Last updated:
November 12, 2024
- Describe the B cell developmental stages
- Haematopoietic or Pluripotent stem cell (HSC):
- Can divide into any lineage
- Common lymphoid progenitor cell:
- Multipotent, can differentiate into B or T-cell ****
- B progenitor cell (pre-pro-B cell):
- ****Earliest recognizable stage, no heavy chain, no light chain
- Pro-B cell:
- D to J rearrangement (early) and V to DJ rearrangement (Late) of the IgH chain gene via RAG1 and RAG2
- Germline IgL chain gene
- No Ig protein
- IL-3, IL-7, IGF-1, SCF are required for growth
- Express: Pax-5, CD19, HLA-DR, CD34
- Large Pre-B cell:
- V to DJ rearrangement of IgH chain gene
- Germline IgL chain gene
- pre-BCR
- Stage implicated in X-linked (Bruton) agammaglobuliemia
- Small Pre-Bcell:
- VDJ rearranged IgH chain gene, ****
- V to J rearrangement of IgL chain gene,
- Intracellular $\mu$ receptor
- Express: CD79a, CD10, CD20, CD22, TdT
- Immature B cell:
- VDJ rearranged IgH chain gene
- VJ rearranged IgL chain gene
- IgM protein on the cell surface
- Locate in the Bone Marrow (BM)
- Negative selection occurs at this stage
- Express: HLA-DR, CD19, CD20, CD40
- Stops expressing CD10, CD34, RAG1, RAG2, TdT
- Mature naive B cell:
- VDJ rearranged IgH chain gene
- VJ rearranged IgL chain gene
- IgM and IgD on the cell surface
- Located in the spleen and secondary lymphatic organs
- Express: surface IgM, IgD, CD19, CD20
- Antigen-activated B cell (Plasma cells and memory B cells):
- ****Undergoes somatic hypermutation and class switching after antigen exposure
- Long-lived cells from lymph follicles are found in the BM
- Short lived cells are non-follicular
- Express: Bcl-6, Pax, CD19, CD20
- Described as: CD38+, CD138+
- Haematopoietic or Pluripotent stem cell (HSC):
- Briefly describe Positive and Negative selection as it occurs in T-cells
- T-cell precursor: Committed to T-cell lineage, Migrates to the thymus, does not express surface proteins
- Double negative stage (Pre-TCR): Somatic recombination of Beta TCR chain, proliferate, express pre-TCR on surface, express CD3
- Double positive stage: Somatic recombination of alpha TCR chain, Positive selection at cortex, express CD4, CD8, TCR
- Single positive: Migrate to the medulla of thymus, Negative selection against self antigen,
- Mature T-cell: Exit into blood stream and migrate btw peripheral tissue, blood vessels and secondary lymphoid organs, to await peripheral activation, Express TCR, either CD4 or CD8
- Describe negative selection as it occurs in B cells
- Immature B cell stage
- IgH chain genes have already undergone VDJ recombination and the IgL gene has undergone VJ recombination
- IgM is expressed on the cell surface
- If IgM interacts strongly with membrane bound self-antigens (such as those bound on MHC), the B-cell undergoes:
- Apoptosis OR,
- Receptor editing
- This prevents the formation of self-reacting B-cells
- Immature B cell stage
- Briefly describe somatic hypermutation and antibody class switching
- Somatic hypermutation
- Occurs during subsequent antigen exposures to contribute towards affinity maturation, Point mutations that create random alterations in the variable region of the antibody gene, mediated by activation-induced cytosine deaminase (AID) and uracil nucleoside glycosylase (UNG), allows error prone DNA polymerase to introduce mutations
- Isotype (class) switching
- Activated B cells within germinal centres change the antibody isotype in response to cytokines secreted by T-cells, antibody gets different function but same affinity,
- Mediated by switch recombinase
- First signal is by Antigen presentation by MHCII to TCR of Th cell, Secondary costimulatory signal by CD40 and CD40L,
- IL-4 and IL-13 for IgE,
- IL-5, TGFB for IgA,
- IL-6 for IgM,
- IFNy, IL-4, IL-21 for IgG
- Somatic hypermutation
- Outline the clinical applications of B and T cell ontogeny
- Determines antibody response to antigens (T dependent and T-independent response)
- Structural organization of Lymph nodes (Follicles + Germinal centres have B-cells, Cortex mainly composed of T-cell)
- Central tolerance in B and T cells (negative selection)
- Congenital immunodeficiencies involving T and B cells (Bruton’s agammaglobulinemia, DiGeorge syndrome)
- WHO classification of haematological malignancies (AML, ALL, CML, CLL)
- Diagnosis of lymphomas by flow cytometry (B-cell CD10, CD19, CD20; T-cell CD3, CD5, CD7)
Differentiate between somatic recombination and somatic hypermutation
| Somatic recombination | Somatic hypermutation | |
|---|---|---|
| Definition | Random combination of heavy chain gene segments | Random mutations introduced into the gene segments coding for the variable region of T and B cell receptors |
| Stimulus | Antigen presentation to T-cell receptor via MHC + Cytokine production | Antigen binding |
| Affinity maturation | No | Yes |
| Class switching | Yes | No |
- Briefly describe the subsequent stages that follow after immature B cells leave the bone marrow up to antibody generation (write B cell activation in detail)
- Mature naive B cell:
- VDJ rearranged IgH chain gene, VJ rearranged IgL chain gene, IgM and IgD on surface, Located in the spleen and secondary lymphatic organs, Express surface IgM, IgD, CD19, CD20
- B cell activation
- Exposure to antigen or polyclonal mitogens causes activation and proliferation
- T dependent or T-independent activation causes the B-cell to undergo Somatic hypermutaion, Class switching and Affinity maturation
- Memory B cell and Plasma cells are formed
- Interaction (In-detail)
- Plasma cell
- Secrete antibodies
- Long lived from follicles
- short lived cells are non-follicular,
- Express: Bcl-6, Pax-5, CD19, CD20 positive
- Described as CD39, CD138 positive
- Memory B cell
- Identical to resting mature B cell
- More sensitive to antigen stimulation,
- Produce high affinity antibodies and persist for many years
- Mature naive B cell: