9. Lymphocyte Development

Question 1

lymphopoiesis is _____ antigen dependent

Answer 1

self

Question 2

where does lymphopoiesis occur?

Answer 2

primary lymphoid organs

Question 3

what are the three main branches/outcomes of lymphopoiesis?

Answer 3

1. differentiation
2. acquisition of antigen recognition (diversity, clonality, development checkpoints)
3. proliferation

Question 4

antibodies serve different functions at different stages of humoral response….explain how this pertains to membrane bound vs secreted Abs.

Answer 4

membrane bound antibodies on B cells recognize antigens to initiate response

secreted Abs neutralize and eliminate microbes and their toxins in the effector phase of humoral immunity

Question 5

In cell-mediated immunity, the effector function of microbe elimination is mediated by what?

Answer 5

T lymphocytes themselves and by other leukocytes responding to the T cells (the antigen receptors of T cells are involved only in antigen recognition and T cell activation and these proteins are not secreted and do not mediate effector functions)

Question 6

In antibodies, each light chain is attached to one heavy chain, and the two heavy chains are attached to each other - all by what type of bonds?

Answer 6

disulfide

Question 7

how many V and C regions does each light chain have? each heavy chain?

Answer 7

light chain: 1 V and 1 C domains

heavy chain: 1 V and 3-4 C domains

Question 8

which CDR contributes most to antigen binding?

Answer 8

CDR3

Question 9

the two types of light chains, kappa and lambda, differ in which region? The 5 types of heavy chains (mu, delta, gamma, epsilon, alpha) differ in which region?

Answer 9

C region for both

Question 10

the antigen receptors of naive B lymphocytes, which are mature B cells that have not yet encountered antigen, are what isotype?

Answer 10

membrane bound IgM and IgD

Question 11

after stimulation by what do the antigen-specific B cell clones expand and ddifferentiate into progeny that secrete antibodies (some of the progeny of IgM and IgD progeny of the same B cells may produce antibodies of other heavy-chain classes via isotype switching)

Answer 11

antigen and helper T lymphocytes

Question 12

although heavy chain C regions may switch during humoral immune responses, each clone of B cells maintains its specificity how?

Answer 12

V regions do not change

Question 13

the strength with which one antigen-binding surface of an Ab binds to one epitope of an antigen is called what?

Answer 13

the affinity of the interaction (affinity increases with repeated stimulation - ie secondary immune response in affinity maturation)

Question 14

the total strength of binding between antigen and antibody is much greater than the affinity of single antigen-antibody bond and is called what?

Answer 14

avidity of interaction

Question 15

antibodies produced against one antigen may bind other, structurally similar antigens….this binding to similar epitopes is called what?

Answer 15

cross reaction

Question 16

what proteins make up the BCR complex?

Answer 16

membrane bound Ig molecules, Igalpha, IgBeta (when BCR binds antigen, Iga and IgBeta transmit signals to the interior of the B cell that initiate the process of B cell activation)

Question 17

what are myeloma cells and what makes them unique?

Answer 17

tumors of plasma cells and can be propagated indefinitely in tissue culture (but can’t grow in the presence of toxic drug)

Question 18

Fused cells containing both myeloma and normal B cell nuclei do what?

Answer 18

grow in the presence of drug because normal B cells provide missing enzyme…so can grow just these specific cells that don’t die, called hybridomas (can select a specific clonal line to produce monoclonal antibodies)

Question 19

what complex of proteins is associated with TCR to transmit some of the signals that are initiated when the TCR recognizes the antigen?

Answer 19

CD3 and zeta proteins (along with TCR make up the TCR complex)

Question 20

the development of lymphocytes from bone marrow stem cells involves commitment of hematopoietic progenitors to the B and T cell lineage, the ______ of these progenitors, the ________ and expression of antigen receptor genes, and _______events to identify and expand cells that express potentially useful antigen receptors

Answer 20

proliferation, rearrangement, selection

Question 21

______ interactions define T-lineage in the thymus.

Answer 21

Notch receptor-ligand interactions

Question 22

selective induction of ________ define B-lineage in bone marrow.

Answer 22

TFs EBF and Pax5

Question 23

antigen receptors are encoded by several gene segments that are separate from one another in the germline and that do what during lymphocyte maturation?

Answer 23

recombine

Question 24

what receptors are on the surface of proB and preB cells?

Answer 24

CD19+ (but IgM-)

Question 25

chromosome translocations and activating point mutations of ____ are found frequently in T-ALL.

Answer 25

Notch-1

Question 26

chromosome translocations and point mutations that disable ______ are found frequently in B-ALL.

Answer 26

Pax5, EBF

Question 27

in T cell maturation, which TCR chain is rearranged first?

Answer 27

Beta (preT) (then alpha (immature T))....or gamma/delta before any of that on the proT

Question 28

which Ig is rearranged first on B cells?

Answer 28

IgH (D-J on proB and V-DJ on preB)...makes IgM first!....then IgL (kappa or lambda on immature B cells)

Question 29

what enzyme mediates VDJ recombination?

Answer 29

VDJ recombinase (RAG1/RAG2 only expressed in immature B and T lymphocytes

Question 30

where do gamma/delta T cells localize?

Answer 30

epidermise and epithelium as well as other tissues, but very few and relatively unknown functions

Question 31

what makes up the pre-BCR complex?

Answer 31

mu chain, surrogate light chains (no variable domain), Igalpha and IgBeta

Question 32

first checkpoint in B cell development?

Answer 32

- Pre-BCR delivers signals promote the survival and prolif of B lineage cells that have made a productive rearrangement at the IgH locus ○ Selects and expands the pre-B cells that express a functional mu heavy chain (essential component of BCR and pre-BCR) ○ Pre-B cells that make out of frame (nonproductive) rearrangements at the H locus fail to make mu protein, cannot express a pre-BCR or receive pre-BCR signals, and die by apoptosis

Question 33

pre-BCR and allelic exlusion

Answer 33

- Pre-BCR complex also signals to shut off recombination of IgH genes on the second chromosome, because of which each B cell can express an IgH from only one of the two inherited parental alleles ○ Called allelic exclusion and helps ensure that each cell can only express a receptor of a single specificity

Question 34

pre-BCR light chain recombination

Answer 34

- Pre-BCR also triggers recombination at the Igkappa light chain locus (the lambda chain is produced only if the recombined K chain locus fails to express a functional protein or if the K chain generates a potentially harmful self-reactive receptor and has to be eliminated via receptor editing.

Question 35

second checkpoint of B cell maturation

Answer 35

The light chain/mu chain form the complete IgM and delivers signals that promote survival - Preserves cells that express complete antigen receptors and thus is the SECOND CHECKPOINT during B cell maturation - Signals from receptor also shut off production of the recombinase enzyme and furhter recombination at the unrecombinedlight chain loci - So each B cell produces either one kappa or gamma light chain from one of the inherited parental alleles - Presence of 2 sets of light chain genes simply increases the chance of completing successful gene recombination and receptor expression

Question 36

immature B cell is the ____ expressing lymphocyte

Answer 36

IgM

Question 37

what is the final maturation step in B cell maturation?

Answer 37

- Final maturation step involves coexpression of IgD with IgM, which occurs because in any given B cell, the recombined VDJ heavy chain gene exon may be spliced to Cmu exons or Cdelta exons, giving rise to mu or delta mRNA - Ability of B cells to respond to antigens develops together with the coexpression of IgM and IgD, but we don't know why we need both IgM+/IgD+ B cell is the mature B cell - able to respond to antigen in peripheral lymphoid tissues

Question 38

B cell negative selection

Answer 38

- If immature B cell binds a multivalent antigen in the bone marrow w/high affinity, it may reactivate the VDJ recombinase, undergo additional light-chain V-J recombination, generate a different light chain, and thus change the specificity of the antigen receptor = receptor editing - Antigens most often found in bone marrow are self antigens that are abundantly expressed throughout the body - Negative selection may also involve deletion of self-reactive B cell - Therefore, negative selection eliminates potentially dangerous cells that can recognize and react against ubiquitous self antigens

Question 39

AIRE

Answer 39

autoimmune regulator - RF responsible for expression of many (but not all) ectopic self antigens in the thymic medulla

Question 40

autoimmun epolyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED)

Answer 40

human AIRE mutation (so inefficient negative selection and wind up with self-reactive T cells) - endocrinopathy (addison's disease, hypoparathyroidism, hypogonadism, Type I DM, pancreas failure) - mucocutaneous cadidiasis - alopecia, keratitis

Question 41

Foxp3 is required for the developent of which cells?

Answer 41

CD4+CD25+ regulatory T cells mutation: - enteropathy - type I DM - Eczema ``` Mus = x-linked Hs= immune dysfunction polyendorrinopathy enteropathy x-linked syndrome (IPEX) ```