Immunogenetics Flashcards by Sarah Gillen

Ig receptors, TCRs, class I MHCs, CD4s, CD28s, and ICAM-1 are all members of what receptor family?

Immunoglobulin superfamily

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What makes up the BCR?

Surface Ig

2 invariant chains (Igalpha and Igbeta)

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What roles do the 2 invariant chains Ig-alpha and Ig-beta play in the BCR?

Ensure surface expression of Ig molecule and function in signal transduction

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What makes up the TCR complex?

TCR (alpha and beta chains)

2 CD3 complexes (epsilon/gamma and epsilon/delta)

Zeta chains

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At what stage in general lymphocyte development is there growth factor-mediated committment, proliferation, and initiation of antigen receptor gene rearrangement?

From Stem –> pro-lymphocyte –> pre-lymphocyte

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At what stage in general lymphocyte development does the following occur:

Selection of cells that express pre-antigen receptors as well as reside in generative organ

Pre-lymphocyte

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At what stage in general lymphocyte development does the following occur:

Selection of repertoire and acquisition of functional competence

Immature lymphocyte

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During hematopoeisis, what is the most important cytokine for the development of the lymphoid cell lineage?

IL-7

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What process involves gene rearrangement events occurring in the absence of antigen?

Clonal selection

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Allelic exclusion is __________, meaning it occurs for the specific epitope

Monospecific

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What are the 3 major mechanisms for generation of lymphocyte receptor diversity?

Combinatorial diversification (somatic recombination)
Junctional diversity
Somatic hypermutation

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What mechanism for generation of lymphocyte receptor diversity involves point mutations occurring in fully assembled V-J and V-D-J regions during an immune response?

Somatic hypermutation

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What major mechanism for generation of lymphocyte receptor diversity involves addition of nucleotides during the process of D-J or V to D-J joining?

Junctional diversity

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What major mechanism for generation of lymphocyte receptor diversity involves V-J or V-D-J recombination of multiple germline genes?

Combinatorial diversification = somatic recombination

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True or false: the mechanisms accounting for immune diversity for BCR/antibodies and TCRs are identical

True

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In what receptor type does somatic hypermutation occur?

BCRs ONLY, it does not occur in TCRs

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The production of which chains in the T cell correspond to the production of the heavy and light chain in the B cell?

Production of heavy chain in B = Beta chain in T

Production of light chain in B = alpha chain in T

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During combinatorial diversification, what is the primary difference between heavy and light chains?

Heavy chain has VDJ and C regions

Light chain has VJ and C regions (no D)

[this is the same in TCR - beta chain has VDJC, alpha chain as VJC]

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What are the two loci associated with the BCR light chain and what chromosome are they each associated with?

Ig-kappa chain locus = Chr 2

Ig-lambda chain locus = Chr 22

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What chromosome is the H chain locus associated with for the BCR?

Chr 14

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During combinatorial diversification in BCRs, which chain forms first?

Heavy

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During combinatorial diversification of TCRs, which chain forms first?

Beta

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The heavy chain of the BCR corresponds to which Ig by default?

IgM (mu)

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Combinatorial diversification in BCRs consists of:

Heavy chain: _____ to ______, followed by ______ to _______ rearrangement

D to J, followed by V to DJ rearrangement

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What directs the recombination of gene segments in B cells?

Recombination signal sequences (RSS)

What are the 2 major roles of recombination signal sequences during VDJ recombination?

1. Provide recognition sites for recognition enzymes that cut and rejoin DNA 2. Ensure gene segments are joined in correct order (especially important for heavy chain since there is D region)

What enzyme is responsible for recombining V, D, and J segments?

VDJ recombinase

What genes, made only by lymphocytes, encode for the two necessary components of the VDJ recombinase enzyme?

Recombination activating genes (RAG-1 and RAG-2)

When would RAG-1 and RAG-2 be expressed in B and T cells?

Only during their developmental stages [once B cell reaches plasma cell status, RAG 1 and 2 will no longer be expressed]

Junctional diversity allows for more diversity in BCR and TCRs; these mechanisms generate diversity in the ____________ region (idiotype)

Hypervariable

Junctional diversity consists of insertion of a series of nucleotides between D and J segments. This is catalyzed by what enzyme?

terminal deoxyribonucleotidyl transferase (TdT)

TdT catalyzes the random polymerization of nucleotides into DNA without the need for a template. ______ nucleotides are added to asymmetrically cleaved hairpins in a templated manner. _______ nucleotides are added in a non-templated manner.

P | N

Recombination between VJ and VDJ is not always perfect. Additional diversity is added by _______ that occur in the recombination events taking place, which can lead to _______________. It is estimated that these inaccuracies can triple the diversity generated by DJ and VDJ joining. The diversity generated by these mechanisms occurs in the _________ region

Errors; frameshifts Hypervariable

At what level of the "central dogma" is VDJ recombination occurring?

DNA; once these segments have been spliced together, they are transcribed into the primary mRNA transcript

The beta chain of the TCR is made first; which chromosome is this chain located on?

Chr 7

On which chromosome would you find the human TCR alpha and delta chain loci?

Chr 14

On which chromosome would you find the human TCR gamma chain locus?

Chr 7

What is the "second type" of combinatorial diversity and when does it take place?

Occurs after both receptor chains have been successfully rearranged, transcribed, and translated The 2 different receptor chains are combined to make the antigen-binding site

In comparing BCRs and TCRs, which one overall has more diversity?

TCR

What is the purpose of adding a surrogate light chain to the completed heavy chain of the BCR prior to continuing its development?

The surrogate light chain allows the surrounding stromal cells to check the structural integrity of the completed heavy chain and determine whether it is able to move forward with development Also prevents further H chain recombination

At what stage in B cell maturation do you have a complete heavy chain and a surrogate light chain?

Pre-B cell

What type of Ig expression would you see on a mature naive B cell?

IgM and IgD

What CD molecules are associated with Pro-B cells?

CD43 CD19 CD10

CD43 is present on stem cells and throughout most of B cell maturation. When does it cease to be expressed on the B cell?

At the immature B cell stage, once the cell has both heavy and light chains

At what stage in B cell development would you have negative selection (deletion), and possible receptor editing?

Immature B cell stage

At what stage in B cell development would you see alternative splicing of VDJC RNA (primary transcript) to form constant mu and delta mRNA?

Mature B cell stage

Once you have your primary mRNA transcript (after VDJ recombination) in BCRs, in what 2 ways can the pre-mRNA be processed?

Bring the VDJ next to the C-mu gene Bring the VDJ next to the C-delta gene The resulting mRNAs have the LVDJ-C__ exons contiguous, and will code for a mu or delta chain

_________ cells assist B cells in developoment and express adhesion molecules and cytokines

Stromal

B-cells and stromal cells interact through what ligand and receptor pair?

VCAM-1 and VLA-4

The initial B cell and stromal cell interaction through VCAM-1 and VLA-4 promotes another interaction between what two factors leading to proliferation?

stem cell factor (SCF) and Kit

Different regions of the thymus are distinguished by the cells present and influence the developmental events of T cells. _________ _______ is the microenvironment for T cell development. _______ _______ = outer cortical region _________= inner cortical region

Thymic stroma Thymic cortex Medulla

When does thymic activity peak in humans?

During puberty; declines thereafter

The immature T cells contained within the thymus are called __________, which are embedded in a network of epithelial cells called thymic ________

Thymocytes | Stroma

What HLA classes are expressed by thymocytes?

Both HLA classes!

The thymus is a primary lymph organ involved in production of mature lymphocytes, not antigen presentation. As such, what is the only route by which progenitor cells enter the thymus and mature T cells leave?

The blood

Pro-T cells leave the bone marrow and enter the thymus to complete their maturation. Where in the thymus are the T cells when they are in the Pro-T and Pre-T stages?

Thymic cortex

Pro-T cells leave the bone marrow and enter the thymus to complete their maturation. Where in the thymus are the T cells when they are in the double positive and single positive stages?

Thymic medulla

What CD markers are found on Stem, Pro-T, and Pre-T cells?

c-kit CD44 CD25

Once the Pre-T cell reaches the double positive stage, its expression changes from c-kit, CD44, and CD25, to what?

CD4+ CD8+ CD3+

At what stage in T cell development do you have positive or negative selection?

Double positive stage

The pre-T cell contains a surrogate alpha chain, what is this chain called?

pT-alpha

At what points during T cell maturation do you have active proliferation?

Between stem and pro-T Between Pre-T and Double positive

How does the double positive T cell select for CD8 or CD4 selection?

The TCR will RANDOMLY interact with either an MHC class I or II molecule

How many estimated clones of B and T lymphocytes exist?

10^7

Selection of B and T lymphocytes involves 2 important checkpoints - what is the first checkpoint?

After heavy or beta chain is created (Pre-B cell)

Selection of B and T lymphocytes involves 2 important checkpoints - what is the second checkpoint?

After the light or alpha chain is added (immature B cell)

True or false: checkpoints ensure that only lymphocytes that have successfully completed Ag receptor gene rearrangement are selected to mature, and eliminates potentially harmful self-reactive lymphocytes

True

Selection deletes or functionally inactivates cells that display antigen receptors that are self-reactive. _________ is acquired by immature B cells that do not become activated when challenged with self-antigen

Tolerance

What happens to an immature B cell in the bone marrow that reacts to a multivalent self-antigen?

Undergoes clonal deletion and apoptosis

What happens to an immature B cell in the bone marrow that reacts to soluble self antigen?

Migrates to periphery and becomes anergic [anergy = unresponsiveness, mechanism of tolerance]

Which type of immune cell can reverse self-reactivity by undergoing receptor editing?

B cells [NOTE T cells cannot do this!]

In what developmental stage are B cells able to undergo receptor editing?

Only occurs in developmentally arrested, immature B cells

How does receptor editing occur in developmentally arrested, immature B cells?

After ligation of IgM with self-antigen, RAG protein synthesis remains on for additional rearrangement of light chain genes. If the new light chain is not reactive with self-antigen, then tolerance is established and the B cell will mature (if it is still self-reactive -- will undergo apoptosis)

_______ ________ in B cells assesses the compatibility of receptors produced from successive gene rearrangements

Receptor editing

Double positive thymocytes exist in the cortex and undergo positive selection, meaning only those cells with TCRs that bind appropriately to MHC molecules on ___________ _________ cells survive

Cortical epithelial

As T cells mature, they migrate from the thymic cortex to the thymic medulla. After undergoing positive selection, they undergo negative selection where they are assessed based on encountering self-peptides on _________ cells in the __________

Dendritic | Medulla

What process in T cell maturation establishes self-restriction and recognition of self MHC?

Positive selection

What process in T cell maturation establishes central self-tolerance, meaning T lymphocytes do not become activated by self-antigen?

Negative selection

True or false: after positive selection, thymocytes are self-MHC restricted, but they may still be able to react to self antigen

True

What would be the result of a CD4+ thymocyte reacting weakly to class II MHC + peptide?

Positive selection

What would be the result of a thymocyte having no recognition of self-MHC + peptide?

Failure of positive selection --> apoptosis (death by neglect)

What would be the result of a CD8+ thymocyte reacting weakly to a class I MHC + peptide?

Positive selection

What would be the result of a thymocyte having strong recognition of either class I or class II MHC + peptide?

Negative selection (apoptosis)

_______ cells are a small population of self-reactive CD4+ T cells that function as peripheral suppressors by inhibiting self-reactive Th1 cells in the periphery

Treg

What are the identifiers present on a Treg cell?

CD3+ CD4+ CD25+

What transcription factor is associated with Treg cells?

FoxP3

What is the purpose of "peripheral tolerance"

Not all self Ags are present in the bone marrow or thymus, so the peripheral mechanism evolved to ensure that the mature B and T cells can be tolerated in the periphery if they encounter self Ag

_________ _________ is the process of gene rearrangement of the lymphocyte receptors and the combinatorial association of the receptor chains during development

Clonal selection

True or false: the clonal selection process is antigen-dependent

FALSE - Clonal selection occurs independent of antigen

Clonal selection ensures that lymphocyte clones expressing all of the possible ____________ are produced during development and ________ simply selects those clones which have the appropriate receptor. The selected clones are then activated, proliferate, and differentiate into lymphocyte ___________ cells.

Specificities Antigen Effector

Immunogenetics Flashcards

(90 cards)