Lecture 1 - B Cell Pathology Flashcards
Stem cell giving rise to all blood cellls
Long-term haematopoietic stem cell
Cell arising from long-term haematopoietic stem cell
Short-term haematopoietic stem cell
From which cell does a short-term haematopoietic stem cell arise?
Long-term haematopoietic stem cell
Cells arising from short-term haematopoietic stem cells
1)
2)
1) Common myeloid progenitor
2) Lymphoid-primed multipotent progenitor
From what cell type do lymphoid-primed multipotent progenitor cells arise?
Short-term haematopoietic stem cells
From what cell type do common myeloid progenitor cells arise?
Short-term haematopoietic stem cells
Which cell type arises from lymphoid-primed multipotent progenitors?
Early lymphoid progenitor
From which cell type do early lymphoid progenitors arise?
Lymphoid-primed multipotent progenitors
Cell types arising from early lymphoid progenitor cells
1)
2)
3)
1) B cell
2) T cell
3) NK cell
Cell types giving rise to B cells 1) 2) 3) 4) 5)
1) Long-term haematopoietic stem cell
2) Short-term haematopoietic stem cell
3) Lymphoid-primed multipotent progenitor
4) Early lymphoid progenitor
5) B cell
Cell types arising from common myeloid progenitor cells
1) Granulocyte myeloid progenitor
2) Myeloid erythroid progenitor
Cell type from which myeloid erythroid progenitor arises
Common myeloid progenitor
Cell type from which granulocyte myeloid progenitor arises
Common myeloid progenitor
Cell types arising from granulocyte myeloid progenitor
1)
2)
3)
1) Granulocyte
2) Eosinophil
3) Macrophage
Cell types arising from myeloid erythroid progenitor
1)
2)
1) Erythrocytes
2) Megakaryocytes
Cell types which give rise to erythrocytes 1) 2) 3) 4) 5)
1) Long-term haematopoietic stem cell
2) Short-term haematopoietic stem cell
3) Common myeloid progenitor
4) Myeloid erythroid progenitor
5) Erythrocyte
Cell types which give rise to macrophages 1) 2) 3) 4) 5)
1) Long-term haematopoietic stem cell
2) Short-term haematopoietic stem cell
3) Common myeloid progenitor OR lymphoid-primed multipotent progenitor
4) Granulocyte myeloid progenitor
5) Macrophage
What is a primary immune disorder?
A disorder of the immune system which is genetic, NOT acquired.
When are most primary immune disorders diagnosed?
Under the age of 1
Examples of combined B and T cell deficiencies
1)
2)
3)
1) Severe combined immunodeficiency disorder
2) Complete DiGeorge syndrome
3) CD40 and CD40L deficiency
Examples of antibody deficiencies
1)
2)
3)
1) CD40 and CD40L deficiencies
2) X-linked agammaglobulinaemia
3) Common variable immunodeficiency
Hyper IgM syndrome
Antibodies cannot undergo isotype switching
Therefore, the only types of circulating antibodies are IgM
What is a severe combined immune deficiency?
Loss of both humoral and cellular immunity
Loss of CD4 T cells
Structure of an antibody
Disulphide-linked dimer of heavy and light chain heterodimers
Number of heavy chain classes
Nine
Types of heavy chain classes
Mu Delta Gamma1, gamma2, gamma3, gamma4 Alpha1, alpha2 Epsillon
Number of heavy-chain constant regions
3 per arm of antibody
Number of heavy chain variable regions
1 per arm of antibody
Number of light chain constant regions
1 per arm of antibody
Number of light chain variable regions
1 per arm of antibody
Order of recombinations in heavy chain
1) DJ
2) VDJ
Order of recombinations in light chain
1) VJ
Which chain type has a diversity region?
Heavy chain
How is diveristy generated in antibodies?
1)
2)
3)
1) Random selection of minigene joining at each locus
2) Independent rearangement at H and L chain loci
3) Imprecision of junctions
Steps in V(D)J recombination
1)
2)
3)
1) Site recognition and cleavage
2) Non-homologous end joining
3) Ligation
Enzymes involved in site recognition and cleavage
1)
2)
3)
1) RAG1
2) RAG2
3) HMG1
Enzymes involved in non-homologous end joining
1)
2)
3)
1) DNA protein kinase catalytic subunit (DNAPKcs)
2) Artemis
3) Ku70 and Ku80
Enzymes involved in ligation
1)
2)
1) Terminal deoxynucleotidyl transferase
2) XRCC4 DNA ligase IV
What does TdT stand for?
Terminal deoxynucleotidyl transferase
What happens during site recognition and DNA cleavage?
1)
2)
1) RAG1/RAG2 complex recognises, binds heptamer-spacer-nonamer sequence, cleaves between RSS and coding sequence
2) Coding ends and signal ends result
What happens to signal ends?
Form a loop of DNA which is excised form the chromosome
Function of Artemis
Makes a nick in DNA hairpins of coding ends
Function of terminal deoxynucleotidyl transferase
Adds random nucleotides to V, D and J exons during recombination
Which cells express RAG1 and RAG2?
T cells and B cells
Which cells express Artemis, DNAPKcs, Ku70, Ku80?
All cells
These enzymes are involved in repair of DNA damage
What is RSS?
Recombination signal sequence
Adjacent to eachminigene segment
Function of recombination signal sequence
Recognised by RAG1/2
Structure of RSS
Heptamer-spacer-nonamer
Spacer can be wither 12 or 23 base pairs long
Function of spacer
length corresponds with either one or two turns of DNA helix
Segment with spacer of 12bp can only join with one of 23bp
Function of RAG
Recombination activating gene
Recognition and cleavage functions
Which cells express terminal deoxynucleotidyl transferase?
Only early B cells and T cells
HMG1
High mobility group 1
Chromatin binding, structural protein required for rearrangement
Not only used in B cell recombination
What does XRCC4 stand for?
X-ray repair complementing defective repair in Chinese hamster cells 4
Function of DNA ligase IV/XRCC4
Joins DNA ends
How are successful Ig gene rearrangements propagated?
B cell development is tied to successful Ig gene rearrangements
Stages of B cell development
1) Pre-pro B
2) Pro B
3) Pre B
4) Pre-BII small
5) Immature IgM+ B cell
What is happening in a pre-pro B?
D-J joining at heavy chain locus
What is happening in a pro-b?
V-DJ joining at heavy chain locus
If successful, progresses to pre B
What is happening in a pre b?
V-J joining at light chain locus
First at kappa, if unsuccessful, at lambda
How many pro b make it to becoming pre b?
1/3
V segment contains AUG start sequence. Must be in frame for correct transcription to occur. 1/3 chance of reading frame being correct
Enzyme necessary for pre-pro b arising from early lymphoid progenitor
E2B
Enzymes necessary for pre-B large to arise from pro b 1) 2) 3) 4)
1) RAG
2) PAX5
3) Syk
4) Igalpha, Igbeta
Enzymes nexessary for pre-B large to give rise to pre-B small
1)
2)
3)
1) BTK
2) BLNK
3) SLC
Function of Iga/b
Scaffolding proteins
Function of Syk and BTK
Kinases
Function of PAX5
Transcription factor that specifies B cell expression program
When is terminal deoxynucleotidyl transferase used?
Heavy chain recombination.
