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IHL Exam 2 > Diversity vs Specificity: Immunoglobulins (Bowden) > Flashcards

Diversity vs Specificity: Immunoglobulins (Bowden) Flashcards

1
Q

Naive B cells

A

Mature B cells that have not encountered antigen

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2
Q

Epitope

A

the parts of antigens that are recognized by antibodies

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3
Q

Lymphocyte Development

A

1) commitment of progenitor cells
2) Proliferation of progenitors
3) Sequential and ordered rearrangment of antigen receptor genes
4) Selection events (of repertoire)
5) Differentiation of effectors

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4
Q

Immunoglobulins

A

AKA Antibodies

All Ab’s are made by a clone that has a very specific antigen specificity

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5
Q

Structure of Antibody

A

Two heavy chains

Two light chains

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6
Q

Immunoglobulin superfamily

A

IgM
T-cell receptor
HLA (MHC class I and class II)
Ig-alpha/Ig-beta heterodimer (b-cell receptor co)

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7
Q

Immune repertoire

A

what the body will respond to

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8
Q

Clonal selection

A

Gene rearrangement events occur in absence of antigen

1) Lymphocyte clones mature in generative lymphoid organs (bone marrow or thymus) in the absence of antigens
2) clones of mature lymphocytes (T or B cells) specific for diverse antigens enter lymphoid tissues
3) Antigen-specific clones are activated (selected) by antigens
4) Antigen-specific immune responses occur

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9
Q

Clone

A

lymphocyte of 1 specific specificity and it’s progeny

you hope when you are exposed to an antigen that you have made a clone or two that the antigen can select…. for protection

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10
Q

1 gene- 1 polypeptide theory

A

1 gene for each antibody clone

a large amount of genome would be required to generate this level of diversity

would be the size of a mouse! too big

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11
Q

Primary Immunoglobulin Rearrangement

A

1) Multiple germ line genes
- combinatorial diversification (V-J or VDJ recombinations)

2) Junctional diversity
- Addition of nucleotides during process of D-J or V to DJ joining

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12
Q

Germ lines

A

have 2 copies (ma and pa)

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13
Q

Secondary Immunoglobulin rearrangement

A

Somatic Hypermutation

  • point mutations occurring in fully assembled V-J or VDJ regions during an immune response
  • provides a significant source of Ab diversity (MAGIC)
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14
Q

IL-3

A

influences immature progenitors (lymphoid progenitor or myeloid)
made by T cells
multi lineage Cytokine

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15
Q

IL-7

A

necessary for commitment to lymphoid lineages

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16
Q

Stem Cell to Pro-B

A

IL-3 and IL-7 directed toward lymphoid lineage so start to proliferate clones at this point

in bone marrow

unrecombined germline DNA

no Ig expression

no response to antigen

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17
Q

Heavy chain

A

chromosome 14

has diversity region (not on light chains)

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18
Q

Light chain kappa

A

only 1 constant (C) region b/c there is only one type of kappa light chain

several joining (J) exons b/w C and V genes

have 35 V regions

chromosome 2

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19
Q

light chain lambda

A

4 C regions

30 V genes
-each V region gene is composed of two eons, one L that codes for leader and the other V that codes for the most variable region

J regions in between each C region

chromosomes 22

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20
Q

C on Ab gene

A

Constant regions

on downstream end (3’ end)

only 1 on kappa chain
7 on lambda

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21
Q

J

A

Joining regions

5 on kappa chain

leader sequence for constant region on lambda chain (so in front of constant regions)

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22
Q

D

A

diversity regions

23 on heavy chain

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23
Q

V

A

Variable regions

100 on heavy chain
35 on kappa chain
30 on lambda

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24
Q

Allelic exclusion

A

Have both ma and pa chromosomes

express heavy chain and light chain from only one chromosome

ensures that B cells never contain more than one light and heavy chain

essential for antigen specificity b/c the expression of both alleles would render B cell multispecific

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25
Q

Pro B to Pre-B

A

proliferating

start upregulating enzyme expression (RAG and TdT)

still germiline, unrecombined

no antigen

still in bone marrow

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26
Q

Making a heavy chain

A

D joined to J

Add V to DJ region

Gene becomes transcriptionally active (b/c Promoter is close to Enhancer)

Introns removed

Resulting mRNA’s have L, V, D, J, and Cmu or Cdelta exons

mRNAs are translated in the cyotplasm

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27
Q

Combinatorial diversity

A

diversity of antigen receptors produced by use of different combinations of V,D, and J gene segments in different clones of lymphocytes

primary Ig rearrangement

28
Q

RSS

A

recombination signal sequences

29
Q

Rag-1 and Rag-2

A

Catalyze recombination events

aka VDJ recombinase

30
Q

Tdt

A

catalyzes random polymerization of nucleotides that are not part of germline genes into DNA without the need for a template

adds P and N nucleotides

leads to further diversity in the third hypervariable region (idiotype)

31
Q

P nucleotide

A

added by tdt to asymmetrically cleaved hairpins in a templated manner

32
Q

Junctional diversity

A

largest contribution to diversity of antigen receptors

changes in nucleotides sequences introduced at the junctions of the recombining V,D, and J gene segments (done using Tdt)

Primary Ig rearrangement

problem with this is that you are adding alot of stop codons and other useless shit (not perfect)… adding frameshifts (since in non-templated manner) so it is not read by machinery and will not make a functional protein

33
Q

N nucleotides

A

added by tdt in a non-templated manner

34
Q

Rearrangment of heavy chain…

A

must be successful for cell survival

if not then undergoes apoptosis

if successful go from preB to immature B cell

35
Q

Pre B cell receptor

A

Complex of IgM chain and surrogate light chains (just imposters)

IgBeta and IgAlpha are the coB cell receptors that are in conjunction now with our Pre-B receptor

now have recombined H chain gene (VDJ), IgM mRNA heavy chain
cytoplasmic mu and pre-B receptor associated mu
still in bone marrow
starting to pick up markers on surface
no antigen
checking for if it works 3-dimensionally

35
Q

Pre B cell receptor

A

Complex of IgM (Ig mu heavy chain protein), surrogate light chains (just imposters), and Ig-alpha and Ig-beta

Ig-alpha and Ig-beta are signaling molecules

pre-BCR delivers signals that promote survival and proliferation of B lineage cells that have made functional (proper) rearrangement of H-chain (this is the first check point)

36
Q

Pre-B to Immature B

A

Once checked for 3-D working properly then start to proliferate again
Rag expression once again
recombine a light chain!!

36
Q

Pre-B to Immature B

A

Once checked for 3-D working properly then start to proliferate again
Rag expression once again
recombine a light chain!!

37
Q

Making a light chain

A

Always make kappa first

V joined with J

premRNA is spliced and V/J region joined with C region

now have RNA that is translated to make light chain

37
Q

Making a light chain

A

Always make kappa first

V joined with J

premRNA is spliced and V/J region joined with C region

now have RNA that is translated to make light chain

38
Q

After we make the light chain, what are the bone marrow stromal cells checking?

A

Checking for recognition of self
checked by being presented bits and pieces of HLA

negative selection vs. positive selection

38
Q

After we make the light chain, what are the bone marrow stromal cells checking?

A

Checking for recognition of self
checked by being presented bits and pieces of HLA

negative selection vs. positive selection

39
Q

Receptor editing

A

This is something unique to light chains

Nonproductive light chain rearrangements can be rescued by further gene arrangement

If 1st is nonproductive then the V can go back and select another J…. can do this up to 5 times b/c there are 5 J regions

If it grabbed the 5th joining region, and it is not recombined successfully, then move on to lambda light chain

39
Q

Receptor editing

A

This is something unique to light chains

Nonproductive light chain rearrangements can be rescued by further gene arrangement

If 1st is nonproductive then the V can go back and select another J…. can do this up to 5 times b/c there are 5 J regions

If it grabbed the 5th joining region, and it is not recombined successfully, then move on to lambda light chain

40
Q

Immature B cell

A

Have IgM (light and heavy chain) on surface

going through negative selection and clonal deletion to cells that respond avidly
receptor editing is part of this

40
Q

Immature B cell

A

Have IgM (light and heavy chain) on surface

going through negative selection and clonal deletion to cells that respond avidly
receptor editing is part of this

41
Q

Alternative splicing of heavy chain mRNA

A

in the first heavy chain rearrangement we removed introns, so the preMRNA was processed in two ways (one to bring VDJ next to Cmu or close to Cdelta)

have both IgM and IgD on membrane surface of B cell b/c of alternative splicing

IgM–> mu heavy chain

IgD–> delta heavy chain

41
Q

Alternative splicing of heavy chain mRNA

A

in the first heavy chain rearrangement we removed introns, so the preMRNA was processed in two ways (one to bring VDJ next to Cmu or close to Cdelta)

have both IgM and IgD on membrane surface of B cell b/c of alternative splicing

IgM–> mu heavy chain

IgD–> delta heavy chain

42
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 in the bone marrow and is independent of antigen.

42
Q

BCR

A

B cell receptor

this is a surface bound IgM plus Ig-alpha and Ig-beta

43
Q

Negative selection by BM stromal cells

A

if the immature b cell responds to avidly with self-Antigens they are targeted for apoptosis

43
Q

Negative selection by BM stromal cells

A

if the immature b cell responds to avidly with self-Antigens they are targeted for apoptosis

there are a lot of self-antigens located in the bone marrow

also… if it does bind too tightly it can activate VDJ recombinase enzyme, undergo light chain recombination (V grabs a different J) and then once again change the specificity of the antigen receptor

44
Q

Positive selection by BM stromal cells

A

if the immature b cells bind with low avidity, clones are selected to be released into the periphery

44
Q

Positive selection by BM stromal cells

A

if the immature b cells bind with low avidity, clones are selected to be released into the periphery

45
Q

Mature B cell

A

has Cmu and Cdelta mRNA

membrane IgD and IgM

now in the periphery

activated by antigens that select their clone

45
Q

Mature B cell

A

has Cmu and Cdelta mRNA

membrane IgD and IgM (due to alternative splicing)

now in the periphery

activated by antigens that select their clone

46
Q

how are TCReceptors made?

A

same exact way as BCR

46
Q

how are TCReceptors made?

A

same exact way as BCR

same V, D, J, N

bigger potential repertoire

47
Q

Pre-B cell

A

now have recombined H chain gene (VDJ),

defined by presence of the Ig mu heavy-chain protein in cytoplasm and some mu on the cell surface in association with surrogate light chains

mu chain and surrogate light chains associate with Igalpha and Igbeta signaling molecules to make pre-BCR

still in bone marrow
no antigen
pre-BCR checking for if it works 3-dimensionally

48
Q

how many progenitor cells actually make it to the end

A

12.5 percent

49
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 in the bone marrow and is independent of antigen.

50
Q

secondary rearrangement

A

Somatic Hypermutation

51
Q

Tahir Muhtar 6 month old

A

IgG: low
IgM: low
IgA: mildly low

WBC: Low
CD19 low
CD3 low
CD8 low
CD4 low
CD56 (NK) high
52
Q

Kid with SCID
Had homozygous mutations in RAG1 and RAG2 gene
What is the result?

A

Cannot rearrange his germiline for heavy or light chains for both B’s and T’s

so cannot make immune response

RAG mutations account for approximately 3-4 percent of SCID

53
Q

SCID

A

Bubble kids

50 percent of SCID cases are result of mutations in cytokine IL-7
the result of this is that neither lymphocyte pool matures into effector cells

54
Q

X-linked Agammaglobulinemia (Bruton’s)

A

Bruton Tyrosine Kinase (Btk) delivers signals from pre-BCR for survival of cell

so basically there is no survival of B or T cells, decreased immune response

55
Q

The primary development of B cells is …

A

antigen independent (DOES NOT SEE ANTIGEN)

IHL Exam 2 (14 decks)

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