B cell activation (bowden 9/5) Flashcards

1
Q

Clonal selection

A

The process of gene rearrangement of the heavy and light chains and the combinatorial association of these chains occurs during B cell development and is independent of antigen.

antigen simply selects those clones which have the appropriate receptor

the selected clones are then activated, proliferate, and differentiate into antibody secreting plasma cells

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2
Q

IL-3

A

acts on immature progenitors

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3
Q

CD20 and CD19

A

on surface of mature B cell

these are pan B cell markers

if you do an analysis of someones lymphocytes in their blood, use antibodies against CD20 or CD19 to look for those

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4
Q

Mature naive B cells exit marrow and enter what?

A

secondary lymphoid organs…

Lymph nodes and spleen

enter via HEV

if not activated by antigen they die

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5
Q

what do B cells that develop from fetal liver-derived stem cells differentiate into?

A

B-1 cells

these response to non-protein Ag in the mucosa

found in GALT/MALT/BALT

have an extra marker on their surface (CD5+)

make predominantly shortlived IgM responses

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6
Q

what do B cells that develop from BM progenitors after birth differentiate into?

A

B-2

Two subsets of B-2 include:
Follicular B cells
Marginal B cells

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7
Q

Follicular B cells

A

of the B-2 subset

re-circulating B cells (Majority)

give rise to long-lived plasma cells (IgG, IgE, IgA)

see protein antigens and require helper T cells

spleen and other lymphoid organs

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8
Q

Marginal B cells

A

of the B-2 subset

reside in the spleen DON”T recirculate

respond to blood-borne polysaccharide antigens

make predominantly IgM

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9
Q

Membrane bound Ig does not have…

A

cytoplasmic tail… so it cannot signal

all of signalling from binding of mIg comes from the Ig-alpha and Ig-beta and B cell co-receptors.

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10
Q

Antigen dependent phase

A

Response initiated by recognition of antigen (its epitope) by B cell specific for that antigen (idiotope)

Antigens binds to membrane Ig on naive cells and activates these cells

activation can be T dependent or T independent

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11
Q

T cell dependent

A

some T cells stimulate, or help, B lymphocytes to produce antibodies

In the absence of T cell help, protein antigens elicit weak or no antibody responses

Protein antigens are processed in antigen-presenting cells (APCs) and recognized by helper T lymphocytes, which play an important role in B cell activation and induce heavy-chain isotype switching and affinity maturation.

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12
Q

T independent

A

Polysaccharides, lipids, and other nonprotein antigens stimulate antibody production without the involvement of helper T cells

The antibodies produced in response to T-independent antigens show relatively little heavy-chain isotype switching and affinity maturation.

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13
Q

Naive B cells in circulation

A

Travel through secondary lymphoid tissue

enter from blood if going to spleen

in lymph if going into nodes

migrate to primary lymphoid follicles which contain FDC’s

enter through HEV

if they don’t encounter antigen they migrate to primary follicle

receive signal to survive from FDC’s

exit through efferent lymphatic vessels

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14
Q

competition of B cells for survival signals

A

too many B cells, not enough FDC’s to provide signals for survival

naive b cells die within weeks in absence of antigen

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15
Q

L selectin

A

expressed on naive b cells

binds to peripheral node addresin (PNAd)

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16
Q

what does CCR7 bind and where is it expressed

A

expressed on Naive B cells

binds to CXCL19 or CXCL21 on lymph node HEV’s

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17
Q

What do naive b cells express

A

L selectin

CCR7

LFA1

CXCR4

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18
Q

what does LFA1 bind?

A

ICAM-1 on lymph node HEV’s

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19
Q

what does CXCR4 bind to ?

A

CXC12 on lymph node HEV’s

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20
Q

B cell homing

A

Cytokines produced by HEV and stromal cells activates integrins

B cell migrates to follicular zone by CXCL13

Dendritic cells migrate in from periphery and bring in antigen (attracted to CCL21)

Dendritc cells secrete CCL18 and CCL19 which attract T cells to the lymph node

B cells respond to CXCL19 and once in the lymph node they migrate to where the FDC’s are secreting CXCL13

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21
Q

CXCL13

A

Mediates follicle migration

is secreted by Follicular dendritic cells (FDC’s) in the lymph node which attracts more B cells

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22
Q

B cell activation first signal (one type)

A

Ag recognition by membrane bound Ig’s

Must crosslink 2 or more BCR

Signaling occurs through Igalpha and Igbeta cytoplasmic tails

prepares cell for interaction with 2nd signal

at this point it is minimally activated

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23
Q

B cell activation first signal (with complement)

A

Ag bound with C3d

C3d binds CR2 (the BCR co-receptor complex)

signaling occurs through the Igalpha and Igbeta, CR2 and CD19 cytoplasmic tails

prepares cell for second signal

you do not need cross linking for signaling of two or more Ig’s if CD3 is involved ***

100 fold more immunogenic

24
Q

what is the BCR co-receptor complex

A

CR2 and CD19

25
Q

after B cells are activated they upregulate and downregulate what?

A

upregulate CCR7

downregulate CXCR5

26
Q

after T cells are activated they upregulate and downregulate what?

A

downregulate CCR7
upregulate CXCR5

done in order to migrate to

27
Q

CCL21

A

secreted by HEV and stromal cells

28
Q

what expresses a receptor for CCL21

A

Dendritic cells

when it binds to CCL21 it migrates into the lymph node

29
Q

CCL18 and CCL19

A

secreted by Dendritic cells

attracts T and B cells to developing lymph node

30
Q

Second signal

A

Stimulation of b cells by antigen induces expression of B7

this allows for interaction with CD28 on Th cells

Th cells are now activated and can perform effector function of providing cytokine help to B cells

T activation causes expression of CD40L that interacts with CD40 on B cells

The interaction of CD40 with ligand on the T cell is the second signal that causes activation and B cell differentiation

31
Q

what is B7 expressed on and what does it bind?

A

B cells

binds CD28

32
Q

what is CD28 expressed on?

A

T cells

constitutively expressed

33
Q

CD40L

A

expressed on T cells after T cells are activated due to the interaction of CD28/B7

34
Q

How does activation of B and T cells maintain specificity of the immune response?

A

B/c the expression of B7 and CD40L are dependent on antigen stimulation, only lymphocytes specifically interacting with antigen (lymphocytes specific for that antigen epitope) are activated

35
Q

CD40

A

constitutively active on B cells

36
Q

Function of cytokines released by Th cells

A

Class switching

Augment B cells differentiation and proliferation (Clonal expansion)

37
Q

IL-4

A

promotes class switching to IgE

38
Q

IFN-gamma

A

induces switch to IgG2a

39
Q

TGF-beta and IL-5

A

lead to switch to IgA

40
Q

Switch recombination in cross switching

A

occurs in germinal center

CD40/CD40L and cytokines trigger isotype switching

Rearranged VDJ gene segment on heavy chain recombines with a downstream C region gene (not being used)

Class switching does not change the specificity of an antibody molecule, only its isotope and therefore potentially its biological function

41
Q

AID

A

activation-induced deaminase

key enzyme in class switching

expressed by CD40 signals

42
Q

Somatic Hypermutation: Affinity Maturation

A

Introduction of point mutations in the Variable regions of Ig genes, resulting in an expansion of the antibody repertoire to generate high-affinity antigen-specifc antibodies =hypermutation

AID converts Cs to Us

after somatic hypermutation occurs B cells still have to be selected by FDC’s

takes place in the germinal center

often occurs simultaneously with class switching

43
Q

after somatic hypermutation, what is the fate of B cells…

A

only B cells with high affinity antigen receptors encounter antigen on the FDC’s and present antigen to T fh cells

these are the B cells that survive

44
Q

Plasma cells

A

Terminally differentiated Ab secreting B cell

surface markers
CD27

loses CD19 and CD20 surface markers

45
Q

Memory cells

A

survive for long periods of time without additional Ag stimulation

capable of mounting a rapid response to subsequent exposure

responsible for secondary immune response

46
Q

why don’t IgM’s undergo affinity maturation…

A

b/c you always are expressing IgM and if you don’t have the CD40 L CD40 interaction you don’t get class switching and you also don’t get somatic hypermutaiton of IgM

no signals from helper T cells –> no switching

CD40: CD40L required for isotype switching: T dependent antigen only

47
Q

Memory cells are only induced by…

A

protein antigens

b/c in order to go through isotype switching and somatic hypermuation you need T cell help, which t-dependent antigens require…

so…. no memory cells are created for t-independent antigens b/c they don’t lead to these final steps

48
Q

Primary response is induced by?

A

all immunogens

49
Q

Secondary response is induced by

A

only protein antigens

50
Q

T-dependent antigens

A

soluble proteins

can do isotype switching

can do affinity maturation (somatic hypermutation)

can have immunological memory

No polyclonal activation

51
Q

T independent antigens

A

Chemical nature:

  • bacterial cell-wall components (LPS)
  • capsular polysaccharides
  • polymeric protein antigens

usually no isotype switching
no affinity maturation
no immunologic memory
no polyclonal activation

52
Q

Control mechanism/Antibody feedback

A

secreted antibody binds to antigen, forms Ag/Ig complex

Antigen/antibody complex binds to B cell IgG and Fc receptor

causes a block in b cell receptor signaling

53
Q

Natural antibodies

A

IgM only

Produced by B-1 (sit in the mucosa) and mariginal zone b cells

specific for bacteria in the area

cross react with blood anlloantigens

54
Q

Primary response

A

time lag after immunization/infection 5-10 days

smaller antibody production

antibody istotype IgM>IgG

Antibody affinity is lower, more variable

relatively high doses of antigens for required immunizations

55
Q

Secondary response

A

time lag after immunization/infection 1-3 days

larger peak response (antibody production)

relative increase in IgG and IgA or IgE

higher average affinity

only induced by protein antigens

required immunization: low doses of antigens