What are the two major phases in B cell development and what takes place in each?
Ag-independent phase: takes place in bone marrow (fetal liver or spleen). Ig gene rearrangement is completed
Ag-dependent phase: upon recognition of Ag (in the periphery or a secondary lymphoid tissue), B cell:
- proliferates
- becomes memory cell OR plasma cell (with the help of T cells)
- class switches
What happens when a newly formed Ig binds to a self antigen?
The Ig will undergo further rearrangement of the V region genes called receptor editing. If the newly arranged Ig still binds to the self-antigen, and there are no more potential rearrangements (no more possible light chain editing), the cell will die.
Once the IgH and IgL bind, there can be no further rearrangement of IgH (allelic exclusion)
How can B cell lymphoma develop?
Ig promotors and enhancers are constitutively ON in mature B cells because they want to continually develop Igs. If an oncogene is placed near the Ig promotors or enhancers, it too will be constitutively ON, leading to the development of cancer
This is seen when the c-myc gene is translocated to be next to an Ig enhancer (IgH or IgL) in B cell lymphoma (Burkitt’s lymphoma) –> over proliferation of the B cells.
What are the two classes of antigens that B cells can respond to?
thymus-dependent antigens are when B cells need T cell help to become stimulated (via cytokines and co-stimulation). -B cells can make memory B cells or class switch
Thymus-independent antigens can be either TI-1 (bacterial cell wall components—> LPS, or mitogens) or TI-2 (polysaccharides)
In the Ag-dependent phase, what signals are needed to produce B cell activation?
signal # 1. B cell must interact with its antigen. the membrane Ig needs to be cross-linked on the B cell surface (the B cell must interact with multiple copies of the antigen). Ig alpha and beta phosphorylate their ITAM regions (immunoreceptor tyrosine-based activation motif) and send a signal internally to the nucleus to cause changes in gene expression.
signal #2. Interaction between CD40 (signaling molecule of the B cell) and CD40L (CD154) on the Th cell. (T cell cytokines can also be a sufficient second signal for the B cell)
when both of these signals are present, proliferation of the B cells will take place.
What are some other molecules that can affect B cell activation? What effect do they have?
Stimulatory:
CR2 (CD21) binds C3d (complement molecule) on microbe and sends another signal (CD19) to the B cell to start signaling cascade
Inhibitory:
CD22 – sends a negative signal to the B cell
has an ITIM (immunoreceptor tryosine phosphate inhibitory motif)
What is BCR?
antibody plus Ig alpha and Ig beta
What two signals are need for T: B cell interaction?
- TCR-Ag/MHC
- CD28-B7
This collaboration between T and B cells leads to increase in cytokine production by T cells and further proliferation of B cells. The T and B cells activate each other
What are B1 B cells (CD5+ B cells)? What are the significant difference in these cells and normal B cells? (6)
B cells that express CD5 on their surface (which is normally a marker for T cells) and are limited to the usage of V region genes–> less diversity than normal B cells
B1 B cells have low affinity and high rate of cross-reactivity (they have polyspecificity-can bind to a number of antigens) making them less picky about the epitope that they bind to.
significant differences between B1 cells and traditional B cells:
- B1 cells react to polysaccharide antigens (don’t need T cells) (normal B cells respond to protein antigens)
- B1 cells can replicate without seeing antigen (traditional B cells will die if don’t recognize antigen)
- B1 cells are often the origin of B-cell CLL
- B1 cells mostly produce IgM (no T cells–> no class switching)
- B1 cells are primarily located in the pleural and peritoneal cavities
- B1 cells are thought to produce “natural antibodies” ex: anti-A/B antibodies
What is a B cell primary response?
When a naive B cell first is exposed to its antigen
- IgM production
- slower response (7-10 days)
- during/after this response, B cells class switch
- doesn’t have to have T cell help but works better with it
What is B cell secondary response?
Memory response- when a B cell is exposed to its antigen after the first exposure
- production of large amounts of IgG or other isotypes (class switching)
- affinity maturation (somatic hypermutation) –> better response to the antigen
- quicker response (1-3 days)
- requires T cell help
How are B cells activated in secondary lymphoid tissues (lymph node)?
the Ag dependent phase for B cell antigens occurs in the lymph nodes
If Ag interact with B cells are in the cortex and T cells are in the paracortex and the proper signaling takes place, the B cells will proliferate and produce millions of clones in the “germinal center”.
B cells destined to become plasma cells move to the inner medulla and begin to secrete their antibodies for release into the blood stream
What are follicular dendritic cells used for?
“trapping” the antigens in the germinal center of lymph nodes to allow B cell antibodies to come into contact with them (NOT internalizing them and presenting Ag to T cells like normal DC’s)
What are the 5 main functions that Igs use to kill microbes?
- pathogen neutralization
- complement fixation –> inflammation, opsonization, cell lysis
- ADCC (antibody dependent cellular cytotoxicity) –> antibody grabs microbe and via Fc region of microbe can be matched to FcR –> when matches, bring together cell, NK cell and microbe to release cytotoxic component and kill the microbe
- opsonization: stimulation of phagocytosis (macrophages), agglutination (cells) or precipitation (soluble) of Ag
- inflammation: mast cells
