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Pathology Kyle > Immunology 3 (Kyle) > Flashcards

Immunology 3 (Kyle) Flashcards

The goal of this lecture is to understand the process of B cell development and to appreciate ow the immune system generates diversity of B cell binding specificity as well as diversity of antibody effector functions.

1
Q

B cell, What is this ?

A

B Cell, a ( Lymphocyte) that is dedicated to making immunoglobulins and antibodies. The primary effector function of B cell s is to produce antigen specific antibodies.

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2
Q

Immunoglobulin, what is this?

A

Immunoglobulins (Ig) is the antigen- binding molecule produced by B cells, commonly referred to as antibodies.

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3
Q

Where are B cells produced?

A

The bone marrow, they also mature in the bone marrow.

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4
Q

Describe the specificity of Ig’s produced by any one B cell.

A

Each of the IG’s produced by any one B cell all have the same antigen specificity.

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5
Q

What is a plasma cell?

A

A terminally differentiated b cell whose primary function os to produce Ab’s.

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6
Q

What is a Memory B cell?

A

A long lived antigen specific B cell that results from antigenic stimulation of a niave B cell during the primary immune response.

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7
Q

What happens when a memory b cell is re-exposed to a specific antigen?

A

Upon subsiquent exposure to a specific antigen these cells are reactivated to differentiate into plasma cells as a comonent of a secondary immune response.

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8
Q

What is an antibody repertoire?

A

The complete collection of antibody specificities available within an individual. There can be as many as 10^11 different antibody specificities generated by somatic recombination of If genes in any individual .

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9
Q

What creates the diversity of antobody molecules?

A

The hypervariable regions of both the heavy and light chains.

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10
Q

Why is somatic recombination of Ig Genes such an important mechanism?

A

The Ig genes code for up to 10^11 different Ab molecules ( B cell receptors )

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11
Q

What are the two gene segments that are combined to create the variable region which is associated with a constant ( C ) region gene segment to form the complete light chain gene?

A

Light chain genes contain Variable ( V ) and Joining ( J ) gene segments.

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12
Q

What are the components of the heavy chain gene that encode the variable region and combine with a constant region gene?

A

Variable ( V ), Constant ( C ), and Diversity ( D ).

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13
Q

In regard to the somatic recombination within the variable region genes during construction…

Are the rearrangements random?
When do they occur?

A

The rearrangements that take place are random and occur during B Cell otongeny in the bone marrow.
**These developments are totally independent of interaction of the developing B cell with antigen.

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14
Q

What is the first step in light chain gene construction?

A

The first step is the random rearrangement of a single V gene segment with a single V gene segment to form a contunuous piece of DNA that encodes the entire variable region of the light chain.

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15
Q

In light chain construction is the C segment separate from the VJ segment?

A

Yes, the C gene segment adjacent to the J gene segment is separated from the VJ junction by non-coding (intronic) DNA sequence.

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16
Q

In light chain construction what brings the VJ junction together with the C gene segment?

A

RNA processing following transcription of the rearranged DNA brings the VJ junction together with the C Gene.

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17
Q

What are the gene segments that the variable region of the heavy chains are constructed from how many gene segments?

A

Three ( Vh, Dh, Jh )

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18
Q

What is the first step in heavy chain construction?

A

Random rearrangement of a single Dh gene segment with a single Jh gene segment to form a DJh junction.

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19
Q

What is the second step of heavy chain gene construction ?

A

Random rearrangement of a single Vh gene segment with the previously joined DJh segment.

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20
Q

What is the end result in heavy chain construction?

A

Look this up

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21
Q

In heavy chain construction what is the C gene segment?

A

Cu ( always )

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22
Q

Where is this Cu gene segment? Heavy Chain Construction

A

The Cu gene segment is adjacent to the J gene segment and is separated from the VDJh junction by non-coding (intronic) DNA sequence.

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23
Q

How are the Cu and the VDJ junction brought together?

A

RNA processing following transcription.

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24
Q

Are these recombination events precise?

A

No, but this offers a source of diversity in the Ab pool.

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25
Q

Once the V regions have been rearranged is there any further rearrangement ?

A

Once the V regions genes have rearranged ( to productively form VJ or VDJ exons ) no further rearrangement of that chromosome can take place. All progeny of that B cell will express the same V region genes.

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26
Q

What are the three main processes that help generate antibody diversity?

A
  1. Different pairing of the many gene segments to form the cariable domains of both the light and heavy chains.
  2. Imprecise goining of gene segments during the somatic recombination process
  3. Different pairing of the many possible light chains with the many possible heavy chains that can be produced.
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27
Q

What is Allelic Exclusion?

A

The process by which the protein from only one allele is expressed while the other allele are silenced.

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28
Q

Is somatic Hypermutation and affinity maturation Antigen-Dependent?

A

Yes it is an Antigen dependent process.

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29
Q

What is somatic hypermutation?

A

Somatic Hypermutation: Single nucleotide substitutions that occure at a very high frequency in the rearranged variable region of DNA of immunoglobulin genes

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30
Q

What is affinity maturation

A

A result of somatic hypermutation. An antibody population will mature resulting in Ab populations that have increased affinity for specific antigen.

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31
Q

Where do most point mutations ( of hypermutation) take place?

A

In the hyper-variable region.

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32
Q

Is Isotype switching antigen dependent?

A

Yes Isotype switching is an antigen dependent process. During the course of an imune response the Vh exon can associate with different Ch genes.

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33
Q

When are the V-region eons produced by any given B cell ?

A

They are determined during the pro- and pre- B cell development stage of maturation.

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34
Q

Does IgD undergo Isotype switching?

A

No, as IgM and IgD are simultaneously expressed on mature niave B cells.

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35
Q

Can Ch region genes expressed by a Bcell line change as a response matures?

A

Yes, Ch can switch but a given B-cell and all its progeny will express the same Vl and Vh genes.

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36
Q

When does isotype switching occur?

A

After B cells have been stimulated by an antigen and hace received T cell “help” in the form of cytokine signals produced by T helper cells.

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37
Q

How does switching occurs?

A

Switching occurs through a specialized recombination mechanism that is guided by stretches of DNA known as switch regions that lie i the introns between the V-region exon and the Cu gene.

38
Q

When does somatic hypermutation take place?

A

This process occurs on activated B cells during a germinal center reaction and results in production of variant antibodies.

39
Q

Where does hypermutation take place?

A

This is an antigen dependent process that takes place in secondary lymph tissue.

40
Q

What is isotype switching?

A

During the course of an immune response the Vh exon can associate with different Ch genes.

41
Q

Provide an example of Isotype switching

A

Each B cell initially produces IgM. Later in the response, the same V-region exons can be expressed with a different Ch gene resulting in wither IgG, IgE, or IgA Ab’s with the same specificity as the initial IgM antibody.

42
Q

What type of cell directs isotype switching?

A

CYTOKINES communicate to the B cell what type of immune response is needed to most efficiciently eliminate the particular pathogen and the B cell switches to the most appropriate chain.

43
Q

After a B-cell has made a switch can further switching occurs?

A

Only if the Ch gene the isotype is switching to rests downstream from the genes

**For example once switching from Cu to Ca1, further switching only to Ch genes downstream of the Ca1 can occur, cannot switch to Cy3 for example.

44
Q

What are B-Lymphocytes?

A

B cells are lymphocytes that are dedicated to making immunoglobulins ( antibodies )

45
Q

How many phases are there in B cell development?

What is the First Stage?

A

6

  • Expression of the surface receptor molecules (immunoglobulins); rearrangement of light and heavy chain genes must occur.
46
Q

What is the second phase of B cell development?

A

Negative selection in the bone marrow to remove B cells bearing receptors that bind to “Self” antigens.

47
Q

What is the third phase of B cell development?

A

Positive selection of developing B cells that will continue to develop into mature B cells

48
Q

How do B cells search for infection?

A

B cells circulate between lymphoid tissue until they become activated.

49
Q

What is the first step of B cell activation?

A

Binding to a cognate antigen

50
Q

What is the second step for B cell activation?

A

T cell activation.

51
Q

What do proliferating B cells give rise to?

A

Plasma cells and Memory cells

52
Q

What are the two phases of B cell maturation?

A

Antigen Dependent and Antigen independent.

53
Q

What is the first stage of B cell maturation?

A

Pro-B Cell: earliest of the lineage. Rearrangement of the Ig lineage

54
Q

What type of rearrangement takes place in an early Pro-B cell ?

A

D-J rearrangement

55
Q

What type of rearrangement takes place in late Pro-B Cell rearrangement?

A

V- DJ rearrangement

56
Q

What occurs in the Pre-B Cell ?

A

Productive VDJ is complete and the u chain is expressed on the B cell surface, next light chain rearrangement occurs.

57
Q

What is a large Pre-B cell ?

A

u-chain is expressed on B cell surface

58
Q

What is a small Pre-B cell ?

A

V-J rearrangement takes place.

59
Q

Describe the maturation state of an Immature B cell.

A

Light chain rearrangement is complete and IgM is now expressed on the cell surface.

**Up until this point the entire process has taken place in the bone marrow.

60
Q

Where is the immature B cell located and where is it transported to continue its maturation process?

A

The bone marrow. Immature B cells will migrate from the bone marrow to the peripheral lymphoid tissue and undergo self tolerance selection.

61
Q

What is clonal deletion?

A

Clonal deletion is when immature B cells that specifically interact with multivalent “self” antigens in the bone marrow undergo apoptosis and are depleted from the B cell population.

62
Q

What is anergy?

A

Immature B cells that specifically interact with soluble antigen in the bone marrow are signaled to down- regulate cell surgace expression of IgM and are left anergic (unable to respond to specific antigen binding) These cells usually do not survive past a few days.

63
Q

When is B cell maturation complete?

A

When the cell surface expresses both IgM and IgD

64
Q

What is a mature B cell ?

A

An immature B cell that has survived self tolerance selection and further differentiated to become a mature B cell.

65
Q

What is B cell development in the bone marrow dependent on?

A

Stromal cells which provide specialized microenvironments for B cells ar various stages of development.

66
Q

What function do stromal cells serve?

A
  1. They make specific cell-surface contact with B cells through interactions between their adhesion molecules
  2. They produce growth factors that are essential survival signals for B cells.
67
Q

What will happen if B cell precursors do not productively rearrange both its heacy and light chains and express IgM on its surface?

A

IT WILL DIE

68
Q

What is somatic recombination dependent on?

A

Recombination Activation Genes ( RAG-1 and RAG-2 )

69
Q

What will deficiencies in RAG-1 and RAG 2 cause ?

A

Sevire autoimmune disease

70
Q

What enzyme catalyzes the addition of N ucleotides at the junctions between rearranging gene segments ?

A

Terminal Deoxynucleotideyl Transferase ( TdT )

71
Q

What is Brutons Thymidine Kinase

A

It is involved in the transduction of signals from cell surface receptors during B cell development.

72
Q

What enzyme catalyzes the recombination events that result in class switching?

A

Switch Recombinase.

73
Q

When and Where does negative selection occurs?

A

In the bone marrow one heavy and light chain are expressed and IgM is displaed on the surface of cells, negative selection occurs

74
Q

What happens if B cell receptor molecules bind to self cell surface molecules ?

A

They are induced to undergo aopotosis

75
Q

What happens to B cells whose B cell receptor molecules bind to soluble self antigens ?

A

They are rendered unresponsive and they migrate to the periphery, become anergenic, and die.

76
Q

What is antigen dependent B cell development?

A

When a mature B cell is circulating through the peripheral lymphoid tissues until it binds an antigen. Once the B cell encounters specific antigen and receives the appropriate T cell derived signals in the T cell areas of the Lymphoid tissues. The B cell is activated and begins to proliferate.

77
Q

Where does affinity maturation take place?

A

In Germinal centers where their variable region sundergo somatic mutations.

78
Q

After somatic mutations what happens to activated B cells?

A

They are stimulated to undergo class switching.

79
Q

What is a plasma cell?

A

A terminally differentiated B cell whose primary function is to produce antibodies.

80
Q

Where do IgG producing plasma cells migrate?

Where do IgA cells migrate?

A

To the Bone marrow

IgA cells migrate to the lamina proproa of mucosal surfaces

81
Q

What is a memory B cell ?

A

A long - lived antigen specific B cell that results from antigenic stimulation of a niave B cell during the primary immune response.

82
Q

What happens when a memory B cell is re-exposed to a specific antigen?

A

These cells reactivate to differentiate into plasma cells as a component of a secondary immune response.

83
Q

What do mature B cells express on their cell surface?

A

IgM and IgD surface antigens.

84
Q

What is the first function of the surface immunoglobulin?

A

Serves as a receptor for a specific antigen: Delivers the 1st activation signal to the B cell following interaction with specific antigen.

85
Q

How does the surface Ig deliver the specific antigen to the interior of the B cell where it is degraded?

A

Receptor mediated endocytosis. The antigen will then be degraded and combined with a MHC cell surface molecule.

86
Q

What are lymphokines?

A

Proteins made by cells that affect the behavior of other cells. These proteins bind to specific receptor molecules on their target cells. Lymphokines are cytokines produced by lymphocytes.

87
Q

What is class switching dependent on ?

A

Helper T interactions with activated B cells.

88
Q

What are the two forms that isotypes of an antibody can be present in?

A

Membrane form and secreted form.

89
Q

Describe the structure of membrane bound Antibodies?

A

Monomeric form

90
Q

What cell surface molecules do all niave B cells initially present?

A

IgM and IgD

91
Q

What anchors membrane bound antibodies to a cell membrane?

A

The transmembrane domain.

92
Q

What determines wether an antibody will be membrane bound or secreted?

A

RNA processing yields either a membrane bound or secreted Ab molecule is depicted for the u heavy chain.

Pathology Kyle (13 decks)

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