Humoral Immunity Flashcards
What are something antibodies bind?
Proteins, polysaccharides, lipids, nucleic acids, pretty much anything
What are the numbers for clonal selection theory of B cells?
1 B-Cell –> 4000 plasma Cells –> 10^12 antibodies produced per day
Where does B cell activation occur?
Spleen is 50-60% B cells
Tonsils are 60-80% B cells
LN is 30-40% B cells
Describe the important structural parts of the spleen
Important part is the white pulp which includes:
- T cell zone
- B cell zone (made of the follicles, germinal centers, and marginal zone)
- marginal zone is unique to the spleen and is most important
How does antigen get to B cells?
Blood flows through the marginal zone sinuses and is trapped by the macrophages
-the macrophages carry the antigen into the folliceles and display the antigen to the B cells (this is different then antigen presentation, the macrophages are simply holding the pathogen there, macrophage hold antigen down while the B cells beat them up)
What is the first step of BCR signaling?
Antigen binds causing kinase recruitment to ITAM motifs thus phosphoylating a portio of the ITAMs
Describe the actiation of the NF-kB pathway
BCR ligation leads to PKC acitvation leading to activation of IkB kinase which will phosphorylate IkB (inhibitor of Kappa B) this will free NK-kB so that it can translocate to the nucleus for transcription
Describe the NF-AT pathway?
IP3 bind to IP3 receptor causing Ca2+ to be released from the ER.
Ca2+ makes calmodulin dimer with calcineurin which will dephosphorylate NF-AT allowing it to translocate to the nucleus for transcription
What are the calcineurin inhibitors?
Cyclosporine, Tacrolimus
How do B-cells compare to T-cell in regard to co-receptors? What is a common co-receptor on B cells?
B cells do not require co-receptors for activation like T cells do.
-B-cells can be co-activated by Complement (CR-2)
Describe how Complement co-activates B cells?
What Ig is already expressed on B cell surfaces?
IgM is already expressed so all you have to do is cut the connector region and then you will have soluble IgM
Do B cell present MHC I or MHC II?
Trick question, they are professional APCs and nucleated cells and they present both MHC I and MHC II
Describe the events of the Germinal Reaction
While B cells are being activated in the follicle, so are T cells being activated. They will then meet up at the extrafollicular focus where:
- B cells present antigen to T cells
- T cells express CD40L and IL-4 (B cells have CD40 and are activated by this ligand binding)
- Antibody production is initiated (IgM)
Then the T and B cells will migrate back to the follicle and T cells that were re-activated by the B cells will become Follicular Helper T (T_fh) cells
Just look at this nice diagram
What does Th interaction wil B cells promote in regards to the B cells?
It further activates them:
- B cell proliferation
- Ig isotype switching
- Somatic hypermutation/affinity maturation
- plasma call differnetiation
- Memory B cell differentiation
- all effects are enhanced by contant with cytokine produces by Th Cell
- T cell deficiencies can diminish Antibody production,
- B cells rely on T cells so any T cell problem will affect B cells too
What is isotype switching? and how is it performed?
it is a genomic rearrangement that results in the production of different Ig isotypes
-basically you delete a constant region that we don’t want allowing us to switch isotypes. But once we switch isotypes we can never go back to the previous one because we already deleated that constant region
What is somatic hypermutation?
The introduction of point mutations into hypervariable regions of Antibody genes
affinity maturation
Compare isotype class switching with B cell recepter vs. soluble antibody
Isotype class-switching is genomic rearrangment and takes longer
B cell receptor to soluble antibody is an mRNA splicing event and gives you soluble antibody from the B cell receptor
How do B cells know which isotype to make?
The respond the the signal they receive.
- IgM is always the first antibody made and has low affinity
- IgE responds to IL-4, IL-5, IL-14 (th2 response)
-IgG responds to IFN-gamma
-IgA -responds to TGF-beta
Describe the process of affinity maturation?
Somatic hypermutations induce changes in the affinity of the antibody for the antigen
- increased affinity results in positive selection
- decreased affinity results in clonal deletion
- The cells are undergoing somatic hypermutation are selected under conditions of decreasing antigen concentrations
- folluclar dendiritc cells use Fc receptors and complement receptors to display antigen-antibody complexes
- B cells bind, internalize, and present antigen to survive. Failure to bind antigen result in death
- this is happeneing at the germinal center
What is Type I Hyper IgM syndrome?
Ther is an absence of CD154 (CD4) on the Th cells and therefore poor signaling with B cells and therfore no Ig class switching.
-Type I is a T cell deficiency
What is type II Hyper-IgM syndome?
Deficiency of activation-induced cytidine deaminase (AID)
- leads to poor class witching and poor somatic mutation
- this is a B cell defiency
Tell me what you should know about Memory B and Long-lived plasma cells?
Emergo from the germinal center reaction (retain class-switching and somatic hypermutation)
- survive months or years
- plasma cells migrate to the bone marrow
memory b cells reside in the tissues
What antibody would be produced during repeat exposure and why?
During a repeat exposure the memory cell elicit the response, so IgG can already be produced and there is no need to undergo the germinal center reaction
-can look at this clinically, if patient has lots of IgG instead of IgM then it could be long term resposne or infection
What is the relationship between Ig Half life and Ig concentration?
inverse
Ig Half life decreases as Ig concentration increases
-the greater the concentration the shorter the half life, allows return to homeostasis
What is the inhibitory receptor for B cells?
co-crosslinking of BCR and Fcgamma-receptors turns of the B cell, the Fc gamma receptor intracellular portion blocks the B cell receptor signaling portion
What are the two types of antibody response?
T-dependent = CD4 T cells become activated, stimulate B cells through CD40 and cytokines
T-independent = non-protein antigens, no CD4 T cell help
What are some important things about T-independent antigens?
Example are polysaccharides, LPS which binds TLR4
There is less Ig class switching
there is little somatic hypermutation
there is little memory
Compare the T indepednet and T dependent forms of the influenza vaccine?
HibPS = T independent with poor memory, low affinity for ab, and induces IgM
HiB-DT = T cell dependent, memory b cells, high affinity fo Ab, induces IgG >> IgM
What are the first antibodies produced during infancy?
“Natural Antibdodies”
they are B-1 B cells that are mostly in the peritoneum, produce most of the IgM in serum, and IgM binds carbohydrates in the cell wall of bacteria.
they are induced byh carbohydrate antigens of microbial flora
- some of these ab’s cross-react with carbohydrates on mammalian cells
- IgM class; low titer and low affinity
example: antibodies to ABO erthrocyte antigens; “isohemagglutinins”
