B cell development & Ab maturation (1/3)

Question 1

What are teh 2 locations that B cells develop?

Answer 1

Marrow and lymph nodes (including spleen)

Question 2

What is allelic exclusion?

Answer 2

That one B cell expresses only one antibody

Question 3

How is immunological tolerance generated

Answer 3

By deleting self-reactive clones

Question 4

What is the order of rearrangement of Ig genes during B cell development in the marrow?

Answer 4

First, heavy chain arrangement occurs

Then the light chain develops

Question 5

What occurs during heavy chain rearrangement?

Answer 5

First, VDJ recombination creates a variable region

If it’s a funcitonal heavy chain (no stop codons, frame is ok), it’s expressed with a surrogate light chain

Signals tell the cell that it has a functional heavy chain

1/9 generate a functional heavy chian; it’s a limiting step

Question 6

What is a pre B cell receptor?

Answer 6

Proteins that resemble a light chain

includes membrane lambda 5 (like a constant region) & VpreB(similar to variable region), two proteins that bind miu heavy chains in a way that mimics a light chain

Question 8

Once the the heavy chain has done VDJ rearrangement & assembled a preBCR, then what happens?

Answer 8

Heavy chain rearrangement stops & light chain rearrangement begins

Question 9

How many light chain recombinations occurs?

Answer 9

There are three VJ recombinations in the light chain at the same locus (can lead to rescue of nonproductive rearrangements)

There is a higher chance of generating a funcitonal light chain: 1/3 (as compared to 1/9 for making heavy chain)

Question 10

How many checkpoints are there for B cells? When do they occur?

Answer 10

2 checkpoints: one at the pre B cell receptor before light chain rearrangement. A second at the end after light chain rearrangement (BCR)

Question 11

How is regulation at these checkpoints accomplished?

Answer 11

Changes in levels of proteins involved in rearranging the Ig genes i.e. RAG 1/2 expression is reduced, access of the HC locus to the recombinase machinery is reduced

There’s also testing of the quality of Ig chains

Question 12

What is the BTK gene?

Answer 12

It’s downstream of the BCR and is required for B cell development

Question 13

What are the 2 types of B cell tolerance and where do they develop?

Answer 13

Central tolerance: to self antigens. Occurs in lymphocytes in central lymphoid organs i.e. marrow. Clonal deletion is the main mechanism (cell death)

Peripheral tolerance: to self antigens. Occurs in lymphocyt4es in the peripheral tissues i.e. spleen/lymph nodes. Clonal deletion, anergy (nonresponsive to signals), and clonal ignorance (cells don’t die)

Question 14

What is the GC reaction?

Answer 14

Germinal center reaction: antigen-dependent B cell development

3 main steps:

1. T cell dependent activation of antigen specific naive B cells (the precursor cells of GC rxn)
2. Somatic hypermutation & Ig class switch –> high-affinity antigen-specific B cells with specialized effector functions
3. Differentiation of antigen-selected GC B cells into memory B cells & plama cells, the carriers of antibody-dependent immunity

Question 15

What 3 processes occur in 3 specific compartments of the GC?

Answer 15

1. T cell zone = T-cell dependent activation
2. GC dark zone = somatic hypermutaiton (SHM) & proliferation
3. GC light zone = class switch recombination (CSR) & memory cell/plasma cell differentiation & selection for high-affinity B cell clones/against newly generated self-reactive B cell clones

Question 16

What is somatic hypermutation (SHM)?

Answer 16

random mutagenesis, mostly single bp changes

limited to V(D)J regions (not C)

hypermutation is 10^6 more than normal mutation rate

Occurs only in mature, antigen-activated B cells

Combined with selection, results in clones making Ab’s with increased affinity for antigen (affinity maturation), particularly prominent in memory immunizations

Question 17

What is class switch recombination? (CSR)

Answer 17

A DNA rearrangement that allows the same VDJ to be expressed with different heavy chain constant regions

Allows you to have a particular V region but a different effect/use of it

Question 18

What are the two mechanisms of CSR’s?

Answer 18

1. RNA processing: IgM to IgD
2. DNA rearrangement: IgM to IgG, IgA, or IgE

Question 19

What are the 2 differentiated B cell states that result following the GC reaction?

Answer 19

Memory B cell: no Ig secretion, but rapid response to renewed Ag encounter w/high affinity & switched isotypes. Circulate b/w lymphoid tissues through the blood

Plasma cell: Ig secretion of high affinity and switched isotypes; home to the bone marrow

Question 20

What is X-linked agammaglobulinemia?

Answer 20

A human immunodeficiency syndrome caused by loss of Btk tyrosine kinase –> no B cells

Pt’s are susceptible to extracellular bacteria & viruses

Question 21

What is hyper IgM syndrome?

Answer 21

Human Immunodeficiency syndrome caused by deficiency of: AID, CD40 ligand, CD40, or NEMO (IKK). Result is no isotope switching and/or no somatic hypermutation. Susceptible to extracellular bacteria, pneumocystis carinii, and cryptosporidium parvum

Question 22

What is common variable immunodeficiency?

Answer 22

A human immunodeficiency syndrome caused by ICOS deficiency. It causes defective IgA and IgG production & leaves patients susceptible to extracellular bacteria

Question 23

What causes most B cell lymphomas?

Answer 23

Most derive from GC somatic mutations. You can tell because the cancer cells have undergone the class switch. Many GC-derived lymphomas are characterized by reciprocal balanced chromosome translocations i.e. follicular lymphoma is due to t(14;18) and affects the BCL2 gene