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CMOD- Block1 > Immuno 3: B Cell Development > Flashcards

Immuno 3: B Cell Development Flashcards

1
Q

Immunoglobulin genes encode the ____ and ____ ____ of B cell receptors or antibody molecules.

A

light and heavy chains

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2
Q

What process accounts for the unique antigen specificity that each antibody produced by a given B cell possess?

A

somatic recombination, that is: rearrangement of immunoglobulin genes

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3
Q

What is negative selection?

A

the process by which B cells bearing receptors that bind components of the host are removed

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4
Q

True or False: all antibodies produced by a given B cell are identical with regard to antigen-binding specificity.

A

True. And don’t you forget it.

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5
Q

True or False: the B cell receptor is a membrane-anchored version of the antibody that is secreted by that B cell.

A

True. What else would it be.

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6
Q

What is the antibody repertoire?

A

the complete collection of antibody specificities generated by somatic recombination (there’s a lot)

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7
Q

Where is the antibody repertoire established?

A

bone marrow (where somatic recombination takes place)

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8
Q

When does somatic recombination occur?

A

throughout the life of the host

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9
Q

What gene products mediate somatic recombination?

A

RAG genes/enzymes (recombination activation genes)

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10
Q

What is the clinical result of a RAG gene deficiency?

A

extreme clinical susceptibility to virtually all pathogens, because there is a marked decrease in the variation within the antibody repertoire

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11
Q

Is somatic recombination antigen dependent or independent?

A

antigen independent

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12
Q

What are the steps of somatic recombination for light chains?

A
  1. V and J gene regions joined; catalyzed by RAG
  2. primary RNA transcript is made
  3. splicing to generate final mRNA;
  4. C region is joined to the VJ region
  5. translation of final mRNA transcript into light chain protein
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13
Q

What are the different gene cassette segments available for recombining light chains?

A

variable, joining, and constant

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14
Q

What are the different gene cassette segments available for recombining heavy chains?

A

variable, diversity, joining, and constant

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15
Q

On what chromosome are the genes for each of the following found: lambda light chain, kappa light chain, heavy chain

A

lambda = 22
kappa = 2
heavy chain = 14

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16
Q

In every B cell germline DNA, rearrangement of ____ chain DNA occurs first, followed by rearrangement of ____ chain DNA.

A 
heavy chain (first)
light chain (second)
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17
Q

What are the steps of somatic recombination for heavy chains?

A
  1. D and J regions are joined to make DJ junction
  2. V region is joined to DJ junction to make VDJ junction; this composes the complete coding region for the variable region of the heavy chain
  3. transcription to primary RNA
  4. splicing to create mRNA
  5. translation to heavy chain protein
  6. each heavy chain becomes disulfide bridged to a light chain; then two of these light/heavy chains disulfide bond to each other
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18
Q

What is the significance of somatic recombination to the immune system?

A

it allows for the creation of a tremendous array of distinct B cell receptor antibody specificities

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19
Q

How do RAG-1 and RAG-2 catalyze somatic recombination?

A

make double-stranded breaks in DNA, facilitating the recombination event

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20
Q

What is the function of TdT?

A

catalyzes the addition of N nucleotides in the junctions between rearranging gene segments of Ig heavy chain genes (but not light chain genes) as well as for beta rearrangements in T cells; this also increases the diversity of B cell receptor specificities by introducing additional variability into the heavy chain genes

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21
Q

What is somatic hypermutation?

A

mutation that occurs at high frequency in the rearranged variable-region DNA Ig genes in activated B cells, resulting in the production of variant antibodies, some of which have higher affinity for the antigen

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22
Q

Where does somatic hypermutation occur?

A

in follicles in secondary lymphoid tissue

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23
Q

B cells that have higher affinity for the antigen are ____ selected for continued maturation.

A

positively

24
Q

All B cells initially produce antibodies of which isotype, and why?

A

IgM, because it is the first cassette in the constant region gene sequence

25
Q

Class/Isotype switching changes what component of the antibody?

A

the constant region of the heavy chain

26
Q

Class switching changes the ____ of the antibody made by a specific B cell, without altering the _____ of that antibody.

A

function; specificity

27
Q

What is the significant advantage of the class switching phenomenon?

A

only one B cell needs to be activated in order to to make all anitbodies needed for a complete antibody response to a pathogen, instead of 5 different B cells to make each one

28
Q

What are the basic steps of isotype switching?

A
  1. signal to switch is received (that is, activation signal to B cells in germinal center)
  2. cytidine deaminase catalyzes recombination event between the gene segments
  3. intervening germline DNA is circularized and excised
  4. the first coding region is now expressed and the excised regions can’t ever be expressed because they’re gone (but downstream regions can be expressed because recombination can occur again)
29
Q

Which heavy chain constant domain coding region lacks a switch region, and therefore will never be the result of class switching?

A

IgD

30
Q

What is the order of constant domain coding regions?

A

M D G3 G1 A1 G2 G4 E A2

31
Q

What is the presentation of AID (activation-induced cytidine deaminase) deficiency, aka hyper-IgM syndrome?

A

B cells can’t undergo class switching, therefore these patients are at increased susceptibility to extracellular infection such as bacteria, fungi, parasitic, and some viruses such as the flu because neutralizing antibodies are most effective against flu

32
Q

What is IL-7?

A

interleukin 7, an important B cell growth factor produced by bone marrow stromal cells, needed for continued B cell development

33
Q

What are the cell stages/names in B cell development?

A 
lymphoid progenitor cell
early pro-B cell
late pro-B cell
pre-B cell
immature B cell
34
Q

What antibody receptor do immature B cells express on their cell surface?

A

IgM

35
Q

What is Bruton’s tyrosine kinase?

A

enzyme involved in signal transduction from cell-surface receptors in B cell development; this is a critical factor for B cell survival

36
Q

True or False: a developing B cell will first express rearranged light chains on its surface, then express rearranged heavy chains on the surface.

A

False. Heavy chain rearrangement occurs first (always) and is the first to be expressed on the surface. Light chain rearrangement occurs after heavy chain expression.

37
Q

When is a B cell considered mature?

A

when it expresses both IgD and IgM antibodies on its cell surface.

38
Q

Once a B cell is mature, where does it go?

A

to B cell zone of a secondary lymphoid tissue

39
Q

The process of allelic exclusion ensures that…

A

Ig gene rearrangements occur only on one chromosome at a time; tries one copy and if rearrangement is successful it won’t try the other chromosome; if a B cell fails rearrangement at everything, it will die

40
Q

B cells that are bind to self-determinants will cause ____ to the host.

A

damage

41
Q

During development, how are self-intolerant B cells recognized and eliminated from repertoire?

A

they will bind to a multivalent self molecule in bone marrow; if they bind too tightly intracellular signals will induce apoptosis

42
Q

Developing B cells that bind too tightly to soluble self molecules in the bone marrow will become ____ and will die within a couple days.

A

inergic (unresponsive to antigen stimulation)

43
Q

What happens to B cells that bind weakly to self molecules in the bone marrow?

A

they continue to mature and will encounter peripheral tolerance mechanisms (which we will discuss later)

44
Q

What makes an Ig gene rearrangement successful? Does Ab have to have specificity for some antigen?

A

The resulting Ig chain must be stable. Ab does NOT have to have specificity for a particular antigen.

45
Q

In addition to the rearrangements of VJ and VDJ gene segments to generate variable domain coding regions, what other “factors” contribute to diversity of the B cell receptor repertoire?

A
  1. TDT- adds non-templated nucleotides randomly, up to 5-6 bases. Added to heavy chains of B/T cells. A TDT deficiency will not inhibit you from rearranging heavy chain genes, but the diversity will be reduced.
  2. recombinations of heavy and light chain loci. “somatic recombination”
46
Q

A deficiency of Bruton’s Tyrosine Kinase will result in a complete absence of:

A

B cells

47
Q

B cells are collected from the blood smear of a healthy 8 y/o child. what percentage of those B cells express antibodies that have both kappa and lambda light chains?

A

0%

48
Q

How does somatic hypermutation impact B cell repertoire?

A

It will either increase or decrease affinity.

49
Q

Does isotype switching have any impact on the diversity of the B cell repertoire?

A

No.

50
Q

Is it possible to class switch to IgM?

A

Never.

51
Q

Is class switching to different isotypes random?

A

No, it is dictated by helper T cells

52
Q

Allelic exclusion during B cell development allows for immunoglobulin gene rearrangements to occur on ______ chromosome(s) at a time.

A

Only one.

53
Q

What is the consequence of allelic exclusion with respect to Ig production by each B cell?

A

It ensures that you only get 1 type of Ig (specificity) on each B cell

54
Q

What is a major problem that may result if allelic exclusion did not occur during B cell development?

A

The B cell would be underactive because not enough signals would activate the cell. (need multiple signals per cell) If you have many species of receptors, they will not all be activated by the same antigen and the cell will remain nascent.

55
Q

Where do self-reactive B cells come from?

A

because antibody generation is a random process, self-reactive B cells are made just like all other B cells, they just randomly happen to have a surface antibody receptor with affinity for a host component

56
Q

What is an effector B cell?

A

a plasma cell, functions as an “antibody factory”

CMOD- Block1 (36 decks)

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