Lecture 15: B Cell Activation and Antibody Production II Flashcards

1
Q

What results in the formation of mRNA for the membrane or secreted form of the u (mu) heavy chain

A

Alternative processing of primary RNA transcript

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2
Q

What results in an increasing fraction of the u protein produced as a secreted form

A

Ag activation of B cell

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3
Q

What are required for somatic hypermutation of Ig V genes to occur

A

Tfh cells and CD40:CD40L interaction

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4
Q

Where does affinity maturation occur

A

In the germinal center

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5
Q

Affinity maturation is a process that occurs through

A

A repeated process of somatic hypermutation of B cell receptors and subsequent clonal selection

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6
Q

Hypermutation can occur where (on gene)

A

Anywhere along the VDJ region of Ig genes

Can be heavy or light chains or both

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7
Q

What is expressed by B cells that initiates somatic hypermutation in the GC, and how does it work

A

AID
Induces cytosine to uracil deamination
-This is a mismatch that can be repaired by base excision

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8
Q

Where do Ig V genes undergo point mutations at a very high rate

A

In the dark zone of the GC

Can occur at an average rate of almost one per cell division

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9
Q

Can Ig V mutations continue to occur in progeny of B cells

A

Yes, any B cell clone can accumulate more and more mutations during its life in the GC

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10
Q

IgG vs IgM # of mutations

A

IgG has many more mutations

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11
Q

Mutations correlate with

A

Increased Ab affinity for Ag that induced response

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12
Q

Why do B cells with highest affinity for Ag have selective advantage

A

Because they are more likely to bind Ag on FDC which will rescue them from apoptosis

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13
Q

Where is a site of tremendous apoptosis

A

Germinal center, because somatic mutation also generates many B cells that do not express high affinity Ag receptors and die

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14
Q

Where do B cells migrate after somatic hypermuation

A

FDC-rich light zone of the GC

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15
Q

Reasons that high affinity B cells survive

A
  • Binding to Ag induces increased expression of anti-apoptotic protein Bcl2
  • High affinity B cells will endocytose and present Ag for Tfh cells in GC and induce CD40:CD40L signaling
  • Expression of endogenous inhibitors of Fas may occur in high affinity B cells that have bound Ag on BCR
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16
Q

What is a primary cause of B cell lymphomas

A

Translocation of various oncogenes into Ig gene loci

-DNA breaks associated with somatic hypermutation and isotype switching facilitate these translocations

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17
Q

Isotype switching primarily occurs where and is facilitated by who

A

Germinal centers facilitated by Tfh cells

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18
Q

Some isotype switching my also occur where and facilitated by

A

Extrafollicular foci, driven by extrafollicular Th cells

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19
Q

Antibody specificity is determined by what region of the Ig chains

A

Variable regions

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20
Q

Intracellular pathogen leading to IgG switching- how does this happen

A

Intracellular pathogen activate Th1 cells which make IFN-y, which also likely induces IFN-y+ Tfh cells to make more IFN-y
IFN-y induces IgG switching

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21
Q

Helminth leading to IgE switching

A

Helminths likely influence Tfh cell differentiation in to IL-4+ Tfh cells which produce Th2 type cytokines like IL-4 to induce IgE switching

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22
Q

B cells in mucosal areas would likely switch to what Ab class- and what would cause this

A

IgA switching, caused by TGF-b produced by many cells including Treg cells and macrophages

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23
Q

What co-stimulates the switch to IgA

A

BAFF produced by DCs and macrophages

24
Q

Isotype switching and affinity maturation are critically dependent upon ___ which is induced by

A

AID, which is induced by CD40 engagement from Tfh cells

25
Q

Immunodeficiencies related to CD40-CD40L might cause what Ab to dominate

A

IgM, because class switching wont occur without CD40/CD40L and AID

26
Q

Every C gene is preceded by a ______ that controls rearrangement process

A

Switching sequence

27
Q

AID switches C to U, and then what happens

A

UNG removes U residue, then endonuclease APE1 creates nicks that lead to DS breaks- probably fixed by NHEJ

28
Q

CSR is preceded by

A

Expression of germline transcripts which open the chromatin structure of a specific S region and make it accessible to the recombinase

29
Q

Switch regions are comprised of

A

Repetitive sequences of palindrome rich motifs and result in looped out deletions

30
Q

Short lived plasma cells are generated in

A

Extrafollicular compartments during T-independent responses

-may also be generated early during T-dependent responses in extrafollicular B cell foci

31
Q

Short lived plasma cells typically found where

A

In secondary lymphoid organs or peripheral non-lymphoid tissues

32
Q

Long lived plasma cells are generated

A

In T-dependent responses to protein Ag in the GC

-Signals from BCR and IL-21 are involved via stage of their precursors called plasmablasts

33
Q

Plasmablast to long lived plasma cell route

A

Generated in GC and home to one marrow where they differentiate into long lived plasma cells

34
Q

Long lived plasma cells are maintained by

A

BAFF

35
Q

% of Ab in blood produced by long lived plasma cells

A

50%

36
Q

B cells generated in the bone marrow exit as _____ which are ____ and express ____

A

Exit as pre- B cells which are immature and express IgM

-They further mature into naïve B cell and then follicular or MZ B cells in the spleen

37
Q

Activated (T-independent) MZ and Follicular B cells turn into

A

Plasmablasts and short lived plasma cells

38
Q

Activated (T-dependent) MZ and F B cells turn into

A

Memory B cells, and express Abs of switched class/higher affinity

39
Q

When is a long lived plasma cell formed

A

When memory B cells are reactivated by Ag

40
Q

Long lived plasma cells survive where

A

In the bone marrow mostly, but also secondary lymph organs

41
Q

Do memory B cells still require Tfh cell-mediated regulation following Ag recall?

A

Yes, Ag specific memory Tfh cells likely still regulate memory B cells responses

42
Q

What may stimulate Ab production in the absence of Th cells (TI responses)

A

Non-protein Ags such as polysaccharides or lipids

43
Q

What Abs are produced in the absence of Th cells

A

Low affinity IgM mainly, also some IgG and IgA

44
Q

What makes TI Ags able to stimulate B cell activation without T cell help

A

Many TI Ags are multivalent, and induce maximal cross-linking of the BCR complex on B cells, leading to activation without T cell help

45
Q

Which B cells are especially important for response to TI Ags

A

MZ B cells and B-1 B cells

46
Q

MZ B cells are a distinct population of B cells in the ___ that mainly respond to _____ and differentiate into

A

In the spleen, respond to polysaccharides and differentiate into short lived plasma cells that produce mainly IgM

47
Q

B-1 B cells respond to TI Ags mainly where

A

Peritoneum and mucosal sites

48
Q

TI Ags cannot be processed and presented by

A

MHC molecules, and therefor cannot be recognized by CD4+ helper T cells

49
Q

Polysaccharides activate ____ system by the _____ pathway, leading to

A

Activate compliment system by the alternative pathway, generating C3b and then C3d which is recognized by CR2 on B cell

50
Q

Two ways B cells can be activated without T cell help

A
  • Compliment coated Ags can ligate both BCR and CR2

- Simultaneous PAMP recognition and TLR signaling

51
Q

Cytokines produced by ____ may stimulate isotype switching in TI responses. Examples

A

Non-T cells

  • TGF-b secreted at many mucosal sites causes IgA
  • BAFF produced by DCs/MOs induces AID
52
Q

What contributes to the generation of natural antibodies, what are they and who generates them

A

TI Ags
They are low affinity anti-carbohydrate Abs
Produced by B-1 cells in GI tract and MZ B cells in spleen

53
Q

Memory occurs only if vaccines are able to activate

A

T helper cells

54
Q

How are vaccines to capsular polysaccharides produced (as they do not stimulate T cells)

A

Polysaccharide is linked to a foreign Ag

55
Q

What happens when Ab-Ag complex simultaneously bind BCR and the FcyRIIB receptor

A

FcyRIIB associated phosphatases inhibit signaling by the BCR complex and block B cell activation

56
Q

IgG vs IgM and FcyRIIB activation

A

IgM activates complement but do not bind to FcyR are involved in amplification, while IgG leads to feedback

57
Q

FcyRIIB knockout mice show

A

Uncontrolled Ab production