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Immunology > Cellular and Genetic Basis of Antibody Specificity > Flashcards

Cellular and Genetic Basis of Antibody Specificity Flashcards

1
Q

Side-Chain Hypothesis of antibody generation

A
  • theory that a single B cell has potential to generate many different antibodies and had many surface R
  • suffered from its inability to explain how a given B cell would secrete only the antibody that was needed and none against the self…
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2
Q

4 components of the clonal selection hypothesis of lymphocyte activation

A
  1. Monospecificity: all antigen receptors on a given lymphocyte possess the identical specificity
  2. Receptor engagement: physical binding of antigen-specific receptors on lymphocytes by antigen is necessary for lymphocyte activation
  3. Receptor=product: for B cells, the specificity of the Antigen R on a given cell is identical to the specificity of the antibodies produced upon activation of that cell
  4. Clonal integrity: specificity of a given lymphocyte and its daughter cells does not change during the course of an immune response (no change in which Ab is made)
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3
Q

_______ selects naive lymphocytes bearing receptors that bind to an epitope with sufficient affinity.

A

-Antigen

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4
Q

A responding lymphocyte can give rise to _________ daughter cells

A

-5,000 to 50,000

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5
Q

Only __________ can give rise to antibody-secreting plasma cells.

A

-Ag-activated B cells

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6
Q

For B and T cells, the primary response to antigen results in _______________.(general answer)

A
  • generation of increased (10-50 fold) numbers of cells specific for the original antigen
  • therefore, increased numbers of Ag-specific cells are available to respond against the antigen upon secondary exposure
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7
Q

3 general actions upon Ag exposure

A
  1. Ag-bind B-cells that have R with sufficient affinity
  2. Ag-activated B-cells divide (clonal selection)
  3. Release antibodies
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8
Q

The secondary response can also be called the _______ response.

A

-memory

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9
Q

What is one way to think about why secondary responses are more protective than primary responses?

A

-there are a greater number of responding clones that were generated at clonal selection from the primary response

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10
Q

Antigen-driven antibody responses are _________.

A

heterogeneous and NOT mono-clonal

-thousands of different clones (each with unique VL-VH pair) will respond to any given antigen

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11
Q

Antigen-activated cells and their clonally-related daughter cells differentiate into effector cells. Name who these effector cells are for B and T cells

A
  • B cells differentiate into antibody producing cells (plasma cells….and memory cells)
  • T-cells differentiate into cytokine producing cells that regulate other immune cells (helper T cells) and killer cells (cytotoxic T cells) that lyse infected host cells
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12
Q

Although antibody responses are very polyclonal, monoclonal antigen-specific antibodies can be obtained by…..

A
  • fusing B cells with myeloma cells to create hybridomas

- these hybridomas can be propagates in culture indefinitely and secrete large amounts of monoclonal antibodies

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13
Q

Concept and utility of inbred mouse lines

A
  • mice are genetically identical to one another and distinct from other inbred mice
  • inbred mice are homogeneous for all genes
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14
Q

Generating Ig molecules in B cells requires at least ____ genes.

A
  • 2

- heavy chain gene and a light chain gene

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15
Q

T/F: The processes required for generating antigen R on B cells could not be influenced by antigen

A

True; since these receptors are needed to recognize the antigen to begin with

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16
Q

A germ-line view of antibody and antigen receptor diversity

A

-a B cell precursor has genes for every unique VH- VL pair and would turn on only one Ig heavy chain gene and only one Ig light chain gene

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17
Q

What does the germ-line view diversity fail to account for?

A
  • how so many antibodies with unique specificities could use identical constant regions
  • how antibodies with identical specificity might switch constant regions (from IgM to IgG
18
Q

Somatic model for diversity of antibodies and receptors

A
  • all cells have only 1 Ig heavy, kappa, and lamda gene

- these are mutated intentionally in pre-B cells, spreading unique mutation patterns across Ig genes in each pre-B cell

19
Q

Where do the point mutations occur according to the somatic model?

A

-only in the B-cell precursors

20
Q

3 contrasts between somatic model and germline model

A
  1. somatic mutations would not be inherited. In this case, they could occur only in cells of the B cell lineage
  2. entire antibody repertoire would be generated from a very small number of genes in somatic model
  3. somatic model requires the intentional mutation of specific genes
21
Q

Steps in generating a light chain gene

A
  • for each light chain locus, one of 100s of V segments is combined with 1 of a small number of J segments
  • afterwards, the resulting V region coding unit is combined with a constant region exon via RNA processing
  • DNA recombination event (V-J), RNA transcription, RNA splicing
22
Q

A variable region domain of an antibody molecule is the result of the recombination and juxtaposition of ____ (for light chains) or 3 (for heavy chains) genetic elements or gene segments. This gene rearrangement process is called ____.

A
  • 2 for LC or 3 for HC

- V(D)J recombination

23
Q

Steps in generating IgG heavy chain locus

A
  • D-J segment rearrangement
  • V-DJ segment rearrangement
  • After assembly of VDJ coding exon, RNA is generated and the region between the VDJ and first constant region exon (C-mu, for IgM) is spliced away by RNA splicing
24
Q

Final mRNA for IgH chain

A

-VDJCmu

25
Q

Does light chain or heavy chain recombination occur first?

A

-Heavy chain recombination is first

26
Q

Which segment is found in heavy chain loci but not in light chain loci?

A

-D segments

27
Q

In contrast to a single heavy chain locus, there are _______ light chain loci

A

-2; kappa and lamda

28
Q

2 additional sources of diversity, in addition to V(D)J recombination

A
  1. Junctional diversity: recombination joining events are not precise (acentric cleavage of hairpin), causing overhangs that must be filled in with the appropriate nucleotide
  2. Enzyme TdT (Terminal deoxyribonucleotide transferase) adds additional nucleotides called N regions
29
Q

N and P region of VDJ recombination

A
  • P region: due to imperfect recomination

- N region: due to TdT activity

30
Q

Transcriptional expression of Ig genes

A
  • VDJ recombination brings promoter sequences close to the enhancer
  • the enhancer promotes transcription of the rearranged V gene
31
Q

4 sources of diversity for generating unique antibodies

A
  1. V(D)J recombination
  2. junctional diversity aka P nucleotide additions
  3. N-sequence addition by TdT
  4. combination of heavy and light chains
32
Q

What enzymes are unique to lymphocytes and initiated V(D)J recomination? How do these enzymes know where to cut?

A
  • RAG 1 and RAG2 “recombinase activating genes”

- recomination signal sequences (RSS) tell RAG1/2 where to cut

33
Q

What are Recombination Signal Sequences (RSS) and what do they do?

A
  • conserved heptamer and nonamer sequences separated by 12- or 23- bp spacers that are located next to V and J exons for light chain loci or to V,D, and J exons in the heavy chain loci
  • rearrangement always uses what is called the 12/23 rule
  • these signal sequences are recognized by RAG1 and RAG2 and tell them where to cut
34
Q

V(D)J recombination is an ordered process: what genes rearrange first?

A

-heavy chain genes rearrange before light chain genes

35
Q

Successful rearrangement of an Ig heavy chain allele is required for ______ to generate ________. Ig light chain rearrangements occur only in _____________ cells. Therefore, what would a mutation in RAG1 or RAG2 cause?

A
  • pro-B cells to generate pre-B cells
  • pre-B cells
  • prevent formations of pre-B cells and immunodeficiency
36
Q

In pro-B cells, heavy chain protein forms a receptor that signals differentiation. What is this receptor? What comprises this receptor? What does this receptor do? What happens if this process fails?

A
  • proB cell receptor is called a pre-B cell receptor (pre-BCR) that consists of heacy chain and a common surrogate light chain
  • pre-BCR signals proB cells to proliferate and differentiate into pre-B cells, allowing light chain recombination events to initiate.
  • any mutation that results in suboptimal pre-BCR expression or function causes an immunodeficiency due to loss of B cell development
37
Q

Describe the levels of RAG1/2 during B-cell development in the face of allelic exclusion

A
  1. On during pro-B cell to create heavy chain locus in order to make Pre-BCR. If this is productive and produces a signal, RAG1/2 is downregulated, so no recombination can occur
  2. After early pre-B cells proliferate, RAG1/2 expression is reactivated so that light chain recombination can occur. If productive, the resulting new BCR signals to terminate RAG1/2 expression
38
Q

Describe the process of eliminating self-reactive B cells soon after they are generated

A
  • Immature B cells (IgM, but no IgD) should not be able to bind and signal antigens, if they do, they are destroyed; clonal deletion
  • another safety net is that IgD is not functionally added to a B cell until a short time after they exit the bone marrow. This ensures it will not be activated in the presence of self-antigen and if it is, it will become tolerant
  • *While in bone marrow, they should not signal at all. If they do, they die. Shortly after they leave bone marrow, new B cells remain tolerance sensitive so if they bind an antigen, they will signal tolerance.
39
Q

Mutations in any required mediator of V(D)J recombination will result in what deficiency?

A
  • combined (B and T) immunodeficiency

- example is loss of RAG genes

40
Q

Normally every B cell have a unique configuration of Ig heavy and light chain genes, reflecting the polyclonal nature of the B cell antigen receptor repertoire. But, because cancers are almost always monoclonal, the detection of a dominant Ig rearrangement is diagnostic for what?

A
  • lymphoma or leukemia

- ex if all B cells express kappa instead of lamda (these 2 should be fairly even)

41
Q

Lymphoid malignancies often harbor translocation in the Ig or TCR loci. Explain why this is plausible.

A

-VDJ recombination and class switching produce dsDNA breaks that contribute to translocations which, in turn, lead to overexpression of a cellular growth or survival promoting gene

42
Q

Acute Lymphoblastic Leukemia (ALL) and a common diagnostic indicator.

A
  • leukemia derived from preB or preT cells

- expression of TdT is a common diagnostic indicator for ALL

Immunology (13 decks)

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