fragments in the lysosomes, and peptides are bound and transported to the cell surface with class II molecules as we discussed in the antigen processing lecture; such complexes can then be recognized by antigen-specific CD4+ helper T cells to ensure that only antigen-specific B cells become further stimulated in the response.

Question 17

in order to fully activate B cells and enhance their proliferation, T cells must do what?

Answer 17

interact with other molecs on teh B cell surface

two receptor/ligand pairs : B7-CD28 and CD40-CD40L

CD28 and CD40 (on T cells and B cells, respectively) are constitutively expressed, while B7 and CD40L (on B cells and T cells, respectively) are upregulated after APC and T cells are stimulated

Question 18

what happens to T and B cell activation in the absence of costimulation (re B and T cell interaction)?

Answer 18

In the absence of a CD28 engagement by T cells, antigen-specific T cells receive the initial activation via antigen through their TCR, but fail to undergo full differentiation; upon second exposure to the antigen in the context of CD28, such crippled T cells cannot respond and are said to have become ‘anergic’. In the absence of the CD40 interaction, B cells also undergo some level of activation, even to the point of secreting IgM; however, high-affinity responses and switching of Ig isotypes does not occur without this ‘2nd signal’. This need for receptor/ligand interactions besides the TCR/class II-peptide is a fail-safe mechanism to ensure that only foreign antigen-specific cells become activated upon exposure to a pathogen

. Also take note that there is no class switching or germinal center formation leading to high affinity antibody responses in CD40L-deficient patients.

Question 19

Besides the 2nd signals provided by cell surface interactions, cytokines produced by helper T cells are vital for the proliferation and differentiation of B cells; you can think of these cytokines as “Signal 3,” the stimulus which will cause cells to differentiate into a particular pathway. The cytokine that seems most important is what?

Answer 19

IL-21, which is involved in activation and movement of B cells into the GC..

Question 20

4 B cell responses to antigen and the significance of each?

Answer 20

1. mitosis (clonal expansion)
2. cytokine receptor expression increased (ability to respond to cytokines produced by helper T cells)
3. Migration out of lymphoid follicles - upregulate CCR7 which is the T cell chemokine receptor (interaction w/helper T cells)
4. secretion of low levels of IgM (early phase of humoral immune response)

Question 21

antigen-specific B cells are more likely to receive help from antigen-specific T cells via what?

Answer 21

concentration effect (BCR acts not only as a receptor for activation, but as a concentrator of antigen (vacuums up specific antigen) which it takes up as fodder for degranulatino into peptides that will bind got Class II and stimulate antigen-specific T cells)

Question 22

high affinity antibodies specific to carbs can be made my covalently coupling them to what?

Answer 22

protein carriers (CD4 help specific to class II and presented peptide/toxoid, but are helping B cells specific for carbohydrate antigens)

Question 23

B cells are stimulated by antigen in which part of the lymph node?

Answer 23

follicles

Question 24

activation through BCR (and CD21 (CR2)/CD19) results in a change in chemokine receptor expression (upregulate CCR7) and cytokine receptor expression and movement into which phase of cell cycle?

Answer 24

G1

Question 25

T cells are stimulated by antigen/class II complexes on DC in the T cell zone and become competent helper T cells expressing CD40L and the B cell chemokine _____ that does what?

Answer 25

CXCR5 that draws them toward the B cell follicles

Question 26

After B-T cell interaction at the zone/follicle border, what happens to B cells?

Answer 26

some of these B cells go on to differentiate and secrete IgM in the primary response, while other B cells migrate into the follicles, along with the antigen-specific T cells, to initiate the germinal center (GC) reaction. GC contain a ‘dark zone’ of highly proliferative antigen-specific B cells called centroblasts, and a ‘light zone’ of non-dividing B cells called centrocytes. The centroblasts undergo somatic mutation of their heavy and light chain genes, and then express low levels of Ig on the surface of the centrocytes.

B cells that have mutated their receptors away from the epitope on the antigen die because they do not receive a life-saving signal. The antigen is concentrated, probably in the form of antigen/antibody complexes or antigen/complement fragment (C3d- or C3b-coated) complexes, on the surface of the follicular dendritic cells (FDC).

Question 27

what is the big difference between AID deficient patients and CD40L deficient patients?

Answer 27

AID-deficient patients are still capable of forming germinal centers and these are much larger than typical germinal centers

Question 28

It is important to point out that those CD4-positive T cells that move into the follicle to help form germinal centers are absolutely required for this process; such T cells are called “follicular T helper cells” or TFH (or Tfh), and their special cytokine is what?

Answer 28

IL-21

The TFH cells aparently can alos produce other cytokines like IFN-gamma or IL-4, depending on how they have been stimualtes and this may explain how B cells are induced to switch to particular isotypes during the course of a germinal center reaction

Question 29

centroblasts do whta?

Answer 29

divide and mutate in the GC dark zone. Mutations targeted to the V regions and supertargeted to hotspots

Question 30

centrocytes do what?

Answer 30

re-express the BCR and GC response leads to memory and long-lived plasma cells (BM homing)