B-cell Development and Antibody Production - Borghesi Flashcards

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1
Q

Where are fetal B-cells derived and how are they different from adult B-cells.

A

Fetal B-cells are derived from hematopoetic stem cells in the fetal liver and mature into B1 cells. They have a limited repertoire (all IgM).

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2
Q

Where are adult B-cells derived and how are they different from fetal B-cells.

A

Adult B-cells are derived from the bone marrow and mature into B2 cells. They have a massively diverse repertoire and are the source of memory unlike fetal B-cells.

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3
Q

What are some of the hallmarks of adaptive immunity?

A
  1. Clonality - Each B-cell produces Ig’s of a unique specificity.
  2. Specificity - Each receptor binds to a unique antigen.
  3. Diversity - Millions of different antigen specificities exist at any given time.
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4
Q

What are the functions of antibodies?

A
  1. Prevents dissemination of pathogen
  2. Inhibit pathogen replication
  3. Activate complement
  4. Bind to Fc receptors on macrophages, DCs, NK cells
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5
Q

Are antigen-antibody interactions covalent or not? Why is this important?

A

Antigen-antibody interactions are non-covalent. This is important because the longer the antigen sits in the binding pocket, the more persistent the signaling.

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6
Q

What are some shared structural features between Igs and TCRs?

A

Igs have a light and heavy chain composing the antigen binding sites, similar to how TCRs have alpha and beta chains composing their antigen binding sites.

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7
Q

What is a key difference between antibodies (Igs) and TCRs?

A

Antibodies can be both membrane-bound and secreted whereas TCRs are only membrane-bound.

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8
Q

VDJ Recombination: Step 1

A

Recombinational Signal Sequence (RSS) in V and J genes are recognized by Rag1/2.

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9
Q

VDJ Recombination: Step 2

A

Rag complex cuts a single strand of DNA, exposing a free 3’ hydroxyl.

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10
Q

VDJ Recombination: Step 3

A

Free 3’ OH introduced by Rag complex attacks the other strand resulting in a complete double stranded break and hairpin formation.

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11
Q

VDJ Recombination: Step 4

A

Artemis enzyme removes the hairpinned DNA.

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12
Q

VDJ Recombination: Step 5

A

TdT (terminal deoxynucleotidyl transferase) adds or deletes non-coded nucleotides, permanently changing the DNA sequence.

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13
Q

VDJ Recombination: Step 6

A

DNA repair enzymes join V segments with J segments. DNA that used to be between these segments form a signal joint and are lost.

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14
Q

Example Question: What would happen in an infant with a null mutation in the Rag gene?

A

No B or T-cell development.

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15
Q

Example Question: What would happen in an infant with partial loss of function in Rag?

A

Autoimmunity due to lack of regulatory B and T cells, therefore no immune dampening.

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16
Q

Example Question: What would happen in an infant with a null mutation in artemis?

A

No B or T-cell development because the DNA during recombination remains hairpinned.

17
Q

B-cell Development: Step 1

A

VDJ recombination of heavy chain and joins surrogate light chain on B-cell surface. A basal signal is transduced back to the cell to indicate successful formation and trafficking of heavy chain.

18
Q

B-cell Development: Step 2

A

After successful heavy chain selection, the light chain undergoes VDJ recombination. The light chain is trafficked to the surface and combined with the heavy chain. A tonic signal is transduced indicating successful joining of heavy and light chain.

19
Q

B-cell Development: Step 3

A

Test for autoreactivity:
1. Strong self-reactive signaling B-cells undergo clonal deletion by apoptosis
2. Weak reactivity to soluble self molecules leads to anergy –> Non-reactive
3. Weak reactivity to membrane-bound molecules leads to receptor editing of the light chain.

20
Q

Allelic Exclusion in B-cell development

A

You have alleles from each parent. If successful recombination occurs with one allele, the expression of the others shuts down to inhibit further rearrangement.

21
Q

Discover of Bregs

A

Clinical trial which used drugs to block either T-cells or B-cells in the context of tissue transplants. Blocking B-cells resulted in high rejection rates indicating that B-cells have an immune dampening role as well.

22
Q

What is the phenotype of Tregs?

A

Foxp3+ (transcription factor), and CD4/CD25 surface markers.

23
Q

What is the phenotype of Bregs?

A

No consensus definition or transcription factors – Many phenotypes

24
Q

What do Bregs do?

A

Rapidly secrete IL-10 to dampen immune responses.