b cell differentiation

Question 1

what are the steps of b cell development, and how is each cell type characterized?

Answer 1

0. lymphoid progenitor: bone marrow
1. pro b cell: bone marrow, no heavy chains
2. pre b cell: bone marrow, cytoplasmic µ (IgM) heavy chains, pre-BCR receptor without rearranged light chains
3. immature b cell: bone marrow, µ heavy chain + rearranged light chain => IgM surface BCR
4. naive b cell: follicle of secondary lymphoid tissue, IgM and IgD surface BCRs

Question 2

what are the components of an antibody?

Answer 2

two light chains (kappa or lambda)

two heavy chains (gamma, mu, epsilon, alpha, or delta)

Question 3

what determines an antibody’s class?

Answer 3

heavy chain constant region (IgM, IgD, IgG, IgE, IgA)

Question 4

what are the components of a BCR and how is it activated?

Answer 4

1. antigen binds to surface IgM or IgD variable region
2. associated proteins IgAlpha and IgBeta (CD79a and 79b) cross link
3. ITAMs are phosphorylated
4. downstream signaling activated

Question 5

what genes/proteins contribute to B cell receptor diversity?

Answer 5

VDJ recombinase (RAG1 and RAG2 genes)

Question 6

combinatorial diversity

Answer 6

recombination of:
V, D, and J for heavy chain
V and J for light chain

germline = V, D, J, constant
D/J recombination => V/DJ recombination => VDJ/constant region recombination

Question 7

junctional diversity

Answer 7

addition/removal of nucleotides at the joining ends of gene segments during recombination; increases diversity => hypervariable regions

Question 8

clonal deletion/central tolerance

Answer 8

removal of immature B cells in the bone marrow with self reactive IgM => apoptosis or receptor editing

Question 9

receptor editing

Answer 9

occurs when a BCR is self reactive:

1. re-expression of VDJ recombinase (RAG genes)
2. V-J recombination is repeated to express the other light chain
3. new heavy/light chain combo should no longer be self reactive

Question 10

b cell anergy

Answer 10

• occurs when a self reactive b cell escapes negative selection in the bone marrow
• if this cell encounters self antigen in the absence of co-stimulation (complement or T cell response) it will become anergic (non-responsive)

Question 11

allelic exclusion

Answer 11

heavy and light chain alleles from both parents are present, but one set of genes is silenced => a b cell expresses only one light chain and one heavy chain gene

Question 12

what are two b cell second signal pathways?

Answer 12

CD21, CD40

Question 13

CD21 b cell second signal

Answer 13

• CD21 (CR2) is a complement receptor expessed with CD19 on the b cell surface
• interacts with C3d (component of C3b) complement protein that is bound to the antigen
• enhances b cell response 1000x

Question 14

CD40 b cell second signal

Answer 14

• after antigen binding, B cell upregulates B7 and CD40
• BCR takes up antigen and expresses antigens on MHC class II to present to CD4+ cells
• CD4+ T cell TCR binds the presented antigen
• CD4+ T cell CD28 binds b cell B7
• CD4+ T cell CD40L binds b cell CD40

Question 15

what happens after b cell antigen binding?

Answer 15

migrates to secondary lymphoid tissues

in the germinal center b cells:

• divide rapidly
• interact with T cells, APCs, and follicular dendritic cells
• undergo isotype switching, somatic hypermutation, and affinity maturation

Question 16

why and how to b cells undergo isotype switching?

Answer 16

• different isotypes are specialized for different protective responses
• in response to cytokines + CD40-CD40L binding, b cells chainge their heavy chain constant region from IgM to IgG, IgA, or IgE
• antigen specificity is not altered

Question 17

what is the role of follicular dendritic cells?

Answer 17

• in the germinal center
• capture complement/antigen complexes on the cell surface
• present antigen complexes to B cells and allow selection for b cells with higher affinity/avidity antibodies

Question 18

affinity maturation

Answer 18

• selection for increased antibody affinity/avidity by FDCs and T cells
• occurs via hypermutation in the germinal center after t cell co-stimulation => random point mutations

Question 19

affinity vs avidity

Answer 19

affinity = how well it binds

avidity = how many antibodies bind at the same time => overall response

Question 20

how do high affinity/avidity b cells mature?

Answer 20

• plasma cells (antibody producing)

- memory b cells (cell surface antibody)