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Molecular mechanisms in immune cell differentiation and function > B cell Development > Flashcards

B cell Development Flashcards

1
Q

Which cells produce antibodies?

A

Plasma cells (B cells)

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2
Q

What is the structure of the antibody?

A

It has 2 heavy chains and 2 light chains, they are held together by disulfide bonds. It has 2 antigen binding sites.

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3
Q

B cells

A
  • They produce antibodies
  • There is a lot of them and each B cell is unique and recognises different antigen
  • Each B cell expresses many copies of B cell receptor (BCR) and each BCR on that cell recognises the same antigen
  • Foetal B cells are made in the liver and after birth they are made in the bone marrow
  • Majority B cells will die but if they engage their target they can differentiate either in plasma cell or memory cell
  • poor control of B cell responses result in autoimmunity
  • defects in antibody production lead to high susceptibility to infection and very early death
  • Naive B cells express shared molecular signatures (CD19, CD20) but they differ in BCR.
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4
Q

What’s the key aim of vaccination?

A

To induce antibody production

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5
Q

Overview of possible life of a B cell

A
  • B cell precursor rearranges its immunoglobulin genes in the bone marrow
  • If immature B cell binds to self antigen it is removed from the repertoire (negative selection in the marrow)
  • Mature B cell if binds its antigen becomes activated, it migrates to the peripheral lymphoid organs
  • Activated B cell give rise to plasma cells and memory cells
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6
Q

How are B cells made?

A
  • B cells arise from stem cells
  • Firstly, rearrangement of heavy chain (firstly D-J then V-DJ)
  • B cell with rearranged heavy chain has a pre-B receptor on their surface
  • Because they don’t have a light chain yet, they use surrogate light chain to check if the heavy chain is functional
  • Now rearrangement of light chain (V-J)
  • Now you have immature B cells with IgM immunoglobulin on the cell surface
  • B cell leaves the bone marrow and finishes its maturation. The mature B cell expresses IgM and IgD on the surface
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7
Q

What RAG genes do?

A

They are expressed on immature T and B cells. They are needed for the rearrangement of TCR and BCR.

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8
Q

What is allelic exclusion?

A

It’s a process to ensure only one allele of the gene is expressed while the other is silenced.
When it comes to BCR rearrangement:
- Rearrangement can happen from either chromosome, but only one at a time. If the gene rearrangement from the first chromosome was successful, it will stop the rearrangement from the other chromosome but if was not successful then the rearrangement from other chromosome happens
- There are 2 light chains kappa and lambda
- 2 kappa genes are used first and then 2 lambda genes (if not successful)
- This ensures that one B cell will produce an antibody of one specificity

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9
Q

What happens if during development B cell recognises self antigen?

A

It gets removed or edited. There is no AIRE in B cell development, so the antigens these B cells during development can encounter are extracellular antigens and not intracellular. Hence, the negative control for B cells is good but not perfect, and many reactive B cells get through, and they recognise dsDNA or other intracellular antigens.

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10
Q

Reasons for B cells to be deleted during development?

A
  • Multivalent self molecule - if antigens are spaced closely to each other and B cell binds multiple BCRs at the same time to multiple antigens, it causes very strong signal, then its deleted or the receptor is edited,
  • Soluble self molecule - strength of the signal is weaker, usually happens in periphery and it leads to cell anergy.
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11
Q

What happens if B cell does not recognise self?

A

It migrates to the periphery and matures to naive B cell

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12
Q

Summary of development

A
  • Pro-B cells - heavy chain gene rearrangement
  • Pre-B cells - light chain gene rearrangement
  • Immature B cells - express surface IgM and exit bone marrow but if strongly binds antigen is eliminated (negative selection)
  • Mature B cells - express IgM and IgD on their surface, reside in the follicles of lymph nodes and the spleen and circulate between different lymph nodes
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13
Q

What type of cells can naive B cells develop into after encountering their antigens?

A
  • plasma cells - secreting antibodies
  • memory B cells - do not secrete antibodies unless antigen is re-encountered
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14
Q

What are different types of antibodies?

A
  • IgM - on the surface of naive B cells, are first to be released when antigen is encountered, pentamer
  • IgD - on the surface of naive B cells, low level in serum
  • IgG - secreted by memory B cells, there are 4 subtypes (IgG1, IgG2, IgG3, IgG4), the most numerous in serum
  • IgE - are on the surface of Mast cells, low number in serum
  • IgA - found in mucosa serum, there are 2 subtypes (IgA1 and IgA2)
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15
Q

Resting/Naive B cell

A
  • High surface Ig as didn’t encounter its antigen yet
  • High expression of MHC class 2 to communicate with CD4 T cells
  • Does not secrete antibodies
  • Growth
  • Somatic hypermutation
  • Isotype switch
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16
Q

Plasma cell

A
  • Low surface Ig as it already encountered its antigen
  • No MHC class 2 expression
  • High rate of Ig secretion
17
Q

What are 2 main pathways for generating antibody responces?

A
  • T-independent antibody responses - extrafollicular, B cells differentiate to become IgM and IgG plasma cells producing antibody of low affinity.
  • T dependent antibody responses - germinal centre responses, selective process to generate plasma cells of high affinity, class switch, leads to production of antibodies and memory B cells.
18
Q

T independent responses

A
  • purified bacterial capsular polysaccharide
  • no involvement of T cells
  • IgM and IgG, low affinity
19
Q

T dependent responses

A
  • Protein
  • Involvement of CD4 T cells
  • IgM, IgG, IgA, IgE, high affinity
  • Memory
20
Q

How do adaptive responses develop?

A
  • DC recognises a foreign antigen, presents it via MHC class 2 to a CD4 T cell,
  • This T cell interacts with the antigen specific B cell
  • This B cell can then migrate to the red pulp of spleen or medulla of lymph nodes to form short-lived plasma cells
  • Or it can migrate to the follicles and germinal centres together with T cell and it produces long-lived plasma cells and memory cells
21
Q

What 2 signals are required for T-dependent antibody responses?

A
  • Direct, physical contact between CD4 T cell and B cell
  • Cytokines (IL-4 and IL-21)
22
Q

What are Tfh cells?

A
  • CD4 T follicular helper cells
  • Essential for the generation of T-dependent antibody responses
  • Recognise peptides through MHC class 2
  • They get activated by DCs, and they recognise signals from MHC class 2 from B cells
  • Co-stimulation of CD40 and CD40L
  • Co-stimulation with cytokines (IL-4 and IL-21)
23
Q

What happens in the absence of CD40/CD40L?

A

Hyper IgM syndrome where patient does not produce productive antibody responses, no class switch, greater risk of infections

24
Q

T independent response

A
  • TI-2 antigens e.g. purified bacterial capsular polysaccharide, which is a multivalent antigen (repeats over and over and over on the surface)
  • not a protein, so no T cell involvement
  • very important for vaccines
  • Responses are rapid and peak within days, no switching to IgG
  • negligible memory and no boosting effect, second vaccine will show slower response rather than faster (hyporesponsiveness)
  • short lived responses, typically around 2 years
  • TI-2 vaccines not effective in infants under 5 years old because of small range of B cells
25
Q

Conjugate vaccines

A

Conjugate purified capsular polysaccharide with a protein to involve T cells in the response and provide memory. These vaccines are effective in infants, create memory and save lives.

26
Q

Germinal centres

A
  • necessary for the production of long-lived plasma cells and memory
  • class switch, high-affinity antibodies
  • B cells need to undergo further recombination of their Ig V genes
  • needs to be regulated to avoid autoimmunity and cancer
27
Q

The process of forming germinal centres

A
  • DCs pick up antigen
  • B cells pick up antigen
  • they travel to the T zone
  • DC activates the T cell
  • T cell interacts with B cell
  • Some T cells and B cells migrate to the follicles and develop germinal centres
28
Q

Players in germinal centres

A
  • Centroblasts - proliferating B cells that undergo somatic mutation - dark zone
  • Centrocytes - B cells that have undergone affinity maturation and are out of cell cycle - light zone
  • Follicular Dendritic Cells - different to dendritic cells, they have antigen in its naive form bound to their surface - light zone
  • Follicular T helper cells - germinal centre T cells which give survival signals to centrocytes after they come out of the dark zone - light zone
29
Q

AID

A

Essential for class switch and IgV hypermutation

30
Q

BCL-6

A

master transcription factor for the commitment of germinal centre B cells and is required for the generation of Tfh cells

31
Q

What are somatic hypermutations and affinity maturation for?

A

To help antibody to increase its affinity. It happens in the germinal centre

32
Q

germinal centre steps

A
  • centroblast undergoes somatic hypermutations in the dark zone
  • centroblasts leave the dark zone and become centrocytes in the light zone
  • centrocytes compete for the antigen presented by follicular dendritic cells
  • the centrocytes with high affinity get survival signals from Tfh cells, the rest die of neglect
  • surviving cells can differentiate into plasma cells and memory B cells

Molecular mechanisms in immune cell differentiation and function (9 decks)

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