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Immunology 2019 > Lecture 10 > Flashcards

Lecture 10 Flashcards

1
Q

Define “Central Tolerance”. Where, anatomically, does this process occur?

A

Central Tolerance: the process by which self reactive lymphocyte clones are selected to be destroyed (prevents autoimmune diseases)

Central tolerance occurs in the respective “generative lymphoid organ” (Thymus for T cells, Bone marrow for B cells)

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2
Q

All lymphocytes begin as ____ ____.

A

stem cells

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3
Q

Distinguish the order that lymphocytes generate their heavy and light chains of their receptors

A

The heavy chain forms first and then the light chain is formed second

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4
Q

State and describe the 5 processes of lymphocyte maturation that occur in their respective generative organs.

A

Commitment: of progenitor cells to B or T cells lineage

Proliferation: of progenitors AND immature lymphocytes (which have already been committed to a developmental path)

Rearrangement: of Ag receptor genes and the expression of BCR or TCR proteins (this process is sequential and ordered)

Selection: events that eliminate self-reactive cells

Differentiation: of B and T cells into functionally and phenotypically distinct subpopulations

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5
Q

Hematopoietic Stem Cells (HSC’s) give rise to Common Lymphoid Progenitor Cells (CLP’s). What 3 types of immune cells can CLP’s give rise to?

A

B cells

T cells

NK cells

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6
Q

CLP’s can differentiate into Pro-B cells or Pro-T cells. What determines which lineage a cell is committed to?

A

Various Transcription factors

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7
Q

State the 3 specific cells that Pro-B and Pro-T cells can eventually differentiate into (3 each so 6 total)

A

Pro-B cells: stays in the Bone marrow
FO B cells (follicular ; in thymus)
MZ B cells (Marginal zone ; in the spleen)
B-1 cells (generated during fetal stage)

Pro-T cells:
AlphaBeta T cells
GammaDelta T cells
NK cells

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8
Q

What stimulates proliferation of the committed T and B cell progenitor cells? why does proliferation occur?

A

cytokines

Proliferation occurs to ensure that there is a large pool of progenitor cells available for the generation of a “high diversity” of mature lymphocytes

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9
Q

State where the following cell develops and which cytokine stimulates it to do so.

T cells:

B cells:

NK cells:

A

T cells: “proliferate” in the thymus when stromal cells produce IL-7

B cells: develop in the bone marrow when stromal cells produce IL-7

NK cells: develop in the thymus when IL-15 stimulates them

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10
Q

Compare the process by which Developing B cells and developing Alpha/Beta T cells undergo gene rearrangement and expression

A

Developing B cells: the “Ig heavy chain locus” opens up and becomes accessible to proteins that will mediate “Ig gene” rearrangement and expression

Developing Alpha/Beta T cells: the “TCR Beta gene locus” opens up and becomes accessible for “TCR gene” rearrangement and expression

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11
Q

What are the 2 transcription factors that stimulate lymphocytes to develop into T cell lineage?

A

Notch-1 and GATA-3 are transcription factors that stimulate lymphocytes to develop into T cell lineage

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12
Q

Name the 2 proteins that are known to regulate TCR and BCR rearrangement

A

Rag-1 and Rag-2

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13
Q

Describe the Notch family of proteins

A

Notch proteins are cell surface molecules that are proteolytically cleaved when they interact with specific ligands on neighboring cells

the cleaved intracellular portion of the Notch protein then enters the nucleus to modulate the expression of specific target genes

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14
Q

Describe the function of GATA-3

A

GATA-3 induces the expression of genes involved in the development of AlphaBeta T cells

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15
Q

During the process of expression genes for T cell development, what type of recombination do the pre-TCR encoding genes undergo?

A

V(D)J recombination

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16
Q

State the 3 transcription factors that are required for the expression of genes that cause B cell development.

A

EBF (Early B cell Factor)

E2A

Pax-5

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17
Q

_____ mechanisms make gene available or unavailable in chromatin. State the 2 types of chromatin and how that affects the expression of genes.

A

Epigenetic

Euchromatin is loosely packed (may or may not have a histone) and is therefore available to be transcribed

Heterochromatin is tightly packed to the histone and is therefore in a silenced state of gene expression

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18
Q

DNA methylation on _____ residues generally silences genes

A

cytosine

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19
Q

State and describe the 2 different levels at which MicroRNAs can control gene expression

A

They can control gene expression at the post-transcriptional level by impairing translation or by promoting the degradation of the target mRNA

They can control gene expression at the transcriptional level by accumulating in the nuclei and regulating gene expression there

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20
Q

For the following Ig polypeptides that make up the human immunoglobulin genes, state the chromosome they are found on.

H-chain:

K-Chain:

Lambda-Chain:

A

H-chain: 14

K-Chain: 2

Lambda-Chain: 22

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21
Q

People ________ inherit maternal and paternal sets of alleles for L and H chains of their Ig molecules.

A

Codominantly

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22
Q

Define Allelic exclusion and explain the process by which it occurs

A

Allelic Exclusion: describes the method that occurs when inheriting H and L chains. It states that only one of the L chain and one of the H chain alleles will be expressed in a single B cell (or T cell).
(basically, all of the Ag receptors on a single cell will be the same. You will not have different receptors in terms of paternal/maternal inheritance) on the same cell

This occurs because whatever alleles (paternal or maternal) will not be expressed in a specific B cell (or T cell), will be methylated so that that are silenced

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23
Q

True or False:

All maternal and paternal allotypes for lymphocytes will be expressed equally. explain.

A

True

There are many B and T cells so it is easy to express everything equally

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24
Q

Name the 2 types of extracellular receptors that Stem cells have

A

germline Ig (which can be expressed to form a B cell)

TCR (which can be expressed for form a T cell)

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25
Q

By what process is the variable region of a lymphocyte determined? (this same process is also responsible for determining the epitope-specific diversity of BCR and TCR)

A

DNA chromosomal rearrangement

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26
Q

State the 3 mechanisms of the DNA rearrangement that produces the diversity of AG receptors

A

Somatic recombination

mRNA splicing

Junctional diversity

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27
Q

State the mechanism by which RAG1 and RAG2 initiate V(D)J recombination. Include how this mechanism is resolved (2 options)

A

they introduce DNA double strand breaks in the DNA

This is repaired by either:
1. Homologous recombination (HR)

  1. Nonhomologous end-joining (NHEJ)
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28
Q

RAG-mediated breaks are resolved EXCLUSIVELY by what process?

A

NHEJ (Nonhomologous end-joining)

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29
Q

True or False:

BCR’s are composed of a Heavy Chain and a K chain or Lambda chain. TCR’s are composed of an Alpha chain and a Beta chain. This means that BCR’s have a greater potential repertoire with which to form diverse cell surface receptors when compared to TCR’s. explain.

A

False

While the following statement is true “BCR’s are composed of a Heavy Chain and a K chain or Lambda chain. TCR’s are composed of an Alpha chain and a Beta chain.”

TCR’s still have a greater potential repertoire with which to form cell surface receptors when compared to BCR’s. This is because they have more mechanisms available to form diverse receptors when compared to BCR’s.

30
Q

The Heavy chain of a BCR has 4 separate gene segments in chromosome 14 (V, D, J, and C). Explain how BCR diversity is achieved during the maturation process from immature B cell DNA to Mature B cell DNA. (don’t elaborate on the recombination or testing portion of this)

A

Immature B cell DNA has multiple copies of each gene segments on chromosome 14

RAG1 and RAG2 perform the recombination process that randomly selects genes and then splices out all other copies to yield a unique V-D-J sequence

Then the sequence is tested for productive rearrangement

31
Q

Describe the processes that RAG1 and RAG2 conduct during recombination in BCR/TCR development

A

Recombination starts with the Heavy chain (B cell)/Beta chain (T cell)

if the Heavy (B cell)/Beta (T cell) chain passes the “productive rearrangement” test then the process moves to rearrangement

Rearrangement of the light chain (B cell ; K or lambda)/Alpha chain (T cell) then occurs

32
Q

What step in the process of BCR/TCR development marks that end of paternal and maternal H chain competition?

A

when the BCR/TCR passes the “productive rearrangement” test

33
Q

Describe in detail the recombination process creates a single VDJ sequence from genes that have several copies of all of the genes (3 steps)

A

(this is a specific sequential order)
1. D and J are chosen and DNA between them is deleted

  1. A V segment is chosen and DNA between V and DJ is deleted
  2. A C is chosen and DNA between CDJ and C is deleted

Productive rearrangement testing then occurs

34
Q

State what occurs if a VH (Variable Heavy chain of BCR or TCR) rearrangement is productive.

A

The exact same recombination rules for the heavy chain occurs for the light chains
(this randomly chooses between Kappa and Lambda light chains in BCR’s)

There will also be a 2nd “productive rearrangement” test that is conducted after recombination of the light chains is complete

The final result will be only one kind of VH and VL for the cell

35
Q

Compare the final sequences that are present in the light chain and the heavy chain in a BCR

A

Light chain: LVJC

Heavy chain: LVDJC

(Heavy chains have a D segment)

36
Q

What are the 2 possible types of “C” segment that can occur in the light chain portion of a BCR?

A

Kappa or Lambda

37
Q

Explain what process controls the process of the VDJ rearrangement segment facilitating the synthesis of a Mu or Delta heavy chain (in BCR’s). What occurs shortly after this?

A

Alternative mRNA splicing controls this rearrangement and synthesis of a heavy chain

After the heavy chain has been synthesized, a light chain associates with the heavy chain, forming an IgM OR IgD molecule to be displayed on the surface of the cell

38
Q

Define CSR

A

CSR (Class-Switch Recombination) is a process that exchanges the constant region on the heavy chain (on a BCR) in order to produce “other non-Igm/IgD heavy chains”

39
Q

State the 2 methods that can form both types of BCR heavy chains

A

Alternative mRNA splicing

CSR (Class-Switch Recombination)

40
Q

Explain the CSR mechanism

A

CSR requires the AID (Activation-Induced cytidine Deaminase) enzyme, which introduces Uracil residues into the DNA of the S regions

this introduction of Uracil induces the generation of DNA breaks at “switch regions”
(Excised DNA forms loops here)

DNA repair occurs to resolve these DNA breaks

41
Q

What type of cells and at what developmental stage is the only time you can find AID being expressed?

A

AID enzyme is only expressed in activated B cells

42
Q

When it comes to Germline TCR formation, state the final sequence that will occur in the Alpha and the Beta chain

A

Alpha Chain: LVJC
(does not contain “Diversity” D segments)

Beta Chain: LVDJCDJC

(C and L chains basically “bookend the sequence” ; V, J, and D are the portions that are chosen from many many copies of the same gene)

43
Q

What enzyme helps create junctional diversity by adding or removing nucleotides to the exposed ends of the V, D, or J genes before they are reunited? why is this important?

A

TdT (Terminal Deoxynucleotidyl Transferase)

The inaccuracies of joining (achieved by TdT) is what greatly increases the diversity of TCR’s when compared to BCR’s

44
Q

Compare P and N nucleotides that are added to DNA during rearrangement and recombination processes that occur in the development of a TCR (where they are and what creates them)

A

P nucleotides are single strands generated on the asymmetric openings (overhangs) in DNA caused by RAG cleaving hairpin loops
(P nucleotides basically add to the shorter strand to even the DNA strands)

N nucleotides are double strands generated by TdT in order to link the DNA strands back together after RAG cleaves them
(makes the entire strand whole again)

45
Q

Junctional diversity result from the loss of nucleotides through the action of _____ activity and from the addition of _ ____ __ ________.

A

Exonuclease

N and P nucleotides

46
Q

Describe why P nucleotides received their name

A

P stands for palindromic

this describes their palindromic appearance that is due to the self-complementarity of P nucleotides

47
Q

Describe the 2 checkpoints that lymphocytes must undergo during the selection process in order to be selected to be able to mature into a fully functional lymphocyte

A

Checkpoint 1: occurs after the production of the 1st polypeptide chain of the 2 chain Ag receptor is completed

Checkpoint 2: occurs after the production of the 2nd polypeptide chain of the Ag receptor is completed

48
Q

Why must there be checkpoints that occur during the selection process for lymphocytes? what occurs if a cell does NOT pass a checkpoint?

A

These checkpoints eliminate potentially harmful self-reactive lymphocytes (that form due to the random nature of Lymphocyte cell surface receptors)

Upon failing a checkpoint, a cell will NOT receive a survival signal and as a result, will die via apoptosis

49
Q

State the 2 chains that are present in pre-Ag receptors (pre-BCR’s in B cells ; pre-TCR’s in T cells)

A

1 polypeptide chain (which is present in a mature Ag receptor)

1 surrogate receptor chain (which is NOT present in a mature Ag receptor)

50
Q

State the polpeptide chain that is present in the mature Ag receptor for pre-TCR’s and pre-BCR’s.

A

pre-BCR’s contain the Ig Mu heavy chain

pre-TCR’s contain the TCR Beta chain

51
Q

Compare the maturity level of B and T cells when they are allowed to leave their respective generative lymphoid organs.

A

T cells are considered “mature” and ready to circulate once they leave the thymus

B cells are considered “immature” when they leave to go to the spleen and then circulate through the blood.
“B cells need a master’s degree lol”

52
Q

For the first checkpoint, describe the “Pass rate” of B and T cells make productive in-frame rearrangements of Ag receptor genes?

A

about 30% of B and T cell rearrangements create productive in-frame rearrangements that pass checkpoints and are allowed to express survival signals

53
Q

Describe the process of positive selection of T cells

A

Positive selection of T cells ensures the maturation of CD8 or CD4 T cells whose receptors DON’T recognize self antigens but CAN recognized MHC molecules (this includes class I and class II

(CD8 cells will become cytotoxic T cells while CD4 cells will become helper T cells)

positive selection basically preserves lymphocytes that express potentially useful receptors

54
Q

What mechanism is most important for maintaining the central tolerance to self antigens?

A

Negative selection

55
Q

Describe how negative selection occurs with B and T cells

A

Negative selection in T cells eliminates the T cells that react to self antigens

Negative selection in B cells alters B cells that react to self antigens and allows them to “try again” with a newly rearranged receptor.
If the B cell still reacts with self antigens after round 2, negative selection will then induce apoptosis of the B cell.

56
Q

Define Clonal deletion. Describe the way it occurs to B and T cells

A

Clonal deletion: the destruction of a lymphocyte via apoptosis of self reactive lymphocytes

T cells undergo clonal deletion after just ONE attempt at rearrangement of receptor genes

B cells undergo clonal deletion after TWO attempts at rearrangement of receptor genes

57
Q

Define Receptor editing as it occurs with B cells

A

Receptor editing: the process by which B cells with high affinity for self Ags are allowed to conduct a “second attempt” at producing a useful Receptor that DOESN’T react to self antigens

58
Q

Describe what can be determined by knowing if a B cell is expressing the Kappa light chain or the Lambda light chain.

A

B cells with Kappa light chains have only undergone the primary rearrangement in an attempt to produce a useful Ag receptor
(clonal deletion will not occur to these B cells)

B cells with Lambda light chains have undergone the SECOND rearrangement in another attempt to produce a useful Ag receptor
(clonal deletion will occur to these B cells with a Lambda light chain if they react with self antigens, unlike B cells with a Kappa light chain which will get a second chance at producing a useful Ag receptor rearrangement)

59
Q

Compare B1 and B2 Lymphocyte lineages in terms of the age they are developed, where in the body they are developed, and when they are considered to be mature (really just for B2 cells)

A

B1 lineage cells develop from “Fetal liver derived stem cells”

B2 lineage cells develop from Bone Marrow precursors after birth
B2 cells are considered “immature” once they leave the Bone marrow are are considered “mature” (are either follicular or marginal Zone B2 cells) once they reach the spleen

60
Q

Describe the level of junctional diversity that is found in B1 cell populations and explain it.

A

There is NO junctional diversity in B1 cell populations bc they do not express TdT (which is the enzyme that conducts rearrangement in order to produce diversity in adult B cells)

61
Q

Large numbers of B1 cells are found as a ____-_______ population in what 2 locations of the body?

A

self-renewing

peritoneum and mucosal sites

62
Q

Which Abs are known an “natural antibodies”? describe what 3 antigen types that these will interact with

A

Natural antibodies = IgM (because they are present even in people without over immunization ; they are NOT a specific type of Ab)

IgM’s often react with polysaccharides, lipids, and oxidized lipids

63
Q

Describe what B1 B cells contribute to most in the early phases of an infection

A

B1 cells contribute to most of the serum IgM during early phases of infection

64
Q

What must occur to B2 cells before they relocate to the spleen as “immature B2 B cells”?

A

they must undergo a screening via central tolerance in order to remove all autoreactive cells

this occurs AFTER the rearrangement of their BCR chain genes

65
Q

What property of a BCR may contribute to the differentiation of B2 cells into FO B2 cells or MZ B2 cells? Describe the differences between FO B2 cells and MZ B2 cells

A

The “affinity of the BCRs for self Ags” may contribute to the differentiation of B2 cells into FO B2 or MZ B2 cells

FO B2 cells: are recirculating lymphocytes

MZ B2 cells: are abundant in the splenic marginal zone

66
Q

Compare what FO and MZ B2 cells respond to AND the manner in which these 2 B cell populations are replenished

A

FO B2 cells respond to protein antigens in a “T cell dependant” manner
Require constant replenishment from the bone marrow

MZ B2 cells respond to blood-borne antigens in a “T cell Independent” manner
Are predominantly self-renewing populations

67
Q

Which subset of B2 cells can develop into plasma cells or Memory B cells?

A

only mature FO B2 cells

68
Q

What 2 processes do FOB2 cells progressively undergo?

A

Isotype switching

Affinity maturation

69
Q

Which is the more specific type of B cell, FO B2 cells or MZ B2 cells?

A

FO B2 cells

FO B2 cells are much more specific and are therefore selected to be a circulated B cell

70
Q

Describe how a MZ B cell responds to a blood-borne pathogen. Also name the 2 places in the body where you can expect to find MX B cells

A

MZ B cells respond very rapidly to blood-borne pathogens and differentiate into short-lived plasma secreting cells (secrete IgM)

MZ B cells can be found in the spleen or in the lymph nodes

71
Q

Describe how AlphaBeta and GammaDelta T cells respectively develop. Also include the percentage of Total T cells that each type accounts for.

A

AlphaBeta T cells, which account for 90% of T cells, and GammaDelta T cells, which account for 10% of T cells, have a common precursor.

The “rearrangement process for the 3 TCR loci (Beta, Gamma, and Delta) all begin SIMULTANEOUSLY

If a cell first succeeds in productively rearranging it’s TCR Gamma or TCR Delta loci prior to producing a productive TCR Beta loci, then it will be selected into the GammaDelta T cell lineage.

72
Q

Describe the level of diversity found in GammaDelta T cell populations and why

A

GammaDelta T cells have “limited diversity” bc there are only a few available V, D, J segments that are used to form mature GammaDelta T cells
(it is unknown why there are so few available segments for this type of T cell)

Immunology 2019 (22 decks)

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