MCM 2-11 B-Cell Immunity

Question 1

steps of B cell development

Answer 1

1. stem cell develops into early pro-b cell
2. rearrange D and J loci of its heavy chain on both chromosomes
3. successful - becomes late pro-b cell and begins rearranging its DJ locus with V loci on first chromosome, unsuccessful, will begin rearranging other chromosome
   4, successful - will produce a pre-BCR (with productive heavy and surrogate light) which will signal its success and allow it to become a large pre-B cell
4. large pre-B cell will rearrange the loci of its light chain genes on both chromosomes (one kappa gene and one lambda gene on each chromsome
5. becomes small pre-b cell, will start by rearranging loci of kappa gene on first, then move to second kappa if fails
6. if either produces productive light chain, will become immature B expressing mu (heavy) and kappa
7. if both fail, will go on to lambda, if either successful, expresses mu and lambda as immature B cell
8. result of the light chain rearrangements is a cell wiht a functional IgM (B cell receptor)

having multiple genes to rearrange developing B cells more chances to produce a productive IgM and avoid apoptosis

Question 2

what eliminates self reactive B-cells?

Answer 2

central tolerance - if immature B reacts with membrane bound self-antigen it will be retained in bone marrow and eventually die. If it does not react with membrane bound self antigen, it will leave bone marrow.

peripheral tolerance - if an immature b cell outside of bone marrow interacts with free floating soluble self antigen, it will be signaled to produce IgD and no functional IgM and to become unresponsive to antigen.
-This inactive state is referred to as anergy. Anergic B cells enter the peripheral circulation and die soon afterwards.

Question 3

describe how receptor editing can rescue self-reactive b cells

Answer 3

if a membrane bound self antigen in bone marrow ligates an immature B-cells IgM, it will undergo receptor editing.

it will rearrange light chain genes to produce new IgM with a different specificity. If self-reactive, will continue until it creates an IgM that is not self reactive or dies.

If and when it creates a non self-reactive IgM, the b-cell will leave the bone marrow

Question 4

Describe B cell receptor and co-receptor

Answer 4

Receptor - composed of a mu heavy chain and either a kappa or lambda light chain

Co-receptor - assists in antigen recognition and signaling. They are made up of CD19, a complement receptor CR2, and CD81

Question 5

describe the process involving the final maturation of B-cells

Answer 5

Naiive b-cells (having passed both central and peripheral tolerance tests aka negative selection) are attracted to the lymph node and primary follicle through a series of chemokines.

Naiive B-cells will search for a specific antigen displaced on the FDC within the primary follicle “B-Cell Area”. Naiive T-cells search for specific antigen presented by classical dendrites in the T-cell area

Antigen activated T-cells proliferate and differentiate
Antigen activated B-cells move to boundary region and present antigen on their MHCII molecules to the CD4 T-cells forming cognate pairs.

The helper T-cell conjugates with the B-cell, begins expressed CD40 ligand (critical for activation of other cells) and synthesized cytokines (to let the B-cells know to switch properly and give the correct type of response to that antigen). The T-cell reorients cytoskeleton towards the b-cell, secretes cytokines which drives B-cell diversification/class switching.

antigen-activated b-cells will either move to medullary cords (primarily) or the primary follicle to generate the germinal center (area that promotes receptor class switching and somatic hypermutation)

in germinal center, the b cells that will bind antigen, interact with T-cells, survive, and divide will be ones with highest affinity BCR’s.

B cells with lower affinity BCRs will be outcompeted and die.

this is how high affinity b-cells are selected for. The end results are high-affinity b-cells that have differentiated into memory or plasma cells.

Question 6

describe t-cell independent b-cell stimulation by antigen

Answer 6

highly cross-linking, repetitive antigens can stimulate B-cells independent of T-Cell assistance. After an antigen cross links B-cell receptors, a signalling cascade is induced that leads to changes in gene expression in molecules.

Question 7

describe the properties of memory B cell

Answer 7

relatively rare, resting, long-lived cells.

typically class switched cells that produce high-affinity antibodies following secondary infection.

they express IgG or IgA

Question 8

describe B1 cells

Answer 8

B1 - more primitive, produced early in fetus, not much TDT, there for first line of defense, produce natural antibodies even though no pathogen has been seen. Self renew, don’t need to come from bone marrow, T-cell independant, no memory

almost all IgM

Question 9

Describe B2 cells

Answer 9

derived after birth, more variability, replaced from bone marrow, Mostly IgG. high somatic hypermutation, can develope into memory cells

Question 10

what are the options for dealing with a faulty b cell?

Answer 10

kill the cell, change its receptor, or render it anargic with the soluble self-antigens it binds to and then dies

Question 11

______ brings antigen and b-cells together

Answer 11

lymph

Question 12

describe how Tcells help drive B cell proliferation and differentiation

Answer 12

antigen recognition by T-cell induces expression of effector molecules by T-cell, which act on and activate the B-cell

the b-cell proliferates, and differntiates into resting memory cells and antibody secreting plasma cells

Question 13

describe how naiive B cells and T cells find each other

Answer 13

naive b cells search for specific antigen displayed by follicular dendritic cell in the b-cell area; naive t-cells search for specific antigen presented by classical dendritic cells in the T-cell area (Surface)

antigen activated t-cells proliferate and differentiate, antigen activated b-cells move to boundary region

antigen-activated b cells present antigen to effector (Tfh) cells, forming cognate interactions and cognate pairs

Question 14

what occurs in the germinal center?

Answer 14

final maturation of high affinity B-cells occurs. they interact with t-cells and FCD’s

Question 15

describe plasma cells

Answer 15

sit in bone marrow, antibody factories

lose surface Ig, no longer looking for antigen. don’t need to grow or switch or interact iwth T-cells

Question 16

what is the output of the germinal center?

Answer 16

somatic hypermutation and survival of the fittest generates high-affinity memory and plasma cells

Question 17

Describe the process that occurs when a naiive B-cell enters a lymph node

Answer 17

Naïve B cells are exposed to specific antigen on the surface of a follicular dendritic cell (FDC) in the B-cell area of a secondary lymph tissue, while naïve T cells are exposed to specific antigen on the surface of an FDC in the T-cell area of a secondary lymph tissue. Antigen-bound B cells move to the boundary region, whereas T-cells become activated by antigen and differentiate. B cells present their antigens on MHC II molecules to CD4 T cells. The T cell (helper TFH) will conjugate with the B cell, beginning to synthesize cytokines and CD40 ligand (which is critical to the ability of CD4 T cells to activate other cells). It will then reorient its cytoskeleton towards the B cell, and secrete cytokines into the narrow space between the cells. The particular cytokines secreted will drive B cell diversification (i.e. class switching of the B cell). The antigen-activated B cells will then either move to the medullary cords (primarily) or the primary follicle (secondarily) to create the germinal center. The germinal center promotes receptor class switching and somatic hypermutation. In the germinal center, the B cells that will bind antigen, interact with T cells, survive, and divide will be the ones with the highest-affinity BCR’s; B cells with lower-affinity BCR’s will be outcompeted by those with higher-affinity BCR’s and die. This is how high-affinity B cells are selected for. The end results are high-affinity B cells that have differentiated into memory cells or plasma cells.