Lecture 3 B: B-Cell Development Flashcards
The main purpose of lymphocyte development is to develop their _______.
Receptors
What are the 4 goals of B cell development?
To generate diverse receptors
To alter or eliminate self reactive B cells/ B cell receptors
To promote foreign B cell receptors to become mature in the secondary lymphoid organs
Differentiate to Antibody-Secreting plasma cells & memory cells in secondary lymphoid organs
What are the 6 general phases in the life of a B cell?
(what happens)
Repertoire assembly
Negative selection
Positive selection
Searching for infection
Finding infection
Attacking infection
Right Now, Please Send Five Aliens
What occurs during repertoire assembly (phase 1)?
The generation of diverse and clonally expressed b-cell receptors in the bone marrow
What occurs during negative selection (phase 2)?
The attraction, elimination, or inactivation of b-cell receptors that bind to components of the human body
What occurs during positive selection (phase 3)?
A fraction of immature B cells are promoted to the secondary lymphoid tissues to become mature B cells
What occurs during phase 4 (searching for infection)?
Mature B cells continuously circulate through lymph, blood, and secondary lymphoid tissues.
What occurs during phase 5 (finding infection)?
Pathogen-derived antigens in secondary lymphoid tissues are found, and activate B cells and clonal expansion occurs.
What occurs during phase 6 (attacking infection)?
B cells are differentiated into either antibody-secreting plasma cells or memory B cells in the secondary lymphoid tissue.
Bone marrow is a ____ lymphoid tissue.
primary
Hematopoietic stem cell matures into a _____.
Common lymphocyte progenitor
All immune cells originate from ______.
Pluripotent hematopoietic stem cells
What do stromal cells provide developing B cells?
- Adhesion molecules for attachment
- Growth factors like Interleukin 7 for growth and proliferation
How many B cells are generated each day, and what percentage survives?
Tens of billions; 50% survive
B cell receptor (BCR) is also known as ______, or ________.
Immunoglobulin (IG), fixed antibody
What are the 5 types of proteins that are secreted?
Mu, delta, gamma, epsilon, alpha
My Dead Goldfish Eats Air
Epsom salt bath at salon (epsilon)
What are the cell developmental stages in the bone marrow?
- Common lymphoid progenitor
- Early Pro-B cell
- Late Pro-B cell
- Large Pre- B
- Small Pre-B cell
- Immature B cell
C.E.L.L.S. I
What are the two types of protein chains of a B cell?
Heavy (H) and Light (L)
The heavy chain determines the _________ class (the antibody cell will secrete) the receptor becomes.
immunoglobin class (IgM, IgD, IgA, IgG, IgE)
What are the 3 protein segments of the antigen binding site?
V (variable)
D (diversity)
J (joining)
The region where the H and L chains come together forms a unique protein structure called the ________.
It is capable of binding lipids, carbohydrates, and other things the B cell may encounter.
antigen binding site.
What is specificity?
The ability to discriminate between closely related molecules.
What is shuffled to make unique protein structures?
the VDJ genes
For the heavy chain, how many of each gene segment does each person have?
V-gene: 44
D-gene: 27
J-gene: 6
6 Jaguars ate #2 7-course Dinners, and went Very fast at 44 mph
Each B cell has ____BCR (B cell receptor), ____ AA sequence at the CDR → specific antigen
one, one
By which method do B and T cells sense antigens?
Lymphocyte antigen receptors (Immunoglobulin & T cell receptors)
How are lymphocytes able to bind antigens?
Through receptor molecules
What is the specificity of a receptor determined by?
The shape of the variable region (V-gene) of the receptor
When does the genetic rearrangement in a lymphocyte take place?
When the lymphocytes generated from stem cells first become functional
early pro-B cell
How many types of receptors can each mature lymphocyte make?
one type
What does a hematopoietic stem cell mature into?
A common lymphoid progenitor cell
What does the common progenitor cell mature into in the bone marrow?
An immature B cell
Once an immature B cell matures, it differentiates into either a ___ or ___, located in the ___ and ___.
antibody-secreting cell/memory cell; plasma cell
lymph nodes; spleen
What is the immature form of a T cell called?
thymocyte
All immune cells originate from _____ _____ _____ ___.
pluripotent hematopoietic stem cells
The pluripotent hematopoietic stem cells give rise to what two types of cells?
The common myeloid precursor cell and the common lymphoid precursor cell
What are multipotent mesenchymal stem cells that can differentiate into many cell types, like macrophages and epithelial cells?
Stromal cells
The heavy chain has ____ segments, while the light chain only has ____ segments.
V, D, and J; only V and J
What makes a unique protein structure?
The shuffling of the VDJ genes
How is the variable portion of the heavy chain (VH) formed?
By 👀 random selection of one
V coding segment, one D coding segment and one J coding segment
How is the variable portion of the light chain (LV) formed?
By 👀 random selection of one
V coding segment and one J coding segment, but no D coding segment
How are DNA segments brought together when forming antibody variable portions?
By looping out ✂(cutting) portions of the DNA and then recombining the remaining DNA
Which enzymes are responsible for cutting and splicing the DNA to form the variable domains which will become the antigen binding site of the antibody?
Recombinase enzyme complex
*Hint..Re-combine enzymes. Their function is in their name.
When is the recombinase enzyme produced?
When the pre-B and pre-T cells express the Recombination Activating Genes (RAG 1 & RAG 2)
Pre- B and T cells wave RAGS in the air to get the enzyme’s attention
What does a deficiency of RAG genes cause?
Severe Combined Immunodeficiency or Omenn syndrome
SCIDS, oldmen syndrome
What sends the signals to the nucleus to start proliferation of small late pre-B cells?
Ig-alpha and Ig-beta molecules
What are the 2 light chain types?
Kappa and Lambda
When is a B cell not functional?
When it is self-reacting
Which light chain variant does each small B-cell start with?
Kappa
What happens if the light chain variant does not bind well?
It will try again, tries a different arrangement, or dies
What is the order of Ig in the germline DNA?
Ig-M, D, G, E A
My dead goldfish eats air
What is the first coding segment for the constant region of the heavy chain ?
Cµ ♥
What is somatic hypermutation mediated by?
T-cells
What is affinity maturation?
an immune system process that produces antibodies that are better able to fight pathogens
Antibody produced _______ has a lower affinity than an antibody produced _______.
first; later
If the VDJ region of DNA has many mutations, it results in ______ affinity. These will undergo _____.
lower ; apoptosis
If the VDJ region of DNA has fewer mutations, it results in ______ affinity. How are they stimulated?
higher; preferentially stimulated
The tighter the binding, the more ____, which leads to _____, and more ______.
stimulation; mitosis; clones.
Plasma cells from high affinity binding BCR secrete what?
high affinity antibodies
What Ig is required for a mature B cell to leave the bone marrow?
mIgM + mIgD
*Mom and Dad
What are the various isotypes of the memory B cells?
IgG, IgA, IgE
*Goldfish eats air
Why is it important for a B cell with a self-reactive receptor to be prevented?
1) they may not be functional
2) may attack self-tissues and cause diseases 😷☠ (auto immune disorders)
What is expressed by the primary lymphoid organ (bone marrow) to identify self-reactive immature B cells?
AIRE, autoimmune regulator gene
Regular guy named Gene
Explain how receptor editing can save small pre-B cells with self-antigen receptors?
They bind intermediately to the self-antigen and the receptor genes are rearranged to reduce the strength of the binding to self antigen. If successful, it can be a B-Cell; if not, it must die by apoptosis.
What is clonal deletion?
deletion of B-cells that react to themselves
What is ignorance?
self-specific B cells have some self proteins, but it is not enough to trigger autoimmunity
What is anergy?
the biochemical inactivation of self-specific B cells.
What are the 3 major checkpoints to ensure that recombined B-cell receptors are non-autoreactive?
- Small pre B-cell BCR
- negative selection of immature B-cells in the bone marrow
- negative selection of transitional B cells in the spleen.
Negative selection of immature B-cells in the bone marrow establishes _______ tolerance.
central
Negative selection of transitional B cells in spleen establishes _______ tolerance.
peripheral
When a B cell finds an Ag (antigen), it undergoes _______ and needs the help of __ cells.
mitosis; T-cells
What is the only type of immunoglobulin that covers the surface of immature B cells?
IgM
What do follicular dendritic cells use to trap antigens?
Fc and C3b (CR1) receptors
B cells also recognize the antigens on ________ ________ cells, by looking at their Fc and C3b receptors
follicular dendritic cells
If a T cell finds an antigen, it undergoes ______ and requires the help of __ cells.
mitosis; B cells
A mature B cell that has antigen specificity has which 2 BCRs on its surface?
IgM and IgD
What signals class switching in a B cell after an antigen has been met?
The mixture of cytokines in the environment, and signals from T helper cells.
What is the most abundant antibody isotype in mucosal secretions?
IgA
What is class switching?
After activation of a mature B cell via its membrane-bound antibody molecule (BCR), a B cell’s antibody (isotype) production changes from one class to another, and DNA recombination occurs to remove the portions that code for the antibody that will no longer be produced.
Does the DNA for a previous antibody that was produced get removed from the cell after a class switch?
No. Everything is still there, so if the cell needs to switch back to the previous antibody, it has the DNA.
What is the function of the transmembrane portion in a B cell?
It secures the Ig (BCR) in the B cell membrane.
Why do plasma cells make Ig without a transmembrane portion?
So the immunoglobulin can be secreted and is not bound to the membrane.
What are the two forms of immunoglobulin?
secreted and membrane bound.
What does RAG stand for?
Recombinase Activating Gene
What is somatic hypermutation?
When an enzyme makes many random mutations in the antibody variable region of the receptors due to new foreign elements being encountered. Results in affinity maturation.
result-lower affinity = apoptosis, result-higher affinity = selected
What does AIRE stand for?
Autoimmune regulator gene
What does CDR stand for?
Complementarity determining region
What does AID stand for?
Activation-induced cytidine deaminase
Ahh! Ingested Cyanide; Death (first AID will not help)
At what stage of B cell development does rearrangement of the light chain and negative selection occur?
The small pre-B cell stage
