Day 4 Lymphocyte Development, Movement, Receptors Diversity and Central Tolerance

Adaptive immune responses are mediated by the activities of ______________

lymphocytes

Lymphocyte targeting to new locations is mediated by

expression of cell surface adhesion proteins that correspond to endothelial surface receptors of the target organ

Antigens initially encountered ________ create more common responses.

locally

Immature lymphocyte precursors derive from ___________________ replicating in ____________.

pluripotent stem cells, bone marrow

Primary organs develop....

early in fetal life

Destruction of lymphoif organs causes what?

loss of lymphocytes and their functions

What are the primary lymphoid organs?

thymus, bursa of fabricius (birds), ileocecal Peyer's patches (pigs, ruminants), bone marrow

The foreign antigen-independent phase is two fold and occurs via:

generation of diversity, central tolerance to self antigens

Every lymphocyte has thousands of identical receptors on the surface. True/False

True

Each receptor on the same cell has the _________ antigen binding specificity, that is different from those of other lymphocytes.

same

What happens to developing lymphocytes that bind self-antifens?

undergo apoptosis

Where does gene segment rearrangement and receptor diversity generation take place?

primary lymphoid organs

Immature T or B cells have antigen-sensitive surface receptors. True/False

False

What is the first event of an immature t or b cell?

express antigen-binding receptor genes

What is TCR?

T cell receptor

What is BCR?

B cell receptor

What happens in order to generate antigen-binding diversity of TCR or BCR?

random reorganization of genes that encode antigen-binding sites

What is a hazard of randomness that has the potential to create billions of different antigen-binding specificities?

new receptor may bind strongly to a self-epitope

Removal of one or a few secondary lymphoid organs has little effect on immune responses. True/False

True

Where is the site of foreign antigen dependent differentiation?

secondary lymphoid organs

The secondary lymphoid tissues are populate by all cell types required to initiate specific adaptive responses. True/False

True

In secondary lymphoid organs, are many mature T and B cells specific for any one encountered antigen?

no

Only cells that have __________ or ________ bind strongly to an antigen to undergo clonal selection.

TCR or BCR

Activated B cell clones differentiate further to secrete what?

antigen specific antibodies

Activated T cell clones differentiate further to secrete what?

cytokines (T helper cells) or kill host cells that display foreign antigens (cytolytic T cells)

What does clonal selection ensure?

responses that are best suited for specific antigen elimination

Positive and negative selection in the thymus is important in what?

prevention of autoimmunity

B cell gene segment rearrangement is important for what?

generation of antibody diversity

The animal body can generate at least an antibody for every antigen in the universe. True/False

true

Avidity of antibodies is determined by what?

sum of non-covalent interactions

How does the immune system recognize a vast array of known and unknown antigen?

variable domains, limited number of genes encode large number of antigen binding sites

What are the steps of the DNA blueprint?

assemble gene, synthesize peptide chains, transcription, peptide chain assembly, expression of peptide chains

What are the peptide chains that can be expressed from the DNA blueprint?

TCR/BCR, antibodies, MHC 1 or 2

What are gene clusters?

multiple gene segments that encode for domains

What are gene complexes?

cluster of related genes occupying a restricted area of a chromosome

What are exons?

coding regions that are expressed

What are introns?

non-coding regions that are not expressed

What are promoters?

short sequences that allow expression of coding region to begin

What are enhancers?

sequences that can increase expression of coding regions

Where do enhancers occur?

light chain genes

What are the three BCR gene clusters?

IGK/kappa light chain, IGL/lambda light chain, IGH/heavy chain

Where are the BCR gene clusters found?

on separate chromosomes

What is 'V" of BCR gene clusters?

variable region

What is 'C" of BCR gene clusters?

constant region

What is the "J" of BCR gene clusters?

joining region

What is the "D" of BCR gene clusters?

diversity region

The affinity of immunoglobins produced by stimulated B cells increases after B cells are activated. This fine tuning of the antibody/antigen affinity is accomplished by:

somatic hypermutation

What are the ways in which to create receptor diversity?

germline diversity, combinatorial diversity, junctional diversity

What is germline diversity?

multiple copies of V, D, J, gene segments

What is combinatorial diversity?

VJ and VDJ gene segments can recombine in multiple combinations

What is junctional diversity?

junction between gene segments

What genes constitutes the IGH cluster in BCR genes?

V, J, D, Cu, Cgamma, Calpha, Cepsilon

What are some ways to create receptor diversity?

multiple combinations of light and heavy chains, somatic hypermutation, affinity maturation

BCR diversity varies by...

species

Is there somatic mutation in TCR diversity?

no

What does 'looping out' accomplish?

discards introns and may place promoter near an enhancer

The immunoglobulin light chain consists of genetic recombination of what genes?

V and J

In the immunoglobulin light chain, recombination is joined with the c gene as what?

mRNA splice

What does the D region presence on immunoglobulin heavy chain mean?

more rearrangement that increases variability

B cells may rearrange genes when in a...

germinal center

T cells may utilize what process continually?

editing or receptor editing

What is the significance of TdT in BCR diversity?

adds short sequences or single nucleotides

What do endonucleases remove?

endonucleotides

Somatic mutation is _______ ___________ in individual cell DNA.

point mutation

What converts cytosine to uracil?

cytosine deaminase

When does cytosine deaminase conversion occur?

after class switch from IgM

What is unique about gene conversion in chickens?

only one V gene for light/heavy chains, pseudogenes, in bursa

What is unique about gene conversion in rabbits?

only one V gene for light/heavy chains, occurs in appendix, need microbes for selection

Where does gene conversion occur in ruminants?

heavy chains

Where does gene recombination occur in ruminants?

light chain

Where is BCR/Ig variation generated?

delete and splicing, pseudogenes delete self-reactive cells, somatic mutation

Where does gene recombination typically occur?

bone marrow

Where does gene conversion and cell selection typically occur?

bursal equivalent

Where does gene conversion or somatic mutation usually occur?

lymph node germinal center

What is the summary of the antibody diversity generation?

germline heavy and light chain gene segments, VDJ recombination transcription and translation, chain polypeptides, immunoglobulin assembly

In TCR diversity, first attempts in development are for...

gamma/delta

In TCR diversity, if first attempts in development are not productive, what results?

alpha/beta

What is another theory that explains TCR diversity other than first attempt?

2 separate cell lines that independently express these receptors

There are ____ TCR gene clusters that are found on separate chromosomes.

3

What types of chains exist for T cells?

alpha/beta and delta/gamma chains

What is the main difference between MHC molecule and the BCR and the T cell receptor?

diversity of MHC genes enables the presentation of more peptides to T cells

How many forms (specificity) of immunoglobulin and TCR can be expressed can be expressed on the same cell surface?

one

How many forms (specificity) of MHC can be expressed on the same cell surface?

more than one

The presentation of more peptides to T cells by MHC genes means what?

less likely that the pathogen can express epitopes that won't be found by the MHC molecules

IgG can cross placenta in many animal species. True/False

True

What is the progenitor stage?

early differentiation

What is the immature stage?

precursor cells undergo selection

What is the mature stage?

fully functional lymphocytes ready for activation

What is chemotaxis?

lymphocyte movement toward chemical signals (chemokines)

What is V(D)J recombination?

process by which B and T cell receptors generate diversity

Hematopoiesis

blood cell formation

Thymocyte

immature t cell in the thymus

Chemokines

signaling proteins that direct lymphocyte movement

Autoimmunity

immune response against the body's own cells

What is the main site of hematopoeisis?

bone marrow