Jitt # 3 Lymphocyte Development and Antigen Receptor Gene Rearrangement ( 171 - 176 & 184 - 190) Flashcards Preview

Medical Immunology Bios 443/843 > Jitt # 3 Lymphocyte Development and Antigen Receptor Gene Rearrangement ( 171 - 176 & 184 - 190) > Flashcards

Flashcards in Jitt # 3 Lymphocyte Development and Antigen Receptor Gene Rearrangement ( 171 - 176 & 184 - 190) Deck (31)
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1
Q

What are the five steps in Lymphocyte development?

A

1) Commitment of progenitor cells
2) Proliferation
3) Gene rearrangement
4) Selection events
5) Differentiation of B/T cells

2
Q

What is the progenitor of all lineages of blood cells and lymphocytes? Where are they located?

A

HSCs Hematopoietic stem cells are the progenitors of all blood cells, including lymphocytes. They are located in the fetal liver and bone marrow.

3
Q

What two transcription factors commit developing lymphocytes to the T cell lineage?

A

Notch-1 and GATA-3; Notch-1 is cleaved and intracellular portions migrate to the nucleus which, along with GATA-3 induce genes that cause development of T cells.

4
Q

What are the three transcription factors that help commit developing lymphocytes to the B cell lineage?

A

EBF, E2A, and Pax-5 induce the expression of genes (Rag-1, Rag-2, surrogate light chains, Ig alpha and Ig beta) which are all involved in B-cell development.

5
Q

What is the role of IL-7 in lymphocyte maturation?

A

IL-7, in humans, is responsible for the proliferation of B/T cell progenitors. IL-7 is produced by stromal cells of the bone marrow and epithelial cells of the thymus.

6
Q

X-SCID

A

X-linked severe combined immunodeficiency disease; caused by mutations in the gamma chain, which is a protein shared by receptors for several chemokines (IL-2, IL-7 and IL-15); characterized by a block in T cell and NK cell development.

7
Q

What is the role of IL-15 in development of ILCs?

A

Recall that ILCs are bone marrow derived cells with lymphoid morphology and function to that of T cells, but lack T cell antigen receptors. IL-15 is important for the proliferation and maturation of NK cells.

8
Q

Where are functional receptor genes for B/T cells developed?

A

Bone marrow for B cells, Thymus for T cells by gene rearrangement.

9
Q

What are checkpoints? Why are they important?

A

Checkpoints are steps in lymphocyte development that check for functionality (lymphocyte has complete receptor), non reactivity to self antigens, and to move lymphocytes for maturity

10
Q

pre-BCRs/pre-TCRs

A

Pre antigen receptors are expressed by early lymphocytes. Ig u and TCR beta respectively. This is the first checkpoint. After the first checkpoint, rearrangement occurs again, of the light chains to generate a complete BCR or TCR

11
Q

Positive selection

A

The process by which lymphocytes that are non-pathogenic to self and that have useful receptors are chosen to continue on with maturation.

12
Q

Positive selection for T Cells

A

In the T-Cell lineage, all T cells that recognize self MHC molecules continue on to maturation. (also express coreceptor CD8 or CD4)

13
Q

Negative selection

A

the process that eliminates or alters developing lymphocytes whose antigen receptors bind strongly to self antigens present in the generative lymphoid organs.

14
Q

Receptor editing

A

The process by which self-reactive immature B cells are induced to make further Ig gene rearrangements, thus evading self-reactivity. RAG reactivated and new light chains are generated. If this doesn’t work, then lambda chains are used

15
Q

Clonal deletion

A

The process by which developing T/B cells with high affinity for self are eliminated by apoptosis

16
Q

VDJ recombination

A

V- Variable region; D - Diversity region; J - Joining region. Three segments on chromosomes that are responsible for the generation of diverse receptors on lymphocytes

17
Q

D segments are not found in what type of Ig chain?

A

1) Ig light chains (Both produce recombination with only V/J segments) 2) Ig heavy chains have V regions that are coded by VD&J (also TCR ß)

18
Q

What are the sources of hyper-variability in receptors?

A

1) VDJ recombination (Each letter having different gene selection within itself) 2) variability in the junctional sequences between the V and D segments and the D and J segments 3) Variability in the V and J region and the J segment itself

19
Q

CDR3

A

Complementarity-determining region 3 variability in the junctional sequences between the V and D region and the D and the J region

20
Q

How are the developmental stages of B lymphocytes distinguished from each other?

A

By distinct cell surface markers and a specific pattern of Ig gene expression.

21
Q

Pro- B cell

A

The earliest bone marrow cell committed to B-cell development. Does not express Ig, but is distinguishable by the presence of CD19 and CD10. Rag-1 and Rag-2 are first generated. D/J recombine first, then V joins. Rearrangement occurs at the Ig H locus.

22
Q

Pre-B cells

A

Developing B lineage cells that express the Ig u protein but have yet to rearrange their light chain loci.

23
Q

pre-BCR

A

pre B cell receptor. Made up of u heavy chains associated with lambda 5 and V pre-B proteins (surrogate light chains). (Ig alpha, Ig beta are in mature lymphocytes)

24
Q

BTK

A

Burton’s Tyrosine Kinase. Kinase activated downstream of the pre-BCR receptor. BTK is responsible for the transmission of signals that mediate survival, proliferation, and maturation

25
Q

What is the first checkpoint in B Cell maturation?

A

the expression of pre-BCR

26
Q

XLA

A

X-linked agammaglobulinemia. mutation in the BTK gene. Causes failure of B Cell maturation.

27
Q

What are the two ways that pre-BCR regulates further rearrangement of Ig genes?

A

1) One heavy chain is rearranged, while the other is left in the germ-line configuration, due to signals received by pre-BCR. If neither alleles produce Ig heavy chains, then they cannot generate a pre-BCR-dependent survival signal signal (undergoes apoptosis) 2) Stimulation of k light chain rearrangement/ inactivation of surrogate light chain gene expression.

28
Q

Allelic exclusion

A

The process by which only one allele of a heavy chain is expressed, while another is left constant. This is what causes a B cell to have only one RECEPTOR!!!!!

29
Q

Immature B Cells

A

IgM expressing B cell. IgM is produced when k light chains interact with u chains to produce a complete IgM protein.

30
Q

What happens if the k chain is not rearranged correctly or is self-reactive?

A

the lambda chain becomes rearranged and production of IgM occurs. If both lambda and k chains are non-functional, the cell stops receiving survival signals BCR and undergoes apoptosis.

31
Q

Mature B Cell

A

Co-express IgD and IgM. Production of IgD is associated with functional competence. Are now reactive to antigens.

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